Visible Light Absorption and Long-Lived Excited States in Dinuclear Silver(I) Complexes with Redox-Active Ligands.

Well-defined dinuclear silver(I) complexes have been targeted for applications in catalysis and materials chemistry, and the effect of close silver-silver interactions on electronic structure remains an area of active inquiry. In this study, we describe the synthesis, structure, and photophysical properties of dimeric silver complexes featuring a redox-active naphthyridine diimine ligand. Unusually for silver(I), these complexes display absorption features in the visible region due to metal-metal to ligand charge transfer (MMLCT) transitions, which arise from the combination of close silver-silver interactions and low-lying ligand π* orbitals. The complexes' photophysical properties are explored via a combination of spectroscopic and computational studies, revealing MMLCT excited state lifetimes that exceed 1 µs. These results portend previously unforeseen applications of silver(I) dimers in visible light absorption and excited state reactivity.

Accidental dural puncture during labor analgesia and obstetric outcomes in nulliparous women.

BACKGROUND: The effect of accidental dural puncture during labor epidural analgesia on obstetric outcomes remains unexplored. In this retrospective cohort study, we tested the hypothesis that accidental dural puncture is associated with prolonged second stage of labor. METHODS: Anesthetic and obstetric data from nulliparous parturients who suffered an accidental dural puncture at term labor (n=89) during the years 2006-2012 were compared with randomly selected parturients with uncomplicated epidural analgesia (n=232). The primary outcome was the proportion of parturients with prolonged second stage of labor: secondary outcomes were the proportion of instrumented and cesarean deliveries. Statistical analysis included student t-test for continuous variables, chi-square test for binary variables, and logistic regressions for associations between accidental dural puncture and outcomes. RESULTS: Demographic and obstetric characteristics of parturients were comparable except for a non-significant increase in prolonged second stage of labor in the accidental dural puncture group (27% vs. 17%, P=0.06). After adjusting for known potential confounders, multivariate logistic regression analyses revealed a significant association between accidental dural puncture and prolonged second stage of labor (adjusted risk ratio [aRR] 1.99, 95% CI 1.04 to 3.82; P=0.037). This was not accompanied by an increase in instrumented (aRR 0.57, 95% CI 0.27 to 1.21; P=0.15) or cesarean delivery (aRR 1.83, 95% CI 0.89 to 3.77; P=0.10). CONCLUSION: Accidental dural puncture during labor analgesia was associated with prolonged second stage of labor in nulliparous parturients. Prospective studies are needed to assess the relationship between the quality of neuraxial block after accidental dural puncture and obstetric outcomes.

Argentophilic Interactions in Solution: An EXAFS Study of Silver(I) Nitrene Transfer Catalysts.

Silver(I) catalysts have been developed for nitrene transfer reactions such as aziridination and C-H insertion. For some catalysts, structures determined by X-ray crystallography reveal dimers with silver-silver interactions, leading to mechanistic speculation about the potential role of dinuclear silver complexes in catalysis. However, it is often unclear if the silver-silver interactions persist in solution. Here we use EXAFS to directly interrogate the solution-phase structures of several silver(I) nitrene transfer catalysts. Retention or loss of the silver-silver interaction in solution can be clearly observed.

Desipramine inhibits salivary Ca(2+) signaling and aquaporin translocation.

OBJECTIVE: Desipramine is a tricyclic antidepressant with a negative side effect of dry mouth. The Na(+) /H(+) exchanger was suggested to be a target of desipramine in salivary gland cells. However, it is unclear whether desipramine has other targets in the salivary secretion pathway. Here, we studied the effect of desipramine on salivary Ca(2+) signaling. MATERIALS AND METHODS: Cytosolic free Ca(2+) concentration ([Ca(2+) ]i ) was determined with the fluorescent Ca(2+) indicator fura-2/AM. Aquaporin translocation was analyzed by Western blotting and immunocytochemistry of confocal microscopy. RESULTS: Desipramine inhibited the carbachol- and histamine-mediated increase in cytosolic Ca(2+) ([Ca(2+) ]i ) in a concentration-dependent manner. However, desipramine did not affect increases in [Ca(2+) ]i mediated by extracellular ATP, sphingosine-1-phosphate, or thapsigargin. The adrenergic receptor blockers prazosin and propranolol did not reverse the desipramine-mediated inhibition of carbachol- and histamine-induced increases in [Ca(2+) ]i . We also found that desipramine inhibits the increase in membrane aquaporin-5 level triggered by carbachol and histamine treatments. CONCLUSIONS: These results imply that desipramine blocks muscarinic and histamine receptor-mediated Ca(2+) signaling and the subsequent translocation of aquaporin-5 in human salivary gland cells, suggesting a novel mechanism for the xerogenic effects of desipramine.

