D11Y SOD1 mutation and benign ALS: a consistent genotype-phenotype correlation

We describe three sporadic ALS patients in which a D11Y SOD1 mutation was detected. All three patients disclosed a prolonged survival and a stereotypical distal limbs involvement in the initial stages of the disease. By this report we demonstrate that D11Y SOD1 mutation is associated with a peculiar phenotype and we confirm its probable pathogenetic role.     

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans

Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 μU/ml versus 4.4 μU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.     

(35)S]GTPγS binding and opioid tolerance and efficacy in mouse spinal cord

The present study examined efficacy of a series of opioid agonists and then using chronic in vivo treatment protocols, determined tolerance to opioid agonist stimulated [³⁵S]GTPγS (guanosine 5′-O-(3-[³⁵S] thio)triphosphate) binding in mouse spinal cord membranes and compared it directly to spinal analgesic tolerance. The [³⁵S]GTPγS binding assay was used to estimate efficacy (E_max and τ; Operational Model of Agonism) of a series of opioid agonists for G-protein activation in mouse spinal cord. The rank order of opioid agonist efficacy determined in the [³⁵S]GTPγS assay using the Operational Model and E_max was similar. These efficacy estimates correlated with historical analgesic efficacy estimates. For tolerance studies, mice were continuously treated s.c. for 7 days with morphine, oxycodone, hydromorphone, etorphine or fentanyl and [³⁵S]GTPγS studies were conducted in spinal cord membranes. Other mice were tested in i.t. analgesia dose response studies (tailflick). Tolerance to DAMGO ([D-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin) or morphine stimulated [³⁵S]GTPγS binding (decrease in E_max) was observed following etorphine and fentanyl treatment only. These treatment protocols downregulate μ-opioid receptor density whereas morphine, oxycodone and hydromorphone do not. Spinal analgesic tolerance was observed following all treatment protocols examined (morphine, oxycodone and etorphine). Opioid antagonist treatment that specifically upregulates (chronic naltrexone) or downregulates (clocinnamox) μ-opioid receptor density produced a corresponding change in opioid agonist stimulated [³⁵S]GTPγS binding. Although receptor downregulation and G-protein uncoupling are among potential mechanisms of opioid tolerance, the present results suggest that uncoupling in mouse spinal cord plays a minor role and that the [³⁵S]GTPγS assay is particularly responsive to changes in μ-opioid receptor density.     

High-functioning autism spectrum disorder with fluent speech and late-onset epilepsy: an unusual presentation of Inv-Dup (15) syndrome

Many neuropsychiatric phenotypes have been reported in association with rearrangements in the 15q11-q13 region. Clinical presentations can include hypotonia, developmental delay, severe/moderate intellectual disabilities, poor expressive language, difficult to treat epilepsy, and autism spectrum disorders. Here we report an additional case of a girl with inversion duplication on chromosome 15 (Inv-Dup 15) showing a peculiar and milder clinical phenotype, including atypical high-functioning autism disorder, late onset and drug-responsive epilepsy, and a relatively good language development . This report suggests that a diagnosis of Inv-Dup (15) can be suspected during more benign atypical condition with a better outcome than usually reported.     

Peroxynitrite detoxification and its biologic implications

Peroxynitrite is a cytotoxic oxidant formed in vivo from the diffusional-controlled reaction between nitric oxide and superoxide radicals. Increased peroxynitrite formation has been related to the pathogenesis of multiple diseases, thus underlining the importance of understanding the mechanisms of its detoxification. In nature, different enzymatic routes for peroxynitrite decomposition have evolved. Among them, peroxiredoxins catalytically reduce peroxynitrite in vitro; modulation of their expression affects peroxynitrite-mediated cytotoxicity, and their content changes in pathologic conditions associated with increased peroxynitrite formation in vivo, thus indicating a physiologic role of these enzymes in peroxynitrite reduction. Selenium-containing glutathione peroxidase also catalyzes peroxynitrite reduction, but its role in vivo is still a matter of debate. In selected cellular systems, heme proteins also play a role in peroxynitrite detoxification, such as its isomerization by oxyhemoglobin in red blood cells. Moreover, different pharmacologic approaches have been used to decrease the toxicity related to peroxynitrite formation. Manganese or iron porphyrins catalyze peroxynitrite decomposition, and their protective role in vivo has been confirmed in biologic systems. Glutathione peroxidase mimetics also rapidly reduce peroxynitrite, but their biologic role is less well established. Flavonoids, nitroxides, and tyrosine-containing peptides decreased peroxynitrite-mediated toxicity under different conditions, but their mechanism of action is indirect.     

PERIPHERAL NEUROPATHY IN HEPATITIS C VIRUS INFECTED PATIENTS WITH AND WITHOUT MIXED CRYOGLOBULINEMIA

Objective: To evaluate immunohistochemical and ultrastructural changes in sural nerve biopsies from patients with peripheral neuropathy and hepatitis C virus (HCV) infection.
Methods: Frozen and plastic-embedded nerve specimens were obtained from 19 HCV-positive patients with (16) or without (3) mixed cryoglobulinemia (MC). Immunoperoxidase and immunofluorescence studies were performed on cryostat cross-sections using antibodies recognising cellular subsets and humoral factors involved in the inflammation (CD68, CD11a-b-c, CD20, CD3, CD4, CD45, C1q, C3d, TCC, IgG, IgA, IgM). Semi and ultrathin sections were studied by standard protocols.
Results: Nerve biopsy showed an axonal degeneration with micro- angiopathy (perineurial > endoneurial). IgM and IgG were observed as a thin sub-perineurial band and in the wall of endo and perineurial vessels in MC patients only. Immunoglobulin deposition colocalised in some nerves with complement factors. Macrophages and T memory/activated lymphocytes were seen perivascularly and in endoneurium while rare B-cells were detected in perineurium. In the MC-negative patients, the peripheral neuropathy was characterised by a prominent myelin degeneration. The pattern of distribution of immunoreactivity for humoral and cellular factors was similar but not identical to that of MC patients.
Conclusions: Axonal degeneration characterises the HCV-related MC neuropathy and is likely secondary to ischaemia. The vascular damage is prevailing in perineurium and appears to be mediated by both T-cells and immune complex. Myelin alterations mainly occur in MC-negative patients. These last findings suggest a primary pathogenetic role for HCV in the induction of the nerve damage.