The effect of hemicholinium-3 on the in vivo formation of cerebral phosphatidylcholine

The effect of hemicholinium-3 on the incorporation of [Me-18C]choline into the phospholipids of the subcellular fractions of the canine caudate nucleus was studied. A correlation between the amount of hemicholinium-3 administered and increased choline incorporation into phospholipids was obtained. The analysis of the labeled phospholipids revealed that 93% of the radioactivity was in phosphatidylcholine and the remainder in lysophosphatidyl choline and sphingomyelin + choline plasmalogens. The specific radioactivity of phosphatidylcholine (counts/min per [mu]g phosphorus) determined after its isolation by thin-layer chromatography, increased markedly as a result of the administration of hemicholinium. An unequal time-dependence in the labeling of the phosphatidylcholine in the subcellular fraction containing nerve endings, mitochondria and lysosomes, as opposed to the phosphatidylcholine of the microsomal fraction was also noted, particularly after the administration of hemicholinium and choline in a weight ratio of 500.Discontinuous density gradient centrifugation of the fraction containing the nerve endings, the mitochondria and the lysosomes showed that phosphatidylcholine formation was most affected by hemicholinium in the fraction containing the "heavy" nerve endings, followed by the fraction containing the mitochondria + lysosomes.It is suggested that hemicholinium acts by accelerating the intracellular rate of movement of chorine from the water-soluble into the lipid pool of the caudate nucleus where, by virtue of its presence19, it subsequently also stimulates the incorporation of choline into membrane phosphatidylcholine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32806/1/0000179.pd

Spectral flow and boundary string field theory for angled D-branes

D-branes intersecting at an arbitrary fixed angle generically constitute a configuration unstable toward recombination. The reconnection of the branes nucleates at the intersection point and involves a generalization of the process of brane decay of interest to non-perturbative string dynamics as well as cosmology. After reviewing the string spectrum of systems of angled branes, we show that worldsheet twist superfields may be used in the context of Boundary Superstring Field Theory to describe the dynamics. Changing the angle between the branes is seen from the worldsheet as spectral flow with boundary insertions flowing from bosonic to fermionic operators. We calculate the complete tachyon potential and the low energy effective action as a function of angle and find an expression that interpolates between the brane-antibrane and the Dirac-Born-Infeld actions. The potential captures the mechanism of D-brane recombination and provides for interesting new physics for tachyon decay.Comment: 32 pages, 9 figures; v2 references added; v3 discussion clarifie

Effect of ω-conotoxin MVIIA and Phα1β on paclitaxel-induced acute and chronic pain

AbstractThe treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ω-conotoxin MVIIA and Phα1β, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ω-conotoxin MVIIA (3–300pmol/site) or Phα1β (10–300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ω-conotoxin MVIIA (300pmol/site, i.t.) and Phα1β (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phα1β (30-300pmol/site, i.t.) elicited less adverse effects than ω-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phα1β as a safer alternative than ω-conotoxin MVIIA to treat the pain related to paclitaxel

Soothsaying DOM: A Current Perspective on the Future of Oceanic Dissolved Organic Carbon

The vast majority of freshly produced oceanic dissolved organic carbon (DOC) is derived from marine phytoplankton, then rapidly recycled by heterotrophic microbes. A small fraction of this DOC survives long enough to be routed to the interior ocean, which houses the largest and oldest DOC reservoir. DOC reactivity depends upon its intrinsic chemical composition and extrinsic environmental conditions. Therefore, recalcitrance is an emergent property of DOC that is analytically difficult to constrain. New isotopic techniques that track the flow of carbon through individual organic molecules show promise in unveiling specific biosynthetic or degradation pathways that control the metabolic turnover of DOC and its accumulation in the deep ocean. However, a multivariate approach is required to constrain current carbon fluxes so that we may better predict how the cycling of oceanic DOC will be altered with continued climate change. Ocean warming, acidification, and oxygen depletion may upset the balance between the primary production and heterotrophic reworking of DOC, thus modifying the amount and/or composition of recalcitrant DOC. Climate change and anthropogenic activities may enhance mobilization of terrestrial DOC and/or stimulate DOC production in coastal waters, but it is unclear how this would affect the flux of DOC to the open ocean. Here, we assess current knowledge on the oceanic DOC cycle and identify research gaps that must be addressed to successfully implement its use in global scale carbon models

Amphotericin B plasma monitoring for one burn child using high-performance liquid chromatography

A bioanalytical micromethod was described for the quantification of amphotericin B in plasma by HPLC. The method showed high absolute recovery, good linearity (0.1-10.0 μg/mL, r2 = 0.999), sensitivity (limits of quantification: 0.1 μg/mL), and acceptable stability. Inter/intraday precisions were 6.8 %/2.3 % and mean accuracy was 94.3 %. The method was applied to plasma monitoring of one burn child, 3 years old, 25 kg, thermal injury (18 % total burn surface area - TBSA). Amphotericin B (1 mg/kg) was prescribed from 24th to 35th day of the accident and plasma monitoring and pharmacokinetics was performed by serial blood collections on 27th and 35th days post burn. Plasma concentrations obtained were respectively 0.7 μg/mL and 1.2 μg/mL. Pharmacokinetics at both periods (27th vs 35th day) also was compared: 13.8 vs 14.3 h (t1/2β ); 0.5 vs 0.3 mL/min.kg (CLT) and 0.65 vs 0.38 L/kg (Vdss ). In conclusion, drug plasma monitoring by HPLC was quite useful to guarantee low risk and drug efficacy in a paediatric burn patient.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS)

© 2018 The Author(s). Background: Nocturia is a common urinary symptom of multiple sclerosis (MS) which can affect quality of life (QoL) adversely. Melatonin is a hormone known to regulate circadian rhythm and reduce smooth muscle activity such as in the bladder. There is limited evidence supporting use of melatonin to alleviate urinary frequency at night in the treatment of nocturia. The aim of this study was to evaluate the effect of melatonin on the mean number of nocturia episodes per night in patients with MS. Methods: A randomized, double blind, placebo controlled crossover trial was conducted. 34 patients with nocturia secondary to multiple sclerosis underwent a 4-day pre-treatment monitoring phase. The patients were randomized to receive either 2 mg per night (taken at bedtime) of capsulated sustained-release melatonin (Circadin®) or 1 placebo capsule for 6 weeks followed by a crossover to the other regimen for an additional 6 weeks after a 1-month washout period. Results: From the 26 patients who completed the study, there was no significant difference observed in the signs or symptoms of nocturia when taking 2 mg melatonin compared to placebo. The primary outcome measure, mean number of nocturia episodes on bladder diaries, was 1.8/night at baseline, and 1.4/night on melatonin, compared with 1.6 for placebo (Medians 1.70, 1.50, and 1.30 respectively, p = 0.85). There was also no significant difference seen in LUTS, QoL and sleep quality when taking melatonin. No significant safety concerns arose. Conclusions: This small study suggests that a low dose of melatonin taken at bedtime may be ineffective therapy for nocturia in MS. Trial registration: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869