Cerebrospinal fluid levels of diazepam-binding inhibitor in neurodegenerative disorders with dementia

We investigated CSF levels of diazepam-binding inhibitor (DBI), a recently discovered neuropeptide that allosterically modulates GABAergic transmission, in various neurodegenerative disorders with dementia (28 patients with Parkinson's disease, 10 with Alzheimer's disease, 7 with Huntington's chorea). We applied a battery of neuropsychological tests to determine the degree of dementia and to exclude the presence of mood alterations. CSF DBI levels were elevated in parkinsonian subjects with dementia and in patients with Alzheimer's disease, but decreased in Huntington's chorea patients. We hypothesize that modifications of CSF DBI levels may be related to a functional or structural alteration of the GABAergic system.     

Reproducibility of non-invasive and intra-arterial blood pressure monitoring: implications for studies on antihypertensive treatment.

Ambulatory blood pressure has been shown to be more reproducible than office blood pressure and thus to be more suited for studying the efficacy of antihypertensive drugs. In 34 untreated essential hypertensive subjects, we measured office and 24-h non-invasive or intra-arterial blood pressure twice over a 4-week interval; 24-h intra-arterial blood pressure was obtained by the Oxford method whereas 24-h non-invasive blood pressure was obtained by the automatic SpaceLabs 5300 device, with a 10 min (daytime) or 20 min (night-time) interval between measurements. The standard deviation of the mean difference (s.d.d.) between blood pressures obtained in each recording was taken as the reciprocal of blood pressure reproducibility. The s.d.d. was highest for office blood pressure and for single blood pressure readings taken from 24-h non-invasive recordings. The s.d.d. fell when the two 24-h average non-invasive blood pressures were considered. The fall was progressively greater as the number of ambulatory readings on which the average was calculated increased from two to 24, no further fall being observed when more than 24 values were considered. The maximal reduction in s.d.d. was 59% (systolic) and 42% (diastolic) as compared with the office s.d.d. The two 24-h mean values obtained by the intra-arterial approach were slightly more closely correlated than those obtained non-invasively. However, at comparable sampling rates, the s.d.d. was not substantially lower with 24-h intra-arterial blood pressure and including in the calculation the average of the thousand readings provided by this approach did not cause any further improvement.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-related asymmetric changes of brain microvessel beta-adrenergic receptors in the two hemispheres after carotid occlusion

The effect of short term and long term ischemia induced by right carotid occlusion was studied on beta-adrenergic receptor function in rat cerebral microvessels. The results show a different time-dependent responsiveness of the two hemispheres to ischemia, with a pronounced and more persistent decrease in the number of capillary beta-receptors in the left side of the brain. The data suggest the existence of asymmetries in the control of brain microvasculature which may mediate the different time-course of beta-receptor changes in response to ischemia.     

Dihydroergokryptine vs. placebo in dementia of Alzheimer type: interim results of a randomized multicenter study after a 1-year follow-up

In order to evaluate the efficacy of dihydroergokryptine mesylate (DEK) - a semisynthetic ergot alkaloid having a neuroprotective activity through the activation of antioxidant enzymatic systems - in dementia of Alzheimer type, a long-term, randomized, placebo-controlled, double-blind study was carried out. The interim analysis after 1-year follow-up is here reported. Two-hundred-and-fifteen patients fulfilling the NINCDS-ADRDA criteria for probable Alzheimer's disease were enrolled by 14 geriatric and neurologic Italian centers. The study design included a 1-month pre-treatment phase with placebo; 1-year double-blind treatment with DEK or placebo; a further 1-year open phase of treatment with DEK. The active drug dosage was 5 mg bid orally administered for the first 2 weeks, 10 mg bid for the following 2 weeks, 20 mg bid for the following 11 months. Efficacy was assessed by means of Gottfries-Br?ne-Steen (GBS) Rating Scale for dementia and Mental Deterioration Battery. The univariate analysis showed a significant improvement of GBS subscales and factors (with the exception of the Factor III, depression-anxiety). Multivariate analysis showed a significant difference between treatments in GBS scale (P=0.002) without any influence of age and illness duration. These results were confirmed by the end-point analysis carried out on GBS scores using baseline value as covariate. Minor adverse events were observed in 9 out of 108 patients (8.3%) of the DEK group and in 7 out of 107 (6.5%) of the placebo group. No change in blood pressure, heart rate and routine laboratory tests was observed. These preliminary results suggest positive symptomatic effects of DEK on elderly patients with probable Alzheimer's disease indicating a slowing down of the cognitive decline.     

