Search

The peak of the coronavirus-19 (COVID-19) in New York City significantly impacted communities that lived in the New York City Housing Authority (NYCHA). However, these same communities have been historically reported to test positive for lead poisoning due to neglect of proper lead abatement and the removal of lead sources within these buildings. The consequences of these failed actions by NYCHA resulted in multiple generations of lead-poisoned children, which can be argued as a form of mass atrocity and genocide. The long-term neurodevelopmental and socio-economic outcomes of children exposed to lead and COVID-19 remain to be elucidated. This short communication attempts to bring attention to this overlooked matter and draws upon the scarce, but emerging, reports in the literature to start a conversation on the synergistic potential of these looming public health issues. Further, suggestions for providing consistent blood lead screening and COVID-19 testing could serve to clarify whether a “two-hit” hypothesis of a neurotoxicant (lead) and a neuroimmune (COVID-19) virus that produces an Adverse Childhood Experience (ACE-19). More work is needed in this area to (dis)confirm the potential for this “two-hit” hypothesis, and only time will tell.

The peak of the coronavirus-19 (COVID-19) in New York City significantly impacted communities that lived in the New York City Housing Authority (NYCHA). However, these same communities have been historically reported to test positive for lead poisoning due to neglect of proper lead abatement and the removal of lead sources within these buildings. The consequences of these failed actions by NYCHA resulted in multiple generations of lead-poisoned children, which can be argued as a form of mass atrocity and genocide. The long-term neurodevelopmental and socio-economic outcomes of children exposed to lead and COVID-19 remain to be elucidated. This short communication attempts to bring attention to this overlooked matter and draws upon the scarce, but emerging, reports in the literature to start a conversation on the synergistic potential of these looming public health issues. Further, suggestions for providing consistent blood lead screening and COVID-19 testing could serve to clarify whether a "two-hit" hypothesis of a neurotoxicant (lead) and a neuroimmune (COVID-19) virus that produces an Adverse Childhood Experience (ACE-19). More work is needed in this area to (dis)confirm the potential for this "two-hit" hypothesis, and only time will tell. [ABSTRACT FROM AUTHOR]

Abstract Purpose To report a case of central retinal vein occlusion (CRVO) seven days following the first dose of ChAdOx1 nCoV-19 vaccine and propose a hypothesis for the possible underlying pathogenesis. Observation A 31-year-old male presented with CRVO with cystoid macular edema, one week after receiving his first ChAdOx1 nCoV-19 vaccine dose. Apart from mild hyperhomocysteinemia, no major thrombophilic or systemic risk factors were found. Anti-platelet factor 4 antibodies, specific for vaccine-induced immune thrombotic thrombocytopenia, were also negative. However, he tested strongly positive (> 250 U/mL) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG spike antibodies, 2 weeks post the first dose – suggestive of a prior subclinical infection. Conclusion COVID-19 is known to be associated with an altered host one-carbon metabolism resulting in hyperhomocysteinemia. We hypothesize that a prior subclinical infection with COVID-19, the first hit, may have led to hyperhomocysteinemia in our patient and vaccination must have been the second hit that triggered the thrombotic event. Further studies, including correlation of thrombotic complications with IgG antibody titres post-vaccination, are essential in order to better understand the pathogenesis of such events.

Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown etiology. MMD is characterized by progressive narrowing of arteries of the brain and the formation of a compensatory network of fragile vessels. Genetic studies have identified RNF213 , also known as mysterin , as a susceptibility gene for MMD, but the low penetrance in genetically susceptible individuals suggests that a second hit is necessary to trigger disease onset. Recently, several molecular studies uncovered RNF213 as a key antimicrobial protein with important functions in the immune system. In addition, an increasing number of clinical reports describe the development of moyamoya angiopathy (MMA) associated with infection or autoimmune disorders. Together, this growing body of molecular and clinical evidence points towards immune-related responses as second hits to trigger MMD onset. Moyamoya disease (MMD) is a rare cerebrovascular disorder that develops in genetically predisposed individuals after triggering by an unknown second hit. An increasing number of reports describes the development of moyamoya angiopathy associated with infection or autoimmune disorders. RNF213, encoded by RNF213 , so far the only strongly established MMD susceptibility gene, was recently discovered as a key antimicrobial protein and important immune effector. This growing body of clinical and molecular evidence strengthens the argument for infection and immune-related responses as second hits to trigger MMD onset. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of central retinal vein occlusion (CRVO) seven days following the first dose of ChAdOx1 nCoV-19 vaccine and propose a hypothesis for the possible underlying pathogenesis. Observation: A 31-year-old male presented with CRVO with cystoid macular edema, one week after receiving his first ChAdOx1 nCoV-19 vaccine dose. Apart from mild hyperhomocysteinemia, no major thrombophilic or systemic risk factors were found. Anti-platelet factor 4 antibodies, specific for vaccine-induced immune thrombotic thrombocytopenia, were also negative. However, he tested strongly positive (> 250 U/mL) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG spike antibodies, 2 weeks post the first dose – suggestive of a prior subclinical infection. Conclusion: COVID-19 is known to be associated with an altered host one-carbon metabolism resulting in hyperhomocysteinemia. We hypothesize that a prior subclinical infection with COVID-19, the first hit, may have led to hyperhomocysteinemia in our patient and vaccination must have been the second hit that triggered the thrombotic event. Further studies, including correlation of thrombotic complications with IgG antibody titres post-vaccination, are essential in order to better understand the pathogenesis of such events. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that a suboptimal intrauterine environment confers risk for schizophrenia. The developmental model of schizophrenia posits that aberrant brain growth during early brain development and adolescence may interact to contribute to this psychiatric disease in adulthood. Although a variety of factors may perturb the environment of the developing fetus and predispose for schizophrenia later, a common mechanism has yet to be elucidated. Micronutrient deficiencies during the perinatal period are known to induce potent effects on brain development by altering neurodevelopmental processes. Iron is an important candidate nutrient to consider because of its role in energy metabolism, monoamine synthesis, synaptogenesis, myelination, and the high prevalence of iron deficiency (ID) in the mother-infant dyad. Understanding the current state of science regarding perinatal ID as an early risk factor for schizophrenia is imperative to inform empirical work investigating the etiology of schizophrenia and develop prevention and intervention programs. In this narrative review, we focus on perinatal ID as a common mechanism underlying the fetal programming of schizophrenia. First, we review the neural aberrations associated with perinatal ID that indicate risk for schizophrenia in adulthood, including disruptions in dopaminergic neurotransmission, hippocampal-dependent learning and memory, and sensorimotor gating. Second, we review the pathophysiology of perinatal ID as a function of maternal ID during pregnancy and use epidemiological and cohort studies to link perinatal ID with risk of schizophrenia. Finally, we review potential confounding phenotypes, including nonanemic causes of perinatal brain ID and future risk of schizophrenia. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls are ubiquitous environmental contaminants linkedc with peripheral immune and neural dysfunction. Neuroimmune signaling is critical to brain development and later health; however, effects of PCBs on neuroimmune processes are largely undescribed. This study extends our previous work in neonatal or adolescent rats by investigating longer-term effects of perinatal PCB exposure on later neuroimmune responses to an inflammatory challenge in adulthood. Male and female Sprague-Dawley rats were exposed to a low-dose, environmentally relevant, mixture of PCBs (Aroclors 1242, 1248, and 1254, 1:1:1, 20 μg / kg dam BW per gestational day) or oil control during gestation and via lactation. Upon reaching adulthood, rats were given a mild inflammatory challenge with lipopolysaccharide (LPS, 50 μg / kg BW, ip) or saline control and then euthanized 3 hours later for gene expression analysis or 24 hours later for immunohistochemical labeling of Iba1+ microglia. PCB exposure did not alter gene expression or microglial morphology independently, but instead interacted with the LPS challenge in brain region- and sex-specific ways. In the female hypothalamus, PCB exposure blunted LPS responses of neuroimmune and neuromodulatory genes without changing microglial morphology. In the female prefrontal cortex, PCBs shifted Iba1+ cells from reactive to hyperramified morphology in response to LPS. Conversely, in the male hypothalamus, PCBs shifted cell phenotypes from hyperramified to reactive morphologies in response to LPS. The results highlight the potential for long-lasting effects of environmental contaminants that are differentially revealed over a lifetime, sometimes only after a secondary challenge. These neuroimmune endpoints are possible mechanisms for PCB effects on a range of neural dysfunction in adulthood, including mental health and neurodegenerative disorders. The findings suggest possible interactions with other environmental challenges that also influence neuroimmune systems., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Margaret Bell reports financial support was provided by National Institute of Environmental Health Sciences. Andrea Gore reports financial support was provided by National Institute of Environmental Health Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract Background According to experimental and clinical published studies, patients with keratoconus have a genetic predisposition to corneal ectasia; however, ectasia might not be activated or reactivated unless an additional stressful event triggers the disease. Triggering factors are sources of reactive oxidative stress; among them, mechanical trauma (vigorous eye rubbing, poorly fit contact lenses), exposure to ultraviolet light, and atopy/allergies. The aim of this case report is to present for the first time a case of rapidly progressive corneal ectasia in a patient with keratoconus following uncomplicated phacoemulsification surgery for cataract removal. Case presentation A 38-year-old Caucasian man was referred to our out-patient’s service due to bilateral cataract. He also had bilateral keratoconus and had undergone corneal cross-linking in both his eyes 5 years prior to his referral. Ever since the corneal cross-linking, keratoconus had been stable. He underwent a full ophthalmological examination including slit-lamp biomicroscopy, optical biometry, Scheimpflug tomography, corneal biomechanical assessment, and fundus examination. He presented advanced centrally located cataract with count fingers for preoperative best-corrected visual acuity. An uncomplicated cataract extraction surgery was performed. Preoperative flat keratometry reading was 40.5 diopters, steep keratometry reading was 41.8 diopters, astigmatism was 1.3 diopters, corneal hysteresis was 8.2, corneal resistance factor was 7.5, and thinnest corneal thickness was 503 μm. Within 3 months, he demonstrated rapidly progressing corneal ectasia in his operated eye, while 6 months postoperatively, flat keratometry reading was 45.5 diopters, steep keratometry reading was 48.3 diopters, astigmatism was 2.8 diopters, corneal hysteresis = 6.8, corneal resistance factor = 7.5, and thinnest corneal thickness = 318 μm. Conclusions To the best of our knowledge, this is the first report to describe corneal ectasia in a patient with keratoconus following phacoemulsification surgery. Cataract surgeons should provide extra caution to patients with keratoconus and take into consideration this rare but potentially sight-threatening complication.

TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.

Chronic liver diseases take many forms; alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are two common illnesses that potentially lead to cirrhosis, liver failure, and liver cancer. It is estimated that a quarter of heavy drinkers develop ALD and the same portion of people without heavy drinking habits have NAFLD. Alcohol intake is regularly used to differentiate NAFLD from ALD; however, diagnosis based on the discrimination threshold may be suboptimal when facing an obese patient with a high level of alcohol exposure. Therefore, understanding the common and/or different mechanism(s) driving each disease is extremely important. The ‘two-hit’ or ‘multi-hit’ hypothesis is used to explain the pathogenesis of both diseases. The ‘first hit’ refers to developing steatosis, the accumulation of fat components in the liver, and the ‘second hits’ are factors leading to oxidative stress, inflammation, and fibrosis, such as metabolic syndromes (e.g., morbid obesity, hyperglycaemia, hyperlipidaemia, disturbed circadian cycles, and altered intestinal microbiota) and environmental toxins (e.g., cigarette smoke and pollutants). Heritable factors also affect the probability and disease progression of both ALD and NAFLD. Whereas PNPLA3 and TM6SF2 variants are influential genetic risk factors for the diseases, epigenetic factors, such as DNA methylation, post-translational histone modifications, and small non-coding RNA, are of paramount importance. Moreover, considering that both ALD and NAFLD patients may eventually develop end-stage liver disease and require liver transplantation, the authors extensively investigated the worldwide outcomes from original literature for these two aetiologies, and the results showed no obvious differences in post-transplantation survival between them. Precise percentage determination of these two aetiologies contributing to steatohepatitis and its secondary injuries in the future would allow for better strategies for therapeutic and preventive intervention.

