New adenosine A2A receptor antagonists: actions on Parkinson's disease models

The 8-substituted 9-ethyladenine derivatives: 8-bromo-9-ethyladenine (ANR 82), 8-ethoxy- 9-ethyladenine (ANR 94), and 8-furyl-9-ethyladenine (ANR 152) have been characterized in vitro as adenosine receptor antagonists. Adenosine is deeply involved in the control of motor behaviour and substantial evidences indicate that adenosine A(2A) receptor antagonists improve motor deficits in animal models of Parkinson's disease. On this basis, the efficacy of ANR 82, ANR 94, and ANR 152 in rat models of Parkinson's disease was evaluated. All compounds tested reversed the catalepsy induced by haloperidol. However, in unilaterally 6-hydroxydopamine-lesioned rats, only ANR 94 and ANR 152 potentiated l-dihydroxy-phenylalanine (l-DOPA) effect on turning behaviour and induced contralateral turning behaviour in rats sensitised to l-DOPA. Taken together the results of this study indicate that some 8-substituted 9-ethyladenine derivatives ameliorate motor deficits in rat models of Parkinson's disease, suggesting a potential therapeutic role of these compounds.     

Modulation of cell cycle components by epigenetic and genetic events

Cell cycle progression is monitored by surveillance mechanisms, or cell cycle checkpoints, that ensure that initiation of a later event is coupled with the completion of an early cell cycle event. Deregulated proliferation is a characteristic feature of tumor cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cancer formation and progression. Key among these are p53, the retinoblastoma protein (pRb) and its related proteins, p107 and pRb2/p130, and cdk inhibitors (p15, p16, p18, p19, p21, p27), all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed. The pRb (pRb/p16(INK4a)/cyclin D1) and p53 (p14(ARF)/mdm2/p53) pathways are the two main cell-cycle control pathways frequently targeted in tumorigenesis, and the alterations occurring in each pathway depend on the tumor type. Virtually all human tumors deregulate either the pRb or p53 pathway, and oftentimes both pathways simultaneously. This review focuses on the genetic and epigenetic alterations affecting the components of mechanisms regulating the progression of the cell cycle and leading to cancer formation and progression.     

Alterations of bone metabolism in patients with chronic C virus hepatitis

Patients affected with chronic hepatitis are prone to alterations in bone metabolism, osteoporosis and osteopoenia being the most common manifestations. Bone mineral densitometry is the method of choice for assessing bone mass; nevertheless, this is a static parameter whereas biochemical markers of bone remodelling reveal the dynamics of bone resorption and formation. With this study we used bone mineral densitometry and biochemical markers to evaluate bone metabolism in a group of male patients with chronic C virus hepatitis and in a group of healthy males. In the hepatitis group 56% of the patients proved osteopoenic or osteoporotic and bone depletion increased as the histological score of the disease increased. Crosslaps are a parameter of osteoclastic activity: their measurement showed alterations in all the age groups of the hepatitis patients studied, which goes to show that there is intense bone remodelling in these individuals due mainly to osteoclastic resorption. Hepatitis C is a risk factor for bone depletion: we believe that when this type of hepatitis is diagnosed it is useful to assess bone metabolism with bone mineral densitometry and with the crosslaps assay.     

Venous thrombosis in children with solid tumors

BACKGROUND: The prevalence of venous thrombosis (VT) in children with solid tumor and the role of different risk factors are not defined yet. AIM: A cross-sectional observational study was conducted to evaluate the prevalence of both symptomatic and asymptomatic catheter-associated thrombosis events in children affected with different solid tumors. METHODS: Patients with a solid tumor, admitted as day-care, were consecutively enrolled over a period of 10 months. All of them had a central venous line. Physical examination, D-dimer serum tests, and eco-color-Doppler ultrasonography were performed once at any time before catheter removal. RESULTS: Forty-two patients (14 females and 28 males)-mean age 115 months-were evaluated. Five of the 42 patients (12%) had VT. In 4 of these, VT was catheter-related: 3 asymptomatic and 1 symptomatic. In the last patient, VT was clinically symptomatic and not catheter related. Patients with longer duration of catheter insertion presented with a higher rate of VT (P=0.05). Moreover, patients affected with neuroblastoma showed a higher rate of VT than the others with different solid tumors (P<0.05). CONCLUSIONS: VT was visualized by echo-color-Doppler ultrasonography in 12% of the patients; it was asymptomatic in 7%. In our small series, VT was related to neuroblastoma disease and a longer duration of catheter insertion. Prospective and multicentric studies are required to select risk factors for VT in children with solid tumors.     

