The Benefits and Challenges of Preconsent in a Multisite, Pediatric Sickle Cell Intervention Trial

Enrollment of patients in sickle cell intervention trials has been challenging due to difficulty in obtaining consent from a legal guardian and lack of collaboration between emergency medicine and hematology. We utilized education and preconsent in a pediatric multisite sickle cell intervention trial to overcome these challenges. Overall, 48 patients were enrolled after being preconsented. Variable Institutional Review Board policies related to preconsent validity and its allowable duration decreased the advantages of preconsent at some sites. The utility of preconsent for future intervention trials largely depends on local Institutional Review Board policies. Preeducation may also benefit the consent process, regardless of site differences.

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Comparison of 18F-FDG-PET-CT and Bone Scintigraphy for Evaluation of Osseous Metastases in Newly Diagnosed and Recurrent Osteosarcoma

Background

Bone scintigraphy (BS) is used to detect osseous metastases in osteosarcoma. ¹⁸F-fluorodeoxyglucose-positron emission tomography–computed tomography (¹⁸F-FDG-PET-CT) is being increasingly used for staging. We compared the sensitivity, specificity, and diagnostic accuracy of ¹⁸F-FDG–PET-CT and BS for detecting osseous metastases in osteosarcoma.

Methods

We retrospectively reviewed 39 patients with osteosarcoma who had paired PET–CT and BS at diagnosis and/or first recurrence from 2003 to 2012. Imaging studies were reviewed by two pediatric imaging specialists who were blinded to results of the opposing modality and reference standard. Reviewers categorized lesions as benign, malignant, or indeterminate. Reference standard for lesion histology was biopsy or clinical follow-up. Diagnostic performance of PET–CT, BS, and combined modalities were determined.

Results

There were 40 examinations from 39 patients and 65 distant lesions were evaluated. Median age was 12 years (range 5–19 years). Four patients had 15 osseous metastases at diagnosis (two biopsied and 13 clinically), and two had five osseous metastases at recurrence (one biopsied and five clinically). For distant sites, sensitivity, specificity, and diagnostic accuracy were 79%, 89% and 86% for PET–CT, 32%, 96%, and 77% for BS, and 95%, 85%, and 88% for PET–CT/BS combined. Sensitivity of PET–CT was superior to BS (P = 0.035); combined imaging modalities were superior to BS (P < 0.001) but not better than PET–CT alone (P = 0.25). Specificity for BS approached significance compared to combined imaging (P = 0.063). Examination-based analysis yielded similar results between individual and combined imaging modalities.

Conclusions

¹⁸F-FDG–PET–CT demonstrated superior sensitivity over BS for detecting osseous metastases, supporting the use of ¹⁸F-FDG–PET–CT for staging of osteosarcoma.

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Response: A Call for Psychosocial and Palliative Care Training Standards for Pediatric Hematology–Oncology Physicians, A Reply To: Communication, Documentation, and Training Standards in Pediatric Psychosocial Oncology

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Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review

Children with human immunodeficiency virus (HIV) have an increased risk of developing Kaposi Sarcoma (KS) and non-Hodgkin lymphoma (NHL) compared to HIV-negative children. We compiled currently published epidemiologic data on KS and NHL among children in sub-Saharan Africa (SSA). Among countries with available data, the median incidence of KS was 2.05/100,000 in the general pediatric population and 67.35/100,000 among HIV-infected children. The median incidence of NHL was 1.98/100,000 among the general pediatric population, while data on NHL incidence among HIV-infected children were lacking. Larger regional studies are needed to better address the dearth of epidemiologic information on pediatric KS and NHL in SSA.

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ERRATUM

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A Framework for Adapted Nutritional Therapy for Children With Cancer in Low- and Middle-Income Countries: A Report From the SIOP PODC Nutrition Working Group

The utilization of adapted regimens for the treatment of pediatric malignancies has greatly improved clinical outcomes for children receiving treatment in low- and middle-income countries (LMIC). Nutritional depletion has been associated with poorer outcomes, increased abandonment of therapy, and treatment-related toxicities. Surveys have found that nutritional intervention is not incorporated routinely into supportive care regimens. Establishing nutritional programs based upon institutional resources may facilitate the incorporation of nutritional therapy into clinical care in a way that is feasible in all settings. We present a framework for establishing and monitoring of nutritional care based on the infrastructure of institutions in LMIC.

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Irregular menses predicts ovarian cancer: Prospective evidence from the Child Health and Development Studies

ABSTRACT

We tested the hypothesis that irregular menstruation predicts lower risk for ovarian cancer, possibly due to less frequent ovulation.

We conducted a 50-year prospective study of 15,528 mothers in the Child Health and Development Studies cohort recruited from the Kaiser Foundation Health Plan from 1959-1966. Irregular menstruation was classified via medical record and self-report at age 26. We identified 116 cases and 84 deaths due to ovarian cancer through 2011 via linkage to the California Cancer Registry and Vital Statistics.

