Utility of barium studies for patients with recurrent weight gain after Roux-en-Y gastric bypass.

AIM: To determine the utility of barium studies for detecting abnormalities responsible for recurrent weight gain after gastric bypass surgery. METHODS: A computerized search identified 42 patients who had undergone barium studies for recurrent weight gain after gastric bypass and 42 controls. The images were reviewed to determine the frequency of staple-line breakdown and measure the length/width of the pouch and gastrojejunal anastomosis. A large pouch exceeded 6 cm in length or 5 cm in width and a wide anastomosis exceeded 2 cm. Records were reviewed for the amount of recurrent weight gain and subsequent weight loss after additional treatment. RESULTS: Staple-line breakdown was present in 6/42 patients (14%) with recurrent weight gain. When measurements were obtained, 13/35 patients (37%) with recurrent weight gain had a large pouch, three (9%) had a wide anastomosis, and four (11%) had both, whereas 22/42 controls (52%) had a large pouch, one (2%) had a wide anastomosis, and two (5%) had both. Ten patients (24%) with recurrent weight gain underwent staple-line repair (n = 3) or pouch/anastomosis revision (n = 7). These 10 patients had a mean weight loss of 38.1 lbs versus a mean loss of 8.6 lbs in 19 patients managed medically. CONCLUSION: Only 14% of patients with recurrent weight gain after gastric bypass had staple-line breakdown, whereas 57% had a large pouch, wide anastomosis, or both. Not all patients with abnormal anatomy had recurrent weight gain, but those who did were more likely to benefit from surgical intervention than from medical management.

Utility of chest CT for differentiating primary and secondary achalasia.

AIM: To determine the computed tomography (CT) findings of primary and secondary achalasia and to assess the utility of CT for differentiating these conditions. METHODS: A computerized search revealed 13 patients with primary achalasia and 15 with secondary achalasia who underwent chest CT during a 10-year period. The images were reviewed to determine whether there was distal oesophageal narrowing (including the length/contour of narrowing), oesophageal dilation, oesophageal wall thickening (including degree/symmetry/pattern of thickening), a soft-tissue mass at the gastro-oesophageal junction, mediastinal adenopathy, or other findings of malignant tumour. RESULTS: Eleven (85%) of 13 patients with primary achalasia had distal oesophageal narrowing at CT that was smooth in all patients; four (31%) had oesophageal wall thickening that was smooth and symmetric in all patients; none had a soft-tissue mass at the gastro-oesophageal junction or mediastinal lymphadenopathy; and two (15%) had pulmonary metastases from unrelated lung cancers. In contrast, 12 (80%) of 15 patients with secondary achalasia had distal oesophageal narrowing at CT; 11 (73%) had distal oesophageal wall thickening that was nodular/lobulate and asymmetric in seven (64%) and smooth and symmetric in four (36%); six (40%) had a soft-tissue mass at the gastro-oesophageal junction; seven (47%) had mediastinal lymphadenopathy; and all 15 had other findings of malignant tumour. CONCLUSION: CT is a useful technique for differentiating primary and secondary achalasia. Distal oesophageal wall thickening that is nodular/lobulate and asymmetric, a soft-tissue mass at the gastro-oesophageal junction, mediastinal lymphadenopathy, and pulmonary, hepatic, or osseous metastases are findings that favour secondary achalasia.

Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice.

Inactivation of the mouse homologue of the Huntington disease gene (Hdh) results in early embryonic lethality. To investigate the normal function of Hdh in the adult and to evaluate current models for Huntington disease (HD), we have used the Cre/loxP site-specific recombination strategy to inactivate Hdh expression in the forebrain and testis, resulting in a progressive degenerative neuronal phenotype and sterility. On the basis of these results, we propose that huntingtin is required for neuronal function and survival in the brain and that a loss-of-function mechanism may contribute to HD pathogenesis.

Thalamocortical Projections Are Significantly Impaired in the R6/2 Mouse Model of Huntington's Disease.

