bluuebunny/crossref_metadata_2025 huggingface dataset:
Trigger Factor and DnaK possess overlapping substrate pools and binding specificities
Authors: Deuerling Elke , Patzelt Holger , Vorderwülbecke Sonja , Rauch Thomas , Kramer Günter , Schaffitzel Elke , Mogk Axel , Schulze‐Specking Agnes , Langen Hanno , Bukau Bernd
Published: March 2003

Ribosome‐associated Trigger Factor (TF) and the DnaK chaperone system assist the folding of newly synthesized proteins in Escherichia coli. Here, we show that DnaK and TF share a common substrate pool in vivo. In TF‐deficient cells, Δtig, depleted for DnaK and DnaJ the amount of aggregated proteins increases with increasing temperature, amounting to 10% of total soluble protein (approximately 340 protein species) at 37°C. A similar population of proteins aggregated in DnaK depleted tig+ cells, albeit to a much lower extent. Ninety‐four aggregated proteins isolated from DnaK‐ and DnaJ‐depleted Δtig cells were identified by mass spectrometry and found to include essential cytosolic proteins.

Four potential in vivo substrates were screened for chaperone binding sites using peptide libraries. Although TF and DnaK recognize different binding motifs, 77% of TF binding peptides also associated with DnaK. In the case of the nascent polypeptides TF and DnaK competed for binding, however, with competitive advantage for TF. In vivo, the loss of TF is compensated by the induction of the heat shock response and thus enhanced levels of DnaK. In summary, our results demonstrate that the co‐operation of the two mechanistically distinct chaperones in protein folding is based on their overlap in substrate specificities.
Cytochrome c oxidase genes required for nitrogenase activity and diazotrophic growth in Anabaena sp. PCC 7120
Authors: Valladares Ana , Herrero Antonia , Pils Dietmar , Schmetterer Georg , Flores Enrique
Published: March 2003

N2 fixation is an O2‐sensitive process and some filamentous diazotrophic cyanobacteria that grow performing oxygenic photosynthesis confine their N2 fixation machinery to heterocysts, specialized cells that maintain a reducing environment adequate for N2 fixation. Respiration is thought to contribute to the diazotrophic metabolism of heterocysts and the genome of the heterocyst‐forming cyanobacterium Anabaena sp. PCC 7120 bears three gene clusters putatively encoding cytochrome c oxidases. Transcript analysis of these cox gene clusters through RNA/DNA hybridization identified two cox operons, cox2 and cox3, that are induced after nitrogen step‐down in an NtcA‐ and HetR‐dependent manner and appear to be expressed specifically in heterocysts. In contrast, cox1 was expressed only in vegetative cells. Expression of cox2 and cox3 occurred at an intermediate stage (about 9 h) during the process of heterocyst development following nitrogen step‐down. Inactivation of genes in the two inducible cox operons, but not separately in either of them, strongly reduced nitrogenase activity and prevented diazotrophic growth in aerobic conditions. These results show that the nitrogen‐regulated cytochrome c oxidase‐type respiratory terminal oxidases Cox2 and Cox3 are essential for heterocyst function in Anabaena sp. PCC 7120.
An integrated analysis of the genome of the hyperthermophilic archaeon Pyrococcus abyssi
Authors: Cohen Georges N. , Barbe Valérie , Flament Didier , Galperin Michael , Heilig Roland , Lecompte Odile , Poch Olivier , Prieur Daniel , Quérellou Joël , Ripp Raymond , Thierry Jean‐Claude , Van der Oost John , Weissenbach Jean , Zivanovic Yvan , Forterre Patrick
Published: March 2003

The hyperthermophilic euryarchaeon Pyrococcus abyssi and the related species Pyrococcus furiosus and Pyrococcus horikoshii, whose genomes have been completely sequenced, are presently used as model organisms in different laboratories to study archaeal DNA replication and gene expression and to develop genetic tools for hyperthermophiles. We have performed an extensive re‐annotation of the genome of P. abyssi to obtain an integrated view of its phylogeny, molecular biology and physiology. Many new functions are predicted for both informational and operational proteins. Moreover, several candidate genes have been identified that might encode missing links in key metabolic pathways, some of which have unique biochemical features. The great majority of Pyrococcus proteins are typical archaeal proteins and their phylogenetic pattern agrees with its position near the root of the archaeal tree. However, proteins probably from bacterial origin, including some from mesophilic bacteria, are also present in the P. abyssi genome.
A novel portable perfused manometric system for recording of small intestinal motility
Authors: Samsom  , Smout  , Hebbard  , Fraser  , Omari  , Horowitz  , Dent
Published: March 2003