Contrary to expectation, women with irregular menstrual cycles had a higher risk of ovarian cancer incidence and mortality over the 50-year follow-up. Associations increased with age (p <0.05). We observed a 2-fold increased incidence and mortality by age 70 (95% Confidence Interval (CI) = 1.1, 3.4) rising to a 3-fold increase by age 77 (95% CI = 1.5, 6.7 for incidence; 95% CI = 1.4, 5.9 for mortality). We also found a 3-fold higher risk of mortality for high-grade serous tumors (95% CI = 1.3, 7.6) that did not vary by age.

This is the first prospective study to show an association between irregular menstruation and ovarian cancer – we unexpectedly found higher risk for women with irregular cycles. These women are easy to identify and many may have polycystic ovarian syndrome. Classifying high-risk phenotypes such as irregular menstruation creates opportunities to find novel early biomarkers, refine clinical screening protocols and potentially develop new risk reduction strategies. These efforts can lead to earlier detection and better survival for ovarian cancer. This article is protected by copyright. All rights reserved.

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Subtype-specific micro-RNA expression signatures in breast cancer progression

Abstract

Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast cancer is a heterogeneous disease and biological mechanisms for carcinogenesis vary between subtypes. Stratification by subtype is therefore necessary in order to identify relevant and robust signatures of invasive disease. We have identified miRNA alterations during breast cancer progression in two separate datasets and used stratification and external validation to strengthen the findings.

We analysed two separate datasets (METABRIC and AHUS) consisting of a total of 186 normal breast tissue samples, 18 ductal carcinoma in situ (DCIS) and 1338 invasive breast carcinomas. Validation in a separate dataset and stratification by molecular subtypes based on immunohistochemistry, PAM50 and integrated cluster classifications were performed.

We propose subtype-specific miRNA signatures of invasive carcinoma and a validated signature of DCIS. miRNAs included in the invasive signatures include down-regulation of miR-139-5p in aggressive subtypes and up-regulation of miR-29c-5p expression in the luminal subtypes. No miRNAs were differentially expressed in the transition from DCIS to invasive carcinomas on the whole, indicating the need for subtype stratification. A total of 27 miRNAs were included in our proposed DCIS-signature. Significant alterations of expression included up-regulation of miR-21-5p and the miR-200-family and down-regulation of let-7 family members in DCIS samples. The signatures proposed here can form the basis for studies exploring DCIS samples with increased invasive potential and serum biomarkers for in situ and invasive breast cancer. This article is protected by copyright. All rights reserved.

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Identification of Novel BRCA Founder Mutations in Middle Eastern Breast Cancer Patients Using Capture and Sanger Sequencing Analysis

Abstract

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, 9 different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p=0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy. This article is protected by copyright. All rights reserved.

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Vitamin B2 intake and colorectal cancer risk; results from the Nurses' Health Study and the Health Professionals Follow-up Study cohort

Abstract

Vitamin B2 serves as a cofactor to enhance one-carbon metabolism, maintain mucous membranes, and has been implicated in lowering colorectal cancer (CRC) risk. However, few prospective studies have examined the association between vitamin B2 intake and CRC. In this study, we estimated the associations between vitamin B2 intake and CRC risk using the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) cohorts. Vitamin B2 intake was measured by a validated food frequency questionnaire every 4 years. Among 100,033 women in the NHS and 44,007 men in the HPFS we documented a total of 3,037 incident CRC cases (2,093 women and 944 men) during 24-26 years of follow-up until 2010. Intakes of total (from food and supplements), dietary (from food only), and supplemental vitamin B2 were inversely related to CRC risk in age-adjusted analysis in NHS. However, the association was attenuated and no longer statistically significant in multivariate analysis (P-trend ≥0.08). The pooled multivariate relative risks (95% confidence interval) comparing individuals in the extreme quintiles of intakes were 0.93 (0.81-1.06) for total vitamin B2, 0.89 (0.61-1.28) for dietary vitamin B2 and 0.94 (0.81-1.08) for supplemental vitamin B2. These associations of total vitamin B2 intake were similar for risk of CRC with varying lag-time periods (0-4, 4-8, 8-12, or 12-16 years), for risk of CRC subtypes by tumor location, and across strata of intake of folate or alcohol. Our prospective data do not support a beneficial role of vitamin B2 intake in lowering incidence of CRC. This article is protected by copyright. All rights reserved.

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Reply to: Statins and the risk of pancreatic cancer in type 2 diabetic patients: Immortal time bias in survival analysis? -Author reply

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Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1–3 metastases

Abstract

We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1–3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min–Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70–100), 28 (21–30) and 143 (98–153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32–59 % for FACT-Br and 0–16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.

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Cancer-Related Information Seeking Among Cancer Survivors: Trends Over a Decade (2003–2013)

Abstract

The demonstrated benefits of information seeking for cancer patients, coupled with increases in information availability, underscore the importance of monitoring patient information seeking experiences over time. We compared information seeking among cancer survivors to those with a family history of cancer and those with no history of cancer. We identified characteristics associated with greater information seeking among cancer survivors, key sources of cancer-related information, and changes in information source use over time. Data from five iterations of the Health Information National Trends Survey (HINTS) spanning 2003 to 2013 were merged and analyzed. Frequencies, cross-tabulations, multivariate logistic regression, and multinomial regression analyses were conducted. All data were weighted to provide representative estimates of the adult US population. Cancer information seeking was reported most frequently by cancer survivors (69.8 %). The percentage of cancer survivors who reported information seeking increased from 66.8 % in 2003 to 80.8 % in 2013. Cancer information seeking was independently associated with age, education, and income; seeking was less likely among older adults, those with less education, and those with lower incomes. Compared to respondents in 2003, those in 2005 (odds ratio (OR) = 0.40, 95 % confidence interval (CI) = 0.24–0.65) and 2008 (OR = .43, 95 % CI = 0.26–0.70) were about half as likely to use the Internet as the first source of cancer information compared to a healthcare provider. Despite overall increases in cancer information seeking and access to health information from a variety of sources, healthcare providers remain a key source of health information for cancer survivors.