As Huntington's disease (HD) progresses, there is a significant loss of neurons in the striatum in addition to a distinct thinning of the cerebral cortex. Despite an early presence of sensorimotor deficits in patients with HD, electrophysiological studies designed to assess the integrity of thalamocortical circuits are sparse. Using the R6/2 mouse model of HD, we provide evidence of reduced connectivity between thalamic cells and their targeted cortical regions. Whole-cell patch clamp recordings from ventral anterolateral nucleus (VAL; motor) and ventral posteromedial nucleus (VPM; somatosensory) thalamic neurons in ex vivo brain slices of R6/2 and wild-type (WT) mice revealed that cells in both thalamic nuclei of R6/2 mice exhibited significant differences in passive and active cell membrane properties (smaller cell membrane capacitances, faster decay time constants and increased input resistances) compared with WT cells. Although only cells in the VPM of symptomatic R6/2 mice had more depolarized resting membrane potentials compared with WTs, cells in both nuclei displayed increased excitability in symptomatic, but not presymptomatic, R6/2 mice. Optical activation of VAL and VPM terminals elicited smaller magnitude current responses in cortical pyramidal neurons (CPNs) in both motor cortex (M1CTX) and somatosensory barrel cortex (BCTX) of symptomatic R6/2 mice compared with CPNs in WT mice. Furthermore, we observed a decrease in the frequency of thalamocortical excitatory quantal events in R6/2 BCTX CPNs, with no genotype-dependent differences in AMPA:NMDA response amplitude ratios. These data suggest there is a decrease in the transmission of thalamocortical information that is likely because of impaired neurotransmitter release.

Alterations in corticostriatal synaptic plasticity in mice overexpressing human alpha-synuclein.

Most forms of Parkinson's disease (PD) are sporadic in nature, but some have genetic causes as first described for the alpha-synuclein gene. The alpha-synuclein protein also accumulates as insoluble aggregates in Lewy bodies in sporadic PD as well as in most inherited forms of PD. The focus of the present study is the modulation of synaptic plasticity in the corticostriatal pathway of transgenic (Tg) mice that overexpress the human alpha-synuclein protein throughout the brain (ASOTg). Paired-pulse facilitation was detected in vitro by activation of corticostriatal afferents in ASOTg mice, consistent with a presynaptic effect of elevated human alpha-synuclein. However basal synaptic transmission was unchanged in ASOTg, suggesting that human alpha-synuclein could impact paired-pulse facilitation via a presynaptic mechanism not directly related to the probability of neurotransmitter release. Mice lacking alpha-synuclein or those expressing normal and A53T human alpha-synuclein in tyrosine hydroxylase-containing neurons showed, instead, paired-pulse depression. High-frequency stimulation induced a presynaptic form of long-term depression solely in ASOTg striatum. A presynaptic, N-methyl-d-aspartate receptor-independent form of chemical long-term potentiation induced by forskolin (FSK) was enhanced in ASOTg striatum, while FSK-induced cAMP levels were reduced in ASOTg synaptoneurosome fractions. Overall the results suggest that elevated human alpha-synuclein alters presynaptic plasticity in the corticostriatal pathway, possibly reflecting a reduction in glutamate at corticostriatal synapses by modulation of adenylyl cyclase signaling pathways. ASOTg mice may recapitulate an early stage in PD during which overexpressed alpha-synuclein dampens corticostriatal synaptic transmission and reduces movement.

Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice.

Huntington's disease is a neurodegenerative disorder, caused by an elongation of CAG repeats in the huntingtin gene. Mice with an insertion of an expanded polyglutamine repeat in the mouse huntingtin gene (knock-in mice) most closely model the disease because the mutation is expressed in the proper genomic and protein context. However, few knock-in mouse lines have been extensively characterized and available data suggest marked differences in the extent and time course of their behavioral and pathological phenotype. We have previously described behavioral anomalies in the open field as early as 1 month of age, followed by the appearance at 2 months of progressive huntingtin neuropathology, in a mouse carrying a portion of human exon 1 with approximately 140 CAG repeats inserted into the mouse huntingtin gene. Here we extend these observations by showing that early behavioral anomalies exist in a wide range of motor (climbing, vertical pole, rotarod, and running wheel performance) and non-motor functions (fear conditioning and anxiety) starting at 1-4 months of age, and are followed by progressive gliosis and decrease in dopamine and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP32) (12 months) and a loss of striatal neurons at 2 years. At this age, mice also present striking spontaneous behavioral deficits in their home cage. The data show that this line of knock-in mice reproduces canonical characteristics of Huntington's disease, preceded by deficits which may correspond to the protracted pre-manifest phase of the disease in humans. Accordingly, they provide a useful model to elucidate early mechanisms of pathophysiology and the progression to overt neurodegeneration.

