Antidepressant-like effects of N-acetyl-L-cysteine in rats

Oxidative stress disturbances have been reported in depressed patients and in animals submitted to stress. Recent evidence suggests that antidepressants may have antioxidant properties. However, the therapeutic potential of antioxidants as antidepressant drugs has not been systematically investigated. Therefore, this study tested the hypothesis that N-acetyl-L-cysteine (NAC), a cysteine prodrug with powerful antioxidant activity, would possess anti depressant-like properties in the forced swimming test. Male Wistar rats were subjected to 15 min of forced swimming and immediately afterward, 5, and 23 h later received intraperitoneal injections of NAC (5, 15, 50, 150, and 250 mg/kg), imipramine, 0 5 mg/kg) or vehicle. One hour later they were submitted to the 5 min test swimming session, where immobility time was recorded. Independent groups of animals received the same treatments and their exploratory activity was measured in an open arena for 5 min. NAC (at the doses of 15, 50, and 150 mg/kg) and imipramine induced a significant decrease in immobility time without changing exploratory behavior measured in an open arena. These results suggest that antioxidants such as NAC may have antidepressant effects. Behavioural Pharmacology (C) 19:747-750 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Compound 48/80 induces endothelium-dependent and histamine release-independent relaxation in rabbit aorta

Compound 48/80 (C48/80) is a synthetic condensation product of N-methyl-p-methoxyphenethyl am me with formaldehyde and is an experimental drug used since the 1950s to induce anaphylactic shock through histamine release. This study was carried out to further elucidate the mechanism by which this drug induces nitric oxide (NO) release. Our specific goals were: (a) to verify if C48/80`s relaxation occurs through the stimulation of histamine receptors; (b) to evaluate the endothelium-dependent relaxation induced by C48/80; (c) to identify NO as the endothelium-relaxing factor released by C48/80; (d) to identify the NO synthase (NOS) responsible for NO release; and (e) to verify if the relaxation induced by C48/80 is calcium and cyclic guanidine monophosphate (cGMP) dependent. Rabbit aorta segments, with and without endothelium, were suspended in organ chambers (25 ml) filled with Krebs solution maintained at 37 degrees C, bubbled with 95% O-2/5% CO2 (pH 7.4). Phenylephrine was used to contract the segments. Other protocol drugs included H-1- and H-2-receptor antagonists, cyclooxygenase, NOS, guanylyl cyclase and phospholipase C (PLC) inhibitors. Endothelium-dependent relaxation induced by C48/80 was also studied in calcium-free Krebs solution associated with a calcium chelator. In summary, our investigation demonstrated that the C48/80 vasodilating action: (a) does not depend on H-1 and H-2 histamine receptors; (b) is NO endothelium-dependent; (c) is dependent on the endothelial constitutive NOS (NOS-3) isoform activation; (d) is cGMP-dependent; and that NOS-3 activation by C48/80: (a) is independent of PLC up to 25 mu g/ml and (b) is partially dependent of this lipase in higher doses. (C) 2007 Elsevier Inc. All rights reserved.

Diabetes and Vascular Disease: Basic Concepts of Nitric Oxide Physiology, Endothelial Dysfunction, Oxidative Stress and Therapeutic Possibilities

The vascular manifestations associated with diabetes mellitus (DM) result from the dysfunction of several vascular physiology components mainly involving the endothelium, vascular smooth muscle and platelets. It is also known that hyperglycemia-induced oxidative stress plays a role in the development of this dysfunction. This review considers the basic physiology of the endothelium, especially related to the synthesis and function of nitric oxide. We also discuss the pathophysiology of vascular disease associated with DM. This includes the role of hyperglycemia in the induction of oxidative stress and the role of advanced glycation end-products. We also consider therapeutic strategies.

Influence of Final Rinse Technique on Ability of Ethylenediaminetetraacetic Acid of Removing Smear Layer

Introduction: There is ongoing debate regarding the ideal sequence, volume, and concentration of irrigants, length of time for irrigation, and irrigation technique to achieve debridement of the root canal system. The aim of this study was to verify the impact of the final rinse technique on smear layer removal ability of 17% ethylenediaminetetraacetic acid (EDTA). Methods: Sixteen single-rooted human teeth were instrumented and divided into 2 groups at the final rinse step according to the following final rinse techniques used: continuous rinse group, continuous rinse with EDTA during 3 minutes, and rinse and soaking group, rinse with 1 mL of EDTA, soaking of the canal for 2 minutes and 30 seconds, and rinse completion with the remaining 4 mL for 30 seconds. The specimens were split lengthwise and observed under scanning electron microscope. Results: Data were analyzed with Kruskal-Wallis and Dunn tests. The continuous rinse group presented more debris-free surfaces when compared with the rinse and soaking group (P <. 01). When the root canal areas were compared within the groups, no statistical differences were found (P > .05). Conclusions: It can be concluded that a continuous rinse with 5 mL of EDTA for 3 minutes can more efficiently remove the smear layer from root canal walls. (J Endod 2010;36:512-514)

