Examination of the Safety of Pediatric Vaccine Schedules in a Non-Human Primate Model: Assessments of Neurodevelopment,Learning, and Social Behavior

Background

In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today.

Objectives

The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model.

Methods

We administered vaccines to six groups of infant male rhesus macaques (n = 12–16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles–mumps–rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate.

Results

We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors.

Conclusions

This comprehensive 5-year case–control study, which closely examined the effects of pediatric vaccines on early primate development, provided no consistent evidence of neurodevelopmental deficits or aberrant behavior in vaccinated animals.

Citation

Curtis B, Liberato N, Rulien M, Morrisroe K, Kenney C, Yutuc V, Ferrier C, Marti CN, Mandell D, Burbacher TM, Sackett GP, Hewitson L. 2015. Examination of the safety of pediatric vaccine schedules in a non-human primate model: assessments of neurodevelopment, learning, and social behavior. Environ Health Perspect 123:579–589; http://dx.doi.org/10.1289/ehp.1408257     

Antibody-mediated enhancement of respiratory syncytial virus infection in two monocyte/macrophage cell lines

Monoclonal antibodies (MAbs) specific for two surface glycoproteins of respiratory syncytial virus (RSV) were found to enhance RSV infection in two macrophagelike cell lines (P388D1 and THP-1). MAbs to an irrelevant antigen (pneumococcal polysaccharide) and to the nucleocapsid of RSV did not enhance infection. Blocking either the Fc segment of the monoclonal antibody of the Fc receptor on the cells diminished the enhancement, suggesting that this phenomenon involves attachment of the monoclonal antibody to the virus followed by attachment of the Fc of this complex to the Fc receptor on the cells. These data indicate that antibody-mediated enhancement of RSV infection can occur in vitro in macrophages. This enhancement may contribute to the pathogenesis of RSV bronchiolitis and the more severe RSV disease seen in recipients of formalin-inactivated RSV vaccine.     

Impact of multiple cardiovascular risk factors on femoral artery intima-media thickness in asymptomatic young adults (the Bogalusa Heart Study)

Femoral artery intima-media thickness (IMT), like carotid IMT, is a surrogate indicator of atherosclerotic coronary and peripheral vascular diseases in middle-aged and older adults. Although risk factors for coronary artery disease are also associated with increased IMT, especially as measured in carotid arteries, there is a paucity of information with respect to the femoral artery in this regard in the asymptomatic, younger adult population. This study examined the impact of multiple risk factors on the common femoral artery IMT as measured by B-mode ultrasonography in 1,080 black and white subjects aged 24 to 43 years (71% white and 43% men) enrolled in the Bogalusa Heart Study. Femoral IMT showed gender difference (men more than women, p = 0.001), but no racial difference. In a multivariate model, systolic blood pressure, age, male gender, cigarette smoking, and total cholesterol/high-density lipoprotein cholesterol ratios related independently, in that order, to IMT. Mean IMT increased with an increasing number of risk factors defined as values above the age-, race-, and gender-specific 75th percentile of systolic blood pressure, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, and insulin along with smoking status (p for trend = 0.003), with respective mean IMT values of 0.66, 0.69, 0.73, and 0.79 mm for 0, 1 to 2, 3, and 4 to 5 risk factors. The odds ratio for patients with >/=3 risk factors versus no risk factors having IMT in the top fifth percentile was 4.7 (p = 0.01). The observed adverse trend of increasing femoral IMT with an increasing number of risk factors in free-living, asymptomatic young subjects underscores the need for multiple risk factors profiling in early life. Further, ultrasonography of the femoral artery in conjunction with multiple risk factor profiling can be helpful in risk stratification.     

丙型肝炎病毒非结构蛋白5A反式激活基因8的克隆化研究

目的 丙型肝炎病毒(HCV)的非结构蛋白5A(NS5A)是一种具有显著反式激活作用的病毒蛋白质。为了探索HCV NS5A病毒蛋白反式激活作用的新的靶基因，我们应用抑制性消减杂交(SSH)技术对于转染和未转染的肝母细胞瘤细胞系HepG2进行分析。研究结果将有助于阐明HCV感染相关疾病的发病机制。方法 以HCV NSSA表达质粒peDNA3．1(-)-NSSA转染HepG2细胞，以空载体pcDNA3．1(-)为平行对照，提取mRNA并进行SSH分析。对于所获基因片段序列分析表明，其中之一为新型基因片段，与GenBank中注册的已知功能基因序列没有同源性，利用表达序列标签(EST)序列的搜索和比对，进行电子拼接。根据基因起始密码子的Kozak规则和终止密码子下游保守的多聚腺苷酸信号序列，确定新型基因序列。结果 结果从HepG2细胞提取总RNA，多聚酶链反应(RT-PCR)技术扩增获得该新基因的全长序列，测序证实，命名为NSSATP8在GenBank中注册，注册号为．AF529369.NSSATP8基因的编码序列全长为1449(nt)，编码产物由483个氨基酸残基(aa)组成。结论 HCV NS5A反式激活新型靶基因NSSATP8筛选与克隆，进一步研究HCV NS5A反式激活作用的分子生物学机制和探索新型治疗技术奠定基础。     

