New Insights Into Fatty Liver Preservation Using Institute Georges Lopez Preservation Solution

Institute Georges Lopez preservation solution (IGL-1) has been demonstrated to be useful for fatty liver preservation. The mechanisms responsible for this effective graft protection against ischemia-reperfusion injury are pivotal actions on generation of nitric oxide a diffusible molecule with vasodilator properties, that facilitates the up-regulation of other well-known cytoprotective genes, such as hypoxia-inducible factor-1 alpha (HIF-1α) and heme-oxygenase 1 (HO-1). During normoxic reperfusion, the presence of nitric oxide permits HIF-1α accumulation to inhibit prolyl-hydoxylases, thus promoting an additional overexpression of the HO-1 in steatotic and nonsteatotic graft livers preserved in IGL-1.     

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer-affected patients

Aluminium is not a physiological component of the breast but has been measured recently in human breast tissues and breast cyst fluids at levels above those found in blood serum or milk. Since the presence of aluminium can lead to iron dyshomeostasis, levels of aluminium and iron‐binding proteins (ferritin, transferrin) were measured in nipple aspirate fluid (NAF), a fluid present in the breast duct tree and mirroring the breast microenvironment. NAFs were collected noninvasively from healthy women (NoCancer; n = 16) and breast cancer‐affected women (Cancer; n = 19), and compared with levels in serum (n = 15) and milk (n = 45) from healthy subjects. The mean level of aluminium, measured by ICP‐mass spectrometry, was significantly higher in Cancer NAF (268.4 ± 28.1 μg l^?1; n = 19) than in NoCancer NAF (131.3 ± 9.6 μg l^?1; n = 16; P < 0.0001). The mean level of ferritin, measured through immunoassay, was also found to be higher in Cancer NAF (280.0 ± 32.3 μg l^?1) than in NoCancer NAF (55.5 ± 7.2 μg l^?1), and furthermore, a positive correlation was found between levels of aluminium and ferritin in the Cancer NAF (correlation coefficient R = 0.94, P < 0.001). These results may suggest a role for raised levels of aluminium and modulation of proteins that regulate iron homeostasis as biomarkers for identification of women at higher risk of developing breast cancer. The reasons for the high levels of aluminium in NAF remain unknown but possibilities include either exposure to aluminium‐based antiperspirant salts in the adjacent underarm area and/or preferential accumulation of aluminium by breast tissues. Copyright © 2011 John Wiley & Sons, Ltd.     

Variation in the Levels of Inflammatory Cytokines Depending on Ischemic Time: Effects on Respiratory Variables

Objectives

We sought to evaluate the association between ischemic times, cytokines—interleukin (IL)-6, IL-1b, tumor necrosis factor-alpha, sIL-2r, IL-8, and IL-10—and alterations in gaseous exchange.

Materials and Methods

This prospective study of 42 orthotopic liver transplantation (OLT) recipients examined ischemic times and respiratory variables measured as alterations in intrapulmonary shunt and in the Po₂/Fio₂ ratio. Centrifuged blood samples were frozen at −80°C for storage. The Inmulite-One system (Euro/Dpc, Gwynedd, UK) was used to determine the concentration of cytokines. For statistical analysis, we used the Pearson correlation coefficient.

Results

The average cold ischemic time was 478 minutes (range, 35-929) and warm ischemic time was 69.58 minutes (range, 20-180). The warm ischemic time affected the degree of shunt at the end of the operation (P < .027) and the levels of IL-10 (P < .018) and IL-6 (P < .000). The final degree of shunting and IL-10 (P < .044) showed a correlation. The cold ischemic time affected IL-1 (P < .046) and IL-8 levels (P < .023). The reperfusion syndrome was correlated with the final levels of IL-10 (P < .064) and of IL-8 (P < .066).

Conclusion

Warm and cold ischemic times affect the final cytokine levels and the degree of intrapulmonary shunt.     

Amyotrophic lateral sclerosis,frontotemporal dementia and beyond: the TDP-43 diseases

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to α-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.     

Effects of maternal antenatal glucocorticoid treatment on apoptosis in the ovine fetal cerebral cortex