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Cervical Cancer Stigma in Rural Kenya: What Does HIV Have to Do with It?

Abstract

Cervical cancer is a leading cause of cancer-related death amongst women in sub-Saharan Africa, largely due to the lack of early screening and treatment. In addition to poor access to screening services, inadequate uptake of available services is a barrier to early identification of precancerous lesions. Given that cervical cancer is caused by a sexually transmitted virus and is associated with HIV positivity, stigma is one of the potential barriers to the utilization of cervical cancer programs in sub-Saharan Africa. We conducted a cross-sectional survey of 419 women attending health facilities in rural western Kenya to measure levels of cervical cancer and HIV stigma and to measure the associations between cervical cancer stigma, HIV stigma, and HIV status. Women who qualified for cervical cancer screening were asked to complete an oral questionnaire using a modified 9-point HIV stigma scale. Low cervical cancer stigma was reported in this study, with only 85/419 (20.3 %) of respondents answering yes to at least one cervical cancer stigma question. However, cervical cancer stigma was highly correlated with HIV stigma (correlation coefficient 0.72) and was significantly lower in HIV-positive women (p < 0.001). Reducing cervical cancer stigma in the general population is an important part of promoting screening in sub-Saharan Africa.

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Cervical Cancer Knowledge, Perceptions and Screening Behaviour Among Female University Students in Ghana

Abstract

Cervical cancer is becoming a leading cause of death among women in developing countries. Nevertheless, little is known regarding knowledge and perception of cervical cancer and screening behaviour particularly among female tertiary students in Ghana. This study sought to examine the knowledge and perceptions of cervical cancer and screening behaviour among female students in the University of Cape Coast and Ghana Institute of Management and Public Administration in Ghana. A cross-sectional survey design was adopted for the study. Systematic and stratified random sampling techniques were used to select 410 participants for the study. The study found that the participants lacked knowledge on specific risk factors and symptoms of cervical cancer. Also, even though the participants had a fair perception of cervical cancer, they had a poor cervical cancer screening behaviour. Awareness of cervical cancer was significantly influenced by religious affiliation while cervical cancer screening was significantly determined by the working status of the participants. Specific knowledge on cervical cancer and its risk factors as well as regular screening behaviour is paramount to the prevention of cervical cancer. Consequently, the University Health Services should focus on promoting regular cervical cancer awareness campaigns and screening among the students particularly, females.

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Impact of Physiological Symptoms and Complications of Colorectal Cancer on the Quality of Life of Patients at King Abdulaziz University Hospital

Abstract

Colorectal cancer (CRC) is common worldwide. The high prevalence of the disease raises concerns about how CRC influences the health-related quality of life (QoL). To explore the impact of physiological symptoms and complications of CRC on patients' QoL, we conducted a cross-sectional survey using the FACT-C self-report instrument. The chi-square test was used to compare qualitative data. We found that pain was reported by most of the patients (n = 31; 77.5 %). Furthermore, male patients were more likely to complain of pain "mostly" as compared with females (P = .032). We found no significant differences between genders regarding general health-related questions. A greater proportion of male patients often complained of abdominal cramps (P = .542), weight loss (P = .086), and diarrhea (P = .408). More than half of the patients (n = 26; 65 %) reported having a good appetite; a greater proportion of males reported having a good appetite "mostly" (P = .014). Social and psychological qualities of life were not significantly different between male and female patients. Male and female patients did not differ in their report of disease acceptance (P = .420) and ability to enjoy life (P = .744). No difference was also found between genders regarding contentment with QoL (P = .793) or ability to sleep well (P = .695). Furthermore, there were no differences between genders regarding job fulfillment (P = .272). Our results add to the growing body of knowledge about the effect of CRC on QoL. Importantly, the differences in self-reported pain and appetite between male and female patients in our study suggest the importance of gender-based treatments in improving patients' QoL.

