Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus.

Kynurenine 3-mono-oxygenase (KMO, kynurenine hydroxylase) inhibitors increase brain kynurenic acid (KYNA) synthesis and cause pharmacological actions possibly mediated by a reduced activity of excitatory synapses. We used in vivo microdialysis and passive avoidance to study the effects of local KYNA or systemic KMO inhibitor administration on glutamate (GLU) neurotransmission. Local application of KYNA (30-100 nM) through reverse microdialysis reduced GLU content in caudate and cortical dialysates by 75 and 55%, respectively. No changes were found in the hippocampus. Systemic administration of Ro 61-8048 (4-40 mg/kg) increased KYNA levels in dialysates obtained from the cortex (from 10.3 +/- 1.9 to 45.5 +/- 15 nM), caudate (from 2.4 +/- 0.8 to 9.5 +/- 0.9 nM) and hippocampus (from 7.7 +/- 1.7 to 19.2 +/- 3.5 nM). It also caused a parallel robust decrease in GLU levels in the dialysates collected from the caudate (from 2.2 +/- 0.5 to 0.63 +/- 0.05 microM) but not in those collected from the parietal cortex or the hippocampus. In a passive avoidance paradigm, the administration of the NMDA receptor antagonist MK-801 (0.1 mg/kg) reduced, while Ro 61-8048 (4-80 mg/kg) did not change the latency time of entering into the dark compartment on the recall trial. Our data show that KMO inhibitors increase brain KYNA synthesis and selectively reduce GLU extracellular concentration in the basal ganglia.

A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule.

A recently characterized class of compounds, dopamine partial agonists, have been suggested as potential therapeutic candidates for pharmacological intervention in psychostimulant addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are thought to behave as functional antagonists in conditions of high dopaminergic tone, and as agonists in conditions of low receptor occupancy by dopamine. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the D2 receptor subtype, on intravenous self-administration of amphetamine in a progressive ratio schedule and to compare it with the effects produced by the dopamine D2 antagonist eticlopride and the dopamine D2 full agonist quinpirole. Terguride at the doses of 0.2 and 0.4 mg/kg i.p. significantly decreased the maximum number of responses delivered for a single injection of amphetamine ("breaking point"), an effect similar to that produced by the antagonist eticlopride (0.01-0.1 mg/kg s.c.). In contrast, administration of quinpirole (0.1-1 mg/kg s.c.) did not significantly modify the breaking point for amphetamine responding. Also, terguride dose-dependently increased responding for amphetamine self-administration on a continuous reinforcement schedule. These data further confirm the effects of terguride on psychostimulant self-administration and indicate that under these conditions partial dopamine agonists act as functional dopamine receptor antagonists.

Long-term results of the bioprosthesis in elderly patients: impact on quality of life.

BACKGROUND: A wealth of data exists on acceptable mortality and morbidity for valve operations in older patients, yet information documenting quality of life is lacking. METHODS: From October 1974 to May 1998, 2,075 patients aged 65 years and older underwent valve replacement using a porcine bioprosthesis. There were 1,126 men (54.3%) and 949 women (45.7%) with a mean age of 73.9 years (range 65 to 104 years). RESULTS: The elective hospital mortality was 8.5% (158 patients), and urgent/emergent/salvage mortality was 25.8% (54 patients). Follow-up was completed for 1,863 patients (98.2%) and extended from 1 month to 23.0 years (mean 60.8 months) with a cumulative follow-up of 9,442.1 patient-years. At follow-up, surviving patients (n = 849) completed the Short Form-36 Quality of Life Survey. Results showed patients had a more favorable quality of life compared with control subjects matched for age and sex. Functional improvement was significant with 96.3% in New York Heart Association functional class I or II at follow-up. There were 74 valves that failed from all causes (33 aortic and 41 mitral valves). Actuarial freedom from valve failure at 9 years was 94.4%+/-1.1% and at 18 years was 83.7%+/-2.4%. CONCLUSIONS: Valve replacement in older patients provides excellent functional improvement, reduces late cardiac events, and enhances quality of life.

Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines.

