Pros and Cons of APOE4 Homozygosity and Effects on Neuroplasticity, Malnutrition, and Infections in Early Life Adversity, Alzheimer's Disease, and Alzheimer's Prevention.

Fortea et al.'s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer's disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.

Alkylating agents are possible inducers of glioblastoma and other brain tumors.

Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.

Risk factors for glioblastoma are shared by other brain tumor types.

The reported risk factors for glioblastoma (GBM), i.e., ionizing radiation, Li-Fraumeni syndrome, Neurofibromatosis I, and Turcot syndrome, also increase the risk of other brain tumor types. Risk factors for human GBM are associated with different oncogenic mutation profiles. Pedigreed domestic dogs with a shorter nose and flatter face (brachycephalic dogs) display relatively high rates of glioma formation. The genetic profiles of canine gliomas are also idiosyncratic. The association of putatively different mutational patterns in humans and canines with GBM suggests that different oncogenic pathways can result in GBM formation. Strong epidemiological evidence for an association between exposure to chemical carcinogens and an increased risk for development of GBM is currently lacking. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Weak statistical associations between chemical exposures and GBM reported in epidemiology studies are biologically plausible. Molecular approaches comparing reproducible patterns seen in spontaneous GBM with analogous patterns found in GBMs resected from patients with known significant exposures to potentially carcinogenic chemicals can address difficulties presented by traditional exposure assessment.

Epidemiology studies on effects of lithium salts in pregnancy are confounded by the inability to control for other potentially teratogenic factors.

INTRODUCTION: In bipolar women who took lithium during pregnancy, several epidemiology studies have reported small increases in a rare fetal cardiac defect termed Ebstein's anomaly. METHODS: Behavioral, environmental, and lifestyle-associated risk factors associated with bipolar disorder and health insurance status were determined from an Internet search. The search was conducted from October 1, 2023, through October 14, 2023. The search terms employed included the following: bipolar, bipolar disorder, mood disorders, pregnancy, congenital heart defects, Ebstein's anomaly, diabetes, hypertension, Medicaid, Medicaid patients, alcohol use, cigarette smoking, marijuana, cocaine, methamphetamine, narcotics, nutrition, diet, obesity, body mass index, environment, environmental exposures, poverty, socioeconomic status, divorce, unemployment, and income. No quotes, special fields, truncations, etc., were used in the searches. No filters of any kind were used in the searches. RESULTS: Women who remain on lithium in the United States throughout their pregnancy are likely to be experiencing mania symptoms and/or suicidal ideation refractory to other drugs. Pregnant women administered the highest doses of lithium salts would be expected to have been insufficiently responsive to lower doses. Any small increases in the retrospectively determined risk of fetal cardiac anomalies in bipolar women taking lithium salts cannot be disentangled from potential developmental effects resulting from very high rates of cigarette smoking, poor diet, alcohol abuse, ingestion of illegal drugs like cocaine or opioids, marijuana smoking, obesity, and poverty. CONCLUSIONS: The small risks in fetal cardiac abnormalities reported in the epidemiology literature do not establish a causal association for lithium salts and Ebstein's anomaly.

Apolipoprotein ɛ4-Associated Protection Against Pediatric Enteric Infections Is a Survival Advantage in Pre-Industrial Populations.

Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) ɛ4/ɛ4 genotype, when the ɛ3 allele mutated from the ancestral ɛ4, which elevates the risk of Alzheimer's disease. Modern humans living today predominantly carry the ɛ3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral ɛ4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host's defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in ɛ4 carriers, yet ɛ4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the ɛ3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer's disease.

Categorizing the characteristics of human carcinogens: a need for specificity.

The International Agency for Research on Cancer (IARC) has recently proposed employing "ten key characteristics of human carcinogens" (TKCs) to determine the potential of agents for harmful effects. The TKCs seem likely to confuse the unsatisfactory correlation from testing regimes that have ignored the differences evident when cellular changes are compared in short and long-lived species, with their very different stem cell and somatic cell phylogenies. The proposed characteristics are so broad that their use will lead to an increase in the current unacceptably high rate of false positives. It could be an informative experiment to take well-established approved therapeutics with well-known human safety profiles and test them against this new TKC paradigm. Cancers are initiated and driven by heritable and transient changes in gene expression, expand clonally, and progress via additional associated acquired mutations and epigenetic alterations that provide cells with an evolutionary advantage. The genotoxicity testing protocols currently employed and required by regulation, emphasize testing for the mutational potential of the test agent. Two-year, chronic rodent cancer bioassays are intended to test for the entire spectrum of carcinogenic transformation. The use of cytotoxic doses causing increased, sustained cell proliferation that facilitates accumulated genetic damage leads to a high false-positive rate of tumor induction. Current cancer hazard assessment protocols and weight-of-the-evidence analysis of agent-specific cancer risk align poorly with the pathogenesis of human carcinoma and so need modernization and improvement in ways suggested here.