CREB controls cortical circuit plasticity and functional recovery after stroke.

Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.

Murine Hox-1.7 homeo-box gene: cloning, chromosomal location, and expression.

A new murine homeo-box, called Hox-1.7, has been identified in a rare cDNA from F9 teratocarcinoma stem cells. The Hox-1.7 homeo-box is 68 and 72% homologous to the Drosophila antennapedia (Antp) and iab-7 homeo-boxes, respectively. A major 2.5-kilobase transcript and several minor transcripts were detected by Northern blot (RNA blot) analysis in adult tissues as well as in midgestational embryos. The posterior spinal cord was found to be a major site of Hox-1.7 expression in 12.5-day-old embryos. Somatic cell hybrids were used to map the Hox-1.7 gene to mouse chromosome 6. Restriction fragment length polymorphisms associated with either the Hox-1.7 gene or the previously known Hox-1 complex were identified. Their distribution patterns in recombinant inbred mouse strains were used to determine the linkage between the two loci as well as to other loci on chromosome 6. This maps Hox-1 and Hox-1.7 close to two mouse loci that affect morphogenesis, postaxial hemimelia (px) and hypodactyly (Hd).

Are neostriatal dopamine receptors co-localized?

The postsynaptic effects of dopamine in the neostriatum are mediated by five G-protein-coupled receptors. The extent to which these receptors are co-localized in neostriatal neurons has become controversial. This debate has far-reaching implications for treatment strategies in disorders of dopaminergic signaling, such as Parkinson's disease and schizophrenia. This review examines the molecular and cellular evidence for and against co-localization, including new information derived from single-cell mRNA amplification and patch-clamping of isolated neurons. It is concluded that this evidence is largely consistent with co-localization of functionally significant receptors of the D1 and D2 families in the majority of neostriatal efferent neurons. This conclusion has important implications for parallel processing models of the neostriatum.

Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein.

Overexpression of alpha-synuclein causes familial Parkinson's disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/L-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. l-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of alpha-synuclein led to abnormal pharmacological responses in mice.

Dopamine D4 receptor-deficient mice display cortical hyperexcitability.

The dopamine D(4) receptor (D(4)R) is predominantly expressed in the frontal cortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. However, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D(4)R agonists and antagonists the selectivity and efficacy of which have been rigorously demonstrated in vivo. We have attempted to overcome this limitation by taking a multidimensional approach to the characterization of mice completely deficient in this receptor subtype. Electrophysiological current and voltage-clamp recordings were performed in cortical pyramidal neurons from wild-type and D(4)R-deficient mice. The frequency of spontaneous synaptic activity and the frequency and duration of paroxysmal discharges induced by epileptogenic agents were increased in mutant mice. Enhanced synaptic activity was also observed in brain slices of wild-type mice incubated in the presence of the selective D(4)R antagonist PNU-101387G. Consistent with greater electrophysiological activity, nerve terminal glutamate density associated with asymmetrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D(4)R can function as an inhibitory modulator of glutamate activity in the FC.

Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington's disease.

Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.

Transient failure of opening of the lower oesophageal sphincter on upright oesophagrams: radiographic and clinical findings.

The purpose of our study was to determine the frequency, radiographic features, and clinical importance of transient failure of opening of the lower oesophageal sphincter (LOS) on upright double-contrast views of the oesophagus. A computerized search of radiology records identified 16 patients who had transient failure of opening of the LOS on upright views from biphasic oesophagrams or upper gastrointestinal tract examinations using high-density barium but normal opening of the LOS on prone views using low-density barium. The radiographic findings were reviewed and correlated with the clinical and manometric findings. In all cases, barium studies revealed tapered, beaklike narrowing of the distal oesophagus on upright double-contrast views, with a normal-appearing distal oesophagus, normal opening of the LOS, and intact peristalsis on prone single-contrast views. Only seven patients (44%) had dysphagia. Five of these patients had clinical follow-up, and the dysphagia improved or resolved without specific treatment for LOS dysfunction in four. The remaining patient had persistent dysphagia, but this individual had polymyositis as the likely cause for his dysphagia. Manometry revealed incomplete relaxation of the LOS in two patients and normal relaxation in one. Our experience suggests that failure of opening of the LOS may be observed as a transient finding of little clinical importance on upright double-contrast views of the oesophagus using high-density barium, with normal opening of the LOS on prone single-contrast views using low-density barium. It is important to be aware of this finding, so that it is not mistaken for achalasia or other abnormalities of the distal oesophagus.

