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The aim of this investigation was to determine the influence of CFTR genotype on body water and electrolyte balance during a marathon. Fifty-one experienced runners completed a marathon race. Before and after the race, body mass and a sample of venous blood were obtained. During the race, sweat samples were collected using sweat patches, and fluid and electrolyte intake were obtained using self-reported questionnaires. Thirty-eight participants (74.5% of the total) were 7T/7T homozygotes, 11 (21.6%) were 7T/9T heterozygotes, and one participant presented the rare genotype 5T/7T. Another participant with 9T/9T presented the mutation p.L206W. Participants with 7T/7T showed higher sweat sodium concentrations (42.2 ± 21.6 mmol/L) than 7T/9T (29.0 ± 24.7 mmol/L; P = 0.04). The runner with the 5T/7T genotype (10.2 mmol/L) and the participant with the p.L206W mutation (20.5 mmol/L) exhibited low-range sweat sodium concentrations. However, post-race serum sodium concentration was similar in 7T/7T and 7T/9T (142.1 ± 1.3 and 142.4 ± 1.6 mmol/L, respectively; P = 0.27) and did not show abnormalities in participants with the 5T/7T genotype (140.0 mmol/L) and the p.L206W mutation (143.0 mmol/L). Runners with the CFTR-7T/7T genotype exhibited increased sweat sodium concentrations during a marathon. However, this phenotype was not related with increased likelihood of suffering body water and electrolyte imbalances during real competitions. [ABSTRACT FROM AUTHOR]

Cerebrolysin is a neuropeptide preparation mimicking the effects of neurotrophic factors. This subgroup analysis assessed safety and efficacy of Cerebrolysin in patients with moderate to moderately severe Alzheimer's disease (AD) (ITT data set: N = 133; MMSE: 14-20) included in a dose-finding study (ITT data set: N = 251; MMSE: 14-25). Results of the mild AD subgroup (ITT data set: N = 118; MMSE: 21-25) are also presented. Patients with AD received 100 ml IV infusions of Cerebrolysin (10, 30 or 60 ml diluted in saline; N = 32, 34 and 35, respectively) or placebo (saline; N = 32) over twelve weeks (5 days per week for 4 weeks and 2 days per week for another 8 weeks). Primary efficacy criteria ADAS-cog+ (Alzheimer's Disease Assessment Scale Cognitive Subpart Modified) and CIBIC+ (Clinical Interview-based Impression of Change with Caregiver Input) were assessed 24 weeks after baseline. At week 24, Cerebrolysin improved the global clinical function significantly with all three dosages and induced significant improvements in cognition, initiation of activities of daily living (ADL) and neuropsychiatric symptoms at 10-, 30- and 60-ml doses, respectively. Treatment effects on total ADL and other secondary parameters (MMSE, Trail-making test) were not significant. Cerebrolysin was safe and well tolerated. These results demonstrate the efficacy of Cerebrolysin in moderate to moderately severe AD, showing dose-specific effects similar to those reported for patients with mild to moderate AD. The benefits of Cerebrolysin in advanced AD need to be confirmed in larger trials. [ABSTRACT FROM AUTHOR]

The immune system is subject to destruction and dysfunction as a result of attacks by pathogenic and environmental agents. In addition, many clinical situations exist in which it is desirable to stimulate or suppress the immune system. The present study evaluated the screening efficacy of flow cytometric lymphocyte subset typing in peripheral blood mononuclear cells from healthy individuals (HI) and from patients with non-Hodgkin lymphoma (NHL) treated with different concentrations of FR-91, a standardized lysate of microbial cells belonging to the Bacillus genus, and in vitro cytokine production. Increased expression of subset markers (CD3, CD4, CD8) in NHL and CD3 in HI suggests an immunomodulating effect of FR-91. In addition the results of cytokine production also demonstrated a clear effect of FR-91 on both populations. A significant increase of IL-6, IL-12, IFN-γ and TNF-α was observed in the HI group after treatment with FR-91. In a similar manner an increase of IL-2, IL-6, IL-12, IFN-γ and TNF-α was also observed in the NHL group. In conclusion FR-91 seems to affect lymphocyte subpopulations, in vitro cytokine production, as well as mitogen-induced lymphocyte activation in a dose-dependent manner in both healthy individuals and NHL patients. [ABSTRACT FROM AUTHOR]