Protracted administration of diazepam elicits tolerance, whereas discontinuation of treatment results in signs of dependence. Tolerance to the anticonvulsant action of diazepam is present in an early phase (6, 24, and 36 h) but disappears in a late phase (72-96 h) of withdrawal. In contrast, signs of dependence such as decrease in open-arm entries on an elevated plus-maze and increased susceptibility to pentylenetetrazol-induced seizures were apparent 96 h (but not 12, 24, or 48 h) after diazepam withdrawal. During the first 72 h of withdrawal, tolerance is associated with changes in the expression of GABA(A) (gamma-aminobutyric acid type A) receptor subunits (decrease in gamma(2) and alpha(1); increase in alpha(5)) and with an increase of mRNA expression of the most abundant form of glutamic acid decarboxylase (GAD), GAD(67). In contrast, dl-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit mRNA and cognate protein, which are normal during the early phase of diazepam withdrawal, increase by approximately 30% in cortex and hippocampus in association with the appearance of signs of dependence 96 h after diazepam withdrawal. Immunohistochemical studies of GluR1 subunit expression with gold-immunolabeling technique reveal that the increase of GluR1 subunit protein is localized to layer V pyramidal neurons and their apical dendrites in the cortex, and to pyramidal neurons and in their dendritic fields in hippocampus. The results suggest an involvement of GABA-mediated processes in the development and maintenance of tolerance to diazepam, whereas excitatory amino acid-related processes (presumably via AMPA receptors) may be involved in the expression of signs of dependence after withdrawal.

Antagonism of heroin and morphine self-administration in rats by the morphine-6beta-glucuronide antagonist 3-O-methylnaltrexone.

In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6beta-glucuronide and heroin at doses which are inactive against morphine. We found a similar selectivity in rats. 3-O-Methylnaltrexone antagonized the analgesic actions of 6-acetylmorphine in Sprague-Dawley rats and heroin in Wistar rats at doses that were inactive against morphine. Inclusion of a fixed dose of 3-O-methylnaltrexone significantly shifted the analgesic dose-response curves for 6-acetylmorphine and heroin without altering the morphine dose-response curves. In a self-administration model, 3-O-methylnaltrexone treatment significantly increased both heroin and morphine intake during the first hour, suggestive of an antagonist effect. This effect at doses of 3-O-methylnaltrexone which were inactive against morphine analgesia implied a role for the morphine-6beta-glucuronide opioid receptor in the reinforcing properties of heroin and morphine.

Unusual presentation of aortic pseudoaneurysm: middle lobe pneumonia.

Pseudoaneurysms of the aorta are rare. We report an unusual presentation of an ascending thoracic pseudoaneurysm found with atypical presenting symptoms.

Comparison of secretion of a hepatitis C virus glycoprotein in Saccharomyces cerevisiae and Kluyveromyces lactis.

A C-terminally truncated form of the hepatitis C virus (HCV) putative envelope glycoprotein E2 was expressed in two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis, using a yeast signal peptide sequence to direct the viral glycoprotein to the endoplasmic reticulum (ER) pathway of secretion. Characterization of secreted E2 showed that the protein is endoglycosidase-H-sensitive in both yeasts. Moreover, in vivo inhibition of glycosylation with tunicamycin prevented secretion of E2 and showed that, of its 11 putative N-linked glycosylation sites, at least eight were core-glycosylated. Analysis of the heterologous glycoprotein by SDS-PAGE under nonreducing conditions and by gel filtration demonstrated the formation of multiple disulphides, which resulted in secretion of heterogeneous aggregates with an average molecular mass of 770-1000 kDa in both yeasts. However, variations were observed in the binding of the glycoprotein secreted by the two yeasts to a mannose-specific lectin, and also in its reactivity with anti-E2-specific antibodies. This denotes differences between the two yeasts in folding and/or modification of the E2 glycoprotein.

Risk factors for acute hepatitis B: a case-control study.

Over the period 1989-1991 a case-control study was carried out in the area of Naples comparing 162 subjects with acute hepatitis B and 788 hospitalized control subjects. The results of multivariate analysis showed that surgical intervention (odds ratio 3.8; 95% CI 1.2-11.7), household contact with an hepatitis B surface antigen (HBsAg) positive carrier (odds ratio 2.7; 95% CI 1.1-6.7) and intravenous drug use (odds ratio 13.0; 95% CI 3.2-52.7) were risk factors independently associated with hepatitis B. No association was found with the other risk factors considered, such as blood transfusion, hospitalization, other percutaneous exposures, dental therapy, contact with an icteric case, barber shop shaving and two or more sexual partners. As a significant proportion of the general population undergoes surgical intervention, efficient procedures for sterilization of instruments should be implemented, together with the use of disposable materials, to control the spread of HBV infection in surgical settings.

Effect of a ubiquinone-like molecule on oxidative energy metabolism in rat cortical synaptosomes at different ages.

Persistent stimulation of energy consumption, induced by depolarization with veratridine, mimics a condition of abnormally enhanced energy demand and causes an increase in the oxygen consumption rate (QO2) and in the interconversion of pyruvate dehydrogenase complex (PDHc) into its active form. Wistar rats at the age of 26 months do not show alterations of QO2 and the ability of veratridine to increase QO2 in comparison with 6 month-old animals whereas the active form of PDHc is slightly but significantly reduced. Idebenone, a ubiquinone-like molecule (1 microM), does not affect the QO2 or PDHc activation state in resting conditions but attenuates the veratridine-challenged increase in QO2 at all the ages tested and attenuates the increase in the percentage of PDHa reaching statistical significance in 26-month-old rats. At higher concentration (10 microM) idebenone totally abolishes the veratridine-induced increase in PDHa also in the 6 month-old rats. At the lower concentration, the drug does not affect the increase in QO2 induced by an uncoupler of oxidative phosphorylation. The results obtained suggest a protective effect of idebenone on the cerebral tissue against stressful conditions; this action may be exerted at the level of some mitochondrial component and/or on the Na+ homeostasis.