Gingival Overgrowth Among Patients Medicated With Cyclosporin A and Tacrolimus Undergoing Renal Transplantation: A Prospective Study

Background: The aim of this study is to make a longitudinal evaluation of the incidence and severity of gingival overgrowth (GO) induced by immunosuppressive agents, such as tacrolimus (Tcr) and cyclosporin A (CsA), in the absence of calcium channel blockers in patients undergoing renal transplantation (RT). Methods: This longitudinal study is conducted in 49 patients with RT who were divided into a CsA group (n = 25) and Tcr group (n = 24). The individuals were assessed at four time intervals: before transplant and 30, 90, and 180 days after RTs. Demographic data and periodontal clinical parameters (plaque index, cemento-enamel junction to the gingival margin, probing depth, clinical attachment level, bleeding on probing [BOP], and GO) were collected at all time intervals. Results: The mean GO index was significantly lower in the Tcr group compared to the CsA group after 30 (P = 0.03), 90 (P = 0.004), and 180 (P = 0.01) days of immunosuppressive therapy. One hundred eighty days after RTs, a clinically significant GO was observed in 20.0% of individuals in the CsA group and 8.3% of individuals in the Tcr group. However, this difference was not statistically significant (P = 0.41). There was a reduction in periodontal clinical parameters regarding the time of immunosuppressive therapy for PI and BOP (P<0.001) in both groups. Conclusion: Although there was no statistical difference in the incidences of clinically significant GO after 180 days of immunosuppressive therapy, it was observed that GO occurred later in the Tcr group, and the severity of GO in this group was lower than in patients who used CsA. J Periodontol 2011;82:251-258.

Functional polymorphisms in the promoter of the matrix metalloproteinase-9 (MMP-9) gene are not linked with significant plasma MMP-9 variations in healthy subjects

Background: Matrix metalloproteinase-9 (MMP-9) is involved in the degradation of the extracellular matrix during physiological and pathological processes. Two functional polymorphisms [C(-1562)T and microsatellite (CA)(13-25)] in the promoter region of the MMP-9 gene have been associated with several diseases. The aim of this study was to examine whether these MMP-9 polymorphisms and haplotypes are linked with plasma MMP-9 variations in healthy subjects. Methods: We studied 177 healthy male white volunteers (age range 20-55 years) who were non-smokers and not taking any medication. Genomic DNA was extracted from whole blood and genotypes for the C(-1562)T and the microsatellite (CA)(n) polymorphisms were determined. MMP-9 levels were measured in plasma samples by gelatin zymography. Results: The frequency of the alleles C and T for the C(-1562)T polymorphism were 90% and 10%, respectively. The frequency of the alleles with less than 21 CA repeats Q and with 21 repeats or higher (H) were 47% and 53%, respectively. We found no differences in plasma MMP-9 levels among the genotype groups or among different haplotypes (all p > 0.05). Conclusions: These findings suggest that functional polymorphisms in the promoter of the MMP-9 gene are not linked with significant plasma MMP-9 variations in healthy subjects.

Single Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in C57BL/6 Mice Models Early Preclinical Phase of Parkinson`s Disease

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson`s disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson`s disease

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson`s disease (PD) begin many years before the appearance of the characteristic motor symptoms and that impairments in olfactory, cognitive and motor functions are associated with time-dependent disruption of dopaminergic neurotransmission in different brain areas. Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in many biological processes in the central nervous system such as cell migration, neurogenesis and tissue repair. The abnormal midkine expression may be associated with neurochemical dysfunction in the dopaminergic system and cognitive impairments in rodents. Here, we employed adult midkine knockout mice (Mdk(-/-)) to further investigate the relevance of midkine in dopaminergic neurotransmission and in olfactory, cognitive and motor functions. Mdk(/-) mice displayed pronounced impairments in their olfactory discrimination ability and short-term social recognition memory with no gross motor alterations. Moreover, the genetic deletion of midkine decreased the expression of the enzyme tyrosine hydroxylase in the substantia nigra reducing partially the levels of dopamine and its metabolites in the olfactory bulb and striatum of mice. These findings indicate that the genetic deletion of midkine causes a partial loss of dopaminergic neurons and depletion of dopamine, resulting in olfactory and memory deficits with no major motor impairments. Therefore, Mdk(-/-) mice may represent a promising animal model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Inverse relationship between markers of nitric oxide formation and plasma matrix metalloproteinase-9 levels in healthy volunteers

