Neurotransmitter glutamate has been thought to derive mainly from glutamine via the action of glutaminase type 1 (GLS1). To address the importance of this pathway in glutamatergic transmission, we ...knocked out GLS1 in mice. The insertion of a STOP cassette by homologous recombination produced a null allele that blocked transcription, encoded no immunoreactive protein, and abolished GLS1 enzymatic activity. Null mutants were slightly smaller, were deficient in goal-directed behavior, hypoventilated, and died in the first postnatal day. No gross or microscopic defects were detected in peripheral organs or in the CNS. In cultured neurons from the null mutants, miniature EPSC amplitude and duration were normal; however, the amplitude of evoked EPSCs decayed more rapidly with sustained 10 Hz stimulation, consistent with an observed reduction in depolarization-evoked glutamate release. Because of this activity-dependent impairment in glutamatergic transmission, we surmised that respiratory networks, which require temporal summation of synaptic input, would be particularly affected. We found that the amplitude of inspirations was decreased in vivo, chemosensitivity to CO2 was severely altered, and the frequency of pacemaker activity recorded in the respiratory generator in the pre-Bötzinger complex, a glutamatergic brainstem network that can be isolated in vitro, was increased. Our results show that although alternate pathways to GLS1 glutamate synthesis support baseline glutamatergic transmission, the GLS1 pathway is essential for maintaining the function of active synapses, and thus the mutation is associated with impaired respiratory function, abnormal goal-directed behavior, and neonatal demise.
Labile plasma iron (LPI) represents the redox active component of non–transferrin-bound iron (NTBI). Its presence in thalassemic patients has been recently reported. The aim of the present study was ...to quantify LPI in HFE genetic hemochromatosis (GH) and to characterize the mechanisms accounting for its appearance. We studied 159 subjects subdivided into the following groups: (1) 23 with iron overloaded GH; (2) 14 with iron-depleted GH; (3) 26 with dysmetabolic hepatosiderosis; (4) 33 with alcoholic cirrhosis; (5) 63 healthy controls. Both NTBI and LPI were substantially higher in patients with iron-overloaded GH than in those with iron-depleted GH or in healthy controls. LPI was significantly correlated with serum transaminase increase in this group. LPI was elevated in the alcoholic cirrhosis subgroup of severely affected patients. LPI was found essentially when transferrin saturation exceeded 75%, regardless of the etiologic condition. Transferrin saturation above 75% was related to iron overload in GH and to liver failure in alcoholic cirrhosis. LPI is present in C282Y/C282Y hemochromatosis and may be a marker of toxicity due to its potential for catalyzing the generation of reactive oxygen radicals in vivo.
Hepcidin, secreted by hepatocytes, controls iron metabolism by limiting iron egress in plasma. Hepcidin is upregulated during inflammation through the activation of the signal transducer and ...activator of transcription 3 (STAT3) transduction pathway, which decreases iron bioavailability and may explain the anemia of chronic inflammatory disease. In vitro, it has been shown that curcumin can decrease hepcidin synthesis by decreasing STAT3 activity. We conducted a proof‐of‐concept study to assess the effect of curcuma on hepcidin synthesis in human. This was a placebo‐controlled, randomized, double‐blind, cross‐over, two‐period study performed in 18 healthy male volunteers. Subjects received a single oral dose of 6 g curcuma containing 2% of curcumin or placebo. Serum hepcidin and iron parameters were assessed repeatedly until 48 h after dosing. When compared with a placebo curcuma decreased hepcidin levels significantly at 6 h (−19%, P = 0.004), 8 h (−17%, P = 0.009), and 12 h (−17%, P = 0.007) and tended to decrease hepcidin at 24 h (−15%, P = 0.076). Curcuma also significantly increased serum ferritin levels at 6 and 8 h (+7% for both times, P = 0.018, 0.030, respectively) and had no effects on serum iron, transferrin, and transferrin saturation. This pilot study showed that curcuma decreases serum hepcidin levels in human and supports the idea that curcuma could be useful in treating hepcidin overproduction during inflammatory processes. Confirmatory studies in patients with chronic inflammation are now required to determine the optimal dose and therapeutic scheme of curcuma.
Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Only mass spectrometry detection is currently available to determine sunitinib ...in human plasma. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method with UV-Visible detection for quantification of sunitinib concentrations in human plasma.
After a liquid–liquid extraction with ethyl acetate, sunitinib and ranitidine (internal standard) are separated on cyanopropyl column using a simple binary mobile phase of ammonium acetate buffer (20 mM; pH 6.8):acetonitrile (55:45,v/v). Samples were eluted isocratically at a flow rate of 1 mL/min throughout the 10 min run. Dual wavelength mode was used, with ranitidine monitored at 255 nm, and sunitinib at 431 nm.
The calibration was linear in the range 20–200 ng/mL. Inter- and intra-day coefficients of variation were less than 7%. This method is sensitive, accurate and selective. It has been successfully implemented to monitor trough sunitinib concentrations in plasma samples (
n
=
39) from 14 unselected cancer patients treated with the recommended once daily dose of 50 mg or less.
This method can be used in routine clinical practice to monitor plasma sunitinib concentrations in cancer patients treated with once daily administration.
Liver transplantation (LT) is the best treatment for patients with liver cancer or end stage cirrhosis, but it is still associated with a significant mortality. Therefore identifying factors ...associated with mortality could help improve patient management. The impact of iron metabolism, which could be a relevant therapeutic target, yield discrepant results in this setting. Previous studies suggest that increased serum ferritin is associated with higher mortality. Surprisingly iron deficiency which is a well described risk factor in critically ill patients has not been considered.
To assess the impact of pre-transplant iron metabolism parameters on post-transplant survival.
From 2001 to 2011, 553 patients who underwent LT with iron metabolism parameters available at LT evaluation were included. Data were prospectively recorded at the time of evaluation and at the time of LT regarding donor and recipient. Serum ferritin (SF) and transferrin saturation (TS) were studied as continuous and categorical variable. Cox regression analysis was used to determine mortality risks factors. Follow-up data were obtained from the local and national database regarding causes of death.
At the end of a 95-mo median follow-up, 196 patients were dead, 38 of them because of infections. In multivariate analysis, overall mortality was significantly associated with TS > 75% HR: 1.73 (1.14; 2.63), SF < 100 µg/L HR: 1.62 (1.12; 2.35), hepatocellular carcinoma HR: 1.58 (1.15; 2.26), estimated glomerular filtration rate (CKD EPI Cystatin C) HR: 0.99 (0.98; 0.99), and packed red blood cell transfusion HR: 1.05 (1.03; 1.08). Kaplan Meier curves show that patients with low SF (< 100 µg/L) or high SF (> 400 µg/L) have lower survival rates at 36 mo than patients with normal SF (
= 0.008 and
= 0.016 respectively). Patients with TS higher than 75% had higher mortality at 12 mo (91.4% ± 1.4%
84.6% ± 3.1%,
= 0.039). TS > 75% was significantly associated with infection related death HR: 3.06 (1.13; 8.23).
Our results show that iron metabolism imbalance (either deficiency or overload) is associated with post-transplant overall and infectious mortality. Impact of iron supplementation or depletion should be assessed in prospective study.
Marine predators are ecosystem sentinels because their foraging behaviour and reproductive success reflect the variability occurring in the lower trophic levels of the ecosystem. In an era of ...environmental change, monitoring top predators species can provide valuable insights into the zones of ecological importance that need to be protected. In this context, we monitored the Adélie penguin (Pygoscelis adeliae) as a bio-indicator near Dumont d'Urville, an area of the East Antarctic sector currently being considered for the establishment of a Marine Protected Area (MPA), using GPS-based tracking tags during the 2012/13 austral summer breeding season.