The development of solid‐state catheters with miniature pressure transducers and portable dataloggers with a large memory capacity has allowed recording of gastrointestinal motility in ambulant subjects. Developments in silicone rubber extrusion technology made it possible to build a perfused mano‐metric system, using a perfused manometric assembly requiring a low volume of perfusate. In the present study the feasibility of recording and automated analysis of small intestinal motility using a perfused multiple lumen manometric system was evaluated in seven healthy volunteers. Pressures were recorded from 12 sideholes arranged in four clusters spaced at 10‐cm intervals from the catheter tip. Each channel was perfused at 0.15 mL min−1 with degassed water by a portable, low‐compliance, perfusion pump. The 12 sidehole recording channels were connected to external transducers mounted on a belt. Pressure data were stored in two dataloggers. Motility was recorded in the sitting (30 min), and supine (30 min) position, during walking (30 min) and postprandially (90 min). Using purpose‐built software baseline variations were corrected for and manometric variables (number of pressure waves, mean amplitude and motility index) calculated. Bench testing of the manometric assembly showed a median baseline pressure offset of 4.2 kPa (range 3.7–10.1) and upon occlusion a rise rate of 27.8 kPa sec−1 (range 19.7–30.8). Changes in body position affected baseline pressures so that compared to the supine position changes in baseline pressure varied between 1.5 ± 0.7 kPa and 1.9 ± 0.6 kPa during sitting (P < 0.02), and between 1.7 ± 0.7 kPa and 1.5 ± 0.9 kPa during walking (P < 0.03). Manometric recordings obtained during the fasting period showed an increase in small intestinal motor activity during walking. In the postprandial period no differences in motility variables were observed within one cluster and in time. Recording of small intestinal motility with a multiple‐channel silicone rubber manometric assembly with a portable perfusion system is a feasible technique which is relatively inexpensive. Computer‐assisted data processing allows for adequate elimination of artefacts and automated numerical analysis.
In vitro motility disorders associated with displaced abomasum in dairy cows
Authors: GEISHAUSER  , REICHE  , SCHEMANN
Published: March 2003

The objective of this study was to investigate in vitro abomasal motility in dairy cows diagnosed with displaced abomasum. Longitudinal muscle myenteric plexus preparations originating from the abomasal antrum of control cows, and cows diagnosed with left displaced abomasum (LDA), right displaced abomasum (RDA) or abomasal volvulus (AV) were used. In control preparations electrical field stimulation evoked an immediate cholinergic contractile response exceeding amplitude of basal contractions by 60%. In contrast, contractile activity was significantly inhibited during electrical stimulation in LDA, RDA and AV by 47%, 66% and 45%, respectively. This inhibition was reversed in the presence of L‐NAME. The staining intensity of NADPH‐positive myenteric neurones was significantly higher in displaced abomasa than in controls. Concentration– response curves indicated that preparations from displaced abomasa showed reduced sensitivity to acetylcholine. This study demonstrated motility disorders in displaced abomasa in vitro. The results suggested that abomasal displacement is associated with malfunctions at the level of the intrinsic nervous system combined with impaired cholinergic muscle responses. There appeared to be a predominance of nitrergic inhibitory mechanisms over excitatory mechanisms. These results might be of significance for diseases associated with gastric hypomotility and emptying disorders.
The effect of physical exercise on parameters of gastrointestinal function
Authors: Van Nieuwenhoven  , Brouns  , Brummer
Published: March 2003

Exercise decreases splanchnic bloodflow. Therefore exercise may induce alterations in gastrointestinal (GI) function. In the present study we investigated the effect of high‐intensity exercise on oesophageal motility, gastro‐oesophageal reflux, gastric pH, gastric emptying, orocaecal transit time (OCTT), intestinal permeability and glucose absorption simultaneously, using an ambulatory protocol.

Ten healthy well‐trained male subjects underwent a rest–cycling–rest, and a rest–rest–rest protocol (60–90–210 min). Oesophageal motility, gastro‐oesophageal reflux and intragastric pH was measured using a trans‐nasal catheter. OCTT was measured via breath H2 measurement. A sugar absorption test was applied to determine intestinal permeability and glucose absorption. Gastric emptying was measured using the 13C‐acetate breath test.

Peristaltic velocity was increased during cycling, compared to rest (4.92 (2.86) vs. 4.03 (1.48) cm s–1, P = 0.015). Peristaltic contraction pressure at the mid‐oesophagus and the duration of the peristaltic contractions at the mid‐ and distal oesophagus was lower during cycling. There were no differences between the pre‐exercise, the exercise and the post‐exercise episodes for gastric pH or for both the number and duration of reflux episodes, in both the rest and cycling trials. Neither gastric emptying nor OCTT showed differences between rest and cycling. The lactulose/rhamnose ratio and intestinal glucose absorption were significantly decreased in the cycling trial.

Our model enables multiple GI‐measurements during exercise. Cycling at 70% Wmax does not lead to differences in reflux, gastric pH or gastrointestinal transit in healthy trained individuals. The distal oesophageal pressure decreases and peristaltic velocity increases. The lactulose/rhamnose ratio and jejunal glucose absorption are decreased during exercise.
Glutamate receptors in the enteric nervous system: ionotropic or metabotropic?
Authors: Ren J. , Hu H‐Z. , Liu S. , Xia Y. , Wood J. D.
Published: March 2003

Intracellular recording methods were used to investigate actions of glutamate on morphologically identified neurones in the myenteric and submucous plexuses of guinea‐pig small intestine. Glutamate evoked a tetrodotoxin‐resistant, slowly activating depolarizing response in most of the submucous neurones (86 of 125, 69%) and a smaller number of myenteric neurones (6 of 60, 10%). The depolarizing responses were restricted to S‐type neurones with uniaxonal morphology. The group I metabotropic glutamate receptor (mGluRs) agonists quisqualate, 1S, 3R‐ACPD and DHPG mimicked the depolarizing action of glutamate. A group I mGluRs antagonist, S‐4‐carboxyphenylglycine (S‐4CPG), suppressed the glutamate responses with an IC50 of 357 μM at 30 μM glutamate. Group II or III mGluRs agonists did not produce depolarizing responses and group II or III mGluRs antagonists did not alter glutamate‐evoked depolarization. The ionotropic glutamate receptor (iGluRs) agonists NMDA, AMPA, or kainate did not evoke depolarizing responses and glutamate‐evoked depolarization was unaffected by the iGluRs antagonists D‐APV, MK‐801, or DNQX. No rapidly activating fast depolarizing responses reminiscent of fast excitatory postsynaptic potentials (EPSPs) were ever observed during application of glutamate or AMPA and stimulus‐evoked fast EPSPs were unaffected by DNQX. The results suggest that the excitatory action of glutamate on enteric neurones is mediated by group I metabotropic glutamate receptors and that ionotropic glutamate receptors are not involved. The results also suggest that glutamate‐mediated fast EPSPs may not be present in myenteric and submucous neurones in guinea‐pig small bowel.
Induction of cortical swallowing activity by transcranial magnetic stimulation in the anaesthetized cat
Authors: Hamdy S. , Xue S. , Valdez D. , Diamant N. E.
Published: March 2003