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Combined adjuvants of poly(I:C) plus LAG-3-Ig improve antitumor effects of tumor-specific T cells, preventing their exhaustion

Therapeutic cancer vaccines are designed to treat cancer by boosting the endogenous immune system to fight against the cancer. In the development of clinically effective cancer vaccines, one of the most practical objectives is to identify adjuvants that are capable of optimizing the vaccine effects. In this study, we explored the potential of polyinosinic–polycytidylic acid (poly(I:C)) and LAG-3-Ig (soluble recombinant protein of lymphocyte activation gene-3 [LAG-3] extracellular domain fused with human IgG Fc region) as adjuvants for P1A tumor antigen peptide vaccine in a pre-established P815 mouse tumor model with a transfer of tumor-specific T cells. Whereas the use of poly(I:C) or LAG-3-Ig as a signal adjuvant induced a slight enhancement of P1A vaccine effects compared to incomplete Freund's adjuvant, combined treatment with poly(I:C) plus LAG-3-Ig remarkably potentiated antitumor effects, leading to complete rejection of pre-established tumor and long-term survival of mice. The potent adjuvant effects of poly(I:C) plus LAG-3-Ig were associated with an enhanced infiltration of T cells in the tumor tissues, and an increased proliferation and Th1-type cytokine production of tumor-reactive T cells. Importantly, the combined adjuvant of poly(I:C) plus LAG-3-Ig downregulated expressions of PD-1, LAG-3, and TIGIT on P1A-specific T cells, indicating prevention of T cell exhaustion. Taken together, the results of the current study show that the combined adjuvants of poly(I:C) plus LAG-3-Ig with tumor peptide vaccine induce profound antitumor effects by activating tumor-specific T cells.

This study explored a potential of poly(I:C) and LAG-3-Ig as adjuvants for tumor antigen peptide vaccine in the pre-established mouse tumor model. It was found that poly(I:C) plus LAG-3-Ig combination as adjuvant profoundly augments therapeutic potential of tumor peptide vaccine.

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UICC International Session: What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC – Asia Regional Office organized an international session as part of the 74th Annual Meeting of the Japanese Cancer Association on the topic "What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?" Universal Health Coverage (UHC) is included in the United Nations' Sustainable Development Goals and aims to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The session discussed the growing cost of cancer and the challenges that this poses to the establishment and deployment of UHC in the Asian region, where countries face budgetary and other systemic constraints in tackling and controlling cancer. It was noted how sharing concepts on UHC will assist mutual learning among Asian countries and help in the formation of guidelines that can be adapted to national and regional realities. Presentations included a status report on UHC for cancer control in Thailand, and a report from the WHO Kobe Centre concerning prospects for collaborative research on UHC. Also discussed were the current status of cancer burden and control in China and Korea and Japan's progress in systemizing cost-effectiveness evaluation. The final presentation highlighted the importance of gathering social and economic data across Asia in order to build a picture of commonalities and differences in the region.

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Issue Information

Cover of this issue. Uptake of extracellar vesicles by endothelial cell. See also Fujita, Y., et al. (pages 385–390 of this issue).

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Anti-bevacizumab idiotype antibody vaccination is effective in inducing vascular endothelial growth factor-binding response, impairing tumor outgrowth

Tumors require blood supply and, to overcome this restriction, induce angiogenesis. Vascular endothelial growth factor (VEGF) plays an important role in this process, which explains the great number of antiangiogenic therapies targeting VEGF. The research and development of targeted therapy has led to the approval of bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), in clinical settings. However, side effects have been reported, usually as a consequence of bolus-dose administration of the antibody. This limitation could be circumvented through the use of anti-idiotype (Id) antibodies. In the present study, we evaluated the efficacy of an active VEGF-binding immune response generated by an anti-bevacizumab idiotype mAb, 10.D7. The 10.D7 anti-Id mAb vaccination led to detectable levels of VEGF-binding anti-anti-Id antibodies. In order to examine whether this humoral immune response could have implications for tumor development, 10.D7-immunized mice were challenged with B16-F10 tumor cells. Mice immunized with 10.D7 anti-Id mAb revealed reduced tumor growth when compared to control groups. Histological analyses of tumor sections from 10.D7-immunized mice showed increased necrotic areas, decreased CD31-positive vascular density and reduced CD68-positive cell infiltration. Our results encourage further therapeutic studies, particularly if one considers that the anti-Id therapeutic vaccination maintains stable levels of VEGF-binding antibodies, which might be useful in the control of tumor relapse.

1. Anti-bevacizumab idiotype 10.D7 mAb elicits VEGF-binding anti-anti-Id response.
2. 10.D7 anti-Id mAb mouse vaccination led to impaired tumor outgrowth.
3. Idiotypic network approach impairs in vitro tube formation and tumor angiogenesis.

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In This Issue

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A clinical evaluation of the TK 210 ELISA in sera from breast cancer patients demonstrates high sensitivity and specificity in all stages of disease

Abstract

Thymidine kinase (TK1) is an enzyme involved in DNA synthesis that leaks into the blood as a result of high cell turnover, particularly in the case of cancer. Serum TK1 activity has been used for prognosis and monitoring of leukemia and lymphoma patients for many years. Here, we describe the first clinical results with the newly developed TK 210 ELISA from AroCell AB. Sera from 124 breast cancer patients with known TNM classification along with sera from 53 healthy females were analyzed by TK 210 ELISA for TK1 protein and TK1 activity levels by the ³[H]-deoxythymidine (dThd) phosphorylation assay. The limit of detection for the TK 210 ELISA was 0.17 ng/ml, and 60 % of the sera from female blood donors were below this value. The median TK1 levels found in sera from breast cancer patients with T1 to T4 stage disease were 0.31, 0.46, 0.47, and 0.55 ng/ml, and these levels significantly differed from healthy controls. The median values of the biomarker CA 15-3 were also increased in patient sera from T1 to T4 patients (16, 34, 36, 40 U/ml, respectively). TK 210 ELISA showed significantly higher sensitivity for the T1 and T2 breast cancer patients compared to the TK activity assay. The combination of the TK1 ELISA and CA 15-3 biomarkers demonstrated a significant increase in sensitivity up to 15 % compared to each marker alone. This evaluation of the TK 210 ELISA strongly suggests that it can provide independent and complementary information for patients with breast cancer.