The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain.

Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1µM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca(2+) channels were substantially enhanced by application of 1µM lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain.

Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations.

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase-negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway.

Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease.

BACKGROUND: Screening overweight and obese children for non-alcoholic fatty liver disease (NAFLD) is recommended by paediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation. AIM: To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to paediatric gastroenterology resulted in a correct diagnosis of NAFLD. METHODS: Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to paediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal (ULN) for alanine aminotransferase (ALT) was assessed. RESULTS: Non-alcoholic fatty liver disease was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternative diagnosis. Children with NAFLD had significantly (P < 0.05) higher screening ALT (98 ± 95) than children with liver disease other than NAFLD (86 ± 74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical ULN had a sensitivity of 57% and a specificity of 71%. CONCLUSIONS: Screening of overweight and obese children in primary care for NAFLD with referral to paediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral, to identify children with liver disease in the most appropriate manner.

The importance of measuring the velocity of diameter expansion on MRI in upfront management of suspected WHO grade II glioma - case report.

A right insular lesion was incidentally discovered in a 48-year-old male. Morphological and metabolic radiological characteristics on magnetic resonance imaging (MRI) were in favor of a World Health Organization (WHO) grade II glioma. Despite being advised that surgery was appropriate, the patient elected for conservative management. A second MRI was performed 5 months after, and interpreted as unchanged. A third MRI 4 months later demonstrated a significant increase in tumor size and enhancement in a new distant tumor focus. The patient was referred to our center and underwent surgical resection. Histopathology revealed a grade III astrocytoma. A retrospective quantitative measurement of the radiological growth between the two first MRIs yielded a growth rate of 12 mm/year. This value, highly suggestive of a malignant glioma, should have triggered surgery at the time of the second MRI. We conclude that, whenever surgical treatment of a suspected WHO grade II gliomas is postponed, assessing tumor kinetics quantitatively is important to identify patients whose tumor is indeed a WHO grade III glioma. The tumor should be indeed followed by serial MRIs with quantitative measurement of tumor growth, not just "eyeball" qualitative examination. Immediate treatment is indicated in patients with radiological tumor expansion of greater than 8mm/year.

Evaluating the Ozioma cancer news service: a community randomized trial in 24 U.S. cities.

OBJECTIVE: This community randomized trial evaluated effects of the Ozioma News Service on the amount and quality of cancer coverage in Black weekly newspapers in 24 U.S. cities. METHOD: We created and operated Ozioma, the first cancer information news service specifically for Black newspapers. Over 21 months, Ozioma developed community- and race-specific cancer news releases for each of 12 Black weekly newspapers in intervention communities. Cancer coverage in these papers was tracked before and during the intervention and compared to 12 Black newspapers in control communities. RESULTS: From 2004 to 2007, we coded 9257 health and cancer stories from 3178 newspaper issues. Intervention newspapers published approximately 4 times the expected number of cancer stories compared to control newspapers (p(12,21 mo)<.01), and also saw an increase in graphics (p(12,21 mo)<.01), local relevance (p(12 mo)=.01), and personal mobilization (p(12 mo)<.10). However, this increased coverage supplanted other health topics and had smaller graphics (NS), had less community mobilization (p(21 mo)=.01), and is less likely to be from a local source (NS). CONCLUSION: Providing news releases with localized and race-specific features to minority-serving media outlets can increase the quantity of cancer coverage. Results are mixed for the journalistic and public health quality of this increased cancer coverage in Black newspapers.

Comparing the use of cobalt chromium stents to stainless steel stents in primary percutaneous coronary intervention for acute myocardial infarction: a prospective registry.

OBJECTIVES: To determine clinical outcome and rates of target vessel revascularization (TVR) in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI who were treated with cobalt-chromium stents compared to stainless steel bare metal stents (BMS). BACKGROUND: The newer generation cobalt chromium stents were reported to achieve lower rates of TVR compared with conventional BMS. METHODS: Consecutive STEMI cases admitted within 12 h of symptom onset and undergoing primary angioplasty and bare metal stent implantation 1 January 2002 and 31 December 2008 were identified. Primary outcomes were rates of clinically-driven TVR at six months as well as occurrence of major adverse cardiovascular events (MACE) either of all-cause death, repeat myocardial infarction or TVR at six months. RESULTS: 1030 cases with 1175 lesions (84% males) and median age of 58 years underwent primary PCI for STEMI in our registry. Overall procedural success rate was 98%. Stainless steel stents were inserted in 65% of the culprit lesions (stainless steel, n = 766 versus cobalt chromium, n = 264). Primary outcomes of TVR (3.5% in the stainless steel group and 3.4% in the cobalt chromium group, P = 0.93) and MACE (8.4% in the stainless steel group and 5.3% in the cobalt chromium group, P = 0.11) after six months were no different between the two groups. However, there were more deaths at 30 days in the stainless steel group compared to the cobalt chromium group (3.5% versus 0.4%, HR 4.04 (1.03-3.88), P = 0.04). CONCLUSION: Both cobalt-chromium and stainless steel coronary stents were associated with similar and low risk of clinically-driven TVR.

Effect of dairy and non-dairy calcium on fecal fat excretion in lactose digester and maldigester obese adults.

BACKGROUND: The effect of dietary calcium (Ca) on fecal fat excretion in lactose maldigestion is not known. OBJECTIVE: To investigate the effect of dairy and non-dairy dietary Ca on fecal fat excretion in lactose digesters and maldigesters during moderate energy restriction. DESIGN: A randomized cross-over trial comparing the effect of 500 mg versus 1500 mg dairy and non-dairy Ca on fecal fat excretion in 34 healthy adults during moderate (-30%) energy restriction induced weight loss for 12 weeks. The participants were classified as lactose digester or maldigester on the basis of breath hydrogen test. MEASUREMENTS: Anthropometric parameters and body composition, resting energy expenditure, energy and nutrient intake, fecal fat, physical activity, blood pressure, blood and urine sampling for pertinent measurements. RESULTS: Fecal fat loss expressed as percent of fat intake was significantly higher with 1500 mg (high Ca) as compared with 500 mg (low Ca) Ca intake per day (mean: 3.0%; 95% CI: 2.3 to 3.7%; P<0.001) independent of Ca source and lactose digestion status. CONCLUSIONS: During a moderate energy restriction induced weight loss, a high-Ca diet causes an increase in fecal fat excretion independent of Ca source. Ca intake related fecal fat loss is also independent of the ability to digest lactose and it is not diminished over time (US Clinical Trial Registration: Clinicaltrials.gov NCT00808275).

Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors.

BACKGROUND: Children less than 5 years of age with malignant central nervous system (CNS) tumors, continue to have a high rate of morbidity and mortality following administration of conventional therapy. In an attempt to avoid the neurologic sequelae associated with craniospinal radiation, strategies such as high-dose chemotherapy (HDCT) followed by peripheral stem cell rescue have been used successfully. Metronomic chemotherapy has also been reported as a potential new treatment strategy in solid tumors, particularly in adults. PROCEDURE: A retrospective chart analysis was performed on 10 patients less than 5 years of age with CNS tumors treated with metronomic chemotherapy shortly after HDCT as part of their clinical care. RESULTS: Metronomic chemotherapy was associated with minimal toxicity and all patients maintained a good quality of life. At the time of this report, all 10 patients are alive. Two patients have relapsed, and the remaining eight, including six patients with metastatic disease, continue to have stable clinical and radiographic disease at a mean of 20 months from the time of diagnosis. CONCLUSIONS: Metronomic chemotherapy in this patient population is feasible and shows encouraging preliminary results, especially in patients with metastatic disease who have not received craniospinal radiation. Further investigation of this strategy in newly diagnosed patients with CNS tumors is warranted.

Flow and particle deposition patterns in a realistic human double bifurcation airway model.

Velocity profiles, local deposition efficiencies (DE), and deposition patterns of aerosol particles in the first three generations (i.e., double bifurcations) of an airway model have been simulated numerically, in which the airway model was constructed from computed tomography (CT) scan data of real human tracheobronchial airways. Three steady inhalation conditions, 15, 30, and 60 L/min, were simulated and a range of micrometer particle sizes (1-20 mum diameter) were injected into the model. Results were then compared with experimental and other numerical results which had employed either similar model geometry or test conditions. The effects of inhalation conditions on velocity profiles and particle deposition were studied. The data indicated that the local deposition efficiencies in the first bifurcation increased with a rise in the Stokes number (St) within St range from 0.0004 to 0.7. Within the same St range, DE in the second bifurcations (both left and right) was dropped dramatically after St increased to 0.17. Also, the second bifurcation in the right side (B2.1, closer to first bifurcation than left side, B2.2) was found to show a much higher (almost double) DE than the left side. This may be due to the fact that the left main bronchus is longer and has greater angulation than the right main bronchus. Generally, the present simulation using a computational fluid dynamic (CFD) technique obtained concurrent results with subtle differences compared to other works. However, due to omission of larynx in the model, which is known to significantly modify airflow and hence particle deposition, the present model may only serve as the "stepping stone" to simulating and analyzing dose-response or inhalation risk assessment visually for clinical researchers.

