C3D deposition in peritubular capillaries indicates a variant of acute renal allograft rejection characterized by a worse clinical outcome

BACKGROUND: C4d deposition in peritubular capillaries (PTCs) is a sign of humoral renal allograft rejection and an independent predictor of graft survival. Few investigators have focused on the meaning of capillary C3 deposition in rejecting grafts. Because C3 production can result from both classic and alternative pathway activation of the complement cascade, it is not clear whether C3 deposition indicates a distinct entity of acute rejection (AR) or merely represents a separate form of C4d-positive AR. METHODS: We examined the deposition of C3d in the PTCs of recipients with AR in the first year posttransplantation (n=30). Clinical outcome variables and histology were compared with C3d-negative control patients (n=82). RESULTS: C3d-positive patients demonstrated more frequent preexisting T-cell antibodies (57%) and more re-transplants (37%), and they received more blood transfusions (mean 10.3 units). C3d-positive patients experienced more frequent multiple AR episodes (57%) and delayed graft function (36.7%). All nine C3d-positive recipients screened for posttransplantation donor-specific human leukocyte antigen antibodies demonstrated positive results. Graft failure occurred in 23% of C3d-positive recipients (7.3% in the control group) (P=0.03). C3d-positive biopsies showed significantly less tubulitis (P=0.03), whereas congestive PTCs with intraluminal accumulation of polymorphonuclear leukocytes were conspicuous. Thrombi, fibrinoid necrosis, and acute tubular necrosis were not more pronounced. In 19% of rejection biopsies, C3d deposition in PTCs was present without C4d deposition. In the remaining biopsies, C3d and C4d deposition was found simultaneously. CONCLUSIONS: The deposition of complement factor C3d in PTCs indicates a variant type of AR characterized by a worse clinical outcome.     

Mechanisms and role of lymphangiogenesis in cancer metastasis

An important critical point in tumor progression is the acquisition of metastatic potential. The presence of metastases in regional lymph nodes is an indicator of poor survival. The vascular endothelial growth factor (VEGF) family of growth factors and receptors is involved in vasculogenesis and angiogenesis. Among them, VEGF-C and VEGF-D regulate the lymphatic vessels development and growth via their binding to their receptor VEGFR3. The expression of VEGF-C or VEGF-D is demonstrated in various human tumors and can be used as pronostic factors in some of them. With the aid of these molecules and the discovery of specific lymphatic markers, lymphatic endothelial cells can be isolated and lymphatic vessels can be identified within tumors. The role of lymphangiogenesis in promoting the metastatic spread of tumor cells has been studied in animal models.     

Inhibition of ErbB-2 and ErbB-3 expression by quercetin prevents transforming growth factor alpha (TGF-alpha)- and epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell proliferation

Because ErbB-2 receptor is involved in hormone-independency for growth and metastasis of prostate cancer cells, the aim was to investigate the effects of quercetin on ErbB-2 and ErbB-3 expression and its critical components such as MAP kinase and PI-3 kinase. Hemocytometric counts and [3H]-thymidine incorporation were used to determine the effects of quercetin, EGF and TGF-alpha on cell proliferation and DNA synthesis in PC-3 and LnCap cells. Changes in ErbB-2, ErbB-3 and components of MAPK and PI-3K pathways were analyzed by Western blot analysis. Treatment of PC-3 and LnCap cells with quercetin resulted in a dose-dependent growth inhibition. The rate of DNA synthesis was decreased by 40, 55 and 65% on treatment with 14.5, 29.0 and 58.0 microM of quercetin, respectively. Concomitantly, these treatments led to a dose-dependent decrease in ErbB-2, ErbB-3 and their basal autophosphorylation levels as compared to controls. Cyclin D1 expression and basal phosphorylation of c-Raf, MAPK, Elk-1 and Akt-1 in PC-3 cells was also inhibited by quercetin treatment. Co-treating PC-3 cells with quercetin significantly attenuated EGF- and TGF-alpha-induced growth and phosphorylation of ErbB-2, ErbB-3, c-Raf, MAPK kinase 1/2 (MEK1/2), MAPK, Elk-1 and Akt-1. Since ErbB receptor is important for growth, metastasis and drug resistance, inhibition of ErbB-2 and ErbB-3 by pharmacological doses of quercetin may provide a new approach for treatment of prostate cancers.     

