Comparison of the Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot and CMV QuantiFERON Cell-Mediated Immune Assays in CMV-Seropositive and -Seronegative Pregnant and Nonpregnant Women

Human cytomegalovirus (CMV) infection is a major cause of congenital infection leading to birth defects and sensorineural anomalies, including deafness. Recently, cell-mediated immunity (CMI) in pregnant women has been shown to correlate with congenital CMV transmission. In this study, two interferon gamma release assays (IGRA), the CMV enzyme-linked immunosorbent spot (ELISPOT) and CMV QuantiFERON assays, detecting CMV-specific CMI were compared. These assays were performed for 80 CMV-infected (57 primarily and 23 nonprimarily) pregnant women and 115 controls, including 89 healthy CMV-seropositive pregnant women without active CMV infection, 15 CMV-seronegative pregnant women, and 11 seropositive or seronegative nonpregnant women. Statistical tests, including frequency distribution analysis, nonparametric Kruskal-Wallis equality-of-populations rank test, Wilcoxon rank sum test for equality on unmatched data, and lowess smoothing local regression, were employed to determine statistical differences between groups and correlation between the assays. The CMV ELISPOT and CMV QuantiFERON assay data were not normally distributed and did not display equal variance. The CMV ELISPOT but not CMV QuantiFERON assay displayed significant higher values for primarily CMV-infected women than for the healthy seropositive pregnant and nonpregnant groups (P = 0.0057 and 0.0379, respectively) and those with nonprimary infections (P = 0.0104). The lowess local regression model comparing the assays on an individual basis showed a value bandwidth of 0.8. Both assays were highly accurate in discriminating CMV-seronegative pregnant women. The CMV ELISPOT assay was more effective than CMV-QuantiFERON in differentiating primary from the nonprimary infections. A substantial degree of variability exists between CMV ELISPOT and CMV QuantiFERON assay results for CMV-seropositive pregnant women.     

Prospective Evaluation of the Effect of an Aminoglycoside Dosing Regimen on Rates of Observed Nephrotoxicity and Ototoxicity

The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for >/=72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P 相似文献   

Mid-portion Achilles tendinopathy in runners with metabolic disorders

European Journal of Orthopaedic Surgery & Traumatology - Running is a very popular modality of physical activity, which may help to lose weight and normalize pathological values of blood...     

Cone beam computed tomography for dental and maxillofacial imaging: technique improvement and low-dose protocols

Objective

The aim of this study was to evaluate images quality and radiation doses of Cone Beam Computed Tomography (CBCT) for dental and maxillofacial imaging testing five different acquisition protocols.

Methods

Dose measurements of different acquisition protocols were calculated for Pax Zenith three-dimensional (3D) Cone Beam (Vatech, Korea) and for conventional orthopantomography (OPT) and cephalometric skull imaging Ortophos (Sirona Dental Systems, Bernsheim, Germany). The absorbed organ doses were measured using an anthropomorphic phantom loaded with thermoluminescent dosimeters at 58 sites related to sensitive organs. Five different CBCT protocols were evaluated for image quality and radiation doses. They differed in FOV, image resolution, kVp, mA, acquisition time in seconds and radiation dose. Measurements were then carried out with the orthopantomograph. Equivalent and effective doses were calculated.

Results

The reference protocol with large FOV, high resolution quality images, 95 kVp, 5 mA and acquisition time of 24 s resulted in a DAP value of 1556 mGy cm² instead the protocol with reduced kVp from 95 to 80 kVp translated into a value of DAP inferior to 35% (from 1556 to 1013 mGy cm²). Going from a high resolution to a normal resolution, there was a reduction of the acquisition time to 15 s which allowed further dose reduction of approximately 40% (628 mGy cm²); this protocol resulted in a value of effective dose of 35 microSievert (μSv). Moreover, the effect of changing FOV has been evaluated, considering two scans with a reduced FOV (160 × 140  and 120 × 90 mm, respectively).

Conclusions

CBCT low-dose protocol with large FOV, normal resolution quality images, 80 kVp, 5 mA and acquisition time of 15 s resulted in a value of effective dose of 35 microSievert (μSv). This protocol allows the study of maxillofacial region with high quality of images and a very low radiation dose and, therefore, could be proposed in selected case where a complete assessment of dental and maxillofacial region is useful for treatment planning.

     

Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors

New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.     

Analogues of σ receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with added polar functionality and reduced lipophilicity for potential use as positron emission tomography radiotracers

1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) represents an excellent lead candidate for therapeutic and/or diagnostic applications in oncology. However, because its utility is limited by its relatively high degree of lipophilicity, novel analogues of 1 with reduced lipophilic character were designed by substituting methylene groups with more polar functional groups in the propylene linker and at the tetralin C4 position. For the chiral analogues, separate enantiomers exhibited substantial and roughly equal affinities within a given receptor subtype, with the greatest difference observed for compound 9 at σ(1) (7.5-fold; (-)-(S)-9 K(i) = 94.6 nM, (+)-(R)-9 K(i) = 12.6 nM). Compound (-)-(S)-9 was also found to be the most σ(2)-selective agent (σ(2) K(i) = 5.92 nM), to possess a lipophilicity consistent with entry into tumor cells (log D(7.4) = 2.38), and to show minimal antiproliferative activity. However, (-)-(S)-9 exhibited moderate activity (EC(50) = 8.1 μM) at the P-gp efflux pump.     

The sigma-1 receptor antagonist PB212 reduces the Ca²⁺-release through the inositol (1, 4, 5)-trisphosphate receptor in SK-N-SH cells

Sigma-1 receptors are specifically located at the endoplasmic reticulum-mitochondrion interface, but upon stimulation by ligands or under prolonged cellular stress, they translocate to other areas of the cell. Sigma-1 receptors are involved in the regulation of intracellular [Ca(2+)] by affecting the Ca(2+)-influx or the release from intracellular stores. In SK-N-SH cells, we measured the affinity of 4-methyl-1-[4-(6-methoxynaphthalen-1-yl)butyl]piperidine (PB212) at sigma-1 receptor by using a competition binding assay with specific radioligand; we obtained a K(i) value=316 ± 19 nM. PB212 also showed an antiproliferative effect in SK-N-SH cells (EC(50)=32 ± 4 μM) but had no effect in MCF7 cells, which only express sigma-2 receptor; these findings suggest that PB212 behaves as a sigma-1 receptor antagonist. We have studied the effect of PB212 on Ca(2+) homeostasis of the SK-N-SH cell line with the fluorescent probe Fura-2. 100 μM PB212 induced a Ca(2+)-efflux from the endoplasmic reticulum through the inositol (1, 4, 5)-trisphosphate (IP(3)) receptor. Moreover, [PB212] ranging from 1 to 100μM reduced the Ca(2+)-response, triggered by carbachol or bradykinin that engage the phospholipase C/IP(3) pathway; such a response is generally increased by sigma-1 receptor agonists. On the other hand, PB212 did not reduce the Ca(2+)-response mediated by IP(3) in LoVo cells, which do not express neither sigma-1 nor sigma-2 receptors, and in MCF7 cells. The fact that the activity of the sigma-1 receptor can be experimentally modulated by agonists and antagonists supports the intriguing hypothesis that some endogenous molecules, unknown at the moment, modulate the sigma-1 receptor and its cellular targets.