Onychopapilloma: its clinical, dermoscopic and pathologic features.

BACKGROUND: Onychopapilloma is a benign tumour of the nail bed and distal matrix and commonly presents as longitudinal erythronychia, longitudinal leukonychia or longitudinal melanonychia. Because onychopapilloma is rare, its clinical characteristics and dermoscopic findings have not been well investigated in Asia. OBJECTIVES: This study aimed to investigate the clinical characteristics and dermoscopic and pathologic findings of onychopapilloma in Korea. METHODS: We retrospectively reviewed the medical records and clinical/dermoscopic photographs of 39 patients diagnosed with onychopapilloma in the Pusan National University Hospitals (Busan and Yangsan) for 11 years (2010-2021). RESULTS: Among 39 patients, 23 (59.0%) were men, and 16 (41.0%) were women. The mean age was 46.1 (16-77) years. All lesions were single, and most of them were located on the fingers (92.3%), especially the thumb (66.7%). The most common clinical feature was longitudinal erythronychia (56.4%), and the most common dermoscopic finding was distal subungual hyperkeratosis (100%). We found two new dermoscopic features: macrolunula and trailing lunula along the longitudinal band. Among 18 patients who underwent surgical excision, only 6 (33.3%) showed typical acanthosis and papillomatosis on the nail bed. CONCLUSIONS: We found that Asian onychopapilloma has similar clinicodermoscopic findings to the Caucasian one, that is to say, longitudinal erythronychia and distal subungual hyperkeratosis were the most common nail change and dermoscopic finding, respectively. We propose two new dermoscopic features of onychopapilloma: macrolunula and trailing lunula along the longitudinal band.

Genetic analysis of seed-shattering genes in rice using an F3:4 population derived from an Oryza sativa x Oryza rufipogon cross.

Seed shattering of wild plant species is thought to be an adaptive trait to facilitate seed dispersal. For rice breeding, seed shatter-ing is an important trait for improving breeding strategies, particularly when developing lines use interspecific hybrids and introgression of genes from wild species. We developed F3:4 recombinant inbred lines from an interspecific cross between Oryza sativa cv. Ilpoombyeo and Oryza rufipogon. In this study, we genetically analyzed known shat-tering-related loci using the F3:4 population of O. sativa/O. rufipogon. CACTA-AG190 was significantly associated with the shattering trait CACTA-TD according to bulked segregant analysis results, and was found in the qSH-1 region of chromosome 1. Fine genetic mapping of the flanking regions around qSH-1 based on CACTA-AG190 revealed multiple-sequence variations. The highest limit of detection based on quantitative trait locus analysis was observed between shaap-7715 and a 518-bp insertion site. Two other quantitative trait locus analyses of seed-shattering-related loci, qSH-4 and sh-h, were performed using simple sequence repeat and allele-pecific single nucleotide polymor-phism markers. Our results can be applied for rice-breeding research, such as marker-assisted selection between cultivated and wild rice.

Expression of nicotinic acetylcholine receptors and subunit messenger RNAs in the enteric nervous system of the neonatal rat.

In the enteric nervous system (ENS) excitatory nicotinic cholinergic transmission is mediated by neuronal nicotinic acetylcholine receptors (nAChR) and is critical for the regulation of gastric motility. nAChRs are ligand-gated pentameric ion channels found in the CNS and peripheral nervous system. The expression of heteromeric nAChR and receptor subunit mRNAs was investigated in the neonatal rat ENS using receptor autoradiography with the radiolabeled ligand (125)I-epibatidine, and in situ hybridization with subtype specific probes for ligand binding alpha (alpha2, alpha3, alpha4, alpha5, alpha6) and structural beta (beta2, beta3, beta4) subunits. The results showed strong nicotine sensitive binding of (125)I-epibatidine around the stomach, and small and large intestines. The binding was partially displaced by A85380, a nicotinic ligand which differentiates between different heteromeric nAChR subtypes, suggesting a mixed receptor population. Radioactive in situ hybridization detected expression of alpha3, alpha5, alpha7, beta2 and beta4 mRNA in the myenteric plexus of the stomach, and small and large intestines. In the submucosal plexus of the small and large intestines expression of alpha3, alpha5 and beta4 was found in some ganglia. There was no signal for alpha4, alpha6 and beta3 in the ENS but positive hybridization signal for alpha2 transcripts was seen in some areas of the small intestines. However, the signal was not associated with any ganglion cells. The results confirm the presence of heteromeric nAChRs in the ENS similar to those found in the peripheral nervous system, with the majority being composed of alpha3(alpha5)beta4, and a few alpha3beta2 nAChRs. In addition, homomeric alpha7 nAChRs could be present.

