Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks

Autologous haematopoietic stem-cell transplantation has been evaluated over the last years as a possible new therapeutic strategy in severe forms of multiple sclerosis unresponsive to the approved therapies. Up to now, more than 400 patients have been treated and numerous are the phase I and phase II studies which addressed the feasibility of this treatment, the efficacy, side effects and transplant-related mortality. The clinical response is strongly related to the intensity of the conditioning regimen utilized as well as to the phase of the disease course in which the therapy is carried out. Rapidly evolving multiple sclerosis with a relapsing–remitting clinical course and MRI signs of activity are the cases that can take more advantage. The risk of mortality, which dropped in the last years to 2–3%, is still the main problem of this powerful therapy.     

TGF-β and IL-17 serum levels and specific immunotherapy

Two new T cell subsets may be involved in allergic rhinitis (AR) pathogenesis: Th17 and T regulatory cells, mainly producing IL-17 and TGF-β respectively. Successful Sublingual Immunotherapy (SLIT) induces relevant immunological changes, thus the aim of this study was to evaluate serum IL-17 and TGF-β levels in AR patients treated with SLIT for 2 years. Patients' blood samples were collected before initiating SLIT (baseline), three months after the end of the first pre-seasonal SLIT course, and at the end of the second pre-seasonal course. IL-17 was detectable only in the most severe allergic patients. SLIT significantly induced an increase in serum TGF-β levels. There was moreover a significant relationship between TGF-β and symptom severity and drug use at the end of the study. Therefore, this study provides clinically relevant evidence that two pre-seasonal SLIT courses may significantly affect serum TGF-β levels.     

Contribution of Blockade of the Noradrenaline Carrier to the Increase of Extracellular Dopamine in the Rat Prefrontal Cortex by Amphetamine and Cocaine

This study was performed to investigate the relative role of noradrenaline (NA) and dopamine (DA) carrier blockade in the effects of psychostimulants on DA transmission in the rat prefrontal cortex (PFCX). To this end, changes of extracellular DA and NA in the PFCX and of extracellular DA in the nucleus accumbens (NAc) were measured following the administration of amphetamine and cocaine, which are known to bind to both DA and NA carriers, or GBR 12909, a selective DA carrier blocker. After non-intravenous injection, amphetamine (0.25 and 0.5 mg/kg, s.c.) and cocaine (5 and 10 mg/kg, i.p.) increased extracellular DA in the PFCX to a larger extent than in the NAc, while the reverse applied to GBR 12909 (2.5 and 5 mg/kg, i.p.). These differences were obtained in spite of the fact that the three drugs elicited at each dose level a similar peak increase of extracellular DA in the NAc. Amphetamine and cocaine also increased extracellular NA in the PFCX and this effect was quantitatively similar to that on extracellular DA in the same area. Intravenous doses of cocaine and GBR 12909, corresponding to those which maintain self-administration in the rat, while equieffective in raising extracellular DA in the NAG, had different effects on extracellular DA in the PFCX. In fact, in contrast to cocaine, GBR 12909 increased extracellular DA in the PFCX to a lesser extent than in the NAc or did not modify it at all. The peak increase of extracellular DA in the PFCX was highly correlated to that of NA in the same area but was poorly correlated to the increase of extracellular DA in the NAc. These results suggest that amphetamine and cocaine increase extracellular DA in the PFCX largely through the blockade of the NA carrier. Direct evidence for this hypothesis was provided by the observation that, when the NA carrier was blocked by reverse dialysis of the PFCX with desipramine (1 μM), cocaine and GBR 12909 lost their differences in the ability to increase extracellular DA in the PFCX.     

Platyspondylisis+ in beta-thalassemia major]

Platyspondylia was observed in 14 patients affected with thalassemia major (7 males and 7 females, age range: 10-18 years) who received an intensive transfusion regimen combined with continuous chelation therapy (desferrioxamine: 50-80 mg/kg daily). Height/width ratio was decreased at all the investigated tracts--i.e., cervical and/or dorsal and/or lumbar spine. The range of height/width ratio values was 0.41-0.55 at the 5th cervical body, 0.33-0.53 at the 8th dorsal body, 0.43-0.56 at the 12th dorsal body and 0.47-0.62 at the 2nd lumbar body. The flattening of the vertebral bodies seems to be due to the depletion of hematopoetic tissue determined by the high transfusion regimen. The reduced intramedullary pressure is thought to counteract neither weight-bearing nor other biological stresses, which might ultimately provoke the thinning of vertebral bodies.     

Motor neuron disease and optic neuropathy after acute exposure to a methanol-containing solvent mixture.

