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PURPOSE OF REVIEW: In this review, we provide essential background knowledge and an analytical framework for the application of placental-fetal molecular biomarkers in fetal origins chronic disease epidemiology. The widely available and highly quantitative placental hormone human chorionic gonadotropin (hCG) is used as an example. hCG is currently used for diagnosing fetal genetic disorders; yet it can and should be expanded to understanding the fetal origins of chronic diseases. We provide justification and methods to do this. RECENT FINDINGS: Ten papers published in the last 5 years were identified with supportive findings relevant to the application of biomarkers of hCG in epidemiologic studies on the developmental origins of health and disease (DOHaD). SUMMARY: There is increasing and consistent evidence that placental-fetal biomarkers may be highly informative in observational studies, as exemplified by hCG, with the correct approaches for measurement and data analysis.

Nonlinear regression models are commonly used in toxicology and pharmacology. When fitting nonlinear models for such data, one needs to pay attention to error variance structure in the model and the presence of possible outliers or influential observations. In this paper, an M-estimation based procedure is considered in heteroscedastic nonlinear regression models where the standard deviation is modeled by a nonlinear function. The methodology is illustrated using toxicological data.

This article reports the results of an anonymous survey of researchers at a government research institution concerning their perceptions about ethical problems with journal peer review. Incompetent review was the most common ethical problem reported by the respondents, with 61.8% (SE = 3.3%) claiming to have experienced this at some point during peer review. Bias (50.5%, SE = 3.4%) was the next most common problem. About 22.7% (SE = 2.8%) of respondents said that a reviewer had required them to include unnecessary references to his/her publication(s), 17.7% (SE = 2.6%) said that comments from reviewers had included personal attacks, and 9.6% (SE = 2.0%) stated that reviewers had delayed publication to publish a paper on the same topic. Two of the most serious violations of peer review ethics, breach of confidentiality (6.8%, SE = 1.7%) and using ideas, data, or methods without permission (5%, SE = 1.5%) were perceived less often than the other problems. We recommend that other investigators follow up on our exploratory research with additional studies on the ethics of peer review.

Background Nonmotor symptoms are common among patients with Parkinson’s disease (PD) and some may precede disease diagnosis. Methods We conducted a meta-analysis on the prevalence of selected nonmotor symptoms before and after PD diagnosis, using random-effect models. We searched PubMed (1965 through October/November 2012) for the following symptoms: hyposmia, constipation, rapid eye movement sleep behavior disorder, excessive daytime sleepiness, depression, and anxiety. Eligible studies were publications in English with original data on one or more of these symptoms. Results The search generated 2,373 non-duplicated publications and 332 met the inclusion criteria, mostly (n = 320) on symptoms after PD diagnosis. For all symptoms, the prevalence was substantially higher in PD cases than in controls, each affecting over a third of the patients. Hyposmia was the most prevalent (75.5% in cases vs. 19.1% in controls), followed by constipation (50% vs. 17.7%), anxiety (39.9% vs. 19.1%), rapid eye movement sleep behavior disorder (37.0% vs. 7.0%), depression (36.6% vs. 14.9%), and excessive daytime sleepiness (33.9% vs. 10.5%). We observed substantial heterogeneities across studies and meta-regression analyses suggested that several factors might have contributed to this. However, the prevalence estimates were fairly robust in several sensitivity analyses. Only 20 studies had data on any symptoms prior to PD diagnosis, but still the analyses revealed higher prevalence in future PD cases than in controls. Conclusion These symptoms are common among PD patients both before and after diagnosis. Further studies are needed to understand the natural history of nonmotor symptoms in PD and their etiological and clinical implications. Electronic supplementary material The online version of this article (doi:10.1186/2047-9158-4-1) contains supplementary material, which is available to authorized users.

Sulfur mustard (SM) is powerful alkylator and highly cytotoxic blisterogen in both humans and animals. This study in male guinea pigs shows that, at an early stage (5 h) after SM exposure, a marked increase occurred in epithelial nuclear vacuolation, epidermal thickening, and dermal acute inflammation. Topical iodine treatment reduced the severity of these parameters. The rate of DNA synthesis expressed by incorporation of bromodeoxyuridine was reduced upon topical treatment with iodine only or SM only by 46 and 72%, respectively. Iodine treatment following SM exposure exerted an effect similar to that of SM only, indicating that DNA synthesis is not directly involved in the mechanism of action of iodine-induced protection.