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Selenium and Antioxidant Status in Dairy Cows at Different Stages of Lactation

Abstract

Thirty-five multiparous Holstein cows averaging 550 ± 50 kg of body weight and in 2 to 4 parity were divided into three groups according to lactation stage (group A: nine cows from 4 to 1 weeks prepartum; group B: 11 cows from 1 to 30 days postpartum; group C: 15 cows from 30 to 100 days postpartum). Selenium concentration, malondialdehyde (MDA) level, glutathione peroxidase (GSH-Px) activity, thioredoxin reductase (TrxR) activity, and total antioxidant status (TAS) in serum were determined to evaluate selenium and antioxidant status in dairy cows at different stages of lactation. The results showed that mean serum selenium concentration, MDA level, and GSH-Px activity of cows in early lactation increased significantly (P < 0.05) when compared with cows in the dry period and peak lactation. Conversely, serum TrxR activity and TAS declined during this period (P < 0.05). The increase of serum MDA level during early lactation indicate that the reactive oxygen species, including lipid hydroperoxides, increase in this period, thus placing the cows at a greater risk of oxidative stress. The significant decrease in TrxR activity that is accompanied with a decrease in TAS during early lactation suggests that dairy cows have low antioxidant defense in this period and TrxR may be an important antioxidant defense mechanism in transition dairy cows.

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Letter Regarding: Selenium and Preeclampsia: A Systemic Review and Meta-Analysis

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Anti-Apoptotic and Anti-Oxidant Effects of Caffeic Acid Phenethyl Ester on Cadmium-Induced Testicular Toxicity in Rats

Abstract

Cadmium (Cd) is a serious environmental and occupational contaminant and may represent a serious health hazard to humans and other animals. Cd is reported to induce the generation of reactive oxygen species, and induces testicular damage in many species of animals. The goal of our study was to examine the anti-apoptotic and anti-oxidant effects of caffeic acid phenethyl ester (CAPE) on Cd-induced oxidative stress, apoptosis, and testicular injury in rats. A total of 40 male Wistar albino rats were divided into four groups: control, CAPE alone, Cd-treated, and Cd-treated with CAPE; each group consisted of 10 animals. To induce toxicity, Cd (1 mg/kg body weight) was dissolved in normal saline and subcutaneously injected into rats for 30 days. The rats in CAPE-treated group were given a daily dose of 10 μmol/kg body weight of CAPE by using intraperitoneal injection. This application was continued daily for a total of 30 days. To date, no examinations of the anti-apoptotic and anti-oxidant properties of CAPE on Cd-induced apoptosis, oxidative damage, and testicular injury in rat testes have been reported. CAPE-treated animals showed an improved histological appearance and serum testosterone levels in Cd-treated group. Our data indicate a significant reduction in the number of apoptotic cells in testis tissues of the Cd-treated group with CAPE treatment. Moreover, CAPE significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses in testes tissue resulted from Cd administration. These findings suggest that the protective potential of CAPE in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced testicular injury.

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Role of Magnesium Transporter Subtype 1 (MagT1) in the Osteogenic Differentiation of Rat Bone Marrow Stem Cells

Abstract

In the present study, we investigated the role of magnesium transporter subtype 1 (MagT1), a selective Mg transporter protein, in the osteogenic differentiation of rat bone marrow stem cells (rBMSCs). Osteogenic differentiation was monitored by the expressions of alkaline phosphatase (ALP), osteocalcin (OCN), collagen-1 (COL-1) and runt-related transcription factor 2 (RUNX2), and extracellular matrix mineralization of rBMSCs. The expression of MagT1 increased with osteogenic differentiation of rBMSCs, suggesting the importance of intracellular Mg homeostasis to cell differentiation. Alteration of intracellular Mg homeostasis by culture condition with low extracellular Mg significantly reduced the osteogenic differentiation markers ALP, OCN, COL-1, and RUNX2 gene expressions. MagT1 knockdown during the differentiation period also reduced osteogenic differentiation and the extent of matrix mineralization of rBMSCs. In conclusion, our results indicate that Mg and MagT1 play an important role in osteogenic differentiation of rBMSCs and may be involved in the bone regeneration.