Giant cell (cranial) arteritis: a clinical review

Giant cell arteritis is a disease of the elderly which is more common than previously recognized. It is important to be aware of this condition because treatment effectively relieves symptoms and prevents serious complications. The disease is suggested when an elderly patient complains of constitutional symptoms, headache, jaw claudication, or the musculoskeletal manifestations of polymyalgia rheumatica. Abnormalities in temporal arteries or other cranial arteries, or evidence of large vessel involvement may be detected by physical examination. A markedly elevated sedimentation rate in association with other clinical features of the disease strongly suggests giant cell arteritis, but a biopsy should be performed to confirm the diagnosis. Corticosteroid therapy should be started promptly in high doses in order to prevent blindness. Prolonged treatment with lower dose corticosteroids is generally necessary for up to 1 to 2 years, and sometimes longer, for continued symptomatic relief. Long-term follow-up of treated patients has demonstrated no detectable effect on survivorship.     

Intramyocardial Injection of DNA Encoding Vascular Endothelial Growth Factor in a Myocardial Infarction Model

In a previous study, we observed that one injection of 500g of DNA for the plasmid encoding for vascular endothelial growth factor (ph VEGF₁₆₅) into one site in a rat myocardial infarction model resulted in neovascularization confined to angiomatous structures that did not contribute to regional myocardial blood flow. The purpose of the present study was to determine whether a lower dose (125g DNA), which is the same as that being used in some clinical trials, injected into four separate sites could enhance collateral flow and vascularity to the ischemic bed without inducing angiomas. Rats received injections of 125g DNA of the plasmid encoding phVEGF₁₆₅ or control DNA at four separate sites within the anterior free wall of the left ventricle (LV) supplied by the left coronary artery. The left coronary artery was ligated and hearts analyzed at 4 weeks. In vitro studies confirmed that the phVEGF₁₆₅ used was capable of producing VEGF polypeptide in mammalian cells. The infarct size (percentage of endocardial circumference that infarcted) was similar in controls (42±6%) and treated hearts (39±7%); the LV cavity area did not differ between groups. The number of vascular structures per high-power field within the infarct scar was 10.50±0.68 in controls and 10.00±0.85 in phVEGF₁₆₅-treated rats. Relative regional myocardial blood flow determined by radioactive microspheres and expressed as a ratio of radioactive counts within the scar divided by radioactive counts in the noninfarcted ventricular septum was similar in control (0.74±0.25) and treated hearts (0.88±0.30) (p=not significant). No angiomatous structures were observed. Injections of 125g of DNA of phVEGF₁₆₅ into myocardium to become ischemic had no effect on infarct size or LV cavity size. Unlike higher doses of 500g of DNA, it did not cause gross angiomatous structures; however, it failed to improve neovascularization or regional myocardial blood flow in this rodent model of acute myocardial infarction.     

Successful application of burst spinal cord stimulation for refractory upper limb pain: a case series

Spinal cord stimulation (SCS) has been used to treat sustained pain that is intractable despite various types of treatment. However, conventional tonic waveform SCS has not shown promising outcomes for spinal cord injury (SCI) or postamputation pain. The pain signal mechanisms of burst waveforms are different to those of conventional tonic waveforms, but few reports have presented the therapeutic potential of burst waveforms for the abovementioned indications. This current case report describes two patients with refractory upper limb pain after SCI and upper limb amputation that were treated with burst waveform SCS. While the patients could not obtain sufficient therapeutic effect with conventional tonic waveforms, the burst waveforms provided better pain reduction with less discomfort. However, further studies are necessary to better clarify the mechanisms and efficacy of burst waveform SCS in patients with intractable pain.     

Reducing False-Positive Biopsies using Deep Neural Networks that Utilize both Local and Global Image Context of Screening Mammograms

Journal of Digital Imaging - Breast cancer is the most common cancer in women, and hundreds of thousands of unnecessary biopsies are done around the world at a tremendous cost. It is crucial to...