Increased incidences of childhood acute leukaemia were noted among survivors of the atomic bombings of Hiroshima and Nagasaki. In Western societies, Childhood Acute Lymphoblastic Leukaemia has a distinct epidemiology peaking at 3 years old. Exposure to ionising radiation is an established hazard but it is difficult to gauge the precise risk of less than 100 mSv. Since 1983 significant leukaemia incidences have been reported among families residing near nuclear installations. The target cells (naïve neonatal lymphocytes) get exposed to multiple xenobiotic challenges and undergo extraordinary proliferation and physiological somatic genetic change. Population movements and ionising radiation are considered taking account of updated understanding of radiation biology, cancer cytogenetics and immunological diversity. Double Strand Breaks in DNA arise through metabolic generation of Reactive Oxygen Species, and nearly always are repaired; but mis-repairs can be oncogenic. Recombinant Activating Gene enzymes in rapidly dividing perinatal pre-B lymphocytes being primed for antibody diversity are targeted to Signal Sequences in the Immunoglobulin genes. off target pseudo-sequences may allow RAG enzymes to create autosomal DSBs which, when mis-repaired, become translocated oncogenes. Immunogens acting by chance at crucial stages may facilitate this. In such circumstances, oncogenic DSBs from ionising radiation are less likely to be significant. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells of the brain that can regulate neural communication and excitability. Any environmental influence on microglial activity has the potential to alter subsequent neural physiology and behavior. Within the prefrontal cortex, several types of stressors have been shown to increase microglial expression of activation markers such as ionized calcium-binding adapter molecule-1 (Iba-1), which suggests altered microglial activity. Recent reports in rodents suggest that exposure to forms of early-life stress such as maternal separation can alter microglial responsivity to subsequent challenges. Several learning paradigms used in rodents require food restriction to provoke motivational states that facilitate approach behaviors. Here, we tested whether food restriction (increasing from 13 g/day-23 g/day in males and 10 g/day-20 g/day in females, which reduced body weight to 72-84% free-fed weight) in adolescent rats is a sufficient challenge to affect microglial Iba-1 expression, and whether previous exposure to postnatal maternal separation influenced microglial outcomes. We measured prefrontal cortex Iba-1 expression and microglial morphology after 20 days of ad libitum or restricted food availability in males and females with or without exposure to maternal separation. Food-restricted animals displayed higher levels of Iba-1 in the prefrontal cortex, with hyper-ramified microglial morphology in maternally separated males and control females, compared to those that were free-fed. Together, our data provide evidence that food restriction paradigms may have unintended effects in some behavioral protocols. [ABSTRACT FROM AUTHOR]

Dissociative amnesia is an illness that can follow a chronic course, resulting in the life-long inability to work. It apparently occurs clustered in connection with migration, where it then takes a more severe course than in other cases. This illness is generally reversible, since the recall of memories is only blocked. Persons affected are those with a background of unprocessed or inadequately processed stressful experiences who have been exposed to a new stress experience leading to dissociative amnesia. Patients affected are primarily those who could not adequately be integrated in their new country. Their lack of knowledge of the local language and failure to find a proper work situation in accordance with their expectations are most likely reasons. [ABSTRACT FROM AUTHOR]

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex ( TSC), a familial tumor-predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/ Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene ( TSC1/ Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 ( mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1-independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/ Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to localize by neuroimaging the altered structural brain development of these offspring using an autism model of transgenic mice lacking contactin-associated protein-like 2 (Cntnap2). Materials and Methods Pregnant dams were randomly allocated to fructose solution (10% W/V) as only drinking fluid or water. Cntnap2 heterozygous (+/-) offspring from each group were euthanized at 6 months of age and their whole brains evaluated by magnetic resonance imaging. T2-weighted images were acquired to evaluate the volumes of 29 regions of interest involved in autism spectrum disorder (ASD) pathogenesis. Whole brains were washed and processed for Nissl staining. Mann-Whitney U test and one-way analysis of variance were used for statistical analysis (significance: p < 0.05). Results The corpus callosum, anterior commissure, and caudate putamen were significantly smaller in Cntnap2 (+/-) male offspring exposed to fructose. No brain alterations were found in the female counterparts. Nissl staining of the caudate putamen revealed higher neuronal cell count in the male fructose offspring. Female group revealed an increase in caudate putamen neuronal cell count. Conclusion Metabolic dysregulation in pregnancy alters fetal brain development in genetically predisposed offspring. This is consistent with findings in human studies and supports the role of intrauterine factors in the etiology of autism. [ABSTRACT FROM AUTHOR]

BK virus nephropathy (BKVN) occurs in up to 10% of renal transplant recipients and can result in graft loss. The reactivation of BK virus in renal transplant recipients is largely asymptomatic, and routine surveillance especially in the first 12-24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and anti-viral treatment in the early stages may be effective in stopping BK virus replication. Urinary decoy cells, although highly specific, lack sensitivity to diagnose BKVN. Transplant biopsy remains the gold standard to diagnose BKVN, good surrogate markers for surveillance using quantitative urinary decoy cells, urinary SV40 T immunochemical staining or polyoma virus-Haufen bodies are offered by recent studies. Advanced BKVN results in severe tubulo-interstitial damage and graft failure. Retransplantation after BKVN is associated with good outcomes. Newer treatment modalities are emerging. [ABSTRACT FROM AUTHOR]

