Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Molecular mechanisms of platinum resistance: still searching for the Achilles' heel.

The platinum compounds cisplatin and carboplatin are commonly used in cancer chemotherapy. However, tumors frequently develop resistance to these compounds, significantly decreasing their usefulness in the clinic. In the past few years, basic research has unraveled novel and unexpected mechanisms for the development of platinum resistance. For example, it has been reported that MUC1 expression and particularly the localization of its C-terminal subunit to the mitochondria may affect cisplatin resistance. Another recent finding suggests that cisplatin damage may activate DNA-dependent protein kinase (DNA-PK) to initiate a death signal that can be transmitted to neighboring cells through gap junctions, adding to a growing belief that the interactions of cancer cells with their surroundings may be important to the outcome of chemotherapy. While most clinical efforts have focused on identifying alternative regimens for drug-resistant cancer, it might be possible to exploit our knowledge of the mechanism of platinum resistance to specifically reverse resistance and increase platinum efficacy. The strategy of drug resistance reversal therapy (DRRT) may have significant impact on our approaches to the treatment and management of drug-resistant tumors.     

Remote Echography between a Ground Control Center and the International Space Station Using a Tele-operated Echograph with Motorized Probe

Echography is the most appropriate imaging modality for investigating astronauts. Unfortunately, it requires a great deal of training to perform ultrasound examinations, which can be difficult and time consuming, especially if the astronaut does not have a medical background. We designed a new echography system with motorized probes that allows for the majority of exam functions to be controlled by a ground-based sonographer. Using tele-operation, the sonographer controls the orientation of the transducer (tilt, rotation) and echograph settings (gain, depth, freeze) and triggers ultrasound functions (pulsed wave color Doppler, 3-D capture, radiofrequency data collection, elastography). With this system, astronauts are required to hold the motorized probe only at the locations indicated, with the remainder of the exam being conducted by the ground-based sonographer. During spaceflight, ultrasound imaging of the carotid artery, jugular vein, thyroid, liver, gallbladder, biliary tract and portal vein (2-D, 3-D, color, pulsed wave, radiofrequency) were successfully performed.     

Increasing Valid Profiles in Phallometric Assessment of Sex Offenders with Child Victims: Combining the Strengths of Audio Stimuli and Synthetic Characters

Penile plethysmography (PPG) is a measure of sexual interests that relies heavily on the stimuli it uses to generate valid results. Ethical considerations surrounding the use of real images in PPG have further limited the content admissible for these stimuli. To palliate this limitation, the current study aimed to combine audio and visual stimuli by incorporating computer-generated characters to create new stimuli capable of accurately classifying sex offenders with child victims, while also increasing the number of valid profiles. Three modalities (audio, visual, and audiovisual) were compared using two groups (15 sex offenders with child victims and 15 non-offenders). Both the new visual and audiovisual stimuli resulted in a 13% increase in the number of valid profiles at 2.5 mm, when compared to the standard audio stimuli. Furthermore, the new audiovisual stimuli generated a 34% increase in penile responses. All three modalities were able to discriminate between the two groups by their responses to the adult and child stimuli. Lastly, sexual interest indices for all three modalities could accurately classify participants in their appropriate groups, as demonstrated by ROC curve analysis (i.e., audio AUC = .81, 95% CI [.60, 1.00]; visual AUC = .84, 95% CI [.66, 1.00], and audiovisual AUC = .83, 95% CI [.63, 1.00]). Results suggest that computer-generated characters allow accurate discrimination of sex offenders with child victims and can be added to already validated stimuli to increase the number of valid profiles. The implications of audiovisual stimuli using computer-generated characters and their possible use in PPG evaluations are also discussed.     