A study of the psychometric properties of the Fagestrom Test for Nicotine Dependence

A factor analysis of 772 Fagestrom Test for Nicotine Dependence (FTND) was performed in a population of French workers with STATISTICA software, utilizing tetrachoric correlations to account for the dichotomous responses of the FTND. Confirmatory factorial analysis found the two-factor solution recently proposed for the FTND to be unsatisfactory. An exploratory factorial analysis concluded that the best solution was monofactorial when Item 3 was deleted. A confirmatory factorial analysis of the FTND provided support for this monofactorial solution. With the deletion of Item 3, the FTND achieved a high internal consistency (Cronbach's alpha=.86). Thus, a revision of the FTND with the exclusion of Item 3 is proposed. This revised form of the FTND appears to assess a unidimensional construct indicating robust construct validity.     

Regulation of catecholamines by sustained and intermittent hypoxia in neuroendocrine cells and sympathetic neurons

Chronic intermittent hypoxia, a characteristic feature of sleep-disordered breathing, induces hypertension through augmented sympathetic nerve activity and requires the presence of functional carotid body arterial chemoreceptors. In contrast, chronic sustained hypoxia does not alter blood pressure. We therefore analyzed the biosynthetic pathways of catecholamines in peripheral nervous system structures involved in the pathogenesis of intermittent hypoxia-induced hypertension, namely, carotid bodies, superior cervical ganglia, and adrenal glands. Rats were exposed to either intermittent hypoxia (90 seconds of room air alternating with 90 seconds of 10% O2) or to sustained hypoxia (10% O2) for 1 to 30 days. Dopamine, norepinephrine, epinephrine, dihydroxyphenylacetic acid, and 5-hydroxytyptamine contents were measured by high-performance liquid chromatography. Expression of tyrosine hydroxylase and its phosphorylated forms, dopamine beta-hydroxylase, phenylethanolamine N-methyltransferase, and GTP cyclohydrolase-1 were determined by Western blot analyses. Both sustained and intermittent hypoxia significantly increased dopamine and norepinephrine content in carotid bodies but not in sympathetic ganglia or adrenal glands. In carotid bodies, both types of hypoxia augmented total levels of tyrosine hydroxylase protein and its phosphorylation on serines 19, 31, 40, as well as levels of GTP cyclohydrolase-1. However, the effects of intermittent hypoxia on catecholaminergic pathways were significantly smaller and delayed than those induced by sustained hypoxia. Thus, attenuated induction of catecholaminergic phenotype by intermittent hypoxia in carotid body may play a role in development of hypertension associated with sleep-disordered breathing. The effects of both types of hypoxia on expression of catecholaminergic enzymes in superior cervical neurons and adrenal glands were transient and small.     

Differential routing of coexisting neuropeptides in vasopressin neurons

The functional implications of intraneuronal coexistence of different neuropeptides depend on their respective targeting to release sites. In the rat hypothalamic magnocellular neurons, we investigated a possible differential routing of the coexpressed galanin and vasopressin. The respective location of proteins and messengers was assessed with double immunogold and in situ hybridization combining confocal and electron microscope analysis. The various populations of labelled granules were quantitatively compared in three subcellular compartments: perikarya, local processes and posthypophyseal nerve endings. Three subpopulations of granules were detected in all three compartments, but their respective amount showed significant differences. Galanin alone was immunolocalized in some secretory granules, vasopressin alone in others, and both peptides in a third subpopulation of granules. The major part of the granules containing vasopressin, either alone or in association with galanin, is found in neurohypophyseal nerve endings. In contrast, galanin single-labelled granules represent the most abundant population in dendritic processes, while double-labelled granules are more numerous in perikarya. This indicates a preferential distribution of the two peptides in the different compartments of magnocellular neurons. Furthermore, galanin and vasopressin messenger RNAs were detected at different domains of the endoplasmic reticulum, suggesting that translation might also occur at different locations, thus leading to partial segregation of galanin and vasopressin cargoes between two populations of secretory granules. The present study provides, for the first time in mammals, evidence suggesting that galanin and vasopressin are only partly copackaged and undergo a preferential targeting toward dendrites or neurohypophysis, suggesting different functions, autocrine/paracrine and endocrine, respectively.     

Myelin basic protein-reactive T cells induce conduction failure in vivo but not in vitro

The ability of myelin basic protein (MBP)-reactive T cells to induce conduction failure was investigated and. With the model, somatosensory evoked potentials (SEP) were recorded before and during adoptively transferred experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Maximum amplitude SEP were reached within 15 min of anesthesia. During EAE, the SEP decreased considerably and their onset was delayed. However, the compound action potentials (CAPs) recorded from Lewis rat optic nerves incubated with encephalitogenic T cells were not affected, emphasizing the importance of environmental factors. This study shows that the model described here is an useful means of investigating the neurological disorders associated with EAE.     

