Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2- nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane- induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.      

Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake

Context  Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. Objective  To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). Design, Setting, and Participants  Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). Main Outcome Measure  Serum intact PTH as determined by calcium intake and vitamin D. Results  A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). Conclusions  As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.      

Frequency of specific CD8+ T cells for a promiscuous epitope derived from Trypanosoma cruzi KMP‐11 protein in chagasic patients

The K1 peptide is a CD8 ⁺ T cell HLA‐A*0201‐restricted epitope derived from the Trypanosoma cruzi KMP‐11 protein. We have previously shown that this peptide induces IFN‐γ secretion by CD8⁺T cells. The aim of this study was to characterize the frequency of K1‐specific CD8⁺T cells in chagasic patients. Nineteen HLA‐A2⁺individuals were selected from 50 T. cruzi infected patients using flow cytometry and SSP‐PCR assays. Twelve HLA‐A*0201⁺noninfected donors were included as controls. Peripheral blood mononuclear cells were stained with HLA‐A2‐K1 tetramer, showing that 15 of 19 infected patients have K1‐specific CD8⁺T cells (0·09–0·34% frequency) without differences in disease stages or severity. Of note, five of these responders were A*0205, A*0222, A*0226, A*0259 and A*0287 after molecular typing. Thus, a phenotypic and functional comparison of K1‐specific CD8⁺T cells from non‐HLA‐A*0201 and HLA‐A*0201⁺infected patients was performed. The results showed that both non‐HLA‐A*0201 and HLA‐A*0201⁺individuals have a predominant effector memory CD8⁺T cell phenotype (CCR7?, CD62L?). Moreover, CD8⁺T cells from non‐HLA‐A*0201 and HLA‐A*0201⁺individuals expressed IL‐2, IFN‐γ and perforin without any differences. These findings support that K1 peptide is a promiscuous epitope presented by HLA‐A2 supertype molecules and is highly recognized by chagasic patients.     

Characterization of novel Mycobacterium tuberculosis pncA gene mutations in clinical isolates from the Ukraine

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis cases in the Ukraine are increasing. Pyrazinamide (PZA) is critically important for first- and second-line tuberculosis (TB) treatment regimes. However, PZA drug susceptibility testing is time consuming and technically challenging. The present study utilized Next-generation sequencing (NGS) to identify mutations in the pncA gene from clinical isolates and to assess the prevalence of pncA gene mutations in MDR/XDR-TB patients. Clinical isolates were inactivated in molecular transport media and shipped from Kharkiv, Ukraine, to San Antonio, TX. Whole-genome and targeted pncA gene sequencing was carried out using Illumina MiSeq instrumentation. Mutations were noted in 67 of 91 (74%) clinical isolates comprising substitutions, insertions, and deletions in the pncA coding and upstream promoter region. Of 45 mutation types, there were 11 novel, i.e., to date unknown, pncA mutations identified of which 3 were confirmed PZA resistant. Seven isolates contained mixed base mutations, whereas 4 harbored doubled mutations. Data reported here further support use of NGS for pncA gene characterization and may contribute in significant fashion to PZA therapy, especially in MDR- and XDR-TB patients.     

Prevalence of asymptomatic left ventricular systolic dysfunction in hypertensive Nigerians: echocardiographic study of 832 subjects

Background

We sought to determine the prevalence of echocardiographically determined left ventricular systolic dysfunction in asymptomatic hypertensive subjects seen in Abeokuta, Nigeria.

Methods

Echocardiography was performed in 832 consecutive hypertensive subjects referred for cardiac evaluation over a three-year period.

Results

Data were obtained in 832 subjects (50.1% women) aged 56.0 ± 12.7 years (men 56.9 ± 13.3 years, women 55.0 ± 12.0 years, range 15–88). The prevalence of left ventricular systolic dysfunction (LVSD) was 18.1% in the study population (mild LVSD = 9.6%, moderate LVSD = 3.7% and severe LVSD = 4.8%). In a multivariate analysis, male gender, body mass index and LV mass were the predictors of LVSD.

Conclusion

Significant numbers of hypertensive subjects in this study had varying degrees of left ventricular systolic dysfunction. Early introduction of disease-modifying drugs in these patients, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers may retard or prevent the progression to overt heart failure.     

Antigen--antibody complexes related to the baboon endogenous virus in humans with acute lymphoblastic leukemia--hand mirror variant (ALL-HMC)

Hand mirror cells are a morphological configuration that are seen in immunologically stimulated lymphocytes and can be induced by antigen-- antibody complexes. Therefore, the bone marrow and peripheral blood plasma of two patients with acute lymphoblastic leukemia--hand mirror variant were evaluated for the presence of antigen--antibody complexes. Both patients had antigen--antibody complexes in the bone marrow plasma and not in the peripheral blood plasma as determined by double counter- current immunoelectrophoresis. The antigen moiety of these complexes appears immunologically related to components of the baboon endogenous virus (BaEV), and the antibody moiety also appears related to structural components of the BaEV. Bone marrow plasmas from patients without leukemia were evaluated for the presence of antigen--antibody complexes and found to be negative. The antigen--antibody complexes may account for the presence of hand mirror cells in the bone marrow of patients with acute lymphoblastic leukemia--hand mirror variant.     