Dopaminergic function in the neostriatum and nucleus accumbens of young and aged Fischer 344 rats.

Age-dependent alterations in behavioral and neuronal functioning were assessed in young (2-3 month), middle-aged (12 month), and aged (24 month) Fischer 344 rats treated with the indirect dopamine agonist amphetamine (2.25 or 5 mg/kg), the D1 agonist SKF 38393 (7.5, 15, 30 mg/kg), or the D2 agonist quinpirole (0.3, 1.0, 3.0 mg/kg). Drug-induced changes in activity and stereotypy were measured during a 90-min testing session, with Fos immunohistochemistry being used to assess the neuronal response to dopamine agonist treatment. As expected, aged rats given amphetamine (5 mg/kg) had fewer activity counts and higher stereotypy scores than young rats. Middle-aged rats also had fewer activity counts but were similar in stereotypy scores to young rats. Amphetamine also induced different patterns of Fos immunoreactivity in the neostriatum and nucleus accumbens of young and aged rats, as Fos expression in aged rats exhibited a distinctive dorsal to ventral pattern of decline. In general, SKF 38393 had few age-related actions, although aged rats did show a slight relative increase in stereotypy. In contrast, the D2 agonist quinpirole substantially enhanced the motor activity and Fos expression of young rats, while only modestly affecting aged rats. Hence, these results suggest that the D2 receptor is more vulnerable to the effects of aging than the D1 receptor.

Sensory, motor and cognitive alterations in aged cats.

These experiments were designed to assess some of the sensory, motor and cognitive alterations that occur in aged cats. Three groups of cats (1-3, 5-9 and 11-16 years of age) were tested in four behavioral tasks to assess age-dependent changes in locomotor activity, fine motor coordination, reactivity to auditory stimuli and spatial reversal learning. In tests of locomotor activity, 11-16 year old cats displayed altered patterns of habituation compared to 1-3 and 5-9 year cats. There were no decrements in fine motor coordination in the 11-16 year cats as measured by their ability to traverse planks of varying width or by their scores on a neurological examination. The 11-16 and 5-9 year cats both displayed increased reactivity to auditory stimuli. On tests of spatial reversal learning, 11-16 year cats displayed superior performance compared to 5-9 or 1-3 year animals, making fewer errors and requiring fewer trials to reach criterion. These findings indicate that a series of age-related behavioral changes occurs in the cat. Some of these may be related to morphological and neurophysiological alterations in neurons in the caudate nucleus.

Quantitative morphology of medium-sized caudate spiny neurons in aged cats.

These studies were designed to assess some of the morphological alterations that occur in medium-sized spiny neurons of the caudate nucleus in aged cats. Computer assistance was used to quantify in three dimensions the extent of the dendritic trees of 164 neurons from 11 cats (5 1-3 years and 6 over 10 years of age) stained by the rapid Golgi technique. In all animals beyond 10 years of age there was a decrease in the density of spines on distal dendritic segments. This decrease was moderate (16%) in 13 year old cats and reached about 50% in 15 and 18 year old animals. In addition, there was an increase in the frequency of occurrence of spines with enlarged heads in all aged cats. In cats over 13 years there was a marked loss of portions of distal dendritic segments. All measures of dendrite length displayed statistically significant decreases of 30-40% in cats 15 and 18 years of age. There were no significant age-related alterations in numbers of dendrites, number of branches per dendrite or soma diameter. These morphological results indicate that there is a sequence of age-related changes that occurs in caudate medium-sized spiny neurons and provides a basis from which to assess functional alterations.

A process of establishing norms for inpatients length of stay in a community mental health center.