Aim Retinoblastoma (RB) is the most common primary intraocular malignancy affecting children under 5 years of age. This study aims to correlate the clinical parameters with RB1 mutation in the light of Knudson's two-hit hypothesis in Indian RB patients. Methods We analyzed the clinical details of 73 RB patients visiting Aravind Eye Hospital, Madurai, India, between January and October 2012. Data on gender, presenting age and sign, laterality, number of tumors in each eye and family history were collected. A semi log plot was derived based on Knudson's two-hit hypothesis. Genetic analysis of RB1 was carried out to identify the two hits. Results The mean age at diagnosis for unilateral and bilateral cases was 24.0 ± 15.1 and 9.8 ± 11.5 months, respectively. Familial RB was seen in 13 (17.8%) patients of whom 11 were bilateral. Multiple tumors were observed more frequently in bilateral than in unilateral cases. All unilateral and bilateral patients followed the two-hit and one-hit curves, respectively, confirming Knudson's hypothesis in Indian patients. Genetic analysis identified two somatic mutations in tumor samples of sporadic unilateral cases. Among the two bilateral patients, one received the first hit from her father and the other patient developed a de novo germline mutation during early development. Conclusion The two-hit hypothesis has been reestablished in Indian patients. Genetic analysis of tumor samples has also complemented the statistical analysis to reaffirm the two hits in tumor development. [ABSTRACT FROM AUTHOR]

Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two-hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has been demonstrated in animal models. We describe 2 cases of preterm babies sustaining recurrent neonatal seizures in the context of a severe perinatal brain damage who presented with symptomatic epilepsy only after the occurrence of an episode of febrile status epilepticus. In the context of preexisting perinatal brain damage, febrile status epilepticus acted as a second hit for developing epilepsy, confirming animal evidence. [ABSTRACT FROM PUBLISHER]

Abstract: The goal of this study was to determine whether two stressors commonly used to model aspects of neuropsychiatric disease in rats have an additive effect on striatal dopamine type 2 receptor (D2R) expression, a key player in the etiology of neuropsychiatric disease. Animals subjected to early postnatal stress show alterations in function of the dopaminergic system thought to be mediated by stress-induced glucocorticoid release. Subsequent stress during puberty is known to further impact the dopaminergic system and result in dopaminergic hyperactivity analogous to schizophrenia. We exposed rats to maternal deprivation (MD) during the second postnatal week, a time of active striatal development. A subset of these animals were then subjected to pubertal stress induced by immobilization. Both procedures are know to induce glucocorticoid release. At the conclusion of the MD protocol, we observed upregulation in the expression of D2R and of dopamine- and cAMP-regulated phosphoprotein 32-KD (DARPP-32; PPP1R1B), but not of D1R, calcium/calmodulin-dependent protein kinase II beta (CaMKIIβ), CaMKIIα or neurokinin B (NKB). Animals exposed to pubertal stress showed upregulation in expression of both D2R and CaMKIIβ. Furthermore, rats previously exposed to MD showed a much greater upregulation in CaMKIIβ expression, than animals only exposed to pubertal stress. These results support the two-hit hypothesis, indicating that such stressors have an additive effect. The main targets appear to be the D2R and the CaMKIIβ, the latter being an important member of the DR signalling pathway, both of which are associated with schizophrenia. [Copyright &y& Elsevier]

Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 ( NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies ( IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio ( OR) 9.91, 95% confidence interval ( CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes. [ABSTRACT FROM AUTHOR]

Abstract: This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. [Copyright &y& Elsevier]

Abstract: We examined a potential two-hit murine animal model of depression by assessing whether a genetic deficit in reelin increases vulnerability to the depressogenic effects of the stress hormone corticosterone. Stress is an identified risk factor for the onset of depressive symptoms, but depression also has a significant genetic component, suggesting that environmental factors and genetic background likely interact in the etiology of depression. Previous results have revealed that reelin levels are decreased in post-mortem hippocampal tissue from patients with schizophrenia, bipolar disorder and depression, and also in an animal model of depression. Therefore, we hypothesized that heterozygous reeler mice (HRM), with approximately 50% normal levels of reelin, would be more sensitive to the depressogenic effects of corticosterone than wild-type mice (WTM). Mice received subcutaneous injections of either vehicle or 5 mg/kg, 10 mg/kg, or 20 mg/kg of corticosterone for 21 consecutive days, and then they were assessed for changes in depression-like behavior, hippocampal reelin expression, and hippocampal neurogenesis. Corticosterone produced dose-dependent increases in depression-like behavior and decreases in reelin expression, neurogenesis, and cell maturation regardless of mouse genotype. There were no differences between the vehicle-injected HRM and WTM in these measures. However, the effects of CORT on behavior, the number of reelin-positive cells in the subgranular zone or hilus, and hippocampal neurogenesis were more pronounced in the HRM than in the WTM, providing support for the idea that mice with impaired reelin signaling may be more vulnerable to the deleterious effects of glucocorticoids. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’. [Copyright &y& Elsevier]