Bone injury occurs in human hemolytic disorders associated with thrombosis, such as beta-thalassemia and sickle cell disease. Exposure of rats to 2-butoxyethanol (BE) has been associated with hemolytic anemia, disseminated thrombosis, and infarction in multiple organs including bone. This rat model apparently mimics acute hemolysis and thrombosis in humans. To elucidate the extent of bone injury, male and female Fischer F344 rats were given 4 daily doses of 250 mg BE/5 ml water/kg of body weight. Tail vertebrae were studied by histopathology and magnetic resonance imaging (MRI). Thrombosis and infarction were seen in both sexes, but females were more severely affected. Lesions were characterized by extensive medullary fat necrosis, granulomatous inflammation, fibroplasia, growth plate degeneration, and new woven bone formation adjacent to necrotic bone trabeculae. MRI mean and standard deviation tissue-density data for both sexes indicated a significant (Por = 0.05) decrease following 4-days treatment and a significant increase (Por = 0.05) following an additional 24 days without treatment. Thus, MRI was useful in revealing BE-induced bone injury, which was predominantly necrotic initially and subsequently regenerative with proliferation of connective tissue and bone following postischemia recovery.

2,4-Hexadienal (2,4-Hx) was studied for its toxicity and carcinogenicity because of its alpha, beta-unsaturated aldehyde structure and potential link between exposure to lipid peroxidation products in the diet and human malignancies. Male and female F344N rats and B6C3F1 mice received 2,4-Hx in corn oil by gavage for 16 days, 14 weeks, or 2 years. In the 16-day studies 2,4-Hx induced forestomach necrosis and ulceration at 240 mg/kg and forestomach epithelial hyperplasia at 80 mg/kg in rats and mice. In the 14-week studies the chemical induced forestomach hyperplasia and nasal olfactory atrophy or necrosis at 120 mg/kg in rats and mice. In the 2-year studies 2,4-Hx induced squamous cell papilloma and carcinoma of the forestomach in male and female rats at 45 and 90 mg/kg and in male and female mice at 120 mg/kg. Two male mice in the 120 mg/kg group had uncommon squamous cell carcinoma of the oral cavity (tongue). Mechanistic studies indicated that the forestomach carcinogenesis in rats and mice may be due to depletion of glutathione as a result of oxidative stress induced by 2,4-Hx.

Background Recent circadian clock studies using gene expression microarray in two different tissues of mouse have revealed not all circadian-related genes are synchronized in phase or peak expression times across tissues in vivo. Instead, some circadian-related genes may be delayed by 4–8 hrs in peak expression in one tissue relative to the other. These interesting biological observations prompt a statistical question regarding how to distinguish the synchronized genes from genes that are systematically lagged in phase/peak expression time across two tissues. Results We propose a set of techniques from circular statistics to analyze phase angles of circadian-related genes in two tissues. We first estimate the phases of a cycling gene separately in each tissue, which are then used to estimate the paired angular difference of the phase angles of the gene in the two tissues. These differences are modeled as a mixture of two von Mises distributions which enables us to cluster genes into two groups; one group having synchronized transcripts with the same phase in the two tissues, the other containing transcripts with a discrepancy in phase between the two tissues. For each cluster of genes we assess the association of phases across the tissue types using circular-circular regression. We also develop a bootstrap methodology based on a circular-circular regression model to evaluate the improvement in fit provided by allowing two components versus a one-component von-Mises model. Conclusion We applied our proposed methodologies to the circadian-related genes common to heart and liver tissues in Storch et al. [2], and found that an estimated 80% of circadian-related transcripts common to heart and liver tissues were synchronized in phase, and the other 20% of transcripts were lagged about 8 hours in liver relative to heart. The bootstrap p-value for being one cluster is 0.063, which suggests the possibility of two clusters. Our methodologies can be extended to analyze peak expression times of circadian-related genes across more than two tissues, for example, kidney, heart, liver, and the suprachiasmatic nuclei (SCN) of the hypothalamus.