The habitat use and foraging areas of the penguins differed by breeding stage and sex and were strongly associated with patterns in bathymetry and sea-ice distribution. The first trips, undertaken during the incubation phase, were longer than those during the guard phase and were associated with the northern limit of the sea-ice extent. During the guard phase, birds strongly depended on access to a polynya, a key feature in Antarctic marine ecosystem, in the vicinity of the colony. The opening of the ice-free area was synchronous with the hatching of chicks. Moreover, a sex-specific use of foraging habitat observed only after hatching suggests sex-specific differences in the diet in response to intra-specific competition.
Sea-ice features that could be affected by the climate change were important factors for the use of foraging habitat by the Adélie penguins. The extent of the foraging area observed in this study is congruent with the area of the proposed MPA. However, both penguin behavior and their environment should be monitored carefully.
Aims
The prevalence rate of severe fecal incontinence (FI) in adults with spina bifida (SB) is high. The physiological basis of FI in SB has not been clearly established, which contributes to ...inadequate care. The aim was to better characterize a large cohort of adults with special consideration of anorectal physiology.
Methods
A multidisciplinary team from a French referral centre for SB prospectively collected data on patients who had an anorectal manometry. Factors associated with severe FI (Cleveland clinical incontinence score ≥ 9) were assessed in a multivariate analysis model.
Results
A total of 132 adults with SB (sex ratio M/F: 55 41.7%/77 58.3%; mean age of 38.2 11.6 years old) were assessed. Among these patients, 83/132 (62.9%) suffered from severe FI. Rectal perception was not evaluable among 17 patients who had a latex allergy. Overall, 29/115 (25.2%) had maximal tolerable volume (MTV) > 330 mL or no sensation. The absence of anal canal sensitivity, MVT > 330 mL and the amplitude of the recto‐anal inhibitory reflex (RAIR) >75% after a rectal isovolumic inflation of 50 mL were significantly associated with severe FI in the multivariate analysis model. Neither neurological level nor other neurological features were associated with severe FI.
Conclusions
This study showed that FI in patients with SB is mainly associated with rectal abnormalities. This should be taken into consideration to improve incontinence management of patients with SB.
Aims
Spina Bifida (SB) is a rare congenital condition that frequently impairs the neurological control of both fecal continence and defecation. Several therapeutic strategies have been proposed but ...impact assessment is lacking. Our objectives were to quantify the symptomatic improvement and to determine the optimal strategy in this rare condition where randomized controlled trials are difficult to conduct.
Methods
Data were extracted from a prospective database. The present analysis focused on patients having undergone at least two gastroenterological assessments. A standardized therapeutic approach was used from the first visit. Improvement was quantified by the variation of quantified symptomatic scores.
Results
The data of of 57 adults with SB (gender F/M: 30/27 52.6/47.4%; mean age: 33.8 18.5 years) were extracted. After a mean follow‐up of 46 months, 23/57 patients (40.4%) had at least improvement of one point of the Cleveland Clinic Incontinence score (CCIS); 13/57 (22.8%) reported a significant improvement of continence (delta score >50%). Five of the twelve patients (41.6%) with CCIS < 5 at baseline became incontinent over time. The neurological level was not associated with a worse continence outcome. Work on stool consistency and transanal irrigation were the most useful strategies in those with significant improvement of continence.
Conclusions
Using conventional strategies, a benefit on fecal continence occurs in only one out of five patients suffering from Spina Bifida and continent patients at baseline can develop fecal incontinence over time. A strategy targeting improved control of defecation (transanal irrigation) and a standardization of follow‐up protocol might be beneficial.
Purpose
Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its ...disposition. The aims of this study were to characterize
in vitro
sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients.
Results
In vitro
estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 μM CI95 0.20–0.23. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 μM) to 30 g/L (453 μM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75–2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (
p
= 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (
p
= 0.0036) was the single parameter independently associated with CL.
Conclusion
These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.
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