Pain among the oldest old in community and institutional settings

The relationship between pain and increasing age was investigated using data from two different care settings collected on a province-wide basis in Ontario. Home care clients (HC) and complex continuing care patients (CCC) are assessed using the Resident Assessment Instrument-Home Care and Resident Assessment Instrument 2.0 instruments, respectively, as part of normal clinical practice. For this study, the sample was restricted to those aged 65 years and older and totaled 193,158 individuals. Centenarians (those 100 years of age or older) made up 0.41% (n=788) of the sample. Pain was assessed according to a previously validated pain scale embedded in both assessments that uses items on frequency and intensity. Based on 5-year age groups beginning at 65, the mean reported pain score was lower with each increment in age for men and women. Multiple logistic regression models were constructed and the odds ratios for pain in both HC and CCC groups decreased consistently in higher age groups after adjusting for disease diagnoses, cognition, functional status and health indicators. A model that included categories of analgesic medications coded based on the WHO pain ladder showed the relationship persisted after controlling for analgesia. In clinical settings, the oldest old appear to have lower levels of pain compared with the young old after adjusting for a variety of potential confounding variables.     

Metronidazole resistance in Bacteroides spp. carrying nim genes and the selection of slow-growing metronidazole-resistant mutants

OBJECTIVES: Human clinical isolates of Bacteroides spp. originating from patients in the UK were investigated for the presence of metronidazole resistance determinants (nim genes) and their presence was related to the MIC of metronidazole for the isolates. METHODS: Isolates were screened for susceptibility to a metronidazole disc and had their MIC determined by the Etest method. They were investigated for the presence of nim genes by PCR. An experiment to determine the effect of prolonged exposure to metronidazole was applied to nim-positive isolates with MICs below the therapeutic breakpoint. RESULTS: Fifty of 206 isolates (24%) were found to possess nim genes and these had MICs of metronidazole ranging from 1.5 to >256 mg/L with 24 (11.6%) above the therapeutic breakpoint of 16 mg/L. The remaining 26 nim-gene-positive isolates had MICs that were still below the therapeutic breakpoint, ranging from 1.5 to 6.0 mg/L. nim genes were not found in 156 (76%) isolates, and all but seven of these were susceptible to a 5 microg disc of metronidazole. Ten members of the group for which the MICs were below the therapeutic level were found to have slow-growing sub-populations with metronidazole MICs ranging from 8.0 to >256 mg/L that became evident after prolonged exposure to metronidazole in vitro. This resistance selection process was sometimes reversible after passage in the absence of metronidazole; however, seven of the 10 slow-growing mutants converted to stable high-level resistance (MIC >256 mg/L). CONCLUSIONS: Although the presence of nim genes per se does not always equate to therapeutic resistance, and other metronidazole resistance mechanisms may exist, this study has shown that prolonged exposure of nim-gene-carrying Bacteroides spp. to metronidazole can select for therapeutic resistance.     

Tumor necrosis factor-alpha antagonism improves vasodilation during hyperinsulinemia in metabolic syndrome

OBJECTIVE—Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-α. We assessed the effects of TNF-α neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome.RESEARCH DESIGN AND METHODS—Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab.RESULTS—Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab.CONCLUSIONS—TNF-α neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients.Central obesity is associated with low-grade, chronic inflammation, which might affect insulin action and thus contribute to both insulin resistance and vascular dysfunction characteristic of metabolic syndrome. Among various inflammatory cytokines, tumor necrosis factor (TNF)-α seems to play an important role in the pathophysiology of insulin resistance. However, no clear link has been established between the vascular pathology of metabolic syndrome and a particular inflammatory cytokine in humans. This study, therefore, assessed the effects of TNF-α neutralization by the monoclonal antibody infliximab on vascular reactivity during hyperinsulinemia in metabolic syndrome.