Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R² = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.     

Cystic Hydatidosis of the Rib–Case Report and Review of the Literature

The hydatid disease is a zoonosis endemic to rural countries, such as those in the Mediterranean region, South America, North Africa, Central Asia and China. Hydatid cysts commonly affect liver and lungs, but less than 100 cases of costal hydatidosis have been reported in the literature. While diagnosis of the disease in commonly affected organs is relatively easy, uncommon locations can prove to be challenging as is the case with costal hydatidosis. Imaging techniques can suggest the diagnosis, but sometimes it remains uncertain until surgery. The treatment is surgical, assisted by long-time Albendazole chemotherapy. We present a rare case of costal hydatidosis, the first one to be reported in Romania according to our review of the literature.     

Cost-effectiveness analysis of beta-blockers vs endoscopic surveillance in patients with cirrhosis and small varices

AIM:To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in patients with cirrhosis and small esophageal varices.METHODS:A stochastic analysis based on decision trees was performed to compare the cost-effectiveness of beta-blockers therapy starting from a diagnosis of small varices(Strategy 1)with that of endoscopic surveillance followed by beta-blockers treatment when large varices are demonstrated(Strategy 2),for preventing variceal growth,bleeding and death in patients with cirrhosis and small esophageal varices.The basic nodes of the tree were gastrointestinal endoscopy,inpatient admission and treatment for bleeding,as required.All estimates were performed using a Monte Carlo microsimulation technique,consisting in simulating observations from known probability distributions depicted in the model.Eight-hundred-thousand simulations were performed to obtain the final estimates.All estimates were then subjected to Monte Carlo Probabilistic sensitivity analysis,to assess the impact of the variability of such estimates on the outcome distributions.RESULTS:The event rate(considered as progression of varices or bleeding or death)in Strategy 1[24.09%(95%CI:14.89%-33.29%)]was significantly lower than in Strategy 2[60.00%(95%CI:48.91%-71.08%)].The mean cost(up to the first event)associated with Strategy 1[823￡(95%CI:106￡-2036￡)]was not significantly different from that of Strategy 2[799￡(95%CI:0￡-3498￡)].The cost-effectiveness ratio with respect to this endpoint was equal to 50.26￡(95%CI:-504.37￡-604.89￡)per event avoided over the four-year follow-up.When bleeding episodes/deaths in subjects whose varices had grown were included,the mean cost associated with Strategy 1 was 1028￡(95%CI:122￡-2581￡),while 1699￡(95%CI:171￡-4674￡)in Strategy 2.CONCLUSION:Beta-blocker therapy turn out to be more effective and less expensive than endoscopic surveillance for primary prophylaxis of bleeding in patients with cirrhosis and small varices.     

Coaptation/elevation role of the middle deltoid muscle fibers: a static biomechanical pilot study using shoulder MRI

Purpose

It is generally recognized that the middle deltoid muscle fibers (MDMF) have an elevating effect on the humeral head at small abduction angles. These forces are normally counterbalanced by the coaptation effect of the rotator cuff (RC) muscles to maintain shoulder stability. With RC tears, this balance may be jeopardized leading to shoulder dysfunction. Conversely, not all patients with RC tears develop shoulder dysfunction. The purpose of this study was to investigate the coaptation/elevation forces (CEF) ratio of the MDMF in RC tears subjects and in volunteers, using magnetic resonance imaging (MRI).

Methods

Magnetic resonance imaging images in 10 subjects with RC tears and in five volunteers were used to build a three-dimensional model of the shoulder. The CEF ratio of the MDMF was estimated by representing the glenohumeral joint as a pulley.

Results

The CEF ratio increased from the posterior to the anterior fibers of the MDMF.The median and interquartile range (IQR) of the CEF ratios of the posterior-third, middle-third, anterior-third and anterior-surface segments of the deltoid were: 0.16 (IQR = 0.23), 0.61 (IQR = 0.4), 1.42 (IQR = 0.41), 1.94 (IQR = 0.56) in subjects, and 0.06 (IQR = 0.24), 0.45 (IQR = 0.28), 1.32 (IQR = 1.01), 1.49 (IQR = 0.39) in volunteers. In the subjects, the CEF ratio of the anterior-surface segment was greater than all other segments (P ≤ 0.03).

Conclusions

The CEF ratio of the MDMF increased from its posterior segment to its anterior segment, indicating a greater stabilizing effect of the anterior segment both in RC tears subjects and in volunteers. Strengthening of the anterior fibers of the MDMF could potentially improve shoulder function in subjects with RC tears.     