Acute nicotine activates c-fos and activity-regulated cytoskeletal associated protein mRNA expression in limbic brain areas involved in the central stress-response in rat pups during a period of hypo-responsiveness to stress.

In adult rats, acute nicotine, the major psychoactive ingredient in tobacco smoke, stimulates the hypothalamic-pituitary-adrenal axis (HPA), resulting in activation of brain areas involved in stress and anxiety-linked behavior. However, in rat pups the first two postnatal weeks are characterized by hypo-responsiveness to stress, also called the 'stress non-responsive period' (SNRP). Therefore, we wanted to address the question if acute nicotine stimulates areas involved in the stress response during SNRP. To determine neuronal activation, the expression of the immediate-early genes c-fos and activity-regulated cytoskeletal associated protein (Arc) was studied in the central nucleus of the amygdala (CeA), bed nucleus stria terminalis (BST) and paraventricular hypothalamic nucleus (PVN), which are areas involved in the neuroendocrine and central stress response. Rat pups received nicotine tartrate (2 mg/kg) or saline by i.p. injection at postnatal days (P) 5, 7 and 10 and their brains were removed after 30 min. We used semi-quantitative radioactive in situ hybridization with gene specific antisense cRNA probes in coronal sections. In control pups, c-fos expression was low in most brain regions, but robust Arc hybridization was found in several areas including cingulate cortex, hippocampus and caudate. Acute nicotine resulted in significant induction of c-fos expression in the PVN and CeA at P5, P7 and P10, and in the BST at P7 and P10. Acute nicotine significantly induced expression of Arc in CeA at P5, P7 and P10, and in the BST at P10. In conclusion, acute nicotine age dependently activated different brain areas of the HPA axis during the SNRP. After P7, the response was more pronounced and included the BST, suggesting differential maturation of the HPA axis in response to nicotine.

Chronic headache after cranio-cervical trauma--hypothetical pathomechanism based upon neuroanatomical considerations.

BACKGROUND: Chronic headache after whiplash injury is common, but the underlying mechanisms have not yet been elucidated. On the basis of human neuroanatomy, we hypothesize that rear-end collision can cause leakage of the cerebrospinal fluid (CSF) into the epidural space most frequently at the lumbosacral level, inducing chronic headache. METHODS: We considered that the following phenomena would be evident in patients with chronic headache after rear-end collision: (1) orthostatic headache with early onset and long duration, (2) low intracranial pressure (ICP =or< 60 mm H2O), (3) CSF leakage mainly in the lumbosacral region on radioisotope-myelocisternography, and (4) diffuse pachymeningeal enhancement (DPE) on gadolinium enhanced magnetic resonant image (Gd-MRI). The clinical signs and symptoms, ICP and neuroimaging findings were analyzed retrospectively in 20 patients who complained of chronic headache after rear-end collisions. RESULTS: Headaches were orthostatic and started on the day of the accident in 14 patients. The headaches lasted more than 3 months in all patients. Mean ICP was 120 +/- 30 cm H2O. Only one patient showed low ICP. RI-myelocisternography revealed signs of CSF leakage at the lumbosacral level in 10 patients. Gd-MRI showed no abnormalities known to be characteristic of spontaneous intracranial hypotension (SIH). Chronic headache disappeared or was diminished in all patients by epidural blood patching in the lumbosacral region. CONCLUSION: This clinical study partly supports the validity of our verifiable hypothetical mechanism. The ICP is not low and DPE is not observed on Gd-MRI. Therefore, CSF leakage into the epidural space may not occur, but spinal CSF absorption may be over-activated. This condition may represent a new clinical entity.