Cerebrolysin (Cere) is a compound with neurotrophic activity shown to be effective in Alzheimer's disease in earlier trials. The efficacy and safety of three dosages of Cere were investigated in this randomized, double-blind, placebo-controlled, study. Two hundred and seventy-nine patients were enrolled (69 Cere 10 ml; 70 Cere 30 ml; 71 Cere 60 ml and 69 placebo). Patients received iv infusions of 10, 30, 60 ml Cere or placebo 5 days/week for the first 4 weeks and thereafter, two iv infusions per week for 8 weeks. Effects on cognition and clinical global impressions were evaluated 4, 12 and 24 weeks after the beginning of the infusions using the CIBIC+ and the modified Alzheimer's Disease Assessment Scale (ADAS)-cog. At week 24, significant improvement of cognitive performance on the ADAS-cog ( P = 0.038) and global function (CIBIC+; P > 0.001) was observed for the 10 ml dose. The 30 and 60 ml doses showed significant improvement of the global outcome but failed to show significant improvement of cognition. The results are consistent with a reversed U-shaped dose–response relationship for Cere. The percentage of patients reporting adverse events was similar across all study groups. Cere treatment was well tolerated and led to significant, dose-dependent improvement of cognition and global clinical impression. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (susceptibility genetics) and genomic point mutations (mendelian genetics) can be used in Alzheimer's disease (AD) for diagnostic, predictive and therapeutic purposes. Using a matrix genetic model, including APOE, PS1 and PS2 allelic variants, we have studied the distribution of 36 different genotypes in the AD population (N=479) and the genotype-related cognitive response to a multifactorial therapy in AD patients with mild-to-moderate dementia. The 10 most frequent AD genotypes are the following: 1) E33P112P2+ (17.75%), 2) E33P112P2- (15.55%), 3) E33P111P2+ (10.85%), 4) E34P112P2+ (9.60%), 5) E34P112P2- (7.56%), 6) E33P111P2- (7.10%), 7) E34P111P2+ (4.80%), 8) E33P122P2+ (4.38%), 9) E34P111P2- (4.18%), and 10) E34P122P2+ (3.55%). APOE-4/4-related genotypes represent less than 3% in the following order: E44P112P2+> E44P111P2+=E44P111P2->E44P112P2+>E44P122P2+= E44P122P2-. Multifactorial therapy with CDP-choline (1000 mg/day)+piracetam (2400 mg/day)+anapsos (360 mg/day) did improve mental performance during the first 6–15 months in a genotype-specific fashion. The best responders in the APOE series were patients with APOE-3/4 genotype (r=+0.013), while the worst responders were APOE-4/4 patients (r=-0.93). PS1-related genotypes responded in a similar manner; and patients with a defective PS2 gene exon 5 (PS2+) always showed a poorer therapeutic response than PS2- patients. All these data suggest that the therapeutic outcome in AD exhibits a genotype-specific pattern, and that a pharmacogenomic approach to AD might be a valuable strategy for drug development and monitoring. [ABSTRACT FROM AUTHOR]