Transcranial magnetic stimulation (TMS) over human fronto‐central areas of scalp can activate short latency responses in the muscles of the face, pharynx and oesophagus. However, the physiological relationship between this early activity and the swallowing activity programmed by the brainstem central pattern generator (CPG) remains unclear. The aim of this study was to explore the relationship between TMS‐induced early muscle and late swallowing activities in the feline model. Twelve adult cats were studied under light anaesthesia. Mylohyoid and oesophageal EMG, together with pharyngeal, upper oesophageal sphincter (UOS) and upper oesophageal manometry, were recorded to single‐pulse TMS of cat cortex. TMS at low stimulation intensities evoked consistent short latency EMG responses in the mylohyoid and oesophageal muscles (6.1 ± 1.2 ms and 12.7 ± 0.7 ms, respectively), and early contractile activity in the UOS (latency 31.8 ± 3.6 ms). By contrast, TMS at high intensities induced swallowing activity as indicated by mylohyoid EMG, and UOS relaxation (latencies 1.1 ± 0.4 s and 0.8 ± 0.1 s, respectively). Both the early muscle and late swallowing activities were intensity‐dependent, increasing stimulus strength producing a reduction in latency and greater number of swallows. The characteristics of the early response suggest an oligosynaptic projection from cortex to swallowing muscles. The induction of swallows at high intensities suggests a requisite for greater recruitment of cortical motoneurones, or associated swallowing regions.
Gastric emptying: the validity of the paracetamol absorption test adjusted for individual pharmacokinetics
Authors: Medhus A. W. , Lofthus C. M. , Bredesen J. , Husebye E.
Published: March 2003

An algorithm for the paracetamol absorption test for gastric emptying, adjusting for individual pharmacokinetics, was recently developed. The aim of the present study was to validate the use of this algorithm. Furthermore, the algorithm was applied to elucidate whether a gastric tube interferes with the rate of gastric emptying. A caloric liquid meal with paracetamol was administered orally to nine healthy volunteers on two separate days. On one occasion, the subjects were intubated with a nasogastric tube and the meal was aspirated from the stomach 45 min after meal intake. The percentage of the meal retained in the stomach at the time of aspiration was determined by analyses of paracetamol in the aspirate and compared with calculations by the algorithm. On the other examination day, the same meal was ingested without tube and aspiration. The median percentage of the meal retained in the stomach at aspiration was 47% (range 33–70%) calculated by the algorithm and 48% (range 23–61%) based on the aspiration data. The correlation between the emptying parameters was r=0.97 (P < 0.001). The median of gastric emptying parameters was similar when the number of samples included in the calculation by the algorithm was reduced, but the range tended to increase. The gastric tube moderately inhibited gastric emptying during the period 20–40 min after meal intake (P < 0.05), but for the period from meal intake until start of aspiration, no inhibition was found. The present study demonstrates that the novel algorithm for the paracetamol absorption test provides valid estimates for gastric emptying.
Antropyloroduodenal, cholecystokinin and feeding responses to pulsatile and non‐pulsatile intraduodenal lipid infusion
Authors: VOZZO R. , SU Y‐C. , FRASER R. J. , WITTERT G. A. , HOROWITZ M. , MALBERT C. H. , SHULKES A. , VOLOMBELLO T. , CHAPMAN I. M.
Published: March 2003

The contribution of the pulsatile nature of gastric emptying to small intestinal feedback mechanisms modulating antropyloroduodenal motility and appetite is unknown. On separate days, eight healthy male volunteers (18–34 years) received randomized, single‐blind, intraduodenal (ID) infusions of 10% Intralipid (2 kcal min−1), either continuously [CID], or in a pulsatile manner [PID] (5 s on/15 s off) and 0.9% saline (control) administered continuously, each at a rate of 1.8 mL min−1 for 3 h. During each infusion, subjective ratings of appetite were assessed and antropyloroduodenal pressures recorded with a 16‐lumen manometric assembly incorporating a pyloric sleeve sensor. Plasma cholecystokinin was measured from blood collected at regular intervals throughout the infusion. At the end of each infusion the manometric assembly was removed, subjects were offered a buffet meal and the energy and macronutrient content of the meal was measured. Both ID lipid infusions stimulated isolated pyloric pressure waves (IPPWs) (P < 0.001) and basal pyloric pressure (P < 0.01) and suppressed antral (P < 0.05) and duodenal (P < 0.05) pressure waves when compared to controls; there was no difference in the effects of CID and PID lipid on antropyloroduodenal pressures. Infusions of lipid significantly increased plasma CCK concentrations (P < 0.05) compared with saline, but concentrations were not different between the two modes of lipid delivery (P > 0.05, CID vs. PID). Both intraduodenal lipid infusions decreased hunger (P < 0.05), increased fullness (P < 0.05) and reduced energy intake (P < 0.05) when compared with controls; again there was no difference between CID and PID lipid. We conclude that at the infusion rate of ∼ 2 kcal min−1, the acute effects of intraduodenal lipid on antropyloroduodenal pressures, plasma CCK concentration and appetite are not modified by a pulsatile mode of lipid delivery into the duodenum.
Impaired egress rather than increased access: an important independent predictor of erosive oesophagitis
Authors: Jones M. P. , Sloan S. S. , Jovanovic B. , Kahrilas P. J.
Published: March 2003