COMPARISON OF THE CHEMICAL EVOLUTION OF MMVF FOLLOWING INHALATION EXPOSURE IN RATS AND ACELLULAR IN VITRO DISSOLUTION

In the process of developing new fibers or evaluating existing fibers, the dissolution coefficient is often determined using an acellular in vitro assay. This coefficient has been found useful in selecting fibers based on solubility and has been shown to be related to the clearance half-time of long fibers (>20 m) following inhalation in rats. The chemical evolution of fibers following in vitro dissolution and inhalation was examined to evaluate the comparability of these two methods. The fibers studied ranged from compositions similar to commercial insulation materials to new glasses and stone wools that have been developed for enhanced solubility. The inhalation studies were performed using Fischer 344 male rats exposed to a well-defined rat respirable aerosol (mean diameter of 1 m) at a concentration of 30 mg/m3, 6 h/day for 5 days, with postexposure sacrifices at 1 h, 1 day, 5 days, 4 wk, 13 wk, and 26 wk. The in vivo results reported have been from fibers recovered from the lung that were primarily less than 20 m in length. The in vitro dissolution measurements were performed using a continuous-flow model with simulated lung fluid based upon a modified Gamble's media using either 1- or 10- m-diameter fibers without discrimination of length. The inhalation studies show that the composition of many of the fibers recovered from the lung changes with time in the lungs, with a depletion in Na O2, CaO, and MgO and a relative enrichment in SiO2 and Al2O3, with this evolution strongly depending upon glass composition. B2O3 has been found (on 10- m-diameter fibers in vitro as analyzed by secondary ion mass spectrometry) to also be depleted. The chemical evolution of these shorter fibers (L < 20 m) is consistent with that obtained from the in vitro experiments at pH 7.4, although the rate of variation observed with the two methods varied. These results clearly demonstrate that those fibers whose composition changes quickly during in vivo studies are the same as those whose composition changes quickly during in vitro assays. These studies demonstrate that the chemical evolution of the shorter fibers recovered following in vivo inhalation studies mirrors closely the changes found from the in vitro assays. These results complement those already reported for fibers longer than 20 m, which have been shown to be removed from the lung primarily by dissolution. </abs>     

Diagnostic value of soluble CD14 subtype (sCD14-ST) presepsin for the postmortem diagnosis of sepsis-related fatalities

The first aim of this study was to assess the diagnostic performance of presepsin (sCD14-ST) in postmortem serum from femoral blood compared to procalcitonin (PCT) to detect sepsis-related fatalities. The second aim was to compare sCD14-ST levels found in postmortem serum to the values in pericardial fluid to investigate the usefulness of the latter as an alternative biological fluid. Two study groups were formed, a sepsis-related fatalities group and a control group. Radiology (unenhanced CT scans and postmortem angiographies), autopsies, histology, neuropathology, and toxicology as well as other postmortem biochemistry investigations were performed in all cases. Microbiological investigations on right cardiac blood were carried out exclusively in septic cases. The results of this study indicated that postmortem serum PCT and sCD14-ST levels, individually considered, allowed septic cases to be identified. Even though increases in both PCT and sCD14-ST concentrations were observed in the control cases, coherent PCT and sCD14-ST results in cases with suspected sepsis allowed the diagnosis to be confirmed. Conversely, no relevant correlation was identified between postmortem serum and pericardial fluid sCD14-ST levels in either the septic or control groups.     

Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and pregnancy morbidity in association with the persistent presence of circulating antiphospholipid antibodies (aPL). APS remains the most frequent cause of acquired hypercoagulability and recurrent miscarriage. Long-term anticoagulation therapy is the only treatment with proven benefit in the APS. Anticoagulation is not effective in all patients and carries a risk of bleeding. Recent improvements in the understanding of the pathogenic mechanisms have led to the identification of potential targets and future therapies for APS. In contrast to non-specific anticoagulation, the emergence of immunomodulatory drugs provides the possibility of interfering with specific pathogenic pathways. Novel therapies might be used in the future for APS.     

Genetic predictors of inflammation in the risk of occupational asthma in young apprentices

BackgroundThe influence of genetic predictors of inflammation and atopy on occupational asthma in apprentices is not known.ObjectivesTo assess the influence of genetic polymorphisms of IL4RA, IL13, TNFA, IL1A, and IL5 on the decline of lung function and bronchial hyperresponsiveness in a prospective follow-up study of baker/pastry maker and hairdresser apprentices.MethodsA total of 351 apprentices were included in the study. We performed skin testing, spirometry, fractional exhaled nitric oxide measurement, and methacholine hyperreactivity testing at the initial visit and during and at the end of the 18-month training period. Gene variants of IL4RA, IL13, TNFA, IL1A, and IL5 were determined in DNA from nasal lavage.ResultsIL13 R130Q/IL4RA S478P or IL13 R130Q//IL4RA Q551R were significant predictors of the decrease of forced expiratory volume and forced vital capacity (P ≤ .006). Genotype GG of TNFAG308A was associated with bronchial hyperresponsiveness in the whole population and in nonatopic individuals (90.63% vs 9.38%; odds ratio, 3.78; 95% confidence interval, 1.10-12.83). TNFA GA and IL5 CC and TNFA GA and IL1A CC were 2 epistatic predictors of exhaled nitrogen monoxide decrease during follow-up (P = .02 and P = .004, respectively). The association with TNFA GA and IL1A CC was the most significant in nonatopic bakers (P < .001).ConclusionWe evidenced a predicting influence of IL13/IL4RA and TNFA in the early exposure to allergens and irritants that precedes occupational asthma. The significance of the associations in the absence of atopy suggests an influence of the genetics predictors related to inflammatory pathways.