Environmental factors may contribute to autism development and male bias: Effects of fragrances on developing neurons.

BACKGROUND: Autism spectrum disorders (ASDs) are developmental conditions characterized by deficits in social interaction, impairments in verbal and nonverbal communication, and stereotyped patterns of behavior. Previous studies have implicated environmental factors in the development of ASD. Although no reliable neurophysiological network is associated with ASD, low levels of plasma oxytocin (OXY) and arginine vasopressin (AVP) have been reported. The "twin" nonapeptides OXY and AVP are mainly produced in the brain of mammals, and dysregulation of these neuropeptides has been associated with changes in behavior, especially social interactions. METHODS: Previously, we analyzed 91 commonly used fragrances and reported significant mutagenic, neurocytotoxic, and stimulatory effects on fetal neuroblastoma cell lines (NBC). In this study, we analyzed the neuromodifications of three selected fragrances on male and female human fetal brain neurons, utilizing immunohistochemistry. RESULTS: We show that exposure to femtomolar concentrations of fragrances results in morphological changes by light microscopy in the NBC. Importantly, these fragrances significantly reduced the OXY- and AVP-receptor positive (OXYR+ and AVPR+) neurons in male NBC but not in female NBC, possibly contributing to the development of male bias in ASD. CONCLUSION: This study is the first to show a potential link between fragrance exposure, depletion of OXYR+ and AVPR+ neurons, and a male bias in autism.

Differential zinc accumulation and expression of human zinc transporter 1 (hZIP1) in prostate glands.

Zinc (Zn) is essential for a very large number and variety of cellular functions but is also potentially toxic. Zn homeostasis is therefore dynamically maintained by a variety of transporters and other proteins distributed in distinct cellular and subcellular compartments. Zn transport is mediated by two major protein families: the Zip family, which mediates Zn influx, and the ZnTs which are primarily linked to Zn sequestration into intracellular compartments and are, thereby, involved in lowering cytoplasmic Zn free ion concentrations. In the prostate epithelial cell, the accumulation of high cellular zinc is a specialized function that is necessary for these cells to carry out the major physiological functions of production and secretion of prostatic fluids. The loss of Zn accumulation is the most consistent and persistent characteristic of prostate malignancy. Currently, there are no direct methods to determine the relative Zn levels in various cell types of prostate gland (i.e. stroma, glandular epithelia, acini, and muscular) and no reliable ways to compare the Zn in normal versus malignant areas of the gland. Here we report a new method to show a differential Zn staining method that correlates with various stages of prostate cancer development in situ and expression of a human Zn transporter1-hZIP1 -in situ by in situ reverse transcriptase-polymerase chain reaction hybridization (ISRTPCR) that correlate with the relative Zn levels determined by the differential Zn staining method. By utilizing these methods, we show for the first time that: (1) the relative Zn levels are very low to absent in the malignant glands, (2) normal glands show high Zn levels in both glandular epithelia as well as in stromal tissues, (3) the Zn levels begin to decrease in pre-malignant glands and precedes the development of malignancy, and (4) the expression of human Zn transporter1 (hZIP1) appears to correlate with the Zn levels in the prostate glands and may be the major Zn regulator in this organ.

Unusual fentanyl patch administration.

Fentanyl is an extremely potent narcotic analgesic that is becoming more popular as a drug of abuse. Because of the unique way in which the drug is packaged and delivered, the potential for unusual methods of abuse exists. We report the first case of true fentanyl patch ingestion in the medical literature. Initially, though unusual, cases of fentanyl ingestion were thought to have been reported, but further investigation of the literature revealed that in other case reports the patches had been held in the mouth and chewed. Because no reports of swallowing the patch had been published, suicide was initially a strong consideration in this case; however, further investigation showed that the decedent and his brother enjoyed swallowing the patches for quick "highs." Cases such as these serve to remind medical examiners and law enforcement officials of the value of performing thorough death investigations by performing complete autopsies with toxicological testing and correlating with investigation information to form an opinion with regard to the cause and manner of death.

Fibromuscular dysplasia in association with intrauterine cocaine exposure.