Abstract Oesophagitis severity is related to total oesophageal acid exposure, which is in turn dependent upon both the number reflux events and the rate of refluxate clearance. This study examined differences in the frequency of reflux events and the characteristics of oesophageal acid exposure in asymptomatic controls and gastro‐oesophageal reflux disease (GORD) patients both with and without oesophagitis. Nine controls and 38 patients with GORD were studied. All patients underwent upper endoscopy, videofluoroscopy, determination of resting lower oesophageal sphincter pressure (LOSP) and 24 h pH monitoring. Analysis was performed with subjects grouped as controls, non‐erosive GORD and oesophagitis. A second analysis was performed with subjects grouped by hiatal hernia size. Statistical comparisons were made using anovaand unpairedt‐tests. Patients with oesophagitis had significantly larger hiatal hernias, greater oesophageal acid exposure, more prolonged episodes of reflux and longer acid clearance times than did controls and patients with non‐erosive GORD. No significant difference was seen in the number of reflux events. Increasing hiatal hernia size was significantly associated with increasing oesophageal acid exposure, number of prolonged reflux events and prolonged acid clearance times. Oesophagitis patients have significantly greater oesophageal acid exposure than subjects with non‐erosive GORD. Increased oesophageal acid exposure in oesophagitis is attributable to impaired acid clearance and the greatest impairments in refluxate clearance occur in patients with large hiatal hernias.
Gastric electrical stimulation at proximal stomach induces gastric relaxation in dogs
Authors: Xing J. H. , Brody F. , Brodsky J. , Larive B. , Ponsky J. , Soffer E.
Published: March 2003

Abstract Gastric electrical stimulation (GES) improves symptoms in patients with gastroparesis. However, the underlying mechanisms remain unclear. To determine if GES at proximal and distal stomach could affect the biomechanical properties of the stomach, thus contributing to the beneficial effect of GES. Four pairs of electrodes were implanted along the greater curvature of the stomach in seven dogs. Gastric tone and compliance was assessed with a barostat. Measurements were obtained randomly during control and proximal and distal stimulation (4 mA, 375 ms and 6/18 cpm). Data as mean or median (25–75th percentiles). Gastric compliance was not affected by proximal and distal GES. Gastric tone was significantly reduced during proximal GES: 82.0 (66.8, 89.1) mL vs control 49.7 (39.6,75.9) mL at 6 cpm (P = 0.016), and 90.6 (54.5, 117.9) mL vs control 62.8 (39.6, 75.9) mL at 18 cpm (P = 0.031). Tone was not affected by distal GES at 6 cpm: 95.8 (46.3, 106.7) mL vs control 75.2 (49.7, 86.1) mL (P = 0.47) and at 18 cpm: 80.4 (38.1, 170.3) mL vs control 62.8 (44.6, 156.3) mL (P = 0.44). Proximal GES induces gastric relaxation. This effect, if seen also in humans, may explain, in part, the symptomatic improvement associated with GES therapy in patients with gastroparesis.
Endothelial changes in muscle and skin biopsies in patients with CADASIL
Authors: Ruchoux  , Maurage
Published: March 2003

Ruchoux M.‐M. & Maurage C.‐A. (1998) Neuropathology and Applied Neurobiology24, 60–65

Endothelial changes in muscle and skin biopsies in patients with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is characterized by the deposition of granular osmiophilic material in association with vascular smooth muscle cells in many different organs. However, the cause of the subsequent destruction of smooth muscle cells that are surrounded by granular osmiophilic material is unclear. In the present study, the ultrastructural changes that occur in endothelial cells in CADASIL have been evaluated by examining blood vessels in six skin biopsies and seven muscle biopsies belonging to three different CADASIL pedigrees. The appearances have been compared with five skin biopsies and five muscle biopsies from age‐matched controls without vascular disease. The most striking features observed in vessels in the skin of CADASIL patients were attenuation of endothelial cells and increased density of endothelial cytoplasm, accompanied by the presence of compact bundles of microfilaments within the cytoplasm of endothelial cells. Endothelial cells in muscle biopsies from CADASIL patients, on the other hand, were swollen until destruction of tight junctions were observed. These findings suggest that impaired permeability of vascular endothelium may play a role in the destruction of vascular smooth muscle cells in CADASIL. Furthermore, the results of this study suggest that further fine structural investigation of blood vessel endothelium and underlying smooth muscle may lead to a better understanding of the pathophysiology of CADASIL.
Local expression of cytokines in idiopathic inflammatory myopathies
Authors: Lepidi  , Frances  , Figarella‐Branger  , Bartoli  , Machado‐Baeta  , Pellissier
Published: March 2003

H. Lepidi, V. Frances, D. Figarella‐Branger, C. Bartoli, A. Machado‐Baeta & J‐F. Pellissier (1998) Neuropathology and Applied Biology, 24, 73–79