Solar optics-based active panel for solar energy storage and disinfection of greywater.

Smart city and innovative building strategies are becoming increasingly more necessary because advancing a sustainable building system is regarded as a promising solution to overcome the depleting water and energy. However, current sustainable building systems mainly focus on energy saving and miss a holistic integration of water regeneration and energy generation. Here, we present a theoretical study of a solar optics-based active panel (SOAP) that enables both solar energy storage and photothermal disinfection of greywater simultaneously. Solar collector efficiency of energy storage and disinfection rate of greywater have been investigated. Due to the light focusing by microlens, the solar collector efficiency is enhanced from 25% to 65%, compared to that without the microlens. The simulation of greywater sterilization shows that 100% disinfection can be accomplished by our SOAP for different types of bacteria including Escherichia coli. Numerical simulation reveals that our SOAP as a lab-on-a-wall system can resolve the water and energy problem in future sustainable building systems.

Approach to Management of Eyes with no Light Perception after Open Globe Injury.

Loss of light perception (LP) after open globe injury (OGI) does not necessarily mean the patient will have permanent complete visual loss. Findings that seem to be associated reliably with permanent profound vision loss after OGI include optic nerve avulsion, optic nerve transection, and profound loss of intraocular contents, which can be identified with CT/MRI imaging albeit with varying degrees of confidence. Eyes with NLP after OGI that undergo successful primary repair with intact optic nerves may be considered for additional surgery, particularly if there is: (1) recovery of LP on the first day after primary repair; (2) treatable pathology underlying NLP status (e.g., extensive choroidal hemorrhage, dense vitreous and subretinal hemorrhage); (3) NLP in the fellow eye. We counsel patients that the chance of recovering ambulatory vision under these circumstances is very low (~5%).

Phenotypic differentiation during migration of dopaminergic progenitor cells to the olfactory bulb.

A possible source for transplantable neurons in Parkinson's disease are adult olfactory bulb (OB) dopamine (DA) progenitors that originate in the anterior subventricular zone and reach the OB through the rostral migratory stream. We used adult transgenic mice expressing a lacZ reporter directed by an 8.9 kb tyrosine hydroxylase (TH) promoter to investigate the course of DAergic differentiation. Parallel transgene and intrinsic TH mRNA expression occurred during migration of DA interneurons through the mitral and superficial granule cell layers before these cells reached their final periglomerular position. Differential transgene and calcium-calmodulin-dependent protein kinase IV expression distinguished two nonoverlapping populations of interneurons. Transgenic mice carrying a TH8.9kb/lacZ construct with a mutant AP-1 site demonstrated that this element confers OB DA-specific TH gene regulation. These results indicate that DA phenotypic determination is specific to a subset of mobile OB progenitors.

Apolipoprotein B: novel indicator of elevated intraocular pressure.

PURPOSE: Many studies have reported associations between elevated intraocular pressure (IOP) and systemic health parameters, which suggest a common mechanism links IOP elevation and various related cardiometabolic risk factors. Furthermore, according to a recent study, serum apolipoprotein B (APO B) level is a predictor of coronary artery disease. This study was undertaken to analyse the relationship between serum apolipoprotein levels and IOP. METHODS: Healthy people (28,852) who attended a community hospital for a health checkup between January 2011 and December 2013 were enroled in the study. We measured age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein A1 (APO A1) and APO B, APO B/APO A1 ratios, and IOP. RESULTS: Univariate regression analysis showed IOP was positively correlated with BMI, SBP, DBP, TC, LDL-C, TG, APO B, and APO B/APO A1 (P<0.001), and negatively correlated with HDL-C (P<0.001). On the other hand, multivariate regression analysis adjusted for age, BMI, SBP, and DBP, revealed IOP was positive correlated with TC, TG, LDL-C, APO B, and APO B/APO A1, and negatively correlated with HDL-C (all <0.05). CONCLUSIONS: Among the various lipid profiles investigated, APO B was found to be most strongly correlated with IOP, regardless of sex. Additional studies are required to confirm the validity of apolipoprotein level as an index for predicting IOP.