Bioprosthetic valve longevity in the elderly: an 18-year longitudinal study.

The issue of bioprosthetic valve durability has become of critical importance as the number of elderly patients requiring valve operation has continued to increase. Our previous study showed bioprosthetic valve durability to be in excess of 83% at 13 years for patients 70 years of age and older at the time of implantation. There is limited follow-up data in the literature beyond this time point, however. Accordingly a retrospective analysis was conducted of all patients with bioprosthetic valves who were 70 years of age and over at the time of implantation. From September 1974 to April 1994, 1007 patients 70 years of age and over underwent valve replacement using a porcine bioprosthesis. The patients ranged in age from 70 to 104 years (mean, 75.6 +/- 4.3 years). There were 549 men (54.5%) and 458 women (45.5%). Preoperatively 98.8% of the patients were in New York Heart Association functional class III or IV. Operation was performed as an emergency in 66 patients (6.6%). The hospital mortality was 10.9% (110 patients), with 897 hospital survivors. There were 961 valves at risk. Follow-up extended from 1 month to 18.8 years (mean, 56.6 months). The cumulative follow-up is 4232.3 patient-years. A total of 31 valves failed, 12 in the aortic position and 19 in the mitral position (p < 0.0024). The causes of valve failure have included structural deterioration (16 valves), prosthetic endocarditis (7 valves), nonstructural dysfunction (5 valves), prosthetic thrombosis (1 valve), and other (2 valves).(ABSTRACT TRUNCATED AT 250 WORDS)

[Infections due to hard-to-treat germs. Endocarditis and nosocomial opportunistic infections]. / Le infezioni da germi difficili. Endocarditi ed infezioni opportunistiche nosocomiali.

The authors describe some aspects of "difficult to treat" infections, pointing out, on the basis of their experience, infective endocarditis (IE) and nosocomial infections in compromised host. Among difficult-to-treat IE, the authors stress: 1) the peculiar etio-epidemiological features and the frequent causative pathogens multiresistance on early post-surgical IE; 2) the problems in detecting and management of IE by HACEK group microorganisms; 3) the problems related to other unusual agents IE, with particular regard to nutritionally deficient variants of S. viridans and to Coxiella burnetii. Among nosocomial infections in compromised host, Authors underline the relationship between either nosocomial flora or surgical/instrumental practices and possible underlying immunodeficiencies. Clinical and diagnostic remarks of sepsis, pneumonitis, meningitis, enteritis in neutropenic patients are then stressed, pointing out their atypical presentations and severe prognosis.

Alteration of pallidal cholinergic activity in MPTP-treated monkeys: effect of dihydro-alpha-ergocryptine (DEK).

Monkeys, intravenously administered with MPTP at the dose of 0.3 mg/kg for 5 consecutive days, develop a severe Parkinson-like syndrome. Cholinergic enzyme activities are increased in the internal segment of the globus pallidus (GPi) and into a lesser extent in the external globus pallidus (GPe). Cholinergic activities are not significantly affected in the caudate and putamen nor in the frontal, parietotemporal, occipital cortices and in the cerebellum. The treatment of the animals twice daily for 2 weeks with dihydro-alpha-ergocryptine (DEK) starting 5 days before the first MPTP administration counteracts the neurotoxin-induced alteration in the internal pallidum and ameliorates some motor related parkinsonian symptoms.

Octreotide treatment in secretory and cyrptosporidial diarrhea in patients with acquired immunodeficiency syndrome (AIDS): clinical evaluation.

Our objective was to evaluate the efficacy of octreotide in the treatment of AIDS patients with persistent diarrhea refractory to conventional therapy. We have treated 11 patients with AIDS related diarrhea (M/F-5/2, mean age 28 +/- 3 yr). The stool volume was in all pts > or = 21/24h. In 4 pts the diarrhea was secondary to cryptosporidium infection (Group A); in 7 pts the reason for the diarrhea could not be identified (Group B). Octreotide was administered in subcutaneous escalation doses, from 50 micrograms q8h to a maximum dose of 500 micrograms q8h. The minimal dose controlling symptoms was maintained for 21 days. In all patients stool volume and frequency decreased significantly. Group A pts were "partial responders" (stool 50% of initial daily volume); group B patients were "complete responders" (stools < 250-300 ml/day). Drug suspension resulted in a prompt return of diarrhea, especially in group A and in these patients, the cryptosporidium was continuously eliminated in the stool. With octreotide therapy there was a reduction in stool volume and frequency; whether this treatment is effective as long-term therapy for this AIDS manifestation is unknown.