Local expression of cytokines in idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM), are regarded as autoimmune diseases. They are characterized by chronic lymphocytic and macrophagic infiltration in muscle tissue. Of particular importance in understanding the immune response to IIM is the specific pattern of locally produced cytokines. Frozen muscle tissues from IIM (5 DM, 3 PM, and 1 IBM) were used to investigate the cytokine responses. The RT‐PCR technique was instrumental to determine the pattern of expression of pro‐inflammatory (IL‐1β, IL‐6, TNF‐α), Th1 (IFN‐γ IL‐2), and Th2 (IL‐4) cytokines. Immunohistochemistry was also used to localize morphologically IFN‐γ and IL‐4. Our results show that pro‐inflammatory cytokines and Th1 cytokines are mainly expressed in IIM. The accumulation of mononuclear inflammatory cells and the inflammatory syndrome in IIM are probably related in part to the production of pro‐inflammatory cytokines. Moreover, the pattern of local cytokine expression is consistent with a Th1 immune response related to autoimmune diseases.
Non‐nuclear histone H1 is upregulated in neurones and astrocytes in prion and Alzheimer’s diseases but not in acute neurodegeneration
Authors: Bolton  , Russelakis‐Carneiro  , Betmouni  , Perry
Published: March 2003

A non‐nuclear isoform of histone H1 is constitutively expressed in neurones. This protein is the major lipopolysaccharide (LPS)‐binding protein in the brain. Since the major systemic LPS‐binding protein is released in the liver and is an acute phase reactant, we were interested to learn whether this novel CNS histone showed altered expression following neuronal injury. We have therefore examined the changes in the expression of this molecule in acute neuronal injury and in two neurodegenerative pathologies, murine scrapie and Alzheimer’s disease. No upregulation or change in H1 staining was observed in acute neurodegeneration induced by the intrastriatal injection of the glutamate antagonist N‐methyl d‐aspartic acid. In contrast, Western blotting indicated that histone H1 is upregulated in the brains of mice with clinical signs of scrapie. Immunohistochemistry revealed that in the regions of pathology there was increased staining for histone H1 in the neurones and the surrounding neuropil. Cells with an astrocytic appearance were also seen to stain positively for H1 but only in the regions of pathology. Immunofluorescent double staining for glial fibrillary acid protein (GFAP) and histone H1 confirmed that these cells were indeed astrocytes. Alzheimer’s disease brain also showed an increase in the neuronal and astrocytic staining but only in regions of pathology. The function of histone in the CNS is unknown but the data presented here demonstrate an upregulation in areas of neuronal degeneration, which indicates that it may be involved in disease pathogenesis.
Prion protein genes and prion diseases: studies in transgenic mice
Authors: Telling G. C.
Published: March 2003

In the past decade, manipulation of PrP genes by transgenesis in mice has provided important insights into mechanisms of prion propagation and the molecular basis of prion strains and species barriers. Despite these advances, our understanding of these unique pathogens is far from complete. This review focuses on PrP gene knockout and gene replacement studies, PrP structure and function, and transgenic models of human and animal prion diseases. Transgenic approaches will doubtless remain the cornerstone of investigations into the prion diseases in the coming years, which will include mechanistic studies of prion pathogenesis and prion transmission barriers. Transgenic models will also be important tools for the evaluation of potential therapeutic agents for prion diseases.
Loss of neurofibromatosis 1 (NF1) gene expression in NF1‐associated pilocytic astrocytomas
Authors: Gutmann D. H. , Donahoe J. , Brown T. , James C. D. , Perry A.
Published: March 2003

The critical role of the neurofibromatosis 1 (NF1) gene as a tumour suppressor has been clearly demonstrated for malignancies arising in NF1 patients. However, little is known about the more common benign tumours, such as the pilocytic astrocytoma. Most NF1‐associated astrocytomas are benign and clinically non‐progressive, though aggressive tumours are occasionally encountered. In this study, eight pilocytic astrocytomas from six individuals affected with NF1 were analysed for NF1 expression. All eight tumours demonstrated loss of neurofibromin expression by immunohistochemistry, which was confirmed in one case using Western blot analysis. Microsatellite analysis showed loss of a single NF1 allele (LOH) in two of four NF1‐associated tumours. These results demonstrate that, in contrast to sporadic astrocytomas, loss of NF1 expression is an important primary genetic event in the pathogenesis of NF1‐associated pilocytic astrocytomas.
Clinicopathological phenotype of codon 129 valine homozygote sporadic Creutzfeldt–Jakob disease
Authors: Kovacs G. G. , Head M. W. , Bunn T. , Laszlo L. , Will R. G. , Ironside J. W.
Published: March 2003

