Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

Evaluation of early events in the creation of amyenteric opossum model of achalasia.

Benzyldimethyltetradecylammonium chloride (BAC) has previously been used to create amyenteric rat jejunal models. Fifteen opossums (D. virginiana) were injected with 10-15 mL 4 mM BAC or saline in the distal oesophagus and along with controls underwent oesophagoscopy, manometry and barium oesophagrams. Atropine and sodium nitroprusside were studied in six of the BAC-treated and five controls using oesophageal manometry. Histologically several neuronal markers, B-NADPH-diaphorase and acetylcholine esterase histochemical staining were used. NADPH-diaphorase activity was assayed at the lower oesophageal sphincter (LOS) and 3 and 5 cm above LOS in both groups. Oesophagoscopy of the treated animals showed no mucosal inflammation, or strictures. Manometrically, LOS pressures were significantly higher in the BAC-treated group (25.7 +/- 8.6 mmHg) when compared to controls (8.7 +/- 1.8 mmHg). The oesophageal contraction amplitudes were similar in both groups. While sodium nitroprusside (SNP) significantly reduced the LOS pressure, atropine did not alter the resting LOS pressure in the BAC-treated animals. Histologically at the LOS the treated group showed: (i) absence of myenteric neurons, in contrast to prominent NADPH-diaphorase and other neuron and peptide markers in the control and (ii) increase in the number of nerve bundles that were not positive for AchE. No differences were seen in the oesophageal body between the groups. The NADPH-diaphorase assay showed a significant decrease of activity in the BAC-treated LOS, but no differences in the oesophageal body compared to controls. Several of these radiologic, manometric and histological observations resemble features of achalasia and the mechanism of the tonic pressure increase at this early time point appears to be due to a non-cholinergic mechanism.

Neuropeptide Y- and peptide YY-containing colonic cells increase with ageing in male rats.

Colonic mucosal cells are known to contain several neuropeptides. The distribution of various peptide-containing cells in the colon and their possible modulation by aging and diet are unknown. We quantitated various peptide-containing cells from male Lobund-Wistar rat colon at 2, 22, 28, 30 and 33 months of age using indirect immunohistochemical techniques for several peptides including: neuropeptide Y, peptide YY, somatostatin, and chromogranin A. Four diets, varying in total calories and fat content, were examined. Serum gastrin was quantified by RIA at 2 and 33 months. Only NPY-, PYY- and SOM-positive cells were found in the colon. The number per crypt of neuropeptide Y-positive (0.55 +/- 0.04 at 2 months vs 0.80 +/- 0.22 at 33 months, P = 0.015) and peptide YY-positive cells increased with age. Staining for somatostatin and chromogranin, a marker for all enterochromaffin (EC) cells, revealed no change with aging. Diet did not influence the numbers of any peptide-containing cell. Serum gastrin was not different between the groups. A specific increase in NPY- and PYY-positive cells occurs in the aged rat colon. The extent to which this change may be related to age-related colonic dysmotility seen in elderly humans is worthy of exploration.

Electrophysiological and pharmacological responses of chronically denervated lower esophageal sphincter of the opossum.

BACKGROUND & AIMS: Achalasia is characterized by loss of myenteric neurons and incomplete relaxation of the lower esophageal sphincter (LES). The aim of this study was to develop an achalasia model in the opossum using the surfactant benzyldimethyltetradecylammonium chloride (BAC). This study further characterizes the achalasia model. METHODS: BAC or saline was injected circumferentially into the LES of 14 adult opossums. Eight months after injection, manometry, isolated muscle bath studies, electrical field stimulation, and histochemical analysis were performed. RESULTS: Manometrically, the LES of BAC-treated opossums showed higher pressures (38.7 +/- 12 mm Hg vs. 17 +/- 3.0 mm Hg) and reduced esophageal body contraction amplitudes (4.2 +/- 3 mm Hg vs. 27.4 +/- 12 mm Hg). Isolated muscle strips challenged with carbachol and sodium nitroprusside contracted and relaxed similarly to controls. Electrical field stimulation failed to induce relaxation in BAC-treated tissue but did induce contraction. Contractile responses were markedly reduced by tetrodotoxin and atropine in BAC-treated animals and controls. An altered nitric oxide system was shown by the lack of response to L-arginine and N omega-nitro-L-arginine. Histology showed loss of myenteric neurons and increased cholinergic nerve bundles. CONCLUSIONS: Loss of NO inhibitory myenteric neurons markedly reduces the relaxation of the LES, and histology and pharmacological responses suggest a proliferation of cholinergic nerves into the LES contributing to the static elevated pressures of the amyenteric LES.

Peptidergic and nitrinergic denervation in congenital esophageal stenosis.

Congenital esophageal stenosis (CES) is a rare disorder with narrowed esophageal lumen that presents as dysphagia from childhood and that is often associated with tracheobronchial remnants or webs. The pathogenesis of CES is unknown. The aim of this study was to examine the histological and immunohistochemical features of CES. Esophagi from 2 young adults with CES and 3 controls with no motility disorders underwent routine H&E staining, trichrome staining for collagen, and detailed immunocytochemical studies for general neuronal markers (protein gene product 9.5, neuron-specific enolase, and S-100) and neurotransmitters (vasoactive intestinal polypeptide, substance P, and galanin) and nitric oxide synthase by beta-nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and a specific NO synthase antibody. Quantitative experiments compared the numbers of myenteric neurons and amounts of fibers at the circular muscle. CES esophagi showed infiltration of neutrophils in the myenteric plane, without any increase in collagen. NADPH-diaphorase histochemistry showed a significant reduction of myenteric nitrinergic neurons (7 +/- 3.4 vs. 2.7 +/- 1.8 neurons per high-power field) and fibers at the circular muscle. Other peptidergic neurons studied were not significantly reduced in CES. The specific total lack of NO inhibitory innervation may be an important mechanism in the pathogenesis of stenosis and aperistalsis of the esophagus in this disorder.