The right colon differs from the left, in embryological origin, luminal environment, and function. In both sporadic colorectal cancer and Familial Adenomatous Polyposis (FAP), polyp density and cancer susceptibility vary markedly by colonic site. Adenomas in FAP have a different mutational spectrum in small intestine versus colon. This study aimed to investigate whether colonic location also influences the APC mutation spectrum in FAP. 127 1–2 mm mildly dysplastic adenomas from 5 patients with a codon 1309 germline mutation, and 41 from 3 patients with mutations proximal to codon 1265, were analysed to assess the frequency of loss of heterozygosity (LOH). We chose polyps from different locations in the colon. Immunohistochemistry for beta-catenin, caspase-3 and Ki-67 was performed to assess Wnt pathway activation, apoptosis and proliferation. In polyps from patients with a 1309 mutation, the frequency of LOH showed a gradient from rectum (highest) to caecum/ascending colon (lowest), but this was not present in patients with proximal germline APC mutations. Crypt-by-crypt analysis confirmed the LOH findings from whole polyps. Beta-catenin and caspase-3 expression showed no significant variation by colonic region, but Ki-67 expression decreased from ascending colon to rectum in tumours and normal tissue. Colonic site alters the mutational spectrum of APC, and crypt cell proliferation. The higher frequency of LOH in rectal polyps from patients with codon 1309 mutations may help to explain their increased polyp burden at this site compared with patients who have other germline APC mutations. [ABSTRACT FROM AUTHOR]

A 75-year-old previously healthy man presented for elective resection of rectal cancer under general anesthesia. Six days before the operation, he had a high-grade fever, and elevated leukocyte count and C-reactive protein concentration, but this was resolved by an intravenous antibiotic. His condition was well controlled before the operation. Soon after the operation started, severe hypoxemia emerged, with low arterial pressure. Fiberoptic bronchoscopy demonstrated a massive amount of plasma-like edema fluid; the total amount of suctioned fluid was approximately 800 ml at the end of the surgery. This acute pulmonary edema appeared to be due to increased permeability rather than pulmonary congestion as indicated by chest radiography, pulmonary artery occlusion pressure, echocardiogram, and the protein-rich edema fluid. Elevated concentrations of the proinflammatory cytokines, interleukin (IL)-6 and IL-8, in both plasma and the pulmonary edema fluid, suggested a possible role of systemic and pulmonary inflammation in the development of this acute pulmonary capillary leak. According to the “two-hit” hypothesis, the bacterial infection preceding the operation may have primed the immune cells, and the following surgical stress may have then triggered rapid progression of acute respiratory distress syndrome. We should keep in mind that, especially following sepsis, sudden massive pulmonary capillary leak can occur during elective surgery, even though the patient’s condition is well controlled. [ABSTRACT FROM AUTHOR]

Mesial temporal sclerosis (MTS) is found in about two-thirds of patients with refractory temporal lobe epilepsy (TLE), and surgical removal of the sclerotic structures eliminates seizures in the majority of cases undergoing surgical resection. Although multiple factors have been implicated in the genesis of MTS, it is still unclear why some individuals are more likely to develop hippocampal sclerosis than others. Epileptologists have proposed that there must be at least two factors involved—an initial precipitating injury (IPI), such as a prolonged febrile seizure, CNS infection, or head trauma, and a second factor that increases vulnerability to neuronal injury. This has been termed the “two-hit hypothesis.” Three of the many factors that could possibly heighten susceptibility to neuronal injury and MTS are discussed here. These are microdysgenesis, hippocampal dysgenesis, prior seizures, and genetic predisposition. We conclude that there is currently no compelling evidence to support a role for microdysgenesis in MTS. Hippocampal dysgenesis, on the other hand, may account for febrile seizures and possibly MTS in a small subpopulation of patients with TLE. Additional larger studies are needed to confirm these findings. Experimental evidence indicates that an epileptogenic hippocampus can result from prolonged febrile seizures in infant rats, even though these seizures do not cause MTS in the rat. It is not known if this pathophysiological sequence occurs in humans. Lastly, there appears to be a strong genetic component that predisposes some individuals to MTS, regardless of whether they experience an IPI. [ABSTRACT FROM AUTHOR]

Autosomal-dominant polycystic kidney disease represents one of the most common monogenetic human disorders. The cloning of the PKD1 and PKD2 genes, which are mutated in far more than 90% of the patients affected by this disease, has generated high hopes for a quick understanding of the pathogenesis of cyst formation. However, these expectations have not yet been fulfilled, since the function of both polycystin-1 and polycystin-2, the two proteins encoded by PKD1 and PKD2, still remains a puzzle. In this review, we will highlight some of the characteristics of polycystic kidney disease, briefly touch on polycystin-1, and then go on to describe recent results of experiments with polycystin-2, since the latter is the major focus of our work. We will discuss new evidence which suggests that autosomal-dominant polycystic kidney disease actually behaves recessively on a cellular level. Finally, a model will be presented that tries to explain the available data. [ABSTRACT FROM AUTHOR]

The article focuses on research related to schizophrenia, which is a multi-factorial disease characterized by environmental risk factors and a high heritability. It is stated that the development of the disorder is caused by genetic and environmental risk factors interactively (GxE interaction), which occur when the expression of an individual's genetic predisposition is dependent on the environment they are living in.