精神病的跨诊断维度:对精神疾病的分类学与研究的意义（英文）

如果精神病是一种跨诊断的维度,精神病性症状的出现受动态变化的情境和情感因素左右,而后者又是可治疗的,那么目前精神科疾病的分类学和治疗研究的方法可能需要修改。迄今为此,无论在临床工作上还是在疾病概念上,占主导地位的方法是将精神病性症状置于精神分裂症的框架中。然而,终生患病率为1%的精神分裂症只代表了部分预后不佳的精神病谱系障碍,而后者发生更多,终生患病率为3.5%。因此,精神分裂症的研究结果可能反映了预后相关的机制,而非精神病和其他症状维度之间本质上的相关性。同样,常见的非精神病性精神障碍中高达30%的个体有阈下精神病性症状,他们会被归于精神病的跨诊断维度之下,这些精神症状还会影响临床严重程度和治疗有效性。上述发现也同样提示武断区分"精神病性"与"非精神病性"的做法妨碍了临床实践和研究。精神病学诊断手册可以借鉴跨诊断维度(包括精神病的跨诊断维度)的体系。引入跨诊断维度,则既能根据原则进行分类诊断(即疾病分组的特异性),又可结合个体特有的多维度综合评分(即个体特异性)。这样的益处在于促使人们思考在精神病理学中症状之间是如何动态地交互作用的,并思考社会环境是如何影响精神病理症状的。     

Telomere length in relation to insulin resistance,inflammation and obesity among Arab youth

Aim: The aim of this study was to determine the associations of telomere length to markers of obesity, insulin resistance and inflammation in Saudi children. Methods: A total of 69 boys and 79 girls, aged 5–12 years, participated in this cross‐sectional study. Anthropometrics were measured. Serum glucose and lipid profile were measured using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumour necrosis factor‐alpha and active plasminogen activator inhibitor 1 were quantified using customized multiplex assay kits. C‐reactive protein and angiotensin II were quantified using ELISA. Leucocyte telomere length was examined by quantitative real time PCR utilizing IQ cycler. Results: Mean telomere length was significantly shorter in obese boys compared with their lean counterparts (p = 0.049), not in girls. It was not associated to insulin resistance, adipocytokines and markers of inflammation. In girls, the significant predictor of telomere length was waist circumference, explaining 24% of variance (p = 0.041) while in boys, systolic blood pressure explained 84% of the variance (p = 0.01). Conclusion: Childhood obesity in boys corresponds to shorter leucocyte telomere length which is not evident in girls. The association of leucocyte telomere length to blood pressure and waist circumference in children suggests clinical implications as to the contribution of these parameters in premature ageing.     

Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group

Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. BACKGROUND: In the management of patients with mild secondary hyperparathyroidism, it is not known whether calcium supplementation alone is sufficient to correct abnormalities in bone and mineral metabolism or if calcitriol is needed in either physiologic oral or intravenous pharmacologic doses. METHODS: This was a 40-week prospective nonmasked trial of 52 patients [parathyroid hormone (PTH) 150 to 600 pg/mL] who were randomized to receive escalating doses of either calcium carbonate (CaCO3) alone (calcium group, N = 11), daily oral calcitriol (oral group, N = 20), or intermittent intravenous calcitriol (IV group, N = 21). The groups were compared with regard to changes in serum intact PTH, serum bone-specific alkaline phosphatase (BAP), incidence of hypercalcemia (>10.5 mg/dL), and hyperphosphatemia (>6.5 mg/dL). RESULTS: PTH levels decreased in all groups (P < 0.01, paired t-test). In the calcium group, PTH (mean +/- SEM) decreased from 325 +/- 46.2 to 160 +/- 44.5 pg/mL. In the oral group, it decreased from 265 +/- 26.4 to 125 +/- 23.7 pg/mL, and in the IV group, it decreased from 240 +/- 27.7 to 65 +/- 10.0 pg/mL. Upon analysis of covariance, controlling for the initial PTH level, we found no differences in the PTH response between the groups (P > 0.10). In contrast, the BAP concentration increased from 20.7 +/- 7.6 to 27.5 +/- 7.0 microg/L in the calcium group (P = 0.17), decreased from 20. 6 +/- 3.9 to 17.8 +/- 4.5 microg/L in the oral group (P = 0.26), and from 19.1 +/- 2.6 to 10.6 +/- 1.1 microg/L in the IV group (P = 0. 007). Serum calcium increased significantly in all groups from 8.4 +/- 0.25 to 9.0 +/- 0.28, 8.5 +/- 0.16 to 9.2 +/- 0.27, and 8.7 +/- 0.16 to 9.4 +/- 0.18 mg/dL in the calcium, oral, and IV groups, respectively (P = NS difference between groups). Serum phosphorus was significantly lower in the calcium group throughout the study (P = 0.02). Hypercalcemic episodes were 2.0 +/- 0.8, 3.0 +/- 0.6, and 3. 4 +/- 0.6 per patient-year (P > 0.10), and hyperphosphatemic episodes were 0.9 +/- 0.56, 4.2 +/- 0.79 and 4.9 +/- 0.84 in the calcium, oral, and IV groups, respectively (P < 0.01). CONCLUSION: In mild secondary hyperparathyroidism, all three strategies are effective. High-dose CaCO3 alone may be sufficient to control PTH with a favorable side-effect profile, but calcitriol appears to have additional suppressive effects on bone that are greater following the intravenous route of administration and may increase the risk of adynamic bone disease.