bluuebunny/crossref_metadata_2025 huggingface dataset:
Independent cycles of exocrine pancreatic secretion, hormones and gastroduodenal motility in healthy fasting humans: reassessment of a complex partnership
Authors: DOMÍNGUEZ‐MUÑOZ J. E. , BREGULLA M. , NELSON D. K. , GLASBRENNER B. , SAUERBRUCH T. , MALFERTHEINER P.
Published: March 2003

Background: interdigestive pancreatic secretion cycles in close association with the phases of the migrating motor complex (MMC) and release of regulatory hormones. The extrinsically denervated pancreas exhibits an intrinsic cyclic rhythm. We hypothesized that this intrinsic rhythm is normally present in the intact human pancreas. Methods: 19 healthy males (age range 26–35 years) were studied after 12 h fasting. A manometry catheter was positioned with four pressure ports in the antrum and three in the duodenum, and motility was recorded for a complete MMC cycle or 5 h. Duodenal aspirates were sampled at 15‐min intervals, and immediately analysed for amylase, lipase and chymotrypsin activities; enzyme outputs were calculated by standard marker perfusion techniques. Plasma levels of pancreatic polypeptide (PP) and motilin were also determined (RIA) at 15‐min intervals. Results: output of amylase, lipase and chymotrypsin occurred in parallel. All phase III motility fronts were accompanied by a pancreatic secretory peak. However, in 12 subjects at least one secretory peak was observed without the concomitant occurrence of phase III. A total of 16 out of 51 secretory peaks identified across all subjects were independent (31%). These phase III‐independent peaks of pancreatic secretion occurred in subjects with a longer MMC cycle (160 ± 19 min vs 102 ± 13 min, P < 0.05). Phase III‐associated and ‐independent peaks had a similar magnitude (amylase output: 21.6 ± 3.9 kU h−1 vs 21.1 ± 2.8 kU h−1, respectively). Irrespective of MMC phases, antral but not duodenal motor activity was closely correlated with fluctuations of pancreatic secretion (P < 0.05). Cycling of PP and motilin were also closely coordinated with pancreatic enzymes, with a particularly tight link between endocrine and exocrine secretion from the pancreas. Conclusions: peaks of pancreatic secretion invariably occur when a phase III motor activity occurs, but additional secretory peaks occur without a concomitant phase III. Interdigestive phasic pancreatic secretion is tightly coordinated with PP and motilin release as well as with antral motor activity. An intrinsic rhythm of the pancreas distinct from other cyclic activity may be present in healthy humans, expressed as peaks of pancreatic secretion independent of a motor phase III.
Mechanisms of gastro‐oesophageal reflux in the lateral decubitus positions
Authors: KAPUR  , TRUDGILL  , RILEY
Published: March 2003

Gastro‐oesophageal reflux is more common in the right than in the left lateral position but the reasons why are not well understood. We have therefore studied the mechanisms underlying reflux in the lateral decubitus positions in patients with reflux disease. Fifteen patients with symptomatic reflux and excessive oesophageal acid exposure were studied (nine male, age 25–63 years). Each was intubated with a perfused manometric assembly, incorporating a Dent sleeve, and a pH probe. Following a 30‐min basal period, a 400‐kCal meal was infused into the stomach and patients were studied for 60 min in each lateral position. Following infusion of the meal, lower oesophageal sphincter (LOS) pressure fell and transient LOS relaxation (TLOSR) frequency increased. Acid reflux episodes were more common in the postprandial period (fasting 0 (0–6) h, first postprandial hour 1 (0–9) h, P = 0.0002, second postprandial hour 1 (0–22) h, P = 0.02) and occurred more than twice as often in the right lateral position (right 3 (0–22) h, left 0 (0–10) h, P = 0.01). However, TLOSRs, swallow‐related relaxations and low basal LOS pressures were equally common in both lateral positions. In patients with reflux disease, postprandial reflux is twice as common in the right lateral position. This does not relate to differences in gastro‐oesophageal junctional pressure, suggesting that other aspects of barrier function or differences in the intragastric distribution of chyme may be important.
Possible role of nitric oxide in postoperative ileus: a comparative study
Authors: Moojen  , Van Gulik T. M. , Hoek  , Gouma  , Tytgat  , Boeckxstaens
Published: March 2003

In the present study, the possible involvement of nitric oxide (NO) in the pathogenesis of postoperative ileus was investigated indirectly by measuring nitrate, a stabile metabolite of NO.

Plasma levels and 24‐h urinary excretion of nitrate and nitrite were determined in the peri‐operative period in three different groups of patients undergoing surgery: group 1 (LT, n=11) underwent a laparotomy, group 2 (LS, n=12) underwent a laparoscopic procedure, whereas group 3 underwent an extra‐abdominal procedure (EA, n=9).

Duration of postoperative ileus was assessed clinically using first occurrence of flatus and defