Acute postnatal exposure to brominated diphenylether 47 delays neuromotor ontogeny and alters motor activity in mice

Polybrominated diphenyl ethers (PBDEs) are widely used commercial flame retardants that are accumulating in the environment. PBDEs may interfere with the development of key biological systems, thus leaving children vulnerable to functional impairments in adulthood. There is a growing literature of animal studies that show subtle changes in motor and cognitive function following acute or repeated perinatal exposure to PBDEs. 2,2′,4,4′-Brominated diphenyl ether (BDE 47), a very stable PBDE congener, has been shown to accumulate in humans, perhaps as a breakdown product of other PBDEs. The current study examined developmental milestones in male C57BL/6 mice exposed to a single oral dose of BDE 47 (0, 1, 10, or 30 mg/kg) on postnatal day (PND) 10. Behavioral endpoints assessing sensory and motor maturation were examined on PNDs 12, 14, 16, 18, 32, and 88. Motor activity was also examined at 2 and 4 months in a separate group of mice. BDE 47 exposure (particularly the highest dose) significantly increased body weight on PND 47 and thereafter. There was altered ontogeny in a few measures of neuromotor development; however, other developmental milestones and sensory responses were not altered. Motor activity was altered at both 2 and 4 months, with BDE 47-treated mice (all dose groups) displaying pronounced hyperactivity at 4 months. These data indicate that acute exposure to BDE 47 during postnatal development may produce subtle changes in the development of neuromotor systems that may alter adult behavior.     

Bioavailability of water-soluble CoQ10 in beagle dogs

The bioavailability of a novel water-soluble inclusion complex of CoQ10, prepared in our laboratory was determined and compared with the bioavailability of commercially available oil-based form of CoQ10. Experimental work consisted of single dose comparative bioavailability study on seven beagle dogs, with a 14-day washout period between treatments. Identification and quantification of CoQ10 was done with HPLC-MS method using positive APCI ionization and SIM mode, M+ m/z 863.4. The bioavailability results confirm that the water-soluble formulation has nearly three times higher AUC(0-48 h), two times higher Cmax, and Tmax is shortened from 6 to 4 h.     

Development and validation of a LC-MS method with electrospray ionization for the determination of the imidazole H3 antagonist ROS203 in rat plasma

A rapid, simple and sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for the determination of the imidazole H(3) antagonist ROS203 in rat plasma, using the superior homologue ROS287 as internal standard. Analyses were performed on an Agilent 1100 Series HPLC system employing a Supelco Ascentis C(18) column and isocratic elution with acetonitrile-10mM ammonium acetate buffer pH 4.0 (30:70, v/v) at a flow rate of 0.25 mL/min. An Applied Biosystems/MDS Sciex 150-EX single quadrupole mass spectrometer, equipped with an electrospray ionization interface was employed, operating in the positive ion mode. Plasma samples were deproteinized with acetonitrile (1:2), evaporated under nitrogen stream, reconstituted in the mobile phase and 5 microL were injected into the system. The retention times of ROS203 and IS were 2.20 and 2.90 min, respectively. Calibration curves in spiked plasma were linear over the concentration range of 2610-2.61 ng/mL with determination coefficients >0.99. The lower limit of quantification (LLOQ) was 2.61 ng/mL. The accuracy of the method was within 15%. Intra- and inter-day relative standard deviations were less or equal to 9.50% or 7.19%, respectively. The applicability of the LC-MS method was tested employing plasma samples obtained after i.p. administration of ROS203 to female Wistar rats to support a behavioral in vivo study. The specificity of the method was confirmed by the absence of interferences from endogenous substances. The reported method can provide the necessary sensitivity, linearity, precision, accuracy and specificity to allow the determination of ROS203 in rat plasma samples to support further pharmacokinetic assays.     