Prolonged in vivo gene expression driven by a tyrosine hydroxylase promoter in a defective herpes simplex virus amplicon vector.

A 9.0-kb fragment of the tyrosine hydroxylase (TH) promoter, previously shown to direct tissue-specific expression in transgenic mice, was fused to an Escherichia coli LacZ reporter gene in a defective herpes simplex virus type-1 (HSV-1) amplicon vector (THlac). The HSV immediate early (IE) 4/5 promoter (HSVlac) was used as a control. LacZ gene expression was visualized by X-Gal histochemical and TH immunocytochemical analysis. Two days and 10 weeks after THlac injection into rat caudate nucleus (CN), X-Gal-stained cells were observed in the substantia nigra (SN) and locus ceruleus (LC) ipsilateral to the injection site. These blue cells were TH-positive neurons as evidenced by double labeling with immunocytochemistry. Moreover, the number of X-Gal+, TH+ (double-positive) neurons in the SN increased at 10 weeks as compared to that seen 2 days after THlac injection. In marked contrast, few double-positive nigral neurons were observed either 2 days or 10 weeks after direct injection of THlac into SN. However, neither nigral nor striatal injection of HSVlac resulted in prolonged gene expression. These results suggest that a neuronal, but not a viral, promoter in an HSV vector can produce cell-type-specific, prolonged, and stable gene expression following retrograde transport. In addition, THlac produced infrequent gene expression in TH-negative cells (CN and dorsal to SN) after THlac injection into CN and SN, respectively. Overall, these results suggest that in some in vivo contexts cell-type-preferred expression can be achieved by a cellular promoter in an amplicon vector. Moreover, they underscore the need for the careful and systematic study of neuronal promoters in HSV vectors.

Early ontogeny of catecholaminergic cell lineage in brain and peripheral neurons monitored by tyrosine hydroxylase-lacZ transgene.

As the first and rate limiting enzyme in the biosynthetic pathway for catecholamine (CA) neurotransmitters, tyrosine hydroxylase (TH) is a specific phenotypic marker for CA cells in the central and peripheral nervous systems of adult animals. During embryogenesis, TH expression appears permanently within cells destined to be CA-secreting during adult life, and transiently in several cell types that will not express TH in adulthood. In this study, we examined the early ontogeny of TH expression in transgenic mouse embryos by following the expression of a lacZ reporter, driven by the tissue-specific promoter of the rat TH gene. The lacZ reporter product, beta-galactosidase (beta-gal), visualized by X-gal staining, first became apparent in primordia of sensory ganglia serving the glossopharyngeal (IX) and vagal (X) cranial nerves at embryonic day (E)9.0. Between E9.5 and E10.5, beta-gal expression extended to the remaining cranial sensory ganglia serving the trigeminal (V) and facial (VII) nerves, dorsal root ganglia, ventrolateral neural tube and sympathetic ganglion primordia. During that same period, the first beta-gal expression in the embryonic brain also appeared within distinct regions, such as the ventral prosencephalon, the ventral and dorsolateral mesencephalon and the rostral and caudal rhombencephalon. The level of beta-gal expression in all these tissues decreased at E13.5, but a distinct adult pattern of beta-gal expression started to emerge in the substantia nigra and ventral tegmental area in the central nervous system and the adrenal medulla in the periphery. Our findings indicate that the proximal 9.0 kb of the 5' promoter region of the rat TH gene encodes sufficient information to direct development of the appropriate catecholaminergic lineage cells in the central and most peripheral nervous systems during embryogenesis.

