Allopurinol provides long-term protection for experimentally induced testicular torsion in a rabbit model

OBJECTIVE: To assess the effect of five antioxidants on exocrine function of rabbit testes retained in situ for 24 h and 3 months after experimental torsion. MATERIALS AND METHODS: The left testes of peripubertal rabbits were clamped for 60 min, after which the clamps were removed and the testes allowed to reperfuse. The right testes served as internal controls. There were eight rabbits in each of the following experimental groups: (a) sham; (b) 60-min ischaemia followed by reperfusion; (c) 60-min ischaemia followed by left orchidectomy. In five further groups, rabbits were exposed to 60-min ischaemia followed by reperfusion, but received one of the following antioxidants before reperfusion: acetyl salicylic acid, ascorbic acid, allopurinol, quercetin or superoxide dismutase. Both testes were excised at 24 h or 3 months. The degree of lipid peroxidation, a measure of free radical damage, was assessed in testicular tissue homogenates by measuring the tissue levels of malondialdehyde (MDA). The Johnsen score was used to assess the morphological damage at 24 h and 3 months for each group. RESULTS: At 3 months twisted viable testes allowed to reperfuse had higher MDA levels than controls; the left testes of rabbits treated with allopurinol had significantly lower MDA levels than untreated rabbits and rabbits given other antioxidants. Rabbits given quercetin, ascorbic acid or superoxide dismutase had lower (but not significantly) left testicular MDA levels than untreated rabbits, while rabbits given acetyl salicylic acid had even higher levels. Allopurinol-treated rabbits had a Johnsen score of > 7.6 and those given other antioxidants had scores of < 7.6 at 3 months. CONCLUSION: The twisted viable testis treated by orchidopexy contains high free radical levels at 3 months. Of the antioxidants studied, only allopurinol had a beneficial long-term effect, by significantly reducing testicular MDA levels at 3 months.     

Characterization of the frequency distribution for human hematogenous metastases: Evidence for clustering and a power variance function

When groups of mice are injected with cells from a metastasizing tumor, a minority of individuals within a given group tends to sustain disproportionately larger numbers of metastases relative to the remaining group members. This clustering of metastases obeys a power function relationship, σ² = aμ^b, between the variance σ² and the mean number of lung metastases per animal μ (a and b constant). To see whether such clustering occurs with human lung, brain, and liver metastases, a meta-analysis of clinical and pathological series was performed. Thirty-three published series were identified that provided data regarding the numbers of organ metastases sustained by 5582 people. The data were grouped according to the primary tumor, site of metastasis and method of detection of metastases. Clustering of metastases within individuals of each subgroup (similar to the murine systems) was demonstrated by variance to mean ratios greater than 1, and by a strong correlation to the variance to mean power function (a∼0.49, b∼2.24, r ² = 96%, p < 10⁻⁶). The cause of this clustering remains unclear, but it may in part relate to heterogeneities in regional blood flow. As a consequence of this clustering, limited metastases would be expected to occur more frequently than predicted from random chance-providing for some optimism in the management of limited metastasis. As well, the frequency distribution for metastases revealed certain scaling symmetries, likely reflective of the underlying mechanisms of metastasis, that could be of interest to both clinicians and experimentalists working with metastasis. This revised version was published online in July 2006 with corrections to the Cover Date.     

Genetic characterization and progression of B3 measles genotype in Ethiopia: a study of five measles outbreak cases

BACKGROUND: One of the countries where measles remains endemic is Ethiopia. Previously, sequence data from Measles Viruses (MV) circulating in Ethiopia were obtained from clinical specimens. Now the Ethiopian Health and Nutrition Research Institute (ENHRI) has implemented cell culture techniques to isolate measles virus and molecular epidemiologic studies can be generated more easily. OBJECTIVE: To characterize the strains of Measles Virus circulating in Ethiopia during measles outbreaks in 2006 using viral isolates, and compare the results to previously identified Ethiopian strains. METHODS: A case study and convenience sampling method were conducted on five measles outbreak cases tb identify the circulating measles virus genotype in Addis Ababa and Amhara regions of Ethiopia in 2006. RESULTS: Three isolates were obtained from five specimens collected in two regions (1 from Amhara: Bahir Dar, and 2 from Addis Ababa: Addis Ketema and Kolefe Keranio subcities) in Ethiopia during 2006. The viral isolates were analyzed using standard genotyping protocols and were classified as genotype B3, identical to the strain circulating widely in West Africa and imported into Europe (Britain, Netherlands, Germany) and America (Mexico, USA, Canada). CONCLUSION: The conserved sequences among three isolates, covering a 3-month period, suggest that this B3 strain was circulating in Addis Ababa, Bahir Dar and possibly elsewhere in Ethiopia. To interrupt the transmission and circulation of MV, Ethiopia needs a strong national program of epidemiological surveillance, with characterization of circulating MV performed in a timely manner.     