The naturally occurring polymorphism at codon 129 of the human prion protein gene (PRNP) influences susceptibility to sporadic Creutzfeldt–Jakob Disease (CJD); the majority of the patients are methionine homozygotes at this locus, while valine homozygotes represent only 10% of cases. The aim was to study the clinical and neuropathological phenotype of sporadic CJD in valine homozygotes, to estimate the reliability of current clinical diagnostic criteria, and to identify any consistent and distinct features. Twelve cases of sporadic CJD with a codon 129 valine homozygote genotype were identified at the National CJD Surveillance Unit in Edinburgh. In addition to a retrospective clinical analysis, tissue blocks were stained by conventional techniques and by immunocytochemistry for prion protein. Frozen brain tissue was available from five cases for Western blot analysis of PrPRES, which in all cases showed a type 2 mobility. The cases included four males and eight females, average age 63.6 years, with a mean duration of illness of 6 months. Eleven patients presented with ataxia, and none had the characteristic EEG changes found in sporadic CJD. The neuropathological phenotype comprised spongiform change and prion protein immunopositivity most marked in the subcortical grey matter and cerebellum, prion protein positive plaque‐like deposits in all regions, laminar deposition of prion protein in the cerebral cortex, and hippocampal involvement (which is seldom reported in sporadic CJD). In conclusion, these cases exhibited a fairly uniform phenotype, which is relatively distinct from sporadic CJD in methionine homozygotes, and thus diagnosis may be difficult using existing clinical criteria.
Nijmegen breakage syndrome: a neuropathological study
Authors: Lammens M. , Hiel J. A. P. , Gabreëls F. J. M. , Weemaes C. M. R. ,   introduced by, Chakrabarty A.
Published: March 2003

Introduction:  Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, which belongs to the DNA repair disorders. It is characterized by microcephaly, typical facial appearance, immunodeficiency, X‐ray hypersensitivity and predisposition of cancer.

Material and methods:  Neuropathological examination of the brain was performed on a male NBS patient with moderate mental retardation, who was successfully treated for non‐Hodgkin's lymphoma at the age of 19 years. He died at the age of 31 years as a result of carcinomatous peritonitis.

Results:  Severe microcephaly (> 3SD< mean) especially pronounced in the frontal lobe was observed. There was a very simplified gyral pattern with reduction of the tertiary gyri. A myelinated bundle 6 × 3.5 mm thick considered to be a large remnant of the striae longitudinales mediales and laterales was found over the whole length on top of the corpus callosum. There was an incomplete enrolling of the hippocampus and hypoplasia of the inferior vermis.

Conclusions:  The neuropathological findings in this patient are concurrent with radiological findings in NBS patients and with limited earlier neuropathological studies. These findings suggest a role for a DNA‐repair gene in corticogenesis in man as has already been suggested in animal studies of other DNA‐repair genes before.
Guidelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient
Authors: Rüb U. , Brunt E. R. , Del Turco D. , De Vos R. A. I. , Gierga K. , Paulson H. , Braak H.
Published: March 2003

U. Rüb, E. R. Brunt, D. Del Turco, R. A. I. de Vos, K. Gierga, H. Paulson and H. Braak (2003) Neuropathology and Applied Neurobiology 29, 1–13

 Guildelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient

Despite the fact that considerable progress has been made in the last 20 years regarding the three‐phase process of ingestion and the lower brain stem nuclei involved in it, no comprehensive descriptions of the ingestion‐related lower brain stem nuclei are available for neuropathologists confronted with ingestive malfunctions. Here, we propose guidelines for the pathoanatomical investigation of these nuclei based on current knowledge with respect to ingestion and the nuclei responsible for this process. The application of these guidelines is described by drawing upon the example of the lower brain stem of a male patient with spinocerebellar ataxia type 3, also known as Machado‐Joseph disease, who displayed malfunctions during the preparatory phase of ingestion, as well as lingual and pharyngeal phases of swallowing. By way of the representative application of the recommended investigation procedure to 100 µm serial sections through the patient's brain stem stained for lipofuscin pigment and Nissl material, we observed neuronal loss together with astrogliosis in nearly all of the ingestion‐related lower brain stem nuclei (motor, principal and spinal trigeminal nuclei; facial nucleus; parvocellular reticular nucleus; ambiguus nucleus, motor nucleus of the dorsal glossopharyngeal and vagal area; gelatinous, medial, parvocellular and pigmented solitary nuclei; hypoglossal nucleus). In view of their known functional role in the three‐phase process of ingestion, damage to these nuclei not only offers an explanation of the patient's malfunctions related to the preparatory phase of ingestion and lingual and pharyngeal phases of swallowing, but also suggests that the patient may have suffered from additional esophageal phase swallowing malfunctions not mentioned in his medical records.
A history of placental dysfunction and risk of placental abruption
Authors: Rasmussen  , Irgens  , Dalaker
Published: March 2003

In a population‐based historic cohort study, we assessed the possible association of fetal growth retardation, preterm birth and pregnancy‐induced hypertension in the immediately preceding pregnancy with placental abruption in the current pregnancy, which would suggest a shared aetiological factor. We also assessed whether chronic hypertension, diabetes mellitus and a history of Caesarean section are associated with placental abruption. Preterm birth and small‐for‐gestational‐age (SGA) in the immediately preceding delivery were associated with an increased risk of placental abruption with unadjusted odds ratios (ORs) of 2.1 [95% CI = 1.9, 2.4] and 1.6 [95% CI = 1.5, 1.8] respectively. Women with a history of an SGA preterm birth in the immediately preceding delivery and an appropriate‐for‐gestational‐age infant in the current had an adjusted OR of 3.2 [95% CI = 2.3, 4.5]. The adjusted odds ratio of placental abruption in women who had pregnancy‐induced hypertension in the previous pregnancy, but not in the current, was 1.4 [95% CI = 1.2, 1.7]. Women who delivered a preterm or SGA infant in the previous delivery and had chronic hypertension or diabetes mellitus in the current had adjusted ORs of 2.3–5.7 and 2.5–6.0 respectively. Caesarean section in the previous delivery increased the risk of placental abruption by 40%. These results suggest that pregnancy‐induced hypertension, intrauterine growth retardation, preterm delivery and placental abruption share an aetiological factor or represent different clinical expressions of recurring placental dysfunction. Chronic hypertension and diabetes mellitus may cause or aggravate such dysfunction thus causing placental abruption. A history of Caesarean section is associated with an increased risk of placental abruption.
The birth cohorts grow up: new opportunities for epidemiology
Authors: Susser Ezra , Terry Mary Beth , Matte Thomas
Published: March 2003