BACKGROUND: Fibromuscular dysplasia (FMD) is an idiopathic disease of small- and medium-sized arteries, involving one or more vascular beds. Patients may present with a range of symptoms, which may not readily lead to a diagnosis of FMD. While maternal cocaine abuse during pregnancy has previously been associated with vascular alterations in the fetus, an association specifically with FMD has not previously been described. METHODS/RESULTS: In this case report, a 21-month-old male presented with a 3-week history of daily vomiting, with temporary improvement of symptoms, then relapse followed by loss of consciousness. His medical history was significant only for maternal cocaine use. Clinical evaluation revealed dilated cardiomyopathy, and a presumptive diagnosis of myocarditis was rendered. Respiratory arrest and death occurred 2 days after admission. Postmortem examination demonstrated intimal-type multivessel FMD, which was determined to be the cause of the clinical presentation. CONCLUSION: Without a postmortem examination, it is unlikely that a diagnosis of intimal fibroplasia, a rare variant of FMD (5% of cases), would have been made. This case thus illustrates the continuing utility of the classic postmortem examination. More intriguingly, the case suggests a possible relationship between in utero cocaine exposure and the development of fibromuscular dysplasia in the child.

Role of zinc and zinc transporters in the molecular pathogenesis of diabetes mellitus.

Diabetes is one of the most common chronic diseases in the United States. An estimated 18.2 million people in the US (6.3%) have diabetes; among them 2.8 million are African Americans (AAs). On average, AAs are twice as likely to have diabetes as European Americans (EAs) of similar age. AAs disproportionately suffer from various diseases in the US. Many of these diseases include hypertension, cardiovascular disease (CVD), diabetes mellitus (DM-beta predominantly Type II), and cancers of the prostate and pancreas. A number of risk factors such as smoking, a high fat diet, little physical activity, stress, and meager access to health care have been the subject of numerous investigations. However, the factor of the interaction between genetics and the environment has received very little attention in the scientific community. Of note, the content of zinc in pancreatic beta gells is among the highest in the body; however, very little is known about the uptake and storage of zinc inside these cells. We hypothesize that one of the major reason AAs disproportionally suffer from DM (as well as some other illnesses like prostate cancer, CVD and hypertension) is due to their inherent inability to transport appropriate amount of zinc in the crucial cell types that require relatively higher amount of zinc than the other cell types. In this article, we will explore in detail the possible genetic and environmental link between human zinc transporters (hZIPs) and their differential expressions in the islet beta cells from AAs as compared to other racial groups, particularly EAs, in both normal healthy individuals and diabetic patients. We hypothesize that the hZIPs play an important role in the development of diabetes, and the main reason AAs disproportionately suffer from DM (as well as other illnesses like prostate and pancreatic cancers, hypertension, and CVD) as compared to EAs may be due the low degree of expressions of the critical zinc transporters in the beta cells. Understanding the molecular events in the pathogenesis of DM with regards to regulation of zinc uptake would be critical to the evaluation of the natural history of diabetes in humans and especially in various racial groups. If a direct link between zinc transport and diabetes can be established, then a special nutritional formula, medication or other intervention might be especially designed to test the ability to decrease the incidence of this disease in DM susceptible groups, particularly in AAs.

Prostate cancer in African American men is associated with downregulation of zinc transporters.

In the United States, prostate cancer is the most commonly diagnosed male cancer and the second leading cause of all male cancer deaths. Furthermore, incidence rates are higher in African Americans than in any other racial group. Our laboratory is attempting to decipher the environmental and molecular mechanisms involved in the development of prostate cancer in African Americans. Because Africa is a mineral-rich continent, and the zinc levels in the water and diet are high, it is hypothesized that Africans may have genetically downregulated their zinc absorption capacity; otherwise, they would absorb abnormally high levels of zinc, resulting in various serious neurodegenerative and biochemical disorders. It is therefore possible that people of African origin may have a lower capacity to absorb zinc when compared with other racial groups because of their inherent downregulation of zinc transporters. Extensive research has shown that low serum levels of zinc are associated with the increased incidence of prostate cancer. We have evaluated 58 prostate cancer tissues in 2 major racial groups (30 from whites and 28 from African Americans) for their ability to express 2 major human zinc transporters, hZIP1 and hZIP2. In all 30 prostate cancer specimens obtained from white people, the degree of expression of these 2 zinc receptors was high when compared with age-matched and Gleason score-matched specimens obtained from African American patients. We also found a significant downregulation of these 2 zinc transporters in normal prostate tissues from African American men when compared with age-matched white men. The loss of the unique ability to retain normal intracellular levels of zinc may be an important factor in the development and progression of prostate cancer. Our observation that the uptake of zinc may be different in racial groups is intriguing and relevant. Once these data are confirmed in larger groups, this finding could have significant application as a preventive maneuver for at least for some people. Because dietary zinc supplements are relatively nontoxic, any efficacy trial would be low-risk.