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Different Accumulation of Elements in Proximal and Distal Parts of the Left Anterior Descending Artery Beneath the Myocardial Bridge

Abstract

To elucidate the action of the myocardial bridge (MB) on the coronary artery, the authors first prepared the hearts with the MB located in the middle one third of the left anterior descending (LAD) artery and then investigated element accumulation in the LAD artery of the hearts with the MB by direct chemical analysis. Eighty-four formalin-fixed adult Thai hearts were dissected and the MBs were found in 39 of 84 hearts with a total of 44 MBs. The 37 MBs were located in the middle one third of the LAD artery. To examine the action of the MB on element accumulation in the LAD artery, the hearts with the MB which was located in the middle one third of the LAD artery and was longer than 1.5 cm were used as Materials. The left main coronary (LMC) and LAD arteries were removed from these hearts successively and the isolated arteries were divided into eight to ten segments. After incineration of arteries with nitric acid and perchloric acid, seven element contents of Ca, P, S, Mg, Zn, Fe, and Na were determined by inductively coupled plasma-atomic emission spectrometry. To examine the endothelial changes of the LAD artery, the inner surface of segments of the LAD artery was observed by scanning electron microscopy. It was found that the extent of accumulation of Ca, P, Zn, and Na was not uniform throughout the LAD artery and was higher in the proximal part than in the distal part with regard to the LAD artery beneath the MB (the tunneled LAD artery). The extent of accumulation of Ca, P, Zn, and Na in the proximal part of the tunneled LAD artery was similar to that in the segments proximal to the MB, whereas the extent of accumulation of Ca, P, Zn, and Na in the distal part of the tunneled LAD artery was similar to that in the segments distal to the MB.

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Superoxide Dismutase Activity, Hydrogen Peroxide Steady-State Concentration, and Bactericidal and Phagocytic Activities Against Moraxella bovis , in Neutrophils Isolated from Copper-Deficient Bovines

Abstract

Copper (Cu) deficiency increases occurrence of certain infectious diseases in animals, including infectious keratoconjunctivitis in bovines, a bacterial ocular inflammation caused by Moraxella bovis. Neutrophil leukocytes constitute the first phagocytic cells to arrive at infection sites for bacterial neutralization. The objective of this work was to evaluate whether the functionality of neutrophils against M. bovis is impaired in experimentally induced Cu deficiency in bovines using high molybdenum and sulfur levels in the diet. The Cu tissue values and the periocular achromotrichia observed in +Mo animals showed that the clinic phase of Cu deficiency was reached in this group. Instead, +Cu animals have not evidenced clinical signs or biochemical parameters of hypocuprosis. On the basis of our observations, we concluded that Cu deficiency has no effect on phagocytic and bactericidal activities of neutrophils against M. bovis. However, superoxide dismutase activity and peroxide hydrogen generation were significantly different between groups. Therefore, additional research to explain these results is merited to fully characterize the consequences of Cu status on the risk for infections under field conditions.

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Erratum to: Trace Element Levels in Congenital Hypogonadotrophic Hypogonadism

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Effects of Methyl Mercury Chloride on Rat Hippocampus Structure

Abstract

The objective of this study is to investigate the impacts of Methyl Mercury Chloride (MMC) on cognitive functions and ultrastructural changes of hippocampus in Sprague Dawley (SD) rats. Thirty healthy 20-day-old male SD rats weighing 30–40 g were randomly divided into three groups to receive daily injections. Two different dose levels were used: 4 mg/kg as high dose (H-MMC) and 2 mg/kg as low dose (L-MMC).The control group received 4 mg/kg saline solution (N-NaCl). After daily subcutaneous injection for 50 days, 6-day Morris water maze tests were used to assess the learning and memory functions of the rats. After a 5-day continuous training, spatial probe tests were conducted of times and paths crossing to the target quadrant on the 6th day. After the rats were euthanized, their hippocampus sections were stained with hematoxylin and eosin and analyzed under bothoptical microscope and electron microscope. The time H-MMC group spent in finding platform was significantly longer as compared toN-NaCl group on day 2 to day 5 and L-MMC group on day 4 to day 5. The number of crossing times of H-MMC group to the target quadrant was 0.63 ± 0.74, which is much lower than C-NaCl group (3.13 ± 1.56) with P value <0.05. No statistically significant difference in crossing times was found between L-MMC and C-NaCl groups. For H-MMC group, decreasing number of neurons and disorganized nerve cells were examined under light microscope. Swelling and dissolution of Golgi complex were examined under electron microscope, along with endoplasmic reticulum expansion and cytoplasmic edema. Mild cytoplasmic edema was found in L-MMC group. MMC can cause cognitive impairment in terms of learning and memory in SD rats. Additionally, it can also cause changes in the ultrastructure of neurons and morphological changes in the hippocampus, causing significant damage.

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Selenium Deficiency Affects the mRNA Expression of Inflammatory Factors and Selenoprotein Genes in the Kidneys of Broiler Chicks

