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IntroductionIncreased vascular permeability represents one of the hallmarks of sepsis. In the kidney, vascular permeability is strictly regulated by the 'glomerular filtration barrier' (GFB), which is comprised of glomerular endothelium, podocytes, their interposed basement membranes and the associated glycocalyx. Although it is likely that the GFB and its glycocalyx are altered during sepsis, no study has specifically addressed this issue. The aim of this study was to evaluate whether albuminuria -- the hallmark of GFB perm-selectivity -- occurs in the initial stage of sepsis and whether it is associated with morphological and biochemical changes of the GFB.MethodsCecal ligation and puncture (CLP) was used to induce sepsis in the rat. Tumor necrosis factor (TNF)-alpha levels in plasma and growth of microorganisms in the peritoneal fluid were evaluated at 0, 3 and 7 hours after CLP or sham-operation. At the same times, kidney specimens were collected and structural and ultrastructural alterations in the GFB were assessed. In addition, several components of GFB-associated glycocalyx, syndecan-1, hyluronan (HA) and sialic acids were evaluated by immunofluorescence, immunohistochemistry and lectin histochemistry techniques. Serum creatinine and creatinine clearance were measured to assess kidney function and albuminuria for changes in GFB permeability. Analysis of variance followed by Tukey's multiple comparison test was used.ResultsSeptic rats showed increased TNF-alpha levels and growth of microorganisms in the peritoneal fluid. Only a few renal corpuscles had major ultrastructural and structural alterations and no change in serum creatinine or creatinine clearance was observed. Contrarily, urinary albumin significantly increased after CLP and was associated with diffuse alteration in the glycocalyx of the GFB, which consisted in a decrease in syndecan-1 expression and in HA and sialic acids contents. Sialic acids were also changed in their structure, exhibiting a higher degree of acetylation.ConclusionsIn its initial phase, sepsis is associated with a significant alteration in the composition of the GFB-associated glycocalyx, with loss of GFB perm-selectivity as documented by albumin leakage into urine.

Traumatic, toxic or metabolic damage to the nervous system is the etiological foundation of neuropathic pain. Neuropathies are extremely difficult to treat and available drugs rarely joint an anti-hyperalgesic with a neurorestorative effect. From the literature, evidences support the alpha7 nicotinic receptor (nAChR) subtype as having a role in neuropathic pain as well as possessing neuroprotective properties. Aimed to inquire the anti-neuropathic effect of the alpha7 nAChR stimulation, we evaluated the pharmacological profile of the alpha7 nAChR agonist PNU-282987 on pain and on morphological alterations induced in the rat sciatic nerve by loose ligation (CCI). Acute administration of PNU-282987, 10 and 30 mg kg(-1) p.o. (15 days after ligation), was able to reduce hyperalgesia in a methyllicaconitine-reversed manner. This alpha7 nAChR agonist exerted no analgesic effects. Chronic PNU-282987 treatments, 30 mg kg(-1) once a day for 7 days and 10 mg kg(-1) for 28 days, were able to decrease pain perception. The histological studies highlighted that the ligation induces oedema and macrophagic infiltrate. Moreover, osmicated preparations revealed a decrease in axons' compactness and diameter, together with a significant loss of myelin sheath. Repeated treatment with PNU-282987 reduced the presence of oedema and macrophagic infiltrate and, on the coronal sections of the nerve, a significant higher myelin sheath, axonal diameter and number of fibers were observable. These results strongly suggest the pivotal role of alpha7 nAChR in the neuroprotection during neuropathy.

Salvia miltiorrhiza l " Lamiaceae l " tanshinones and depsides l " CNS neuronal injury and degeneration l " in vivo studies l " biochemical mechanisms l " pharmacokinetics

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The aim of the present study was to investigate the distribution of the glycoconjugates sialoderivatives in the human testis. Orchidectomy specimens from men aged 18-30 years (Group 1) and from men aged 70-93 years (Group 2) were obtained at autopsy. The study was performed using digoxigenin-labelled lectins, namely Maackia amurensis II lectin (MAA), Sambucus nigra agglutinin (SNA) and Arachis hypogaea lectin (PNA), in addition to enzymatic and chemical treatments (neuraminidase, KOH-neuraminidase, mild oxidation-neuraminidase, mild oxidation-KOH-neuraminidase, strong oxidation-neuraminidase, strong oxidation-KOH-neuraminidase), to characterise the different glycosidic linkages of the sialoderivatives and to obtain information regarding their structure. In all Group 2 samples, sialic acids linked alpha-2,3 to galactose and alpha-2,6 to galactose/N-acetyl-D-galactosamine (Gal/GalNAc), revealed by MAA and SNA, respectively, were observed in testicular interstitial tissue and in the lamina propria. Sialic acid linked alpha-2,6 to Gal/GalNAc was detected in only some samples from Group 1. After treatment, PNA showed structural changes and/or the gradual disappearance of sialic acid linked to D-galactose-beta(1-3)-N-acetyl-D-galactosamine in testicular components with aging. These findings indicate that changes in the metabolism of sialoderivatives in the testis could be related to morphofunctional changes in various testicular components typical of this organ during aging. This suggests that sialoderivatives are important in the functionality of the mature testis in men, as well as its involution.