Blood and tissue concentration of cesium after exposure to cesium chloride: a report of two cases.

CONTEXT: Complementary alternative medicine therapies based on the use of cesium chloride preparations for the treatment of cancer and radiation poisoning, have generated therapeutic interest; but oral or intravenous administration of cesium chloride (CsCl) to cancer patients as an alternative mode of cancer therapy have not been approved by the US Food and Drug Administration (FDA). OBJECTIVE: Cesium (Cs) levels from human tissue were measured to determine exposure to an alternative medical treatment. Cesium levels are reported from two patients who were administered cesium chloride in conjunction with aloe vera as part of an alternative cancer treatment. DESIGN: The samples were analyzed by graphite furnace atomic absorption spectrometry with Zeeman background correction. As a reference, Cs was also determined in brain, liver, kidney, and whole blood from control case materials retrieved from the National Tissue Repository of the Armed Forces Institute of Pathology. RESULTS: High levels of cesium were found in brain, liver, kidney, bile, gastric content, and whole blood collected at autopsy as compared to reference levels. The administration of cesium chloride resulted in blood levels a factor of 1100 higher than normal. The highest Cs concentrations were found in the liver (1029 microg/g, dry wt), followed by the kidney (815 microg/g, dry wt) and brain (219 microg/g, dry wt). CONCLUSION: The high accumulation in the liver suggests that hepatotoxicity from Cs might be an initial presenting symptom in Cs-poisoning cases. This is the first report describing two cases with high Cs levels in human tissues.

Role of HERV-W syncytin-1 in placentation and maintenance of human pregnancy.

Over half of human genome contains retroelements, including retrotransposons, retroviruses, and other elements. Human endogenous retroviruses (HERVs) comprise about 8% of human genome. The products of 2 of 16 identified genes of HERV-W seem to play a pivotal role in the placentation. These 2 genes are HERV-W env glycoprotein (syncytin-1) and HERV-FRD env glycoprotein (syncytin-2). It has been shown previously that syncytin-1 mediates cell-cell fusions of cytotrophoblasts into syncytiotrophoblasts. In addition, HERV-W env contains an immunosuppressive region that may prevent rejection of a semiallogenic fetus from the mother's immune system. We analyzed 40 full-term placental tissues to localize the expression of syncytin-1-ISR by immunohistochemical staining and by reverse trancscriptase (RT) in situ polymerase chain reaction (PCR). Both the immunostaining and in situ RT-PCR showed strong expression of syncytin-1 in the syncytiotrophoblast layer from the full-term placental tissues. To further analyze the mechanism of early embryo HERV-W env activation, we utilized a HTR-8/SVneo cell line developed from first trimester human trophoblasts and subjected them to various physiologic concentrations of maternal hormones. Quantitative RT-PCR analyses demonstrated that exposure to progesterone significantly upregulated the HERV-W env expression, whereas several other hormones apparently played lesser roles. In conclusion, our findings suggest that expression of syncytin-1 (HERV-W env) in utero is expressed exclusively in the syncytiotrophoblast layer and is upregulated by progesterone.

Sudden death during arrest and phencyclidine intoxication.

Deaths of individuals being arrested are important and complex medicolegal cases. Conclusions regarding the cause and manner of death for such cases must take into account multiple factors that may have played a role, as well as anticipate the forensic issues that will arise. In this article, we review the deaths of 2 individuals in which phencyclidine intoxication was a factor that contributed to death during arrest. Most cases of sudden death during arrest have involved cocaine intoxication; because phencyclidine's pharmacologic properties are quite different from those of cocaine, these cases allow for comparisons to those factors that may have greater importance.