Abstract

The aim of this study was to investigate the influence of Se deficiency on the transcription of inflammatory factors and selenoprotein genes in the kidneys of broiler chicks. One hundred fifty 1-day-old broiler chicks were randomly assigned to two groups fed with either a low-Se diet (L group, 0.033 mg/kg Se) or an adequate Se diet (C group, 0.2 mg/kg Se). The levels of uric acid (UA) and creatinine (Cr) in the serum and the mRNA levels of 6 inflammatory factors and 25 selenoprotein genes in the kidneys were measured as the clinical signs of Se deficiency occurred at 20 days old. The results indicated that the contents of UA and Cr in the serum increased in L group (p < 0.05), and the mRNA levels of the inflammatory factors (NF-κB, iNOS, COX-2, and TNF-α) increased in L group (p < 0.05). Meanwhile, the mRNA levels of PTGEs and HO-1 were not changed. In addition, 25 selenoprotein transcripts displayed ubiquitous expression in the kidneys of the chicks. The mRNA levels of 14 selenoprotein genes (Dio1, Dio2, GPx3, Sepp1, SelH, SelI, SelK, Sepn1, SelO, SelW, Sep15, SelT, SelU, and SelS) decreased, and 9 selenoprotein genes (GPx1, GPx2, GPx4, SelPb, Txnrd1, Txnrd2, Txnrd3, SPS2, and SelM) increased in L group (p < 0.05), but the Dio3 and Sepx1 mRNA levels did not change. The results indicated that Se deficiency resulted in kidney dysfunction, activation of the NF-κB pathway, and a change in selenoprotein gene expression. The changes of inflammatory factor and selenoprotein gene expression levels were directly related to the abnormal renal functions induced by Se deficiency.

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Effect of Silicon Supplementation on Bone Status in Ovariectomized Rats Under Calcium-Replete Condition

Abstract

Previous studies have suggested that silicon (Si) had positive effects on bone, but such benefits from Si may be dependent on calcium status. Also, several biochemical roles of Si in osteoblastic mineralization, the regulation of gene expression related to bone matrix synthesis, and the decrease in reactive oxygen species and pro-inflammatory mediators were reported, but these effects were mostly shown in cell culture studies. Hence, we tested the effect of Si supplementation on bone status and the gene expression related to bone metabolism and inflammatory mediators in young estrogen-deficient rats under calcium-replete condition (0.5 % diet). Results showed that 15-week supplementation of both high and very high doses of Si (0.025 and 0.075 % diet, respectively) could not restore the ovariectomy (OVX)-induced decrease of bone mineral density (BMD) of vertebrae, femur, and tibia. Also, several bone biochemical markers (ALP, osteocalcin, CTx) and mRNA expression of COL-I, RANKL, IL-6, and TNF-α in femur metaphysis were not significantly changed by Si in OVX rats. However, a very high dose (0.075 %) of Si supplementation significantly increased OPG expression and decreased the ratio of RANKL/OPG in mRNA expression comparable to that of sham-control animals. Taken together, Si supplementation did not increase BMD under calcium-replete condition but the decrease in the ratio of RANKL/OPG expression to the normal level suggests the possibility of a bone health benefit of Si in estrogen deficiency-induced bone loss.

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Detectable Blood Lead Level and Body Size in Early Childhood

Abstract

Rates of childhood obesity have risen at the same time rates of high blood lead levels (BLLs) have fallen. Recent studies suggest that higher BLL is inversely associated with body size in older children (ages 3–19 years). No contemporaneous studies have examined if having a detectable BLL is associated with body size in very early childhood. We examined if detectable BLL is associated with body size in early childhood. A total of 299 birth cohort participants completed a study visit at ages 2–3 years with weight and height measurements; prior to this clinic visit, a BLL was drawn as part of routine clinical care. Body mass index (BMI) percentile and Z-score were calculated; children with BMI ≥85th percentile were considered overweight/obese at age of 2 years. Detectable BLL was defined as BLL ≥1 μg/dL. A total of 131 (43.8 %) children had a detectable BLL measured at mean aged 15.4 ± 5.5 months. Mean age at body size assessment was 2.2 ± 0.3 years (53.2 % male, 68.6 % African-American). After adjusting for race, sex, and birth weight, children with a detectable BLL had a 43 % lower risk of BMI ≥85th percentile (P = 0.041) and a 0.35-unit lower BMI Z-score (P = 0.008) compared to children without a detectable BLL. Neither race nor sex modified this association (all interactions P > 0.21). Consistent with recent studies in older children, having a detectable BLL was associated with smaller body size at ages 2–3 years. Additional research on the mechanism of this association is needed but may include mechanisms of appetite suppression via lead.

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Simvastatin Effect on Calcium and Silicon Plasma Levels in Postmenopausal Women with Osteoarthritis

Abstract

Postmenopausal women more often suffered from knee osteoarthritis and its pathogenesis still remains unclear. Calcium and silicon are significant elements involved in bone and joint metabolism, especially in older people. Cardiovascular diseases are common worldwide and simvastatin is the most prescribed drug in such population of patients. The purpose of this study was to evaluate the effect of simvastatin administration on calcium and silicon concentration in the plasma of postmenopausal women with osteoarthritis. Sixty postmenopausal mild hypercholesterolemic women (mean age 61.4 years, range 54–68) were enrolled. Thirty patients received simvastatin (20 or 40 mg/day) for at least 1 year before being enrolled (simvastatin "+" group). Control group consists of remaining 30 women (simvastatin "−"group). Silicon and calcium concentrations were measured spectrophotometrically. Plasma simvastatin level was determined 3 h after the drug administration using HPLC-UV-Vis. Calcium but not silicon level was significantly lower in patients receiving simvastatin in comparison with non-statin group (1.91 ± 0.32 vs. 2.33 ± 0.19 mmol/l, p < 0.05). A weak but significant positive correlation between plasma silicon and simvastatin levels (r = 0.3, p < 0.05) was observed; this may be due to the fact that simvastatin contains silicon dioxide as an inactive ingredient. The mean simvastatin concentration was 9.02 ng/ml. All hypotheses were verified at the significance level of p < 0.05. A statistically significant decrease in the plasma calcium concentration of postmenopausal women, treated with simvastatin suggests that simvastatin may play a role in calcium metabolism in postmenopausal women with osteoarthritis. Positive correlation of simvastatin concentration with silicon level in the plasma suggests that both might prompt the positive effect of osteoarthritis treatment.