The emerging ‘life‐course cohorts’ are a powerful new resource in epidemiology. These are cohorts followed from early gestation until the end of life.1 We shall deal in turn with the history of this phenomenon, the implications for epidemiological research and the consequences for the field of epidemiology itself.
Placental abruption and perinatal death
Authors: Kyrklund‐Blomberg Nina B. , Gennser Gerhard , Cnattingius Sven
Published: March 2003

Studies of risk factors for abruptio placentae (AP) are partly conflicting and studies of risk factors for perinatal death in these pregnancies are scarce. Using the population‐based Swedish Birth Registry from 1987 to 1993, we were able to study these risks in 795 459 singleton pregnancies. Logistic regression analysis was used to estimate odds ratios (OR) for risk of AP and risk of perinatal death in pregnancies with and without AP. Risk factors for AP were: age, primiparity, high parity, not cohabiting with infant’s father, low education, smoking, infertility, pregestational diabetes, essential hypertension, pregnancy‐induced hypertensive diseases, preterm premature rupture of membranes, preterm birth and small‐for‐gestational‐age (SGA) births. Risk factors for perinatal death in pregnancies with placental abruption were smoking (1–9 and ≥10 cigarettes/day; OR 1.4 and 1.7 respectively), severe pre‐eclampsia (OR 2.0) and SGA (OR 1.9), whereas in pregnancies without abruption, risks were also increased in maternal age ≥35 years, primiparity, infertility, essential hypertension and pregestational diabetes. These findings support the theory that, in cases of AP, a general impairment of the placenta and/or a defect placentation may be fatal.
Survival of infants with spina bifida: a population study, 1979–94
Authors: Wong Lee‐Yang C. , Paulozzi Leonard J.
Published: March 2003

This study aimed to investigate the survival of infants born with spina bifida between 1979 and 1994 from the population‐based Metropolitan Atlanta Congenital Defects Program (MACDP) and to identify clinical and demographic factors associated with survival. Survival status was obtained from MACDP records and the National Death Index. Survival rates were calculated using the Kaplan–Meier method. Risk factors potentially associated with survival were examined by the log‐rank test. We assessed the independent effect of risk factors using the Cox proportional hazards model. Overall, 78.4% of children with spina bifida survived during the study period. Of the 235 infants born with spina bifida, 87.2% survived the first year of life. Survival to age 1 for the 1979–83, 1984–88 and 1989–94 birth cohorts was 82.7%, 88.5% and 91.0% respectively. In multivariable analysis, factors associated with increased mortality were low birthweight (<2500 g) (vs. ≥2500g, relative risk (RR) 2.3 [95% CI 1.1, 4.9]) and high lesions (vs. low lesions, RR 3.4 [95% CI 1.6, 7.1]). This study suggests a continuous improvement in survival among children born with spina bifida in Atlanta. Demographic and clinical factors are associated with length of survival. This information is useful for both clinicians and families who need to plan for the long‐term care of these children.
Analysis by gestational age of cerebral palsy in singleton births in north‐east England 1970–94
Authors: Drummond P. M. , Colver A. F.
Published: March 2003

We report from a well‐established cerebral palsy (CP) register the changes in CP rates by gestational age for singleton births over a 25‐year period in north‐east England. The gestational ages of numerators and denominators are of high accuracy back to 1970 because academic units in paediatrics and obstetrics were studying the assessment of gestational age in individual infants, and the distribution of gestational age across all births in the north‐east from the 1960s. The rate of CP rose between 1970–75 and 1990–94 from 1.6 to 2.3 per 1000 singleton neonatal survivors, a rise of 0.7/1000 [95% CI 0.2, 1.3]. There was little change in the rate of CP in term infants whereas in preterm infants (<37 weeks) it rose from 5.5 to 16.8, a rise of 11.3/1000 [95% CI 5.9, 16.8]. Rises occurred in the three preterm gestational age bands <28, 28–31, 32–36 weeks with the most marked rise in those <28 weeks from 0 to 112.7. The proportion of all cases of CP arising in the preterm group rose from 19% to 45%; and the proportion of the severest cases arising in the preterm group rose from 8% to 55%. In those born after 32 weeks, there is a preponderance of small‐for‐gestation infants, with 10% more than two standard deviations below the mean. All types of CP are more common in infants below average weight for gestation and this is most marked for the non‐spastic types that are almost only seen in term, small‐for‐gestation infants. Gestational age is the crucial determinant of rate of CP and the increase in prevalence seen over the past 25 years is due to increased rates in preterm infants, not term infants. Both conclusions, suspected from birthweight analyses, are now demonstrated conclusively, with the contribution coming from those 32–36 weeks gestation as well as very preterm infants.
Maternal characteristics associated with place of delivery and neonatal mortality rates among very‐low‐birthweight infants, Georgia
Authors: Samuelson Julia L. , Buehler James W. , Norris Dianne , Sadek Ramses
Published: March 2003