Chlamydia trachomatis is a leading infectious cause of infertility in women due to its induction of lasting pathology such as hydrosalpinx. Chlamydia muridarum induces mouse hydrosalpinx because C. muridarum can both invade tubal epithelia directly (as a first hit) and induce lymphocytes to promote hydrosalpinx indirectly (as a second hit). In the current study, a critical role of CD8 + T cells in chlamydial induction of hydrosalpinx was validated in both wild type C57BL/6J mice and OT1 transgenic mice. OT1 mice failed to develop hydrosalpinx partially due to the failure of their lymphocytes to recognize chlamydial antigens. CD8 + T cells from naive C57BL/6J mice rescued the ability of recipient OT1 mice to develop hydrosalpinx when naive CD8 + T cells were transferred at the time of infection with Chlamydia. However, when the transfer was delayed for 2 weeks or longer after the Chlamydia infection, naive CD8 + T cells no longer promoted hydrosalpinx. Nevertheless, CD8 + T cells from mice immunized against Chlamydia still promoted significant hydrosalpinx in the recipient OT1 mice even when the transfer was delayed for 3 weeks. Thus, CD8 + T cells must be primed within 2 weeks after Chlamydia infection to be pathogenic, but, once primed, they can promote hydrosalpinx for >3 weeks. However, Chlamydia-primed CD4 + T cells failed to promote chlamydial induction of pathology in OT1 mice. This study optimized an OT1 mouse-based model for revealing the pathogenic mechanisms of Chlamydia-specific CD8 + T cells.

Chlamydia is known to both ascend to the upper genital tract and spread to the gastrointestinal tract following intravaginal inoculation. Gastrointestinal Chlamydia was recently reported to promote chlamydial pathogenicity in the genital tract since mice intravaginally inoculated with an attenuated Chlamydia strain, which alone failed to develop pathology in the genital tract, were restored to develop hydrosalpinx by intragastric coinoculation with wild-type Chlamydia. Gastrointestinal Chlamydia promoted hydrosalpinx via an indirect mechanism since Chlamydia in the gut did not directly spread to the genital tract lumen. In the current study, we further investigated the role of CD8 + T cells in the promotion of hydrosalpinx by gastrointestinal Chlamydia. First, we confirmed that intragastric coinoculation with wild-type Chlamydia promoted hydrosalpinx in mice that were inoculated with an attenuated Chlamydia strain in the genital tract 1 week earlier. Second, the promotion of hydrosalpinx by intragastrically coinoculated Chlamydia was blocked by depleting CD8 + T cells. Third, adoptive transfer of gastrointestinal Chlamydia-induced CD8 + T cells was sufficient for promoting hydrosalpinx in mice that were intravaginally inoculated with an attenuated Chlamydia strain. These observations have demonstrated that CD8 + T cells induced by gastrointestinal Chlamydia are both necessary and sufficient for promoting hydrosalpinx in the genital tract. The study has laid a foundation for further revealing the mechanisms by which Chlamydia-induced T lymphocyte responses (as a 2nd hit) promote hydrosalpinx in mice with genital Chlamydia-triggered tubal injury (as a 1st hit), a continuing effort in testing the two-hit hypothesis as a chlamydial pathogenic mechanism.