Absorption characteristics of EC-MPS--an enteric-coated formulation of mycophenolic sodium.

UNLABELLED: Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine. OBJECTIVE: Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine. METHODS: Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered. RESULTS AND CONCLUSIONS: In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.

Activity and nature of plasminogen activators associated with the casein micelle.

In fresh milk, plasminogen, the zymogen form of plasmin (PL), is the predominant form. Therefore, plasminogen activators (PA) can contribute significantly to PL activity in milk. Both tissue-type PA (tPA) and urokinase-type PA (uPA) exist in milk; however, contradictory findings have been reported for which type of PA is most closely associated with the casein micelles. Little is known about the factors that might lead to variations in the individual activities of the PA. The objective of this work was therefore to investigate possible factors that might affect the association of tPA and uPA with the casein micelle and their activities thereafter. Plasminogen activators were isolated from milk samples with different somatic cell counts following 2 different isolation protocols. Determination of uPA, tPA, and PL activities was carried out quantitatively following chromogenic assays using 2 different substrates, and qualitatively using specialized sodium dodecyl sulfate-PAGE. Different isolation methods and conditions led to differences in uPA, tPA, and PL activities. Urokinase-type PA activity was significantly higher in PA fractions isolated from milk with high somatic cell counts than from milk with low somatic cell counts. Activity results indicated that in pasteurized milk uPA could dissociate from the somatic cells and bind to casein. Moreover, a high level of PL in isolated PA fractions contributed to significantly enhanced PA activities. Overall, results confirmed the association of both uPA and tPA with the casein micelle; however, their amounts, activities, and molecular weights varied based on the nature of the milk and methods of separation, with uPA being the PA with greater potential to affect plasminogen activation in milk.

Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: a multicentre retrospective analysis.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) can adversely affect platelet function and impair haemostasis. Various bleeding complications have been reported in persons taking SSRIs including an increased risk of gastrointestinal haemorrhage (GIH). AIM: To evaluate SSRI use in patients hospitalized with GIH compared with controls. METHODS: A retrospective, multicentre case-control study determined use of SSRIs, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, clopidogrel, coumadin and enoxaparin in patients admitted with GIH and age- and sex-matched controls. Exclusion criteria included liver disease, portal hypertension or bleeding diathesis. RESULTS: A total of 579 cases were matched with 1000 controls. SSRI use was 19.2% in cases and 13.6% in controls [OR (95% CI) = 1.5 (1.2-2.0); P = 0.003]. NSAIDs were used by 7.3% of cases and 3.8% of controls [OR = 2.0 (1.3-3.1); P = 0.003]. SSRI use was more strongly associated with lower [1.8 (1.2-2.8)] rather than upper [1.3 (0.83-1.9)] GIH. Significant interactions existed for SSRI use with NSAIDs and aspirin. CONCLUSIONS: Patients admitted with GIH gastrointestinal bleeding were more likely to be taking SSRIs than controls. This association exists for lower as well as upper GIH. Physicians should be aware of this risk particularly in patients already using medications that increase GIH risk.

Mycophenolic acid metabolite profile in renal transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an effective immunosuppressive treatment in renal transplant recipients but is known to have gastrointestinal side effects. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) is a new formulation for delivering MPA. This open-label, two-period, cross-over study was carried out to characterize the time course of MPA and its metabolites, mycophenolic acid glucuronide (MPAG) and acyl mycophenolic acid glucuronide (AcMPAG) in stable renal transplant patients (n = 40) after 28-day chronic dosing with EC-MPS (720 mg bid) or MMF (1000 mg bid). The relative abundance and exposure of all three compounds was also assessed. EC-MPS demonstrated the typical pharmacokinetic profile of an enteric-coated formulation with a delayed release of MPA compared with MMF (Tmax 2.5 versus 1.0 hours, respectively). Consistent with a similar disposition of MPA, both EC-MPS and MMF treatments resulted in the same ratio of MPAG to MPA exposure, 23:1. Furthermore, comparison of the AUC of MPAG and AcMPAG for both treatments indicated that steady state MPAG exposure was 75 to 90 times that of AcMPAG, confirming MPAG as the predominant metabolite of MPA. AcMPAG has been identified as a possible active metabolite of MPA; the present study indicates that AcMPAG may contribute around 14% of the exposure to active drug after administration of MPA. Both EC-MPS and MMF treatments were well tolerated over the 1-month period of chronic treatment. In summary, consistent with its enteric-coated design, EC-MPS delays delivery of MPA, but results in similar exposure to that provided by MMF.