We have studied the time- and dose-dependent effects of S9977-2 versus tacrine (THA) on psychomotor activity (PMA) and passive avoidance learning (PAL) in intact 3-month-old rats. No significant changes were observed in the levels of PMA in animals tested 0, 30 and 60 min after i.p. injections of S9977-2 (0·125 mg/kg) or THA (1 mg/kg). In a PAL maze paradigm, S9977-2 and THA, administered 30, 60 and 120 min before testing, induced time-dependent improvements in learning indices, with maximum effects during the first hour after administration. In the dose–response study, S9977-2 (0·005, 0·025 and 0·125 mg/kg) tended to increase and THA (0·33, 1 and 3 mg/kg) to decrease PMA scores while the two compounds improved learning in a progressive dose-related manner. The present results indicate that S9977-2 and THA exert opposite actions on exploratory behaviour, S9977-2 increasing this parameter and THA decreasing it, and that both molecules improve learning in a similar time- and dose-dependent manner. On a molar basis S9977-2 is 10–20 times more potent than THA in enhancing learning acquisition. © 1997 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The influence of brain histamine (HA) on learning and memory is not well understood, although some reports indicate that HA improves memory consolidation. We have studied the effects of α-fluoromethylhistidine (FMH) (100 mg/Kg, i.p.), which reduced by 60-80% the concentration of hypothalamic HA, on rat locomotor activity (LA) and learning in several experimental conditions in a computerized system. FMH reduced LA in an open field paradigm (OFP) 3h after injection and tended to inhibit motor habituation after a 3-day trial. In a maze paradigm (MP), where the animals had to learn to avoid a foot-shock (1 mA), FMH reduced LA, rearing (2F), and jumping activity (JA). The peripheral administration of HA to control-trained rats reduced a learning index (N/Sts ratio) by 50%. According to these results, FMH diminished LA, 2F, and JA with no effect on habituation in MP. These observations might indicate that a moderate reduction in the levels of brain HA might enhance attention in solving visuo-spatial tasks under stressful stimuli. [ABSTRACT FROM AUTHOR]

Histamine (HA) acts as a neurotransmitter and/or neuromodulator in mammalian brain. Central HA has been found to be involved in the regulation of behavioral, cognitive, neurovegetative, neuroendocrine and neuroimmune functions. In this study we have evaluated psychomotor activity (PMA) and passive avoidance behavior (PAB) in rats with bilateral neurotoxic lesions in the posterior hypothalamic region (PHR) (L), where histaminergic neurons are located, and in sham-operated rats (S), two weeks after neurosurgery. In an open-field paradigm, lesioned rats showed higher PMA scores than sham-operated animals. However, L rats exhibited a significant decrease in PMA on consecutive days (motor habituation) similar to that found in S rats. In a maze paradigm, in which the animals had to learn to stay on a neutral platform in order to avoid a 1.5 mA electric footshock during 10 trails, no significant differences were observed between L and S rats on the task performance. According to the present results, it seems that bilateral neurotoxic lesions in the PHR induced hyperactivity with no apparent effects on PAB, suggesting that neuronal HA might be involved, directly and/or by influencing arousal/alertness-mediated mechanisms, in the regulation of PMA processes. [ABSTRACT FROM AUTHOR]

Besides the role of histamine (HA) as a neurotransmitter, a new concept has emerged presenting HA as an immunomodulator. Several studies have demonstrated interactions among HA, interleukin-1 β (IL-1 β) and tumor necrosis factor (TNF), suggesting a possible bidirectional communication among them. In this study we have investigated the effects of i.p. administrations of HA diphosphate (6 µmol/kg) and α-fluoromethylhistidine (FMH; 100 mg/kg) on TNF- α levels in the hippocampus, hypothalamus, and posterior hypothalamic region of the rat brain. The concentrations of TNF- α at 0 (Control, C) and 30 min after i.p. administration of HA were 0.26 ± 0.02 pg/mg and 0.32 ± 0.02 pg/mg in the hippocampus, 0.46 ± 0.04 pg/mg and 0.09 ± 0.006 pg/mg (p < 0.01) in the hypothalamus, and 0.47 ± 0.05 pg/mg and 0.26 ± 0.05 pg/mg in the posterior hypothalamic region. Three hours after FMH administration, an increase in the hippocampal levels of TNF- α was observed (0.43 ± 0.04 pg/mg; p < 0.01), while in the hypothalamus (0.11 ± 0.02 pg/mg; p < 0.01) and in the posterior hypothalamic region (0.21 ± 0.04 pg/mg; p < 0.05) a decrease in TNF- α levels was detected. These results suggest that changes in the histaminergic system influence TNF- α production in the brain in an area-specific fashion. [ABSTRACT FROM AUTHOR]