Drastic and selective hyperinnervation of central serotonergic neurons in a lethal neurodevelopmental mouse mutant, Anorexia (anx).

The autosomal recessive lethal anorexia mutation in mice (anx/anx) causes starvation in preweanlings. In addition, this murine neurodevelopmental mutant shows other distinct phenotypic characteristics and dysfunctional behaviors. Previous studies strongly suggested that the mutation results in elevated serotonergic stimulation, because these traits are characteristic of such overstimulation and because brain serotonin is believed to have an inhibitory effect on feeding behavior. In this report, we show extensive serotonergic hyperinnervation in normal target fields (hippocampus, cortex, olfactory bulb and cerebellum) of mutant mice. Despite the extensive hyperinnervation, the normal laminar organization of the brain was retained. The specificity of the mutation to the serotonergic system was confirmed by demonstration of normal catecholaminergic innervation in the central nervous system (CNS), and this specificity was especially striking in a common target field, the cerebellum. Serotonergic hyperinnervation in these mutant preweanling mice may represent the underlying etiology of increased serotonergic stimulation which leads to anorexic starvation, abnormal behavior, and premature death.

5' upstream DNA sequence of the rat tyrosine hydroxylase gene directs high-level and tissue-specific expression to catecholaminergic neurons in the central nervous system of transgenic mice.

Tyrosine hydroxylase (TH), the first and rate-limiting enzyme in the biosynthesis of catecholamine neurotransmitters, is expressed within central and peripheral catecholaminergic cells. To delineate DNA sequences necessary for tissue-specific expression of the rat TH gene, transgenic mice were produced containing 0.15 kb, 2.4 kb, and 9.0 kb of 5' flanking sequence fused to the E. coli lacZ (beta-galactosidase) reporter gene. The reporter gene expression in the transgenic animals was monitored by both X-gal histochemical staining and beta-galactosidase immunohistochemistry and compared to TH mRNA and protein expression. Transgenic mice bearing 9.0 kb, but not the smaller constructs with either 2.4 kb or 0.15 kb of 5' flanking sequence, fused to lacZ were able to direct high level expression of beta-galactosidase at levels equivalent to the endogenous TH in central catecholaminergic cells, and to a lesser degree to adrenal gland. Previously, 4.8 kb of 5' flanking region was reported to contain some tissue-specific element(s) determined by chloramphenicol acetyltransferase (CAT) assay using regional brain dissections and was not able to demonstrate cellular localization of the CAT expression [2]. Using histological procedures which allow for spatial resolution, this study demonstrated that the crucial catecholaminergic neuron-specific DNA element(s) resides between -9 kb and -2.4 kb of the 5' flanking region of the rat TH gene; this assertion is substantiated by the high-level of tissue-specific expression of lacZ in catecholaminergic cells.

A 6.1 kb 5' upstream region of the mouse tryptophan hydroxylase gene directs expression of E. coli lacZ to major serotonergic brain regions and pineal gland in transgenic mice.

Tryptophan hydroxylase (TPH) catalyzes the first step of serotonin biosynthesis in serotonergic neurons and neuroendocrine cells. Serotonin influences diverse vital physiological functions and is thought to play an important role in several human psychiatric disorders. To localize DNA element(s) important for serotonergic tissue-specific expression of TPH, 6.1 kb of the 5' flanking region of the mouse TPH gene was fused to the coding region of the E. coli lacZ gene, and expression of the resulting fusion gene was analyzed in transgenic mice. The 6.1 kb of 5' flanking sequence was able to direct the expression of a lacZ reporter gene to serotonergic tissues in six lines of transgenic mice. A high level of lacZ expression in transgenic mice carrying the fusion gene was detected in the pineal gland as well as a moderate level of lacZ expression in serotonergic brain regions such as the median and dorsal raphe nuclei, the nuclei raphe magnus and raphe pallidus. In contrast, a smaller 5' flanking sequence of 1.1 kb directed no detectable serotonergic tissue-specific lacZ expression in five lines of transgenic mice. These results presented in this paper suggest first that DNA elements critical to serotonergic tissue-specific expression reside between -6.1 kb and -1.1 kb of 5' flanking region of the mouse TPH gene, but second that this region confers a restricted tissue-specific expression.

