Beneficial effect of interferon-beta 1b treatment in patients with relapsing-remitting multiple sclerosis is associated with an increase in serum levels of soluble HLA-I molecules during the first 3 months of therapy

It has recently become clear that interferon-beta (IFN-beta) treatment is effective in ameliorating relapsing-remitting multiple sclerosis (RRMS) through an as yet unidentified mechanism. As there is no recognisable biological indicator to predict responsiveness to IFN-beta treatment, we have investigated fluctuations in serum sHLA-I levels in MS patients undergoing IFN-beta 1b therapy. Serum sHLA-I concentrations measured by enzyme-linked immunosorbent assay (ELISA) were assessed at baseline and, longitudinally, over a period of 18 months after the start of treatment in 29 RRMS patients grouped as responders and nonresponders according to their clinical response to IFN-beta 1b therapy. Thirty-nine healthy volunteers served as controls. Serum sHLA-I concentrations were significantly higher (p<0.001) in pretreated RRMS patients than in healthy donors. In MS patients, changes in mean serum levels of sHLA-I from baseline showed a temporal pattern characterized by a strong increase in the first trimester of treatment, a return toward basal values in the following 6 months, a slight decline at 12th and 15th months and a further moderate increase at the 18th month. Mean serum sHLA-I levels were significantly more elevated in responders than in nonresponders at the first (p<0.02), second (p<0.01), and at third (p<0.02) months after the beginning of treatment and significantly lower (p<0.01) at the time of relapses in comparison to baseline values. Overall, these results seem to indicate that IFN-beta 1b can modulate fluctuations in serum sHLA-I levels and argue in favour of a potential role for serum levels of sHLA-I as a sensitive marker to monitor response to IFN-beta treatment in MS.     

Interference of left and right cerebellar rTMS with procedural learning

Increasing evidence suggests cerebellar involvement in procedural learning. To further analyze its role and to assess whether it has a lateralized influence, in the present study we used a repetitive transcranial magnetic stimulation interference approach in a group of normal subjects performing a serial reaction time task. We studied 36 normal volunteers: 13 subjects underwent repetitive transcranial magnetic stimulation on the left cerebellum and performed the task with the right (6 subjects) or left (7 subjects) hand; 10 subjects underwent repetitive transcranial magnetic stimulation on the right cerebellum and performed the task with the hand ipsilateral (5 subjects) or contralateral (5 subjects) to the stimulation; another 13 subjects served as controls and were not submitted to repetitive transcranial magnetic stimulation; 7 of them performed the task with the right hand and 6 with the left hand. The main results show that interference with the activity of the lateral cerebellum induces a significant decrease of procedural learning: Interference with the right cerebellar hemisphere activity induces a significant decrease in procedural learning regardless of the hand used to perform the serial reaction time task, whereas left cerebellar hemisphere activity seems more linked with procedural learning through the ipsilateral hand. In conclusion, the present study shows for the first time that a transient interference with the functions of the cerebellar cortex results in an impairment of procedural learning in normal subjects and it provides new evidences for interhemispheric differences in the lateral cerebellum.     

Painful neuropathy vasculitis in 2 patients with long-standing human immunodeficiency virus-1 infection

We describe 2 most unusual cases of distal symmetrical painful polyneuropathy in patients with long-standing HIV-1 infection well controlled by HAART. Sural nerve biopsies revealed vasculitis in both cases and steroid therapy led to resolution of symptoms not influenced by analgesics and anti-inflammatory drugs. These unusual cases outline the importance of nerve biopsies in order to reach a diagnosis.     

Abdominal ultrasonography and chest radiography are of limited value in the emergency room diagnostic work-up of severe trauma patients with hypotension on the scene of accident

PURPOSE: To evaluate the reliability of chest radiograph (CR) and abdominal ultrasonography (US) performed in the Emergency Room (ER) in identifying life-threatening thoracic or abdominal lesions in a group of severely injured patients, who developed arterial hypotension immediately after a trauma. MATERIALS AND METHODS: The results of all abdominal US and CX performed in the ER in severe blunt trauma patients, with on-the-scene systolic blood pressure 90 mmHg, from November 2000 to November 2002, were analysed. When these initial investigations failed to identify a possible cause of hypotension, a computed tomography (CT) of the chest and abdomen was obtained. RESULTS: Overall, 54 patients were studied; twenty-two patients (40.8%) were hypotensive both on accident scene and on the arrival at the ER and 32 (59.2%) were hypotensive on accident scene, but not in the ER. Forty-five patients had an US in the ER, in 3 patients it was inconclusive, whereas 2 other patients died before the confirmatory investigations could be performed. Among the remaining 40 patients, 11 had a hemoperitoneum (HP) hat was diagnosed by US in 7 cases and missed in 4. Twenty-nine patients had no HP and their US was negative in 24 cases and positive in 5; the US had a sensibility of 63.6% and a specificity of 82.8% The CR was obtained in the ER in 39 patients and it was able to identify 6 pneumothoraces (PNX) out of 20 and 2 hemothoraces (HT) out of 17; the sensitivity for PNX and HT was 30.0% and 11.8%, respectively. One patient with an aortic dissection had a normal CX. CONCLUSIONS: Both CX and US are not reliable to identify possible PNX, HT and HP in hypotensive trauma patients and can delay the treatment of life-threatening conditions. In these patients, a CT of the torso is warranted.     

Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease

Increasing evidence indicates that mitochondrial dysfunction occurs in the central nervous system as well as in the peripheral tissues from Alzheimer's disease (AD) patients. We have recently shown that mitochondrial cytochrome c oxidase (COX) activity is significantly reduced in brain and platelets from AD patients compared to controls. In the present study we investigated whether impaired COX activity could have functional consequences on energy metabolism. Blood lactate concentration was monitored at rest and during incremental exercise in 22 AD patients in whom COX activity in platelets was decreased compared to controls (35.7 +/- 11.4 vs 48.4 +/- 1.4 nmol/min/mg, P < 0.01). In both resting and exercising conditions, blood lactate was significantly higher in AD patients than in controls. Although the magnitude of exercise-related lactate accumulation was not different between the two groups, an anticipated anaerobic lactate threshold during the incremental forearm exercise was found in AD patients (50% of maximal voluntary contraction MVC compared to 60% in controls). COX activity was inversely related to lactate at a significant level for resting condition (r = -0.65) and borderline for anaerobic threshold exercise level. These results support the hypothesis of a systemic impairment of the mitochondrial function in AD and indicate that decreased COX activity could have functional consequences on metabolism.     

Dendritic cell vaccination and immunostimulation in advanced melanoma

The most recent advances in immunology bear witness to the fact that tumors, in particular melanoma, escape recognition by the host's immune system and can locally inactivate its effectors, T-cells and antigen presenting cells. There is, however, preclinical evidence that the immune system, opportunely stimulated, is capable of recognizing and killing tumor cells. It has been verified that the activation of autologous dendritic cells, derived from peripheral blood and pulsed with tumor antigens, results in the specific stimulation of T-cells against the tumor. Preliminary data from dendritic cell vaccination trials, mainly of advanced melanoma, show unequivocal evidence of immunization and of the first clinical responses. Many questions remain to be answered before more effective and widespread use of this type of vaccination is possible, especially in the early stages of the disease.     

Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism

We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease.     

Percutaneous revascularization of femoropopliteal artery disease: PTA and PTA plus stent. Results after six years' follow-up

PURPOSE: To compare the long-term patency after the treatment of mild-to-moderate femoropopliteal artery disease by percutaneous transluminal angioplasty (PTA) alone (PTA group) and PTA plus stenting (STENT group) in a non-randomised retrospective study. MATERIALS AND METHODS: Eighty-six limbs in 64 patients (mean age 67+/-8 years, 47 males and 17 females) with femoropopliteal artery disease and symptomatic for mild-to-moderate intermittent claudication (Rutherford's category 1-2) were treated by percutaneous revascularization. None of the patients had critical lower limb ischaemia. Of the 86 lesions, 63 (40 stenoses and 23 occlusions) were treated by PTA alone and 23 (12 stenoses and 11 occlusions) by PTA plus stent implantation. The success was defined as a maximal = or < 30% residual stenosis of vessel lumen diameter, as defined by biplane angiography. The angiography findings were confirmed by colour-Doppler sonography of the treated segment. A peak systolic velocity = or < 150 cm/sec in the treated segment and an improvement of the ankle/brachial index by gs; 0.15 were considered indications of haemodynamic success. Restenosis at follow-up (mean 21 months, range 1-72 months) was defined by colour-Doppler sonography as a peak systolic velocity gs; 230 cm/sec or a peak systolic velocity ratio gs; 2.5 in the treated area and a gs; 0.15 decrease in ankle/brachial index compared with post-procedure measurements. RESULTS: Treatment by PTA plus stenting enabled correction of residual stenosis in 15/23 limbs, relief of PTA complications in 7/23 limbs and correction of restenosis after a PTA in 1/23. In the PTA group the treatment was successful in 59/86 limbs (68%) versus 21/23 (91%) in the STENT group (chi squared value= 0,04). As a whole, major complications occurred in 5.8% of cases (n=5), 3 in the PTA group and 2 in the STENT group. The primary patency rates at 6, 12, and 24 months were 70%, 66% and 58% in the PTA group versus 74%, 67% and 46% in the STENT group (Gehan p value=0.96). The secondary patency rates at 6, 12, 24 months were 75%, 73%, 65% in the PTA group versus 84%, 76%, 64% in the STENT group (Gehan p value=0,59). DISCUSSION AND CONCLUSIONS: In this study, stenting and PTA for the treatment of mild-to-moderate femoropopliteal peripheral artery disease improved the primary technical success of PTA by correcting residual stenosis, elastic recoil and occlusive intimal flaps. Moreover, stenting can prevent delayed constrictive remodelling. However, stenting did not improve long-term outcomes in comparison with PTA alone given that stent implantation increases the risk of restenosis due to myointimal hyperplasia. Our findings regarding the complication rates and long-term outcome agree with those published by other authors. Colour-Doppler US monitoring enabled early detection of restenosis in the treated area and its differentiation from the development of new lesions in other areas.     

Breast Cancer Prevention Trials Using Retinoids

Retinoids have been studied as chemopreventive agents in clinical trials. Given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide has extensively been investigated because of its favorable toxicological profile in humans. In a phase III secondary prevention trial, fenretinide showed a trend to a reduction of second breast malignancies in premenopausal women but not in postmenopausal women. This pattern was associated with a similar modulation of circulating IGF-I. A trend towards a reduction of ovarian cancer was also noted. Biomarker studies of fenretinide or novel selective retinoids alone and in combination with different nuclear receptor ligands are being conducted. These studies provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women, and offer clues as to both the pathophysiology of carcinogenesis and the drug mechanisms of action, and help select new compounds and doses for testing in large randomized studies.