Bruce Nathan Ames - Paradigm shifts inside the cancer research revolution.

Dr. Bruce Ames turned 92 on December 16, 2020. He considers his most recent work linking adequate consumption of 30 known vitamins and minerals with successful aging to be his most important contribution. With the passage of time, it is not uncommon for the accomplishments of a well-known scientist to undergo a parsimonious reductionism in the public mind - Pasteur's vaccine, Mendel's peas, Pavlov's dogs, Ames' test. Those of us in the research generation subsequent to Dr. Ames' are undoubtedly affected by our own unconscious tendencies toward accepting the outstanding achievements of the past as commonplace. In doing so, seminal advances made by earlier investigators are often inadvertently subsumed into common knowledge. But having followed Ames' work since the mid-1970s, we are cognizant that the eponymous Ames Test is but a single chapter in a long and rich narrative. That narrative begins with Ames' classic studies on the histidine operon of Salmonella, for which he was elected to the National Academy of Sciences. A summary of the historical progression of the understanding of chemical carcinogenesis to which Ames and his colleagues contributed is provided. Any summary of a topic as expansive and complex as the ongoing unraveling of the mechanisms underlying chemical carcinogenesis will only touch upon some of the major conceptual advances to which Ames and his colleagues contributed. We hope that scientists of all ages familiar with Ames only through the eponymous Ames Test will further investigate the historical progression of the conceptualization of cancer caused by chemical exposure. As the field of chemical carcinogenesis gradually moves away from primary reliance on animal testing to alternative protocols under the rubric of New Approach Methodologies (NAM) an understanding of where we have been might help to guide where we should go.

Clinical epidemiology studies on potential effects of endocrine disrupting chemicals (EDCs) should exclude subjects with obesity as determined by BMI.

Obesity as determined by BMI is a confounder in clinical evaluations of the effects of endocrine disrupting chemicals (EDCs). Validated regulatory tests are used to determine whether a chemical acts via a mode of action (MOA) that affects estrogen, androgen, thyroid or steroidogenic pathways. Test batteries for evaluating EDCs include QSAR, in vitro assays, and animal testing. Studies suggest that EDCs pose the greatest risk during prenatal and early infant development when organ systems are developing. Health effects include lowered fertility, endometriosis, and cancers associated with estrogenic activity. Epidemiology studies on adverse effects of EDCs in the general population are difficult to conduct due to very low exposures of EDCs in non-occupational cohorts, and lack of exposure measurements between cases and controls. In contrast with very low levels of hormonal perturbation from nano-molar to micro-molar exposures to EDCs, adipose tissue in obesity alters estrogen, testosterone, thyroid stimulating hormone, and inflammation levels. Obesity in pregnancy and gestational diabetes are associated with adverse outcomes in infants and children including autism, poor motor skills, lowered IQ, and altered birth weight. Neonatal effects of obesity are confounded by average lower socio-economic status. The already perturbed endocrine balance in overweight or obese persons renders them particularly worthy subjects for clinical epidemiology investigations on the possible effects of endocrine disrupting chemicals. However, inclusion of subjects with obesity requires accounting for potentially confounding effects of the hormonal influences arising from excess adiposity. If subjects with obesity are to be included in clinical epidemiological evaluations related to hormonal effects, the subjects should be classified by body fat percentage rather than by the much less exact measure of body mass index (BMI).

Obesity as a Source of Endogenous Compounds Associated With Chronic Disease: A Review.

In 2014, it was estimated that more than 1.9 billion adults were overweight with over 600 million classifiable as obese. Approximately two-thirds of U.S. adults over 20 years of age are currently overweight with about 35% classified as obese, a figure thought likely to reach 42% by 2030 in those over 18 years of age. Adipose cells from stored body fat secrete estrogen and a very large number (> 500) of biologically active substances termed adipokines, in addition to inducing, by other cell-driven effects, pathological alterations in insulin pathways. The U.S. National Cancer Institute reports that exposure to the hormone disrupting and proinflammatory effects of excess adipose tissue are associated with an increased risk for 11 different cancers. Obesity is also associated with a number of serious non-neoplastic conditions including metabolic syndrome and type 2 diabetes; menstrual cycle irregularities and lowered fertility (men and women); and abnormal bone morphology in a subset of female patients. In men hypogonadism, low testosterone levels, benign prostatic hyperplasia, and lowered sperm counts have been reported. In developed countries, the endogenous adverse health burden associated with obesity is only matched, quantitatively and qualitatively, by the exogenous toxicity of cigarette smoking. The investigation of possible hormonal and/or proinflammatory effects of chemicals should include an assessment of the profound endocrine alterations associated with obesity.

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress.

