Transclival approaches for intradural pathologies: historical overview and present scenario

Neurosurgical Review - Recently, endoscopic transsphenoidal transclival approaches have been developed and their role is widely accepted for extradural pathologies. Their application to intradural...     

Rational design,preparation and characterization of recombinant Ag85B variants and their glycoconjugates with T-cell antigenic activity against Mycobacterium tuberculosis

Tuberculosis is the deadliest infectious disease in the world. The variable efficacy of the current treatments highlights the need for more effective agents against this disease. In the past few years, we focused on the investigation of antigenic glycoconjugates starting from recombinant Ag85B (rAg85B), a potent protein antigen from Mycobacterium tuberculosis. In this paper, structural modifications were rationally designed in order to obtain a rAg85B variant protein able to maintain its immunogenicity after glycosylation. Lysine residues involved in the main T-epitope sequences (namely, K30 and K282) have been substituted with arginine to prevent their glycosylation by a lysine-specific reactive linker. The effectiveness of the mutation strategy and the detailed structure of resulting neo-glycoconjugates have been studied by intact mass spectrometry, followed by peptide and glycopeptide mapping. The effect of K30R and K282R mutations on the T-cell activity of rAg85B has also been investigated with a preliminary immunological evaluation performed by enzyme-linked immunospotting on the different variant proteins and their glycosylation products. After glycosylation, the two variant proteins with an arginine in position 30 completely retain the original T-cell activity, thus representing adequate antigenic carriers for the development of efficient glycoconjugate vaccines against tuberculosis.

Recombinant Ag85B variants were designed and prepared to improve the immunogenicity of a potential glycoconjugate vaccine against tuberculosis.     

Hepatitis C virus-related cryoglobulinemic glomerulonephritis: long-term remission after antiviral therapy

BACKGROUND: Renal involvement in patients with hepatitis C virus (HCV) infection commonly manifests as cryoglobulinemic glomerulonephritis (CGN). The combination of interferon-alpha (IFN-alpha) and ribavirin, which is currently considered the standard antiviral therapy in chronic hepatitis C, could be difficult to carry out in cryoglobulinemic patients who are frequently anemic, even in the absence of renal failure. Clinical and histologic long-term results of this therapeutic regimen have not been so far reported in patients with CGN. METHODS: Three patients with HCV-related CGN and slightly impaired kidney function were treated with IFN-alpha and ribavirin for 12 months, and subsequently were followed up for 24 to 36 months. Two of these patients who were anemic were pretreated with erythropoietin (EPO). In each patient renal biopsy was performed before starting therapy and repeated 14 to 26 months after the end of treatment. RESULTS: In all three patients, antiviral therapy induced sustained virologic response, which was followed by clear improvement in clinical, biochemical, immunologic, and histologic features. Clinical and biochemical improvement steadily progressed in all three patients, achieving normal or nearly normal results at the end of follow-up. In contrast, some immunologic features, such as serum levels of C4 and rheumatoid factor activity, did not normalize in two and three patients, respectively. Posttreatment renal biopsies showed mildly active histologic lesions. CONCLUSION: Antiviral therapy with IFN-alpha and ribavirin may be considerably beneficial in patients with HCV-related CGN who obtain sustained virologic response.     

Efficacy of a new long-acting injectable form of bromocriptine in hyperprolactinaemic patients

OBJECTIVE--The objective of this study was to assess the relationship of different doses of a long-acting bromocriptine preparation (Parlodel LAR) to the degree and duration of PRL suppression. We also measured circulating bromocriptine levels and altered tolerability of the drug. DESIGN--A double-blind randomized study of three different doses 25, 50 and 100 mg of Parlodel LAR. PATIENTS--Twenty-one female patients (seven patients/dose) with both tumoral and non-tumoral hyperprolactinaemia. MEASUREMENTS--After a single injection of Parlodel LAR 25, 50 or 100 mg, serum PRL and plasma bromocriptine levels were assessed during a follow-up of 60 days together with changes in clinical symptoms and signs of hyperprolactinaemia. RESULTS--Serum PRL levels normalized in 19 of 21 patients. The suppression of PRL secretion lasted 28 days in four of seven patients treated with either 25 or 50 mg Parlodel LAR and in five of seven patients who received Parlodel LAR 100 mg. In five of seven patients treated with the 100 mg dose, serum PRL levels were still within the normal range on day 60. Plasma bromocriptine levels remained therapeutically active for 28 days in all three groups. On day 60 they were within the therapeutic range only in the 100 mg group. Clinical data show a rapid disappearance of symptoms and signs of hyperprolactinaemia. Adverse events were mostly mild and transient. CONCLUSIONS--These data support the excellent efficacy and good tolerability of Parlodel LAR in patients with hyperprolactinaemia.     

Malignancies in bullous pemphigoid: A controversial association

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disorder that has been reported to be associated with malignancies. Some authors described several cases of pemphigoid associated with malignancies (PAM); however, the evidence of this correlation still remains controversial. Several theories have been postulated to explain the relationship between malignant neoplasms and BP; the main theory suggests that antibodies directed against tumor‐specific antigens of malignant cells may cross‐react with antigens (like BP antigens) in the basement membrane zone leading to the formation of blisters. We performed an extensive review of the English published work focusing on the epidemiology, the pathogenetic theories and the clinical and histological aspects of the disease. We identified 40 cases of PAM: of these, seven cases were associated with hematological malignancies and 33 with solid tumors. Physicians should be aware of the existence of PAM and we suggest an oncological screening in early‐onset pemphigoid, in patients with a former oncological history, in those with signs and symptoms that could be related to a neoplasm and in BP refractory to common immunosuppressive therapy.     

Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated

Melatonin, the chief product secreted by pineal gland, is capable of reducing free radical damage by acting directly as a free radical scavenger, and indirectly, by stimulating of antioxidant enzymes. Cyclosporine A (CsA) is the most widely used immunosuppressive drug, but its therapeutic use has several side effects including, i.e. nephrotoxicity and cardiotoxicity. This study was designed to examine the beneficial effects of melatonin in preventing CsA-induced cardiotoxicity. Additionally, we investigated the ability of melatonin to protect the rat heart via melatonin receptor. In one group of Wistar rats, melatonin (1 mg/kg/day i.p.) was administered concurrently with CsA (15 mg/kg/day s.c.) for 21 days. In another group of animals, melatonin was injected with CsA and luzindole, an antagonist of melatonin receptors. Oxidative stress in heart tissue homogenates was estimated using thiobarbituric acid reactive substances (TBARS), reduced glutathione levels and antioxidant enzyme activities including catalase and superoxide dismutase. CsA administration for 21 days produced elevated levels of TBARS, marked depletion of cardiac antioxidant enzymes and caused morphological alterations in myocardial fibers. Melatonin markedly reduced TBARS levels, increased the antioxidant enzyme levels and normalized altered cardiac morphology. The protective effects of melatonin were lost when the animals received the melatonin receptor antagonist. In conclusion our study shows that, (a) melatonin significantly reduces CsA cardiotoxicity, and (b) the reduction in CsA-induced cardiotoxicity was mediated by the binding of melatonin to its membrane receptors.