To determine whether the Healthy People 2000 objective to deliver very‐low‐birthweight (VLBW) infants at subspecialty perinatal care centres was met, and if improvements in the regional perinatal care system could reduce neonatal mortality further for 2010, we examined place of delivery for VLBW infants, associated maternal characteristics and the potential impact on neonatal mortality. We used linked birth and death records for the 1994–96 Georgia VLBW (i.e. 500–1499 g) birth cohorts. Among 4770 VLBW infants, 77% were delivered at hospitals providing subspecialty perinatal care. The strongest predictor of birth hospital level was the mother's county of residence, defined using three levels: residence in a county with a subspecialty hospital, residence in a county adjacent to one with such a hospital or residence in a non‐adjacent county. Eighty‐nine per cent of infants born to women who resided in counties with subspecialty care hospitals delivered at such hospitals, compared with 53% of infants born to women who resided in a non‐adjacent county. Women were also more likely to deliver outside subspecialty care if they had less than adequate prenatal care [adjusted odds ratio (AOR) 1.5, P‐value = 0.0001]. The neonatal mortality rate varied by level of perinatal care at the birth hospital from 132.1/1000 to 283/1000 live births, with the highest death rate for infants born at hospitals offering the lowest level of care. Assuming that the differences in mortality were due to care level of the birth hospital, potentially 16–23% of neonatal deaths among VLBW infants could have been prevented if 90% of infants born outside subspecialty care were delivered at the recommended level. These findings suggest that a state's support of strong, collaborative, regional perinatal care networks is required to ensure that high‐risk women and infants receive optimal health care. Improved access to recommended care levels should further reduce neonatal mortality until interventions are identified to prevent VLBW births.
A protective role for IL‐6 during early infection with Toxoplasma gondii
Authors: JEBBARI  , ROBERTS  , FERGUSON  , BLUETHMANN  , ALEXANDER
Published: March 2003

IL‐6 deficient mice were found to be signifcantly more susceptible to peroral infection with Toxoplasma gondii than their wild‐type counterparts as measured by survival, brain cyst burdens and brain pathology at 28 days post‐infection. The physical manifestations of disease, such as weight loss, were not observed in IL‐6 deficient animals until at least seven days later than such changes occurred in wild‐type mice. During this early stage of infection IL‐6+/+ but not IL‐6−/− mice mounted a peripheral blood neutrophilia. Furthermore, between 6–8 days post‐infection there was a significant increase in plasma IFN‐γ levels in wild‐type but not IL‐6 deficient mice. Not until days 18–23 post‐infection, concurrent with the majority of deaths in IL‐6−/− mice, were plasma IFN‐γ levels substantially and significantly raised in IL‐6−/− mice. At this time not only were these plasma IFN‐γ levels 20‐fold higher than background but eight‐fold greater than peak (6–8 days post‐infection) IFN‐γ levels in IL‐6+/+ mice. IFN‐γ dependent parasite specific IgG2a levels were also significantly higher in IL‐6−/− mice over this period and thereafter. Overall the evidence suggests that in the absence of IL‐6 mice are unable to initiate a rapid proinflammatory response against T. gondii, which allows increased parasite growth. Increased mortality in IL‐6−/− mice may be directly due to this increased parasite burden and the excessive inflammatory response this induces three weeks post‐infection.
Human Schistosomiasis mansoni: IL‐10 modulates the in vitro granuloma formation
Authors: FALCÃO  , MALAQUIAS  , MARTINS‐FILHO  , SILVEIRA  , PASSOS  , PRATA  , GAZZINELLI  , COFFMAN  , CORREA‐OLIVEIRA
Published: March 2003

Granuloma formation and modulation around Schistosoma mansoni eggs that are trapped in host tissues play a pivotal role during schistosomiasis. It has been demonstrated that the granuloma reactions differ in patients with the different clinical forms of the disease. The pathology during murine schistosomiasis has been correlated with a Th2 response while resistance to infection with a Th1 type response. In humans, very little is known about the role of different cytokines on the development of the disease. Here we demonstrate that IL‐10 is an important cytokine regulating the in vitro granulomatous reactivity of PBMC from intestinal (INT) patients. This was evidenced by the fact that blockage of this cytokine in the in vitro granuloma assay lead to a significant increase in granuloma size with cells from INT patients but not with individuals in the acute phase or with the hepatosplenic (HS) form of schistosomiasis. These results demonstrate for the first time that, in context with the model, a Th2 cytokine in human schistosomiasis plays an important role in controlling morbidity.
Epitope specificities and antibody responses to the EG95 hydatid vaccine
Authors: Woollard D.J. , Gauci C.G. , Heath D.D. , Lightowlers M.W.
Published: March 2003

Antibody isotype and epitope specificities were examined in sheep immunized with EG95, a protective recombinant vaccine against hydatid disease. All sheep immunized with EG95 as a fusion protein with glutathione S‐transferase (GST) produced prominent IgG antibodies against the EG95 portion of the protein. Linear, antibody‐binding epitope specificities of EG95 were mapped using a series of 25 overlapping synthetic peptides. Three immunodominant regions were identified which generated specific IgG1 and IgG2 antibodies in the majority of vaccinated sheep. These regions corresponded to the EG95‐derived sequences SLKAVNPSDPLVYKRQTAKF, DIETPRAGKKESTVMTSGSA and SALTSAIAGFVFSC. An additional immunogenic region was identified which induced almost exclusively IgG2 antibody. This epitope was located within the sequence TETPLRKHFNLTPV. The anti‐parasitic, protective effects of the EG95 vaccine correlated with the detection of specific antibody to two or more of the four linear immunogenic regions. The identification of these immunogenic peptides of EG95 maybe useful in the development of a synthetic peptide vaccine as a derivative of the EG95 recombinant.