Inheritance of a single copy of the apolipoprotein E (APOE) ɛ4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ3 allele homozygosity. There is a decreased risk associated with the APOE ɛ2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ɛ4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ3 allele. However, possession of the ɛ4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion.

Two Obese Patients with Presumptive Diagnosis of Anaphylactoid Syndrome of Pregnancy Presenting at a Community Hospital.

BACKGROUND: Anaphylactoid syndrome of pregnancy (ASP) is a rare but extremely serious complication, with an estimated incidence in North America of 1 in 15 200 deliveries. Despite its rarity, ASP is responsible for approximately 10% of all childbirth-associated deaths in the United States. At present, there is no validated biomarker or specific set of risk factors sufficiently predictive of ASP risk to incorporate into clinical practice. Toward the goal of developing a methodology predictive of an impending ASP event for use by obstetricians, anesthesiologists, and other practitioners participating in infant deliveries, physicians encountering an ASP event have been encouraged to report the occurrence of a case and its biologically plausible risk factors. CASE REPORT: Herein, we report on 2 patients who presented with a presumptive diagnosis of ASP to the delivery unit of a community hospital. Patient One was a 21-year-old, obese (5'11" tall, 250 lbs., BMI 34.9) white female, 1 pregnancy, no live births (G1P0), estimated gestational age (EGA) 40.2 weeks. Patient Two was a 29-year-old, obese (5'7" tall, 307 lbs., BMI 48.1) Hispanic female, second pregnancy, with 1 previous live birth via C-section (G2P1-0-0-1). Her pregnancy was at gestational age 38 weeks plus 2 days. CONCLUSIONS: Patient One had 2 possible risk factors: administration of Pitocin to induce labor and post-coital spotting from recent intercourse. Patient Two suffered premature rupture of the placental membranes. Both Patient One and Patient Two had very high body mass indices (BMIs), at the 97th and 99th percentiles, respectively. In the relatively few cases of anaphylactoid syndrome of pregnancy described to date, this is the first report of a possible association with high BMI.

Predicting the bioconcentration factor of highly hydrophobic organic chemicals.

Bioconcentration refers to the process of uptake and buildup of chemicals in living organisms. Experimental measurement of bioconcentration factor (BCF) is time-consuming and expensive, and is not feasible for a large number of chemicals of regulatory concern. Quantitative structure-activity relationship (QSAR) models are used for estimating BCF values to help in risk assessment of a chemical. This paper presents the results of a QSAR study conducted to address an important problem encountered in the prediction of the BCF of highly hydrophobic chemicals. A new QSAR model is derived using a dataset of diverse organic chemicals previously tested in a United States Environmental Protection Agency laboratory. It is noted that the linear relationship between the BCF and hydrophobic parameter, i.e., calculated octanol-water partition coefficient (ClogP), breaks down for highly hydrophobic chemicals. The parabolic QSAR equation, log BCF=3.036 ClogP-0.197 ClogP(2)-0.808 MgVol (n=28, r(2)=0.817, q(2)=0.761, s=0.558) (experimental log BCF range=0.44-5.29, ClogP range=3.16-11.27), suggests that a non-linear relationship between BCF and the hydrophobic parameter, along with inclusion of additional molecular size, weight and/or volume parameters, should be considered while developing a QSAR model for more reliable prediction of the BCF of highly hydrophobic chemicals.

Poly-N-acetylglucosamine fibers amplify the effectiveness of recombinant factor VIIA on clot formation in hemophilia B canine blood.

BACKGROUND: Achieving hemostasis in anticoagulated patients is an increasingly important clinical issue. Poly-N-acetylglucosamine (pGlcNAc) nanofibers activate platelets by ß3 subunit (CD61) and the von Willebrand receptor GP1b (CD42b) integrin signaling for generation of a prothrombotic surface membrane. Recombinant coagulation factor VIIa (rFVIIa) functions in hemophilia A and B by catalyzing formation of the Xa/Va complex on the surface of activated platelets. These observations suggest that pGlcNAc nanofibers may amplify the activity of rFVIIa in hemophilic blood. METHODS: The activity of rFVIIa on platelets was tested by performing thromboelastographic analysis with blood from hemophilia B dogs in the presence of pGlcNAc nanofibers and increasing concentrations of rFVIIa. Mechanisms for hemostatic system activation were investigated with inhibitors of tissue factor, factor XIIa, and platelet function. RESULTS: Recombinant FVIIa was observed to partially restore the ability of the hemophiliac blood to form fibrin clots in a dose-dependent manner with thromboelastographic analysis. The addition of pGlcNAc nanofibers amplified the rFVIIa effect. The activity of rFVIIa and the amplification effect of pGlcNAc were dependent on platelet integrin function but independent of FXIIa and tissue factor activities. CONCLUSIONS: The pGlcNAc nanofibers amplify rFVIIa activity in hemophilia B canine blood by activating platelets through integrin-dependent mechanisms.