Evidence that morphine is metabolized to hydromorphone but not to oxymorphone

A minor pathway for the biotransformation of morphine to hydromorphone has been identified in humans. Recently, an unsubstantiated claim that morphine is metabolized to hydromorphone and then to oxymorphone was published. The goal of this study was to determine if credible evidence that oxymorphone is a metabolite of either morphine or hydromorphone exists. Urine specimens from pain patients who were treated exclusively with high daily doses of morphine (N = 34) or hydromorphone (N = 26) were analyzed by liquid chromatography-tandem mass spectrometry for oxymorphone, hydromorphone, and morphine (LOD = 25 ng/mL). Specimens were also tested for a variety of other medications. Criteria for inclusion of patients' specimens were as follows: 1. patients were undergoing exclusive dosing with either morphine or hydromorphone; 2. non-prescribed medications were not detected; and 3. urine concentrations of morphine were > 100,000 ng/mL for the high-dose morphine group and > 1,000 ng/mL of hydromorphone for the high-dose hydromorphone group. Consistent with earlier reports, hydromorphone was detected in patients treated with high-dose morphine. The ratio of hydromorphone to morphine ranged from 0.2 to 2.2%. Oxymorphone was not detected in any specimen from high-dose morphine or high-dose hydromorphone patients. The authors conclude, based on these data, that oxymorphone is not a metabolite of morphine or hydromorphone.     

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.     

The field size matters: low dose external beam radiotherapy for thumb carpometacarpal osteoarthritis

The purpose of this work was to evaluate the efficacy of low-dose radiotherapy (RT) for thumb carpometacarpal osteoarthritis (rhizarthrosis). The responses of 84 patients (n = 101 joints) were analyzed 3 months after therapy (n = 65) and at 12 months (n = 27). Patients were treated with 6 fractions of 1 Gy, two times a week, with a linear accelerator. At the end of therapy, about 70?% of patients reported a response (partial remission or complete remission), 3 months later about 60?%, and 1 year after treatment 70?%. In univariate regression analysis, higher patient age and field size greater than 6 × 4 cm were associated with response to treatment, while initial increase of pain under treatment was predictive for treatment failure. Duration of RT series (more than 18 days), gender, time of symptoms before RT, stress pain or rest pain, or prior ortheses use, injections, or surgery of the joint were not associated with treatment efficacy. In multivariate regression analysis, only field size and initial pain increase were highly correlated with treatment outcome. In conclusion, RT represents a useful treatment option for patients suffering from carpometacarpal osteoarthritis. In contrast to other benign indications, a larger field size (>6 × 4 cm) seems to be more effective than smaller fields and should be evaluated in further prospective studies.     

CT-Guided Superior Vena Cava Puncture: A Solution to Re-Establishing Access in Haemodialysis-Related Central Venous Occlusion Refractory to Conventional Endovascular Techniques

Purpose

The purpose of this technical note is to demonstrate the novel use of CT-guided superior vena cava (SVC) puncture and subsequent tunnelled haemodialysis (HD) line placement in end-stage renal failure (ESRF) patients with central venous obstruction refractory to conventional percutaneous venoplasty (PTV) and wire transgression, thereby allowing resumption of HD.

Methods

Three successive ESRF patients underwent CT-guided SVC puncture with subsequent tract recanalisation. Ultrasound-guided puncture of the right internal jugular vein was performed, the needle advanced to the patent SVC under CT guidance, with subsequent insertion of a stabilisation guidewire. Following appropriate tract angioplasty, twin-tunnelled HD catheters were inserted and HD resumed.

Results

No immediate complications were identified. There was resumption of HD in all three patients with a 100 % success rate. One patient’s HD catheter remained in use for 2 years post-procedure, and another remains functional 1 year to the present day. One patient died 2 weeks after the procedure due to pancreatitis-related abdominal sepsis unrelated to the Tesio lines.

Conclusion

CT-guided SVC puncture and tunnelled HD line insertion in HD-related central venous occlusion (CVO) refractory to conventional recanalisation options can be performed safely, requires no extra equipment and lies within the skill set and resources of most interventional radiology departments involved in the management of HD patients.