Background: Nitric oxide (NO) is a major regulator of cardiovascular homeostasis and has anti-atherogenic properties. Reduced NO formation is associated with endothelial dysfunction and with cardiovascular risk factors. Although NO downregulates the expression and activity of the pro-atherogenic enzyme matrix metalloproteinase-9 (MMP-9), no previous clinical study has examined whether endogenous NO formation is inversely associated with the circulating levels of pro-MMP-9, which are associated with cardiovascular events. We examined this hypothesis in 175 healthy male subjects who were non-smokers. Methods: To assess NO bioavailability, the plasma concentrations of nitrite, nitrate, and cGMP were determined using an ozone-based chemiluminescence assay and an enzyme immunoassay. Pro-MMP-9 and pro-MMP-2 levels were measured in plasma samples by gelatin zymography. Results: We found significant negative correlations between pro-MMP-9 levels and plasma nitrite (P=0.035, rs=-0.159), nitrate (P=0.040, rs=-0.158), and cGMP (P=0.011, rs=-0.189) concentrations. However, no significant correlations were found between pro-MMP-2 levels and the plasma concentrations of markers of NO bioavailability (all P>0.05). Conclusions: There is an inverse relationship between markers of NO formation and plasma MMP-9 levels. This finding may shed some light on the possible mechanisms involved in the increased cardiovascular risk of apparently healthy subjects with low NO bioavailability or high circulating levels of pro-MMP-9. (C) 2008 Elsevier B.V. All rights reserved.

Heritabilities of Apolipoprotein and Lipid Levels in Three Countries

This study investigated the influence of genes and environment on the variation of apolipoprotein and lipid levels, which are important intermediate phenotypes in the pathways toward cardiovascular disease. Heritability estimates are presented, including those for apolipoprotein E and All levels which have rarely been reported before. We studied twin samples from the Netherlands (two cohorts; n = 160 pairs, aged 13-22 and n = 204 pairs, aged 34-62), Australia (n = 1362 pairs, aged 28-92) and Sweden (n = 302 pairs, aged 42-88). The variation of apolipoprotein and lipid levels depended largely on the influences of additive genetic factors in each twin sample. There was no significant evidence for the influence of common environment. No sex differences in heritability estimates for any phenotype in any of the samples were observed. Heritabilities ranged from 0.48-0.87, with most heritabilities exceeding 0.60. The heritability estimates in the Dutch samples were significantly higher than in the Australian sample. The heritabilities for the Swedish were intermediate to the Dutch and the Australian samples and not significantly different from the heritabilities in these other two samples. Although sample specific effects are present, we have shown that genes play a major role in determining the variance of apolipoprotein and lipid levels in four independent twin samples from three different countries.

Cost comparison of hospital- and home-based treatment models for acute chronic obstructive pulmonary disease

This trial compared the cost of an integrated home-based care model with traditional inpatient care for acute chronic obstructive pulmonary disease (COPD). 25 patients with acute COPD were randomised to either home or hospital management following request for hospital admission. The acute care at home group costs per separation ($745, CI95% $595-$895, n = 13) were significantly lower (p < 0.01) than the hospital group ($2543, CI95% $1766-$3321, n = 12). There was an improvement in lung function in the hospital-managed group at the Outpatient Department review, decreased anxiety in the Emergency Department in the home-managed group and equal patient satisfaction with care delivery. Acute care at home schemes can substitute for usual hospital care for some patients without adverse effects, and potentially release resources. A funding model that allows adequate resource delivery to the community will be needed if there is a move to devolve acute care to community providers.

NEW Solutions: An Australian health promotion programme for people with mental illness

The prevalence of people who are overweight or obese is continuing to rise. This is a key risk indicator of preventable morbidity and mortality resulting from many diseases. The increase in the number of obese people is associated with dietary practices and a reduction in physical activity. There is a need to implement strategies for the reduction of obesity in at-risk groups. People with a mental illness are at high risk of many physical illnesses related to behavioural factors, which include poor diet and lack of exercise. Health promotion programmes need to be incorporated into mental-health services to improve the general health and wellbeing of people with a mental illness. An Australian psychiatric rehabilitation service developed and implemented a health promotion programme, NEW Solutions, which aimed to address issues related to weight gain, dietary practice and physical inactivity.