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Prevalence of Selenium, T-2 Toxin, and Deoxynivalenol in Kashin–Beck Disease Areas in Qinghai Province, Northwest China

Abstract

The aim of this study was to determine the levels of selenium, T-2 toxin, and deoxynivalenol (DON) contamination in Kashin–Beck disease (KBD) areas and provide information for understanding the high prevalence of KBD in Qinghai Province. A total of 183 subjects were chosen in a KBD-prevalent county (Guide County) and a non-KBD county (Huangzhong County) in Qinghai Province, northwestern China, and the samples of wheat flour, soil, drinking water and blood, urine, and hair of children were collected from these residents. The selenium concentrations from all these sources were determined using atomic fluorescence spectrophotometry. The levels of T-2 toxin and DON contamination in the wheat flour samples were assayed using HPLC-MS/MS. The average selenium content in the soil, drinking water, and wheat flour samples from KBD areas were 26.93 ± 10.06 μg/kg, 0.097 ± 0.038 μg/L, and 9.50 ± 7.17 μg/kg, respectively. Among these, the selenium levels in the drinking water and wheat flour samples from the KBD endemic county were significantly lower than those from the non-KBD county. For the selenium nutrient status, only the hair selenium concentration of children from the KBD endemic county was significantly lower than that from the non-KBD county. The contents of T-2 toxin in all wheat samples were below the detection limit (0.4 μg/kg). The levels of DON contamination in wheat flour samples from KBD and non-KBD children's households within the KBD endemic county were relatively higher, with average levels of 302 ± 49 and 280 ± 48 μg/kg, respectively. The DON level of wheat flour samples from the children's households in the non-KBD county was significantly lower than that from the KBD endemic county. These results suggest that the lower selenium status in Guide County still remains. While the selenium nutritional status of the local children has improved to some extent, partly due to the introduction of food produce from nonlocal areas. DON contamination in the wheat flour may be involved in the fluctuating high prevalence rates of KBD in children in the KBD endemic Guide County in Qinghai Province.

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Aluminum Trichloride Induces Hypertension and Disturbs the Function of Erythrocyte Membrane in Male Rats

Abstract

Aluminum (Al) is the most abundant metal in the earth's crust. Al accumulates in erythrocyte and causes toxicity on erythrocyte membrane. The dysfunction of erythrocyte membrane is a potential risk to hypertension. The high Al content in plasma was associated with hypertension. To investigate the effect of AlCl₃ on blood pressure and the function of erythrocyte membrane, the rats were intragastrically exposed to 0, 64(1/20 LD₅₀), 128(1/10 LD₅₀), and 256(1/5 LD₅₀) mg/kg body weight AlCl₃ in double distilled water for 120 days, respectively. Then, we determined the systolic and mean arterial blood pressures of rats, the osmotic fragility, the percentage of membrane proteins, the activities of Na⁺/K⁺-ATPase, Mg²⁺-ATPase, Ca²⁺-ATPase, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-pX), and malondialdehyde (MDA) content of the erythrocyte membrane in this experiment. The results showed that AlCl₃ elevated the systolic and mean arterial blood pressure of rats, increased the osmotic fragility, decreased the percentage of membrane protein, inhibited the activities of Na⁺/K⁺-ATPase, Mg²⁺-ATPase, Ca²⁺-ATPase, CAT, SOD and GSH-pX, and increased the MDA content of erythrocyte membrane. These results indicate that AlCl₃ may induce hypertension by disturbing the function of erythrocyte membrane.

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Prolidase-Associated Trace Elements (Mn, Zn, Co, and Ni) in the Patients with Parkinson’s Disease

Abstract

Micronutrients and trace elements have been identified to play an important role in the development of Parkinson's disease (PD). In our previous study, we observed that prolidase activity is associated with oxidative stress and progression of PD. In present study, we aimed to study the association of prolidase-associated trace elements, such as Co, Mn, Ni, and Zn in the plasma of patients with PD by inductively coupled plasma spectrometry. Plasma levels of Co, Mn, and Ni were significantly increased, whereas plasma levels of Zn was significantly decreased (all P < 0.05) in the patients with PD than healthy controls. Plasma prolidase activity was not correlated to its associated trace elements in PD. A positive, linear, and significant correlation was observed between age and Co, and Mn, and Ni while negative and non-significant between age and status of Zn in the patients. Co, Mn, and Ni were continually elevated with increase in age as well as duration of disease in the patients with PD, whereas status of Zn was continually decreased. Thus, the study concluded that trace elements Co, Ni, and Mn status were increased and Zn status was decreased in the plasma of patients with PD. It is also concluded that elevated Co, Mn, and Ni has been associated with progression of Parkinson's disease.

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