The effect of divalent cations on neuronal nitric oxide synthase activity.

Neuronal nitric oxide synthase (NOS I) is a Ca(2+)/calmodulin-binding enzyme that generates nitric oxide (NO*) and L-citrulline from the oxidation of L-arginine, and superoxide (O(2)*(-)) from the one-electron reduction of oxygen (O(2)). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca(2+), which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca(2+) binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca(2+), we demonstrate that Ni(2+), Ba(2+), and Mn(2+) can activate NOS I to metabolize L-arginine to L-citrulline and NO*, and afford O(2)*(-) in the absence of L-arginine. In contrast, Cd(2+) did not activate NOS I to produce either NO* or O(2)*(-), and the combination of Ca(2+) and either Cd(2+), Ni(2+), or Mn(2+) inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO*, O(2)*(-) and products derived from these free radicals.     

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.     

Endovascular treatment of traumatic aortic rupture using iliac extension stent-grafts in patients with small aortic diameters

Open in a separate window OBJECTIVESTo evaluate outcomes after thoracic endovascular aortic repair in young patients sustaining traumatic blunt aortic injury (BAI) using iliac extension stent-grafts because of small aortic diameters measuring <24 mm.METHODSRetrospective analysis regarding clinical presentation, trauma management, endovascular techniques and outcome of patients with a small descending aorta involving an iliac extension stent-graft to treat traumatic BAI.RESULTSAmong 48 patients who suffered a BAI and underwent thoracic endovascular aortic repair, 7 received iliac extension stent-grafts. They were 27.4/[standard deviation (SD): −13.1] years old and 6 out of 7 were male. The iliac extension stent-graft was used as distal stent-graft, and a thoracic stent-graft was used in most patients as proximal extension. We achieved overall technical success in all patients during a procedure lasting 92.6 (SD: 54.9) min. One patient died 2 days after the endovascular procedure of hypoxic brain injury, and another died after 17 days of liver failure. That patient had also suffered a spinal cord injury following the procedure, as the stent-graft had been deployed in Ishimaru Zone 2, and the carotid to subclavian bypass had to be omitted because of his critical condition. Control computed tomographic angiographs was available in 6 patients after 7.7 (SD: 5.1) days and showed no endoleak. The surviving patients were discharged after 18.4 (SD: 13.4) days.CONCLUSIONSTreating traumatic BAI using iliac extension stent-grafts in young patients with small aortic diameters is feasible. We observed no mortality caused by the BAI or related to endovascular therapy within this small patient cohort.     

In vitro metabolism of etoposide (VP-16-213) by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins

We have studied the metabolism of VP-16-213 (etoposide, VP-16), an antitumor agent, by mouse liver microsomes to reactive intermediates and the subsequent covalent binding to microsomal proteins. This metabolism was shown to involve the O-demethylation of VP-16 and resulted in the formation of a 3',4'-dihydroxy derivative (DHVP-16) which was identified by both HPLC and mass spectrometry. The formation of DHVP-16 was cytochrome P-450-mediated as indicated by its dependence on NADPH, its increased production following treatment of mice with phenobarbital, and its marked inhibition by SKF-525A and piperonyl butoxide. Furthermore, DHVP-16 formation required oxygen. Microsomal incubation of VP-16 resulted in an irreversible binding of the drug to the proteins, which was also shown to be cytochrome P-450 dependent. The covalent binding of the VP-16 metabolite(s) was inhibited by DHVP-16 in a dose-dependent fashion, suggesting that the reactive intermediates that bound to proteins were derived from DHVP-16. Electron spin resonance studies indicated that the same semiquinone radical was formed during enzymatic (oxidation or reduction) metabolism of DHVP-16 and the o-quinone derivative of VP-16 (VP-16-Q). VP-16-Q and its semiquinone radical are suggested to be the bioalkylating species.     