An infant sustained a significant depressed skull fracture from a fall. Before the planned surgical repair of the fracture could be carried out, the child sustained a second fall that led to the complete resolution of the depressed fracture. Mechanisms to explain this unusual phenomenon are discussed. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: According to experimental and clinical published studies, patients with keratoconus have a genetic predisposition to corneal ectasia; however, ectasia might not be activated or reactivated unless an additional stressful event triggers the disease. Triggering factors are sources of reactive oxidative stress; among them, mechanical trauma (vigorous eye rubbing, poorly fit contact lenses), exposure to ultraviolet light, and atopy/allergies. The aim of this case report is to present for the first time a case of rapidly progressive corneal ectasia in a patient with keratoconus following uncomplicated phacoemulsification surgery for cataract removal.Case Presentation: A 38-year-old Caucasian man was referred to our out-patient's service due to bilateral cataract. He also had bilateral keratoconus and had undergone corneal cross-linking in both his eyes 5 years prior to his referral. Ever since the corneal cross-linking, keratoconus had been stable. He underwent a full ophthalmological examination including slit-lamp biomicroscopy, optical biometry, Scheimpflug tomography, corneal biomechanical assessment, and fundus examination. He presented advanced centrally located cataract with count fingers for preoperative best-corrected visual acuity. An uncomplicated cataract extraction surgery was performed. Preoperative flat keratometry reading was 40.5 diopters, steep keratometry reading was 41.8 diopters, astigmatism was 1.3 diopters, corneal hysteresis was 8.2, corneal resistance factor was 7.5, and thinnest corneal thickness was 503 μm. Within 3 months, he demonstrated rapidly progressing corneal ectasia in his operated eye, while 6 months postoperatively, flat keratometry reading was 45.5 diopters, steep keratometry reading was 48.3 diopters, astigmatism was 2.8 diopters, corneal hysteresis = 6.8, corneal resistance factor = 7.5, and thinnest corneal thickness = 318 μm.Conclusions: To the best of our knowledge, this is the first report to describe corneal ectasia in a patient with keratoconus following phacoemulsification surgery. Cataract surgeons should provide extra caution to patients with keratoconus and take into consideration this rare but potentially sight-threatening complication. [ABSTRACT FROM AUTHOR]

We focused on the production and evaluation of a modified "double-hit" induced acute lung injury (ALI) model, which closely mimics the clinical situation. Further, tetramethylpyrazine (TMP), an alkaloid contained in ligustrazine was evaluated for its potent anti-inflammatory effects in this model. Rats were randomized into 4 groups: G1 (NS control group), G2 ("double-hit" group), G3 (low dosage TMP group) and G4 (high dosage TMP group). The rats in G2, G3 and G4 were intraperitoneally injected with a low dose of LPS followed by intratracheal injection with median dose of LPS to establish the "double-hit" model. The rats in G3, G4 were intraperitoneally injected with low (G3), high (G4) dosage TMP for the protection against ALI. Upon termination of the experiment, TMP attenuated the harmful changes in animal model reaction, breathing frequency, histological examination, lung W/D-weight ratio, BAL fluid PMNs percentage, MPO activity and ROCK2 mRNA expression. We found inhibiting RhoA/ROCK pathway might attribute to TMP-induced protection against ALI.

Hippocampal sclerosis (HS) is the most common neuropathological pattern observed in pharmacoresistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy syndrome. However, its pathophysiological mechanisms and neuropathological consequences on seizures remain mostly unresolved. The new international classification of hippocampal sclerosis aims at standardizing its description to allow comparisons between different clinical studies. However, several aspects are not considered in this classification (granule cell dispersion, sprouting, glial modifications…). In this chapter, we discuss these different features associated with hippocampal sclerosis in perspective with the "two-hit" hypothesis and propose mechanisms that could be involved in the modulation of some specific neuropathological aspects like early life stress, hyperthermic seizures, brain lesions or hormonal modifications., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Retinoblastoma (RB), a childhood neoplasia of the retinoblasts, can occur unilaterally or bilaterally, with one or multiple foci per eye. RB is associated with somatic loss of function of both alleles of the tumor suppressor gene RB1. Hereditary forms emerge due to germline loss of function mutations in RB1 alleles. RB has long been the prototypic "model" cancer ever since Knudson's "two-hit" hypothesis. However, a simple two-hit model for RB is challenged by an increasing number of studies documenting additional hits that contribute to RB development. Here we review the genetics and epigenetics of RB with a focus on the role of small non-coding RNAs (microRNAs) and on novel findings indicating the relevance of DNA methylation in the development and prognosis of this neoplasia. Studies point to an elaborated landscape of genetic and epigenetic complexity, in which a number of events and pahtways play crucial roles in the origin and prognosis of RB. These include roles for microRNAs, inprinted loci, and parent-of-origin contributions to RB1 regulation and RB progression. This complexity is also manifested in the structure of the RB1 locus itself: it includes numerous repetitive DNA segments and retrotransposon insertion elements, some of which are actively transcribed from the RB1 locus. Altogether, we conclude that RB1 loss of function represents the tip of an iceberg of events that determine RB development, progression, severity, and disease risk. Comprehensive assessment of personalized RB risk will require genetic and epigenetic evaluations beyond RB1 protein coding sequences.