Interleukin-6 and granulocyte macrophage-CSF in the cerebrospinal fluid from HIV infected subjects with involvement of the central nervous system.

We detected the cytokines interleukin-6 (IL-6) and granulocyte macrophage-CSF (GM-CSF) by ELISA in the CSF and serum of 30 HIV-infected patients classified as AIDS dementia complex (ADC), and 20 subjects with other neurological diseases (OND). We have found a high incidence of detectable IL-6 and GM-CSF in the CSF of ADC patients compared with OND patients. No statistical differences were observed between both groups for serum IL-6 and GM-CSF levels. These results suggest an intrathecal synthesis of these cytokines and a possible involvement in the pathogenesis of ADC.

Interleukin-6 and granulocyte macrophage-CSF in the cerebrospinal fluid from HIV infected subjects with involvement of the central nervous system

Detectamos as citocinas interleucina-6 (IL-6) e granulócito-macrófago-CSF (GM-CSF) por ELISA no LCR e soro de 30 pacientes infectados por HIV classificados como tendo AIDS-demência complexo (ACD) e de 20 pacientes com outras doenças neurológicas (OND). Encontramos elevada incidência de IL-C e GM-CSF detectável no LCR de pacientes com ADC, em relaçäo aos pacientes com OND. Diferenças estatísticas näo foram observadas entre os dois grupos de pacientes para níveis de IL-6 e GM-CSF no soro. Esses resultados sugerem síntese intratectal dessas citocinas e sua possível participaçäo na patogenia da ADC

[Clinical-echocardiography of 210 HIV-Ab positive patients: retrospective study]. / Indagine clinica-ecocardiografica su 210 pazienti HIV Ab positivi: studio retrospettivo.

Through the retrospective study of 210 HIV Ab+ patients in different disease's stages, recovered in the "D. Cotugno-Naples" hospital during the period February 1989-February 1991, the authors have valued the prevalence of cardiological alterations underlined by ecocardiograph. Pericardial pouring has been observed in four patients out of thirty, belonged to stages II, III and ARC. Ventricles' movement alterations have been observed in twenty patients out of thirty (66%), belonged prevalently to the fourth group. Kaposi's sarcoma has been observed in two patients out of thirty (6.6%), belonged to the fourth group. In the patients showing alterations, the authors have also noticed a correlation among the observed cardiological alterations and the immunital outline and the frequent homosexuality's presence. The follow up between the alterations' observation and the possible patient's death is on an average 4.3 months (range 1-12). They suggest that a wider and more precocious ecocardiographical research of HIV Ab+ patients is the only way, at the moment, to underline and follow the cardiac alterations' evolution, also in relation to a precocious antiretroviral therapy.

Cerebrospinal fluid beta-2-microglobulin in HIV-1 infection, as a marker of neurological involvement.

Cerebrospinal fluid (CSF) and serum concentration of beta-2-microglobulin (beta-2-m) were evaluated in 30 patients in various stages of HIV-1 infection. CSF beta-2-m and CSF/serum ratio were significantly higher in patients with neurological complications respect to asymptomatic subjects. These findings indicate that CSF beta-2-m and CSF/serum ratio may be a useful marker of neurological involvement in HIV-1 infection.

[Clinical description of three cases of cerebral cryptococcosis in patients with AIDS treated with fluconazole]. / Descrizione clinica di tre casi di criptococcosi cerebrale in pazienti con AIDS trattati con Fluconazolo.

The authors have evaluated the efficacy of Fluconazole (400 mg/iv/die for three days and after 200 mg/iv/die for 18 days) in three AIDS and SNC Cryptococcal infection patients. Two patients have shown healing of meningeal syndrome and negative isolation after 21 days of therapy; one patient, however, died because of Cytomegalovirus pneumonia. It is of note that early spinal puncture in AIDS patients with neurological symptoms enables an early diagnosis and immediate therapy. Fluconazole treatment has been well tolerated and immediately effective to resolve two of the cases observed; the oral prophylaxis with 100 mg/die of Fluconazole after 6 months has been effective to prevent the relapses of the disease.

[Serologic evaluation of circulating immune complexes in patients with HIV infections]. / Valutazione sierologica degli immunocomplessi circolanti (CIC) in pazienti con infezione da HIV.

In AIDS, immunitary system dysfunctions are manifold and regard both T and B-lymphocytes. The increased levels of circulating immune complexes (CIC) in HIV-Ab positive patients, immune complexes abnormalities, should be considered as an epiphenomenon of humoral immunity altered function; therefore, they are devoid of any diagnostic value.