Pregnancy management for a woman with extensive vulvar and pelvic malformations caused by Klippel–Trénaunay syndrome

Klippel–Trénaunay syndrome (KTS) is a rare congenital disorder defined by a triad of capillary malformation, venous malformation, and soft tissue or bone hypertrophy most commonly affecting unilateral lower limbs. Due to the rarity of KTS, evidence‐based guidelines for the management of pregnancy in people with KTS are still lacking. A 34‐year‐old woman (gravidity 1; parity 0) presented at 25 weeks of gestation with malformations of the right side of her body. The extent of the KTS affecting the vulva, pelvis, and right leg was remarkable. As the prenatal MRI showed massive vascular malformations of the pelvis and vulva, we performed an elective cesarean section to avoid severe perinatal hemorrhage during a vaginal delivery. Intraoperatively, we observed varices on the parietal peritoneum within the vesico‐uterine pouch and the isthmocervical transition of the uterus, which were not identifiable in the preoperative MRI. Although KTS patients have been discouraged from pregnancy in the past because of a high risk for complications, successful and uncomplicated pregnancies are possible. For this purpose, we believe a multidisciplinary strategy that is crucial.     

Adolescent binge drinking and risky health behaviours: Findings from northern Russia

Background

Some evidence suggests that in recent years the prevalence of heavy drinking has increased among Russian adolescents. However, as yet, little is known about either heavy alcohol consumption or its relationship with other adolescent health risk behaviours in Russia. The aim of this study therefore was to investigate the association between binge drinking and health risk behaviours among adolescents in Russia.

Methods

Data were drawn from the Social and Health Assessment (SAHA), a survey carried out in Arkhangelsk, Russia in 2003. Information was obtained from a representative sample of 2868 adolescents aged 13–17 regarding the prevalence and frequency of binge drinking (five or more drinks in a row in a couple of hours) and different forms of substance use, risky sexual behaviour and violent behaviour. Logistic regression analysis was used to examine the association between binge drinking and adolescent involvement in various health risk behaviours.

Results

Adolescent binge drinking was associated with the occurrence of every type of health risk behaviour – with the sole exception of non-condom use during last sex. In addition, there was a strong association between the number of days on which binge drinking occurred and the prevalence of many health risk behaviours.

Conclusions

Binge drinking is associated with a variety of health risk behaviours among adolescents in Russia. Public health interventions such as reducing the affordability and accessibility of alcohol are now needed to reduce binge drinking and its harmful effects on adolescent well-being.     

Quantification of active ingredients in suppositories by FT‐Raman spectroscopy

An efficient method for the quantitative determination of acetaminophen (AAP) and diclofenac sodium (DS) in commercial suppositories based on partial least squares (PLS) treatment of FT‐Raman spectra is described. The relative standard errors of prediction (RSEP) were calculated for calibration and validation data sets to evaluate the quality of the constructed models. In the case of DS determination, RSEP error values of 1.9 % and 2.3 % for the calibration and validation data sets, respectively, were found. For AAP these errors amounted to 1.6–2.3 % and 1.8–2.8 %, respectively, for the different calibration models. Four commercial preparations containing 5, 12.5, 16.7 and 33.3 % (w/w) AAP and one containing 5 % (w/w) DS were successfully quantified using the developed models. Concentrations derived from the developed models correlated strongly with the declared values and yielded recoveries of 99.4–100.2 % and 99.6 % for AAP and DS, respectively. The proposed procedure can be used as a fast, economic and reliable method for quantification of the active pharmaceutical ingredients in suppositories. Copyright © 2012 John Wiley & Sons, Ltd.     

Corneal biomechanical changes and intraocular pressure in patients with thyroid orbitopathy