Immortalization of neuroendocrine pinealocytes from transgenic mice by targeted tumorigenesis using the tryptophan hydroxylase promoter.

Tryptophan hydroxylase (TPH) is the first enzyme in both serotonin and melatonin biosynthesis in neuroendocrine cells of the pineal gland. The lack of immortalized neuroendocrine pineal cell lines has been a major obstacle to the study of the tissue-specific and circadian regulation of TPH gene expression in the pineal gland. Previously, we demonstrated that a 6.1 kb 5' upstream region of the mouse TPH gene directs the restricted expression of a lacZ reporter gene to the pineal gland and the raphe nuclei of transgenic mice. Therefore, to develop TPH-expressing pineal cell lines we first established transgenic mice carrying a construct consisting of 6.1 kb of 5' flanking region fused to the SV40 T-antigen. These animals developed highly invasive pineal tumors and died at 12-15 weeks of age. The pineal tumors obtained from the transgenic mice were utilized to establish the immortalized pinealocyte-derived cell lines. These cells express two marker enzymes, TPH and serotonin N-acetyltransferase (NAT). In pineal gland TPH and NAT expressions have been known to be regulated during circadian cycle. The two established cell lines therefore promise to be a valuable in vitro model system for the study of the rhythmic nature of the pineal function at molecular level in mammal.

Identification of potential compounds promoting BDNF production in nigral dopaminergic neurons: clinical implication in Parkinson's disease.

Parkinson's disease (PD) is characterized by the selective loss of dopamine (DA) neurons in the substantia nigral brain region. Currently, there is no cure or treatment that prevents such neuronal loss. Brain-derived neurotrophic factor (BDNF) has been found to support the survival of DA neurons in animal models and in primary cell cultures. However, the large molecular size of BDNF, coupled with the blood brain barrier, prevents its delivery to DA neurons to promote cell survival in the PD brain. The nigral DA neurons have the ability to produce BDNF for neuroprotection via either autocrine or paracrine mechanisms. Low mol. wt compounds were tested to see whether they could increase the production of BDNF in the DA neurons. The compounds tested include neurotransmitters, neuropeptides, intracellular signaling agents, known neuroprotective agents and growth factors. Our results demonstrate that salicyclic acid, cGMP analog, okadaic acid, IBMX, dipyridamole and glutamate significantly enhance BDNF production in DA neuronal cells.

Monitoring catecholamine differentiation in the embryonic brain and peripheral neurons using E. coli lacZ as a reporter gene.

An X-gal based histochemical assay was used to detect catecholamine (CA) cells in transgenic mouse embryos, in which the expression of the lacZ reporter was driven by the tissue-specific promoter of the rat tyrosine hydroxylase (TH) gene. As the first enzyme in the biosynthetic pathway for CA neurotransmitters, TH is a specific phenotypic marker for CA cells in the central and peripheral nervous systems of adult animals. During embryogenesis, TH expression appears permanently within CA-producing cells, and transiently within several other cell types. In this study we were able to monitor TH expression in transgenic mouse embryos by following the expression of the lacZ reporter in substantia nigral dopaminergic neurons in the central nervous system, the trigeminal (V) sensory ganglia, and dorsal root ganglia in the periphery. Our results demonstrate that the rat TH promoter-lacZ transgene provides an important experimental tool for monitoring catecholaminergic lineage cells during embryogenesis.

Neuropeptide Y mRNA and serotonin innervation in the arcuate nucleus of anorexia mutant mice.