We examined the effects of single and multiple maternal glucocorticoid courses on apoptosis in the cerebral cortices of ovine fetuses (CC). Ewes received single dexamethasone or placebo courses at 104-106 or 133-135 days or multiple courses between 76-78 and 104-106 days gestation. In the single-course groups, ewes received four 6 mg dexamethasone or placebo injections every 12 hr for 48 hr. Multiple-course groups received the same treatment once per week for 5 weeks. Neuronal and nonneuronal apoptotic cell numbers per square millimeter were determined with TUNEL and NeuN staining and with caspase-3 enzyme activity on CC tissues harvested at 106-108 (70%) or 135-137 (90%) days of gestation. Apoptotic cell numbers and caspase-3 activity were 50% lower (P < 0.02) after single placebo courses at 90% than 70% gestation; 90% of apoptotic cells were (P < 0.01) nonneuronal at both ages. Nonneuronal apoptotic cells and caspase-3 activity were 40% and 20% lower (P < 0.02) after single dexamethasone than placebo courses at 70%, but not 90%, gestation. Caspase-3 activity was 20% lower (P < 0.01) after multiple dexamethasone than placebo courses, but apoptotic cell number did not differ. We conclude that nonneuronal apoptosis represents the major form of apoptosis in the CC at both 70% and 90% of gestation. Apoptosis in nonneuronal cells decreases with maturity and after a single course of dexamethasone at 70%, but not at 90%, gestation and not after multiple courses at 70% gestation. We speculate that a single course of glucocorticoids exerts maturational changes on the rate of apoptosis in the cerebral cortex of preterm ovine fetuses.     

The neurokinin‐3 (NK3) and the neurokinin‐1 (NK1) receptors are differentially targeted to mesocortical and mesolimbic projection neurons and to neuronal nuclei in the rat ventral tegmental area

Tonic activation of neurokinin‐3 (NK₃) receptors in dopamine neurons of the ventral tegmental area (VTA) has been implicated in the pathophysiology of schizophrenia. This psychiatric disorder is associated with a dysfunctional activity in VTA projection neurons that can affect cognitive function at the level of the medial prefrontal cortex (mPFC) as well as motor and motivational states controlled in part by mesolimbic output to the nucleus accumbens (Acb). To determine the relevant sites for NK₃ receptor activation within this neuronal network, we used confocal and electron microscopy to examine NK₃ receptors (Cy5; immunogold) and retrograde labeling of fluorogold (FG, FITC; immunoperoxidase) in the VTA of rats receiving either Acb or mPFC injections of FG. Comparison was made with neurokinin‐1 (NK₁) receptors, which are also present, but less abundant then NK₃ receptors, in dopaminergic and GABAergic VTA neurons. There were no observable differences between NK₃ and NK₁ receptors in their primary locations in the cytoplasm and on the plasma membrane of VTA somata and dendrites with or without FG. Dendrites labeled with FG retrogradely transported from mPFC, however, contained more NK₃ or less NK₁ immunogold particles (plasmalemmal + cytoplasmic) then those retrogradely labeled following FG injection in the Acb. Moreover, only the NK₃ receptors were detected in neuronal nuclei in the VTA and in the nuclei of human HEK‐293T NK₃‐transfected cells. The enrichment of NK₃ receptors in mesocortical projection neurons and nuclear distribution of these receptors may provide insight for understanding the selective antipsychotic effectiveness of NK₃ antagonists. Synapse 63:484–501, 2009. © 2009 Wiley‐Liss, Inc.     

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

Lysinuric protein intolerance (LPI) is a rare autosomal inherited disease caused by defective cationic aminoacid transport 4F2hc/y(+)LAT-1 at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is a multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. The SLC7A7 gene, which encodes the y(+)LAT-1 protein, is mutated in LPI patients. Mutation analysis of the promoter localized in intron 1 and all exons of the SLC7A7 gene was performed in 11 patients from 9 unrelated LPI families. Point mutation screening was performed by exon direct sequencing and a new multiplex ligation probe amplification (MLPA) assay was set up for large rearrangement analysis. Eleven SLC7A7-specific mutations were identified, seven of them were novel: p.L124P, p.C425R, p.R468X, p.Y274fsX21, c.625+1G>C, DelE4-E11 and DelE6-E11. The novel large deletions originated by the recombination of Alu repeats at introns 3 and 5, respectively, with the same AluY sequence localized at the SLC7A7 3' region. The novel MLPA assay is robust and valuable for LPI molecular diagnosis. Our results suggest that genomic rearrangements of SLC7A7 play a more important role in LPI than has been reported, increasing the detection rate from 5.1 to 21.4%. Moreover, the 3' region AluY repeat could be a recombination hot spot as it is involved in 38% of all SLC7A7 rearranged chromosomes described so far.     

The importance of the length of the first metatarsal and the proximal phalanx of hallux in the etiopathogeny of the hallux rigidus

The purpose of this study was to determine if the relative length of the first metatarsal and the proximal phalanx of the hallux, in respect to the total foot length, were associated with the incidence of hallux rigidus. For this retrospective study, lateral radiographs from 132 cases with hallux rigidus and a control group of 132 normal feet were reviewed.We measured the following parameters: the index between the foot length and first metatarsal length, the proximal phalanx of the hallux length, and the sum of the first metatarsal length and the proximal phalanx of the hallux length.We found a statistically significant difference (p: 0.002) between the two groups in the Foot L/1st Mtt L index, and no statistical difference in the Foot L/Phalanx L index.We think that a greater length of first metatarsal is involved in the etiopathogeny of hallux rigidus.