Periodontal Treatment Combined With Tongue Cleaning Reduces Oral Malodor Among Patients With Periodontitis, Whereas for Patients With Gingivitis, Tongue Cleaning Alone is Sufficient

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Clinical trial of oral malodor treatment in patients with periodontal diseases. Pham TA, Ueno M, Zaitsu T, Takehara S, Shinada K, Lam PH, Kawaguchi Y. J Periodontal Res 2011;46:722-9. REVIEWERS: Khady Ka, DDS, MSc, and Belinda Nicolau, DDS, PhD PURPOSE/QUESTION: To what extent do periodontal treatment and tongue cleaning reduce oral malodor among patients with periodontitis and patients with gingivitis? SOURCE OF FUNDING: Information not available TYPE OF STUDY/DESIGN: Randomized controlled trial LEVEL OF EVIDENCE: Level 2: Limited-quality, patient-oriented evidence STRENGTH OF RECOMMENDATION GRADE: Not applicable.     

Improving oral rehabilitation through the preservation of the tissues through alveolar preservation

When performing a tooth extraction, imminent collapse of the tissue by resorption and remodeling of the socket is a natural occurrence. The procedure for the preservation of the alveolar ridge has been widely described in the dental literatures and aims to maintain hard and soft tissues in the extraction site for optimal rehabilitation either with conventional fixed or removable prosthetics or implant-supported prosthesis.     

Laser irradiation affects enzymatic antioxidant system of streptozotocin-induced diabetic rats

The aim of the present study was to analyze the effect of low-power laser irradiation in the antioxidant enzymatic system of submandibular (SMG) and parotid (PG) salivary glands of streptozotocin-induced diabetic rats. The animals were randomly divided into six groups: three diabetic groups (D0, D5, and D20) and three non-diabetic groups (C0, C5, and C20), according to laser dose received (0, 5, and 20 J/cm², respectively). Areas of approximately 1 cm² were demarcated in the salivary glands (each parotid and both submandibular glands) and after irradiated according to Simões et.al. (Lasers Med Sci 24:202–208, 2009). A diode laser (660 nm/100 mW) was used, with laser beam spot of 0.0177 cm2. The group treated with 5 J/cm² laser dose was subjected to irradiation for 1 min and 4 s (total irradiation time) and the group treated with 20 J/cm² laser dose was subjected to irradiation for 4 min and 16 s. Twenty-four hours after irradiation the animals were euthanized and the salivary glands were removed for biochemical analysis. The total antioxidant values (TA), the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase enzymes were determined. SOD and CAT activities, as well as TA were higher in SMG of irradiated diabetic rats. However, in SMG of non-diabetic rats, laser irradiation decreased TA values and led to an increase in the CAT activity. In addition, there was a decrease in the activity of CAT in PG of diabetic and non-diabetic animals after laser irradiation. According to the results of the present study, low-power laser irradiation can affect the enzymatic antioxidant system of salivary glands of streptozotocin-induced diabetic rats.     

Hematocrit, urea and gender: the Hematocrit, Urea and GEnder formula for prognosing progressive renal failure in diabetic nephropathy

ObjectiveDiabetic nephropathy is a common cause of end stage renal disease. Notwithstanding, wide inter-individual variations in the speed of progression of diabetic nephropathy are frequent. We have used the score of the HUGE formula to predict progression of kidney disease in a group of diabetic nephropathy patients.Design and methodsThe sample consisted of 84 type 2 diabetic patients. At treatment entry, the mean age was 62.1 ± 12.5 years and 59.5% were male. Blood pressure was measured at office at each visit. Serum creatinine, urea, hematocrit and 24 h proteinuria were analyzed every 6 months. HUGE score was calculated from gender, urea and hematocrit.ResultsMean HUGE score was 0.99 ± 3.88. Using as cut off point 1.5, those patients who had a score equal or higher (n = 31) showed a bigger increase in serum creatinine after one year (41.8 ± 62.1%) than those subjects with score < 1.5 (n = 53) (18.7 ± 38.6%, p = 0.041). 5 patients with low HUGE score reached end stage renal failure (9.4%) and 10 patients in the high HUGE score group (32.3, p = 0.008). When logistic regression analysis was performed only a HUGE score higher than 1.5 (p = 0.003) and proteinuria higher than 2 g/day (p = 0.041) were independently associated to CRF progression (creatinine increment > 25%).ConclusionsIn diabetic nephropathy patients the HUGE equation may be useful to detect the subjects prone to progressive renal failure. Wider samples will be needed to confirm this finding and, most important, its applicability to other kinds of nephropathy.