Nitrinergic and peptidergic innervations and their inter-relationships in human colon.

The distribution and colocalization of nitrinergic and peptidergic nerves were examined in six human colons. The tissues were fixed, cryosectioned, and standard immunohistochemistry was performed for several known neuropeptides. The same sections were stained for NADPH-diaphorase to denote nitric oxide synthase. NADPH-diaphorase-positive myenteric neurons were counted and colocalization noted for each peptide, as well as for peptide terminations. Galanin was the only neuropeptide that colocalized to a significant extent (23.0 +/- 7.21%) with NADPH-diaphorase-positive myenteric neurons. Many neuropeptide-containing nerve fibers had extensive terminations onto NADPH-diaphorase-positive neurons. Vasoactive intestinal peptide was the only neuropeptide that colocalized with NADPH-diaphorase to any extent in nerve fibers within circular muscle (59.5 +/- 9.3%). Fiber distribution in the longitudinal muscles showed a similar, but less dense pattern. These observations provide morphological evidence for the presence of nitric oxide, a candidate nonadrenergic noncholinergic neurotransmitter in the human colon.

Postnatal depression: a Christchurch study.

AIMS: The aims of the study were to enquire into the incidence of postnatal depression (PND) and factors associated with it, in a New Zealand population. METHODS: A wide ranging postal questionnaire, which included the Edinburgh postnatal depression scale (EPDS), was administered to a sample of 1330 women 6-9 months after the birth of their babies at Christchurch Women's Hospital, in 1991/2. RESULTS: Measured on the EPDS, 80% of the women were not depressed, 7% were at a threshold level of depression and 13% were more severely depressed. Only 6% recognised their symptoms as depression. The factors having the greatest association with high depression scores were: depressive symptoms before and during the pregnancy; serious deterioration in the partner relationship after the birth; decreased energy, confidence and happiness levels after the pregnancy; moderate or severe premenstrual tension prepregnancy; frequent nausea in later pregnancy; low education and low income. CONCLUSIONS: Postnatal depression appears to be more widespread than is generally realised. The findings suggest that, at the time of postnatal checks on the baby, greater use could be made of the EPDS to increase confidence in a diagnosis of depression. Involvement of male partners in the treatment process is highly desirable.

Nitrinergic and peptidergic innervation of the human oesophagus.

The distribution, colocalisation, and interconnections of nitrinergic and peptidergic neurons and nerves in the human oesophagus were examined. Cryosections of surgically resected tissues from eight subjects were studied with indirect immunofluorescence for the presence of 11 neuropeptides and neuron specific enolase. After immunohistochemistry, nitric oxide synthase was shown on the same sections with the beta nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemical reaction. The histochemical findings were verified immunohistochemically on other sections with an antiserum against nitric oxide synthase. Most myenteric neurons (55%) were nitrinergic. Most (96%) received terminations positive for vasoactive intestinal polypeptide (VIP), calcitonin gene related peptide (CGRP) (80%), and galanin (59%). The neuronal somata of 14% also contained VIP, while 10% had galanin. Of the NADPH-diaphorase containing fibers seen in the muscle layers, many had closely associated VIP and galanin, but only rarely CGRP and substance P. Thus, despite abundant representation of both peptidergic and nitrinergic systems in oesophageal smooth muscle, only VIP and galanin colocalised to any significant extent with the nitrinergic elements. These findings provide morphological support for the role of nitric oxide as the non-adrenergic non-cholinergic inhibitory mediator in the human oesophagus and for its possible interactive role with the peptidergic system.

Early development of glycine- and GABA-mediated synapses in rat spinal cord.

Motoneuron responses to the inhibitory amino acids glycine and GABA, and the contribution of inhibitory synapses to developing sensorimotor synapses were studied in rat spinal cords during the last week in utero. In differentiating motoneurons, glycine and GABA induced Cl(-)-dependent membrane depolarizations and large decreases in membrane resistance. These responses gradually decreased during embryonic development, and at birth they were significantly smaller than in embryos. In motoneurons of embryos and neonates, dorsal root stimulation produced only depolarizing potentials, some of which reversed at -50 mV membrane potential. Reduction of extracellular Cl- concentrations increased the amplitude of these potentials, suggesting that they are generated by Cl- current. Contribution of Cl(-)-dependent potentials to compound dorsal root-evoked potentials was studied by determining the effects of glycine and GABA antagonists on them. In motoneurons of embryos at days 16-17 of gestation (D16-D17), strychnine or bicuculline blocked dorsal root-evoked potentials. This suppression was neither the result of a decrease in neuronal excitability nor the inhibition of glutamate receptors. Strychnine-evoked depression was not blocked by atropine, indicating that it was not due to disinhibition of muscarinic synapses. By D19, strychnine and bicuculline significantly increased dorsal root-evoked potentials rather than blocking them. This reversed function did not result from an increase in neuronal excitability or changes in the specificity of strychnine and bicuculline antagonism. The number of glycine- and GABA-immunoreactive cells increased 20% between D17 and D19. The number of immunoreactive cells and fibers significantly increased in the motor nuclei and dorsal horn laminae. These morphological changes may contribute to establishment of new synaptic contacts on motoneurons, thus changing the actions of strychnine and bicuculline on dorsal root-evoked potentials.