A 34-years-old floor-layer developed optic neuropathy and motor neuron disease after being accidentally exposed to a solvent mixture containing methanol and other substances. Optic neuropathy is a complication of methanol poisoning, but the onset of a motor neuron disorder resembling amyotrophic lateral sclerosis after the exposure to these substances has not been previously described. The temporal onset of the clinical symptoms, biological plausibility, young age of the patient and absence of neurological disorders in the family history raises suspicion of a possible causative relationship.     

Decreased [H]hemicholinium binding to high-affinity choline uptake sites in aged rat brain

The binding of [³H]hemicholinium ([³H]HCh-3) to sodium-dependent high-affinity choline uptake sites provides a useful neuroanatomical and functional marker of the cholinergic system. We examined the autoradiographic distribution of [³H]HCh-3 binding sites in the forebrain of young (4–6 months) and old (32 months) rats. There was a widespread reduction of [³H]HCh-3 binding site density in the aged rat brain. This loss presented regional differences with maximal reduction in the medial and posterior striatum (55%) and in the dentate gyrus (47%), in limbic areas such as basolateral amygdala, tubercle olfactorium and piriform cortex the autoradiographic signal was about 25–30% lower. In aged hippocampus and cerebral cortex the density of [³H]HCh-3 binding sites was about 40% lower, the difference between young and senescent animals being less evident in the medial septum and basal nucleus. No significant alterations were observed in interpeduncular nucleus from old rats. These data are in agreement with the functional results obtained by measuring other cholinergic parameters in the aged rat and confirm the vulnerability of cholinergic system during aging     

Study of folate receptor genes in nonsyndromic familial and sporadic cleft lip with or without cleft palate cases

Folate receptor family members (FOLRs) mediate the delivery of 5-methyltetrahydrofolate to the interior of, out of within, or between cells in a process known as potocytosis. Three FOLRs and a pseudogene map to 11q13.4. The aim of this study was to verify whether FOLRs could be responsible for the onset of nonsyndromic cleft lip with or without cleft palate (CL/P). Linkage and linkage disequilibrium between genetic markers and disorder were analyzed. Patients and their mothers from 71 familial CL/P pedigrees and 75 sporadic cases from Italian population were investigated by PCR-SSCP analysis. Data from mutation scanning allowed us to find only a silent mutation in FOLR1 present in a mother and her child. Our findings do not support FOLR1 and FOLR2 genes in the onset of CL/P.     

Absence of TREM2 polymorphisms in patients with Alzheimer's disease and Frontotemporal Lobar Degeneration

Triggering Receptor Expressed on Myeloid cells (TREM)2 deficiency originates a genetic syndrome characterized by bone cysts and presenile dementia, named Nasu-Hakola disease (NHD). Early onset dementia and marked involvement of frontal regions are features characterizing both NHD and other kinds of neurodegenerative disorders, such as Frontotemporal Lobar Degeneration (FTLD), and, in some cases, Alzheimer's disease (AD). Three Single Nucleotide Polymorphisms (SNPs) in TREM2 coding region were screened by allelic discrimination in a population of probable AD patients as well as FTLD patients as compared with age-matched controls. In addition, mutation scanning of the coding region of TREM2 gene was carried out in 7 patients with early onset AD (EOAD), 16 FTLD, and 20 controls. None of the SNPs analyzed was present, either in patients or controls. Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms. These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes.     

Experimental model for studying the effects of 2-ethylhexyl-phthalate and dialysate on connective tissue

In order to have a model for studying the possible implications of 2-ethylhexyl-phthalate and dialysate on connective tissue, we evaluated their direct effects on the air pouch lining tissue and on fibroblast cultures. Air pouches were formed on the backs of 60 ten-week-old Wistar rats by subcutaneous injections of 10 ml sterile air. On the tenth day 2 ml sterile air, or 2 ml 5 microg/L or 2 ml 10 microg/L 2-ethylhexyl-phthalate in olive oil, or 2 ml olive oil alone, or 2 ml 5 mg/ml or 12 mg/ml lyophilized dialysate were injected into the air pouches. After sampling at seven or twenty-one days, the rats were killed. The biochemical data showed an increase in sulphated glycosaminoglycans with 2-ethylhexyl-phthalate and dialysate. Electron microscopy findings revealed cellular alterations such as vacuolation and cell remnants with 2-ethylhexyl-phthalate, while the cells of the air pouches treated with dialysate showed regular organelles with increased and dilated cisternae of rough endoplasmic reticulum. Moreover, an increase in collagen fibres surrounding the damaged zones was noticed in 2-ethylhexyl-phthalate and dialysate treated rats. The glycosaminoglycan modifications and collagen fibre increase seem to suggest that the morphological changes, with the features of fibrosis, could be the result of 2-ethylhexyl-phthalate and dialysate action on connective tissue. Moreover, the air pouch technique can be considered a good model for studying the direct effects of 2-ethylhexyl-phthalate and other substances, such as uremic toxins, on connective tissue.