A pervasive sense of urgency, stimulated by the Social Security Amendments of 1972 (Public Law 92-603), attends the need to establish norms for length of stay for impatient services in mental health facilities and to provide review mechanisms for extended care cases. The authors describe one model, adaptable to changing needs and federal regulations, that can offer a beginning experience in this endeavor.

Postnatal development of caudate input neurons in the cat.

Lectin-bound horseradish peroxidase (WG-HRP) was pressure-injected into the caudate nucleus (Cd) of neonatal (less than 24 hours of age) and adult cats in order to assess the postnatal development of monosynaptic Cd input neurons. Tissue was processed for peroxidase activity with a benzidine dihydrochloride chromagen. The injection of WG-HRP produced relatively similar labelled zones of marker uptake in the caudate nuclei of both neonates and adults. Similar axonal projections were also labelled in both age groups. While many characteristics of retrogradely labelled CD input neurons were apparently constant throughout postnatal life, each of these features had a particular developmental modification. (1) Regardless of age, neuronal somata that projected to the CD were located in the neocortex, thalamus, substantia nigra, mesencephalic raphe nuclei, and globus pallidus. In each of these brain sites, labelled CD input neurons appeared to migrate postnatally. (2) The Cd afferent axons originated from the same neuronal lines in neonates and adults--small-to-medium-sized cortical neurons and medium-sized-to-large fusiform cells in all other brain sites. In each of the brain sites, labelled neurons displayed marked postnatal somatic growth. (3) In both age groups, there was a characteristic intrasomatic reaction product density in the labelled neurons located in each brain site (substantia nigra greater than thalamus = raphe = globus pallidus greater than cortex). In each of these brain sites, the intrasomatic reaction product density was less in neonates than in adults.

GABAergic basal forebrain neurons project to the neocortex: the localization of glutamic acid decarboxylase and choline acetyltransferase in feline corticopetal neurons.

Our objective was to determine whether GABAergic and cholinergic basal forebrain neurons project to the neocortex. The retrograde connectivity marker wheat germ agglutinin lectin-bound horseradish peroxidase was injected into the neocortex of adult cats. Histo- and immunohistochemical methods were combined to label sequentially connectivity and transmitter markers (glutamic acid decarboxylase; choline acetyltransferase) in forebrain neurons. The labels of each marker were identified by correlative light and electron microscopy. Two principal types of doubly labeled neurons were demonstrated. The connectivity marker was colocalized with glutamic acid decarboxylase or choline acetyltransferase. The neurons were located in the basal forebrain. Their ultrastructural, cellular, and regional organization supported 2 conclusions. (1) GABAergic basal forebrain neurons project to the neocortex. This is important new morphological evidence for the origin of inhibitory neocortical afferents from a subcortical brain site. (2) The GABAergic and cholinergic basal forebrain neurons projecting to the neocortex exhibit remarkable structural similarities. The transmitter diversity of these intertwined neocortical afferents may be significant for the pathology and treatment of human neurological disorders such as Alzheimer's disease.

Patterns of tachykinin expression and localization in developing feline neostriatum.

The development of tachykinins in the neostriatum was determined qualitatively in order to characterize the ontogeny of an early-forming neostriatal peptidergic system. Tachykinins were detected by immunohistochemistry in fetal, postnatal, and adult cats. Neostriatal cells and neurites expressed tachykinins as early as fetal age 30 and increased in frequency progressively with age. Initial tachykinin expression occurred in neostriatal neurons during their postmitotic migration. In the head of the caudate nucleus, clusters of tachykinin-containing cells and fibers formed between fetal days 35 and 45, when the distribution of labeled neurons changed from a dispersed to an aggregated pattern. Between fetal days 45 and 50, tachykinin-rich neuronal clusters increased in frequency and were distributed throughout the rostral caudate nucleus. In contrast to neurons in clusters, neurons in the complementary neuropil expressed tachykinins largely postnatally. Postnatal morphological maturation of tachykinin-containing neurons paralleled the morphogenesis of medium spiny neostriatal cells. In addition, the caudate nucleus and putamen followed different spatiotemporal gradients of tachykinin expression. These results indicate that tachykinins are expressed in neostriatal neurons during the early ontogeny of the neostriatum and may function as trophic factors before synaptogenesis.