Influence of very low dietary intake of marine oil on some functional aspects of immune cells in healthy elderly people

Ageing is a multifactorial process involving decreased antioxidant defences and immune functions. n-3 Polyunsaturated fatty acids have been associated with human health benefits, especially against inflammatory and autoimmune diseases. However, their immunomodulatory effects were usually observed with high dosages (>2 g/d) known to increase lipid peroxidation. In contrast, very low doses, that may prevent lipid peroxidation, might affect the immune system differently. To study the latter hypothesis further, we investigated whether the supplementation of healthy elderly people with very low doses of marine oil (MO), a docosahexaenoate (DHA)- and eicosapentaenoate (EPA)-rich triacylglycerol, was able to affect lymphocyte proliferation and biochemical markers known to be altered with age. In a randomized, double-blind design, twenty healthy elderly subjects were assigned to a placebo group (600 mg sunflower oil/d) or to a group consuming 600 mg MO/d providing 150 mg DHA + 30 mg (EPA) for 6 weeks. At day 42, the proliferative responses of lymphocytes to several mitogens were significantly (P<0.01) decreased in the MO group compared with control values. This was accompanied by a slight lowering of their cytosolic cyclic nucleotide phosphodiesterase (PDE) activity, a marked and significant (P<0.05) increase of their particulate PDE activity (+56-57 %) and a slight but significant (P<0.05) increase in cyclic nucleotide intracellular levels. At the same time, the glutathione peroxidase activity was markedly and significantly (P<0.01) depressed in the MO group. None of these modifications could be seen in the placebo group. Collectively, these results demonstrate that even very low doses of n-3 fatty acids are sufficient to affect the immune responses of elderly subjects.     

Age-associated cerebral atrophy in mouse lemur primates

We assessed the regional brain atrophy in mouse lemur primates from 4.7 T T2-weighted magnetic resonance images. Thirty animals aged from 1.9 to 11.3 years were imaged. Sixty-one percent of the 23 animals older than 3 years involved in the study displayed an atrophy process. Cross-sectional analysis suggests that the atrophy follows a gradual pathway, starting in the frontal region then involving the temporal and/or the parietal part of the brain and finally the occipital region. Histological evaluation of five animals selected according to various stages of atrophy suggested that extracellular amyloid deposits and tau pathology cannot explain by themselves this atrophy and that intracellular amyloid deposition is more closely linked to this pathology. This study suggests that most of the age-related atrophy occurring in mouse lemurs is caused by one clinical, evolving, pathological process. The ability to follow this pathology non-invasively by MRI will allow to further characterize it and evaluate its relationship with neuropathological lesions that are involved in human diseases such as Alzheimer.     

The opening interrupter technique for respiratory resistance measurements in children

Background and objective: The interrupter resistance (Rint) can be calculated from various estimates of alveolar pressure based on mouth pressure during occlusion. We compared Rint, as measured by the opening interrupter technique (Rint1), and the linear back‐extrapolation method (Rint2), with the ‘gold standard’ airway resistance measured by plethysmography (Raw). Methods: The study included 32 asthmatic children and 11 children with cystic fibrosis, aged 5 to 18 years, who were categorized into non‐obstructed (NObs) (n = 27) and obstructed (Obs) (n = 16) groups. Spirometry and the three different resistance measurements were performed on all children. Rint1 and Raw were assessed after a bronchodilator (BD) test in 16 and nine children, respectively, in the Obs group. Results: Raw (0.48 ± 0.20 kPa.s/L) was lower than Rint1 (1.04 ± 0.34 kPa.s/L) and Rint2 (0.63 ± 0.18 kPa.s/L) (P < 0.001). Raw, but neither Rint1 nor Rint2, was significantly higher in the Obs group than in the NObs group (0.57 ± 0.23 vs 0.42 ± 0.16 kPa.s/L, P < 0.05). The differences Rint1‐Raw and Rint2‐Raw were correlated with FEV₁/VC (P < 0.01 and P < 0.001), and Rint1‐Raw was correlated with height (P < 0.001). After BD significant changes in Rint1 and Raw were observed in 5/9 and 7/9 children, respectively. Conclusions: Rint2, as well as Rint1, may be underestimated in the most Obs children and may therefore fail to detect severe obstruction. Rint1 is likely to include a non‐negligible contribution from the tissue component, especially in the youngest children. Although not different between Obs and NObs children at baseline, Rint1 did detect bronchodilation in some Obs children.