Multiple comparisons model-based clustering and ternary pattern tree numerical display of gene response to treatment: procedure and application to the preclinical evaluation of chemopreventive agents

Microarray technology has greatly aided the identification of genes that are expressed differentially. Statistical analysis of such data by multiple comparisons procedures has been slow to develop, in part, because methods to cluster the results of such comparisons in biologically meaningful ways have not been available. We isolated and analyzed, by Northern blot and GeneChip, replicate liver RNA samples (n = 4/group) from rats fed with control diet or diet containing one of three chemopreventive compounds, selected because their pharmacological activities, including RNA expression response, are relatively well understood. We report on a classification tree, based on the results of nonparametric multiple comparisons, which results in the bipolar hierarchical clustering of genes in relation to their response to treatment. In addition to identifying treatment-responsive genes, application of this procedure to our test study identified the known pharmacological relationships among the treatment groups without supervision. Also, small treatment-specific subsets of genes were identified that may be indicative of additional pharmacophores present in the test compounds.     

Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons

Kainate receptors (KA-Rs) are members of the glutamate-gated family of ionotropic receptors, which also includes N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. KA-Rs are important modulators of interneuron excitability in the CA1 region of the hippocampus. Activation of these receptors enhances interneuron firing, which robustly increases spontaneous inhibitory postsynaptic currents in pyramidal neurons. We report here that ethanol (EtOH) potently inhibits this KA-R-mediated effect at concentrations as low as those that can be achieved in blood after the ingestion of just 1-2 drinks (5-10 mM). Pressure application of kainate, in the presence of AMPA and NMDA receptor antagonists, evoked depolarizing responses in interneurons that triggered repetitive action potential firing. EtOH potently inhibited these responses to a degree that was sufficient to abolish action potential firing. This effect appears to be specific for KA-Rs, as EtOH did not affect action potential firing triggered by AMPA receptor-mediated depolarizing responses. Importantly, EtOH inhibited interneuron action potential firing in response to KA-R activation by synaptically released glutamate, suggesting that our findings are physiologically relevant. KA-R-dependent modulation of glutamate release onto pyramidal neurons was not affected by EtOH. Thus, EtOH increases excitability of pyramidal neurons indirectly by inhibiting the KA-R-dependent drive of gamma-aminobutyric acid (GABA)ergic interneurons. We postulate that this effect may explain, in part, some of the paradoxical excitatory actions of this widely abused substance. The excitatory actions of EtOH may be perceived as positive by some individuals, which could contribute to the development of alcoholism.     

Significant mobilization of both conventional and regulatory T cells with AMD3100

In this study, we used the rhesus macaque model to determine the impact that AMD3100 has on lymphocyte mobilization, both alone and in combination with G-CSF. Our results indicate that, unlike G-CSF, AMD3100 substantially mobilizes both B and T lymphocytes into the peripheral blood. This led to significant increases in the peripheral blood content of both effector and regulatory T-cell populations, which translated into greater accumulation of these cells in the resulting leukapheresis products. Notably, CD4(+)/CD25(high)/CD127(low)/FoxP3(+) Tregs were efficiently mobilized with AMD3100-containing regimens, with as much as a 4.0-fold enrichment in the leukapheresis product compared with G-CSF alone. CD8(+) T cells were mobilized to a greater extent than CD4(+) T cells, with accumulation of 3.7 ± 0.4-fold more total CD8+ T cells and 6.2 ± 0.4-fold more CD8(+) effector memory T cells in the leukapheresis product compared with G-CSF alone. Given that effector memory T-cell subpopulations may mediate less GVHD compared with other effector T-cell populations and that Tregs are protective against GVHD, our results indicate that AMD3100 may mobilize a GVHD-protective T-cell repertoire, which would be of benefit in allogeneic hematopoietic stem cell transplantation.     

Comparative analysis of the effects of hubble-bubble (Sheesha) and cigarette smoking on respiratory and metabolic parameters in hubble-bubble and cigarette smokers

OBJECTIVES AND BACKGROUND: Hazard of smoking tobacco is believed to be minimized by smoking hubble-bubble (HB) instead of cigarettes. Our aims were to (i) develop an assay for estimating nicotine and cotinine; and (ii) evaluate the effect of smoking on respiratory and metabolic parameters in cigarette and HB smokers. METHODS: Urine samples were collected from 152 volunteer smokers (75 cigarette and 77 HB) as well as from 16 healthy controls. We optimized an HPLC method for the determination of nicotine and cotinine. Subjects were asked to complete a chronic respiratory symptoms questionnaire and to undergo spirometry. Fasting blood samples were collected for the determination of their lipid profile. RESULTS: The intra-assay coefficients of variation for nicotine and cotinine were 16.6% and 6.6%, respectively. The mean of cotinine in cigarette smokers (1321.4 ng/mL) was significantly (P = 0.008) higher than the mean cotinine (677.6 ng/mL) in HB smokers. The mean nicotine level in cigarette smokers (1487.3 ng/mL) was significantly (P < 0.0001) higher than the mean nicotine (440.5 ng/mL) in HB smoker. The urinary cotinine and nicotine levels of the control subjects were lower than the detection levels of the assay. The mean high-density lipoprotein cholesterol was lower in cigarette smokers (0.99 mmol/L) compared with HB smoker smokers (1.02 mmol/L) but this was not significant (P = 0.28). Spirometric values were comparable among the three groups but the chronic respiratory symptoms in the smoking groups appeared at an earlier age in the HB smokers compared with the cigarettes smokers (P < 0.05). CONCLUSION: Smoking HB does not reduce the risk of tobacco exposure and it's potentially harmful metabolites on health.