Lacidipine and blood pressure variability in diabetic hypertensive patients

The aim of our study was to assess the effects of lacidipine, a long-acting calcium antagonist, on 24-hour average blood pressure, blood pressure variability, and baroreflex sensitivity. In 10 mildly to moderately hypertensive patients with type II diabetes mellitus (aged 18 to 65 years), 24-hour ambulatory blood pressure was continuously monitored noninvasively (Portapres device) after a 3-week pretreatment with placebo and a subsequent 4-week once daily lacidipine (4 mg) or placebo treatment (double-blind crossover design). Systolic blood pressure, diastolic blood pressure, and heart rate means were computed each hour for 24 hours (day and night) at the end of each treatment period. Similar assessments were also made for blood pressure and heart rate variability (standard deviation and variation coefficient) and for 24-hour baroreflex sensitivity, which was quantified (1) in the time domain by the slope of the spontaneous sequences characterized by progressive increases or reductions of systolic blood pressure and RR interval and (2) in the frequency domain by the squared ratio of RR interval and systolic blood pressure spectral power approximately 0.1 and 0.3 Hz over the 24 hours. Compared with placebo, lacidipine reduced the 24-hour, daytime, and nighttime systolic and diastolic blood pressure (P<0.05) with no significant change in heart rate. It also reduced 24-hour, daytime, and nighttime standard deviation (-19.6%, -14.4%, and -24.0%, respectively; P<0.05) and their variation coefficient. The 24-hour average slope of all sequences (7.7+/-1.7 ms/mm Hg) seen during placebo was significantly increased by lacidipine (8.7+/-1.8 ms/mm Hg, P<0.01), with a significant increase being obtained also for the 24-hour average alpha coefficient at 0.1 Hz (from 5.7+/-1.5 to 6.4+/-1.3 ms/mm Hg, P<0.01). Thus, in diabetic hypertensive patients, lacidipine reduced not only 24-hour blood pressure means but also blood pressure variability. This reduction was accompanied by an improvement of baroreflex sensitivity. Computer analysis of beat-to-beat 24-hour noninvasive blood pressure monitoring may offer valuable information about the effects of antihypertensive drugs on hemodynamic and autonomic parameters in daily life.     

Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy

The mechanism(s) and site(s) of the neurotoxic effect of cisplatin (CDDP) are still not entirely elucidated. A more detailed knowledge of these aspects of CDDP treatment might be useful to obtain a better understanding of the pathogenesis of its peripheral neurotoxicity, which is the dose-limiting side effect of CDDP. In the present study, the occurrence of CDDP-induced DNA-platination in dorsal root ganglia (DRG) of rats was evaluated in relation to DRG neuron pathological changes and CDDP-induced neuronopathy. Eight adult Wistar rats were treated with 2 mg/kg i.p. CDDP twice weekly for 9 times to induce sensory peripheral neuropathy. DNA-platination in specimens of DRG and kidney was measured immunohistochemically, with a polyclonal antibody (GPt) detecting CDDP-induced Pt-DNA adducts. Results were compared with those of untreated rats. Chronic CDDP-induced neurotoxicity, in a well described experimental model of chronic CDDP neurotoxicity in the Wistar rat, was confirmed by sensory DRG neuronopathy with secondary neuropathy, and demonstrated by reduced pain detection, decreased nerve conduction velocity in the tail nerve as well as morphological and morphometric changes in DRG neurons. Nuclear immunostaining for Pt-DNA adducts was observed in tubular cells of the kidney in 75% of the evaluated CDDP-treated rats, while in DRG cells CDDP-induced Pt-DNA adducts formation was found in 43% of the evaluated CDDP-treated rats. CDDP-induced DNA-platination was demonstrated in rat DRG neurons using a schedule of chronic CDDP administration which induced the onset of a sensory neuronopathy with secondary peripheral neuropathy. This finding further supports the hypothesis that CDDP is neurotoxic because it directly damages the DRG neurons.     

Hemiparkinsonism. A human model for studying dopaminergic supersensitivity.

The observation of a patient suffering from a parkinsonian syndrome, almost entirely expressed on the right side, and "on-off" attacks with rotatory movement of the trunk, led us to consider that the rotational model of animals may be reproduced in man. The symptoms presented by our patient may reflect a predominant degeneration in the nigrostriatal pathway of the left side. We suggest that his torsion behavior is due to hypersensitivity phenomenon of the dopaminergic receptors on this side.     

Acute noise stress in rats increases the levels of diazepam binding inhibitor (DBI) in hippocampus and adrenal gland

We investigated the effect of acute noise-induced stress on the concentrations of diazepam binding inhibitor (DBI) and its processing products in brain regions and adrenal glands of rats. DBI levels in hippocampus began to increase at 15 and 30 min and became significantly higher (+100%) at 90 and 120 min after stress; they returned to normal values at 360 min. While basal DBI levels were similar in the left and right hippocampus, the stress-induced increase of DBI levels was significantly higher in the left compared to the right side. A significant increase was also detected in the adrenals; here, the time course of DBI increase paralleled that of previously reported plasma corticosterone in stressed rats, being significantly higher 30 min after stress, and recovering to normal values at 60 and 90 min. After acute noise-induced stress, no significant change of DBI levels was detectable in cerebral cortex, striatum, hypothalamus and cerebellum. The present study reports for the first time the occurrence of a modification of DBI and its processing products (ODN-like immunoreactivity) in an experimental model of stress, and suggests a role for these neuropeptides in emotional responses.     

Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis

Abstract Extracorporeal photochemotherapy (ECP) is an immunomodulating procedure consisting of autologous reinfusion of peripheral blood mononuclear cells (PBMC) after direct exposure to 8-methoxy-psoralen and UV-A. It has been described as a successful treatment for different T-cell-mediated diseases and preliminary results suggest that ECP might be effective in the treatment of relapsing–remitting multiple sclerosis, but does not significantly alter the course of the progressive form of MS. In this study, we report the safety data and some preliminary efficacy evidence obtained using ECP in the treatment of five patients with refractory relapsing-remitting (RR) MS: in most cases ECP induced a reduction in the relapse rate and an EDSS stabilisation, with an apparent general MRI stabilisation. In conclusion, our results confirm ECP safety and tolerability and suggest that this treatment might be useful as a therapeutic alternative in the subgroup of RRMS patients not responsive to or not eligible for traditional immunomodulating or immunosuppressive treatments.