AIM: To determine the relevance of the objective parameters addressing the altered biomechanical properties of cornea for glaucoma monitoring in patients with mild or moderate thyroid associated orbitopathy (TAO), and in healthy individuals. METHODS: Twenty-five patients with TAO (group 1) and 25 healthy adults (group 2) were included to the study. Both groups were of a similar age and the ratio women:man. For each patient, the following parameters of both eyes were measured with ocular response analyzer (ORA): corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOPg) and corneal compensated intraocular pressure (IOPcc). In both groups participating in our study, all measurements were performed within minutes to reduce the diurnal effects. RESULTS: The mean age in group 1 was 56±11y and 76% were women, 24% were men. The mean age in group 2 was 64±11y and 68% were women, 32% were men. CH correlated negatively with IOPg in group 1 (r2=0.10, P<0.05). IOPg strongly correlated with IOPcc in both groups (group 1: r2=0.79, P<0.0001; group 2: r2=0.85, P<0.0001). There was positive correlation between CRF and IOPg in group 1 (r2=0.12, P<0.05) and in group 2 (r2=0.31, P<0.0001). Statistical analysis revealed no significant correlation between CRF and IOPcc in group 1 (r2=0.009, P>0.05) and also no significant correlation in group 2 (r2=0.04, P>0.05). CRF mean value in group 2 (11.51±1.72 mm Hg) was higher than in group 1 (10.85±1.45 mm Hg) (P<0.05). IOPg strongly correlated with IOPcc in both groups (group 1: r2=0.79, P<0.0001; group 2: r2=0.85, P<0.0001). There was also strong correlation between CRF and CH in both populations: group 1: (r2=0.58, P<0.0001), group 2: (r2=0.41, P<0.0001). CONCLUSION: Biomechanical parameters of cornea, as quantified by CH and CRF, and measured together with IOPcc, precisely reveal glaucoma staging in TAO and thus are reliable for diagnosing and follow-up in clinical practice.     

Triangulo-{ErIII3} complex showing field supported slow magnetic relaxation

The triangulo-{Er₃} complex [Er₃Cl(o-van)₃(OH)₂(H₂O)₅]Cl₃·nH₂O (n = 9.4; H(o-van) = o-vanillin) (1) was generated by an in situ method. The isolated Er(iii) complex 1 was characterized by elemental analysis and molecular spectroscopy. The results of single crystal X-ray diffraction studies have shown that 1 is built up of trinuclear [Er₃Cl(o-van)₃(OH)₂(H₂O)₅]³⁺ complex cations, chloride anions and water solvate molecules. Within the complex cation the three Er(iii) central atoms are placed at the apexes of a triangle which are bridged by three (o-van)⁻ ligands with additional chelating functions and two μ₃-OH⁻ ligands. Additionally five aqua and one chlorido ligands complete the octa-coordination of the three Er(iii) atoms. AC susceptibility measurements reveal that the compound exhibits slow magnetic relaxation with two relaxation modes.

The triangulo-{Er₃} complex [Er₃Cl(o-van)₃(OH)₂(H₂O)₅]Cl₃·nH₂O (n = 9.4; H(o-van) = o-vanillin) (1) was generated by an in situ method.     

Exposure to power frequency electric fields and the risk of childhood cancer in the UK

The United Kingdom Childhood Cancer Study, a population-based case-control study covering the whole of Great Britain, incorporated a pilot study measuring electric fields. Measurements were made in the homes of 473 children who were diagnosed with a malignant neoplasm between 1992 and 1996 and who were aged 0-14 at diagnosis, together with 453 controls matched on age, sex and geographical location. Exposure assessments comprised resultant spot measurements in the child's bedroom and the family living-room. Temporal stability of bedroom fields was investigated through continuous logging of the 48-h vertical component at the child's bedside supported by repeat spot measurements. The principal exposure metric used was the mean of the pillow and bed centre measurements. For the 273 cases and 276 controls with fully validated measures, comparing those with a measured electric field exposure >/=20 V m(-1) to those in a reference category of exposure <10 V m(-1), odds ratios of 1.31 (95% confidence interval 0.68-2.54) for acute lymphoblastic leukaemia, 1.32 (95% confidence interval 0.73-2.39) for total leukaemia, 2.12 (95% confidence interval 0.78-5.78) for central nervous system cancers and 1.26 (95% confidence interval 0.77-2.07) for all malignancies were obtained. When considering the 426 cases and 419 controls with no invalid measures, the corresponding odds ratios were 0.86 (95% confidence interval 0.49-1.51) for acute lymphoblastic leukaemia, 0.93 (95% confidence interval 0.56-1.54) for total leukaemia, 1.43 (95% confidence interval 0.68-3.02) for central nervous system cancers and 0.90 (95% confidence interval 0.59-1.35) for all malignancies. With exposure modelled as a continuous variable, odds ratios for an increase in the principal metric of 10 V m(-1) were close to unity for all disease categories, never differing significantly from one.