The anorexia (anx) mutation causes reduced food intake in preweanling mice, resulting in death from starvation within 3-4 weeks. In wild-type rodents, starvation induces increased neuropeptide Y (NPY) mRNA levels in the arcuate nucleus that promotes compensatory hyperphagia. Despite severely decreased body weight and food intake at 3-weeks age, anx/anx mice do not show elevated NPY mRNA levels in the hypothalamic arcuate nucleus compared to wild-type/heterozygous littermates. The NPY mRNA levels can be upregulated in normal mice at this chronological age, because 24-h food deprivation increased arcuate NPY mRNA in wild-type littermates. The unresponsiveness of NPY expression in the arcuate of anx/anx mice was paralleled by serotonergic hyperinnervation of the arcuate nucleus, comparable to the serotonergic hyperinnervation previously reported in the rest of the anx/anx brain. This result is consistent with the hypothesis that wasting disorders are accompanied by disregulation of NPY mRNA expression in the arcuate nucleus, and suggests that reduced food intake, the primary behavioral phenotype of the anx/anx mouse, may be the result of altered hypothalamic mechanisms that normally regulate feeding.

Differential expression of monoamine oxidase A, serotonin transporter, tyrosine hydroxylase and norepinephrine transporter mRNA by anorexia mutation and food deprivation.

The Anorexia (anx) mutation causes reduced food intake in preweanling mice, resulting in death from starvation within 3-4 weeks. We have found serotonin (5HT) hyperinnervation in the anx brain; altered noradrenergic (NE) innervation may also mediate eating disorders. We examined the expression of synthetic or catabolic monoamine enzyme genes in brainstem nuclei: serotonin transporter (5HTT) and monoamine oxidase A (MAOA) in the raphe nuclei (RN), and MAOA, norepinephrine transporter (NET), and tyrosine hydroxylase (TH) in the locus ceruleus (LC). We compared 3-week old anx with control and 24-h food-deprived wildtype littermates using in situ hybridization to measure mRNA levels by quantitative autoradiography. The anx mutation was correlated with decreased MAOA mRNA in the LC (but not RN), decreased 5HTT mRNA in the RN, and a trend towards lower NET mRNA in the LC. Food deprivation decreased MAOA mRNA in the LC (but not RN), increased TH mRNA in the LC, and did not alter NET or 5HTT mRNA levels. Thus, the effect of the anx mutation on MAOA expression in the LC paralleled the effect of food-deprivation, but the anx mutation and food-deprivation had differential effects on the expression of TH, NET, and 5HTT genes. Decreased 5HTT expression in the anx RN is consistent with upregulation of serotonergic neurotransmission that may accompany 5HT hyperinnervation. Central NE levels or innervation may be altered in anx mice by decreased expression of NET and MAOA and a lack of TH upregulation induced by food deprivation as in wild-type mice.

Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741.

Chronic exposure to manganese causes Parkinson's disease (PD)-like clinical symptoms (Neurotoxicology 5 (1984) 13; Arch. Neurol. 46 (1989) 1104; Neurology 56 (2001) 4). Occupational exposure to manganese is proposed as a risk factor in specific cases of idiopathic PD (Neurology 56 (2001) 8). We have investigated the mechanism of manganese neurotoxicity in nigral dopaminergic (DA) neurons using the DA cell line, SN4741 (J. Neurosci. 19 (1999) 10). Manganese treatment elicited endoplasmic reticulum (ER) stress responses, such as an increased level of the ER chaperone BiP, and simultaneously activated the ER resident caspase-12. Peak activation of other major initiator caspases-like activities, such as caspase-1, -8 and -9, ensued, resulting in activation of caspase-3-like activity during manganese-induced DA cell death. The neurotoxic cell death induced by manganese was significantly reduced in the Bcl-2-overexpressing DA cell lines. Our findings suggest that manganese-induced neurotoxicity is mediated in part by ER stress and considerably ameliorated by Bcl-2 overexpression in DA cells.