The immune system is subject to destruction and dysfunction as a result of attacks by pathogenic and environmental agents. In addition, many clinical situations exist in which it is desirable to stimulate or suppress the immune system. The present study evaluated the screening efficacy of flow cytometric lymphocyte subset typing in peripheral blood mononuclear cells from healthy individuals (HI) and from patients with non-Hodgkin lymphoma (NHL) treated with different concentrations of FR-91, a standardized lysate of microbial cells belonging to the Bacillus genus, and in vitro cytokine production. Increased expression of subset markers (CD3, CD4, CD8) in NHL and CD3 in HI suggests an immunomodulating effect of FR-91. In addition the results of cytokine production also demonstrated a clear effect of FR-91 on both populations. A significant increase of IL-6, IL-12, IFN-gamma and TNF-alpha was observed in the HI group after treatment with FR-91. In a similar manner an increase of IL-2, IL-6, IL-12, IFN-gamma and TNF-alpha was also observed in the NHL group. In conclusion FR-91 seems to affect lymphocyte subpopulations, in vitro cytokine production, as well as mitogen-induced lymphocyte activation in a dose-dependent manner in both healthy individuals and NHL patients. [ABSTRACT FROM AUTHOR]

Histamine (HA) is a biogenic amine involved in the regulation of neurovegetative, cognitive, neuroendocrine and neuroimmune functions in the central nervous system (CNS). A bidirectional interaction between the CNS and the neuroimmune system has been demonstrated in recent years. However, data concerning brain HA-cytokine interactions are scarce. In this study we have evaluated tumor necrosis factor-alpha (TNF-α) levels in the posterior hypothalamic region (PHR) and hipocampus (HP) of rats with: (a) bilateral ibotenic acid neurotoxic lesions in histaminergic neurons located in the PHR ( I); (b) saline injections in the PHR ( S); and ( c) sham operation ( C), two weeks after neurosurgery. The bilateral disruption of PHR HA neurons with ibotenic acid decreased TNF-α levels in the PHR with respect to shamoperated ( C), but not saline-injected ( S), rats. In contrast, hippocampal TNF-α concentrations were higher in lesioned rats ( I) than in C and S animals. Our results indicate that the neurotoxic destruction of HA neurons decreases TNF-α synthesis in the hypothalamus while enhancing TNF-α production in the hippocampus, suggesting that neuronal HA might be involved in the regulation of the brain TNF-α system. [ABSTRACT FROM AUTHOR]

Some recent studies give support to the potential interaction between histamine (HA) and interleukin-1 (IL-1) in the central nervous system (CNS). At the peripheral level, HA acts as an immune modulator, but little is known on the neuroimmune role of this biogenic amine in the CNS. In the present study we have investigated the effects of HA, mepyramine, famotidine, thioperamide, and L-histidine on hypothalamic IL-1β. HA induced a time- and dose-dependent decrease in the concentration of IL-1β. The maximum effect was obtained 30 minutes after injection. The HA-induced IL-1β response in the hypothalamus was not inhibited by either mepyramine, famotidine or thioperamide. In addition, L-histidine exerted the same effect as HA. The interaction between HA and IL-1β in the CNS might be linked to neuroendocrine regulation as well as to neurotrophic activity and neuroimmune function. [ABSTRACT FROM AUTHOR]

Brain histaminergic and cholinergic systems are involved in the neuromodulation of cognitive functions and altered in some neuropsychiatric disorders such as Alzheimer's disease. In this study we have investigated the effects of betahistine dihydrochloride (BH) on locomotor activity (LA) and passive avoidance behavior (PAB) in control and scopolamine(SC)-treated male rats. In an open-field paradigm, BH increased LA at high doses and inhibited SC-induced hyperactivity at moderate ones, without effect on motor habituation. In an electronic maze paradigm, in which animals had to learn to avoid a 1.5 mA electric shock, BH reduced the number of trials required by SC-treated animals to learn to stay in a neutral platform during two consecutive trials. These results seem to indicate that BH influences basal and SC-induced locomotor activity, and attenuates the learning impairment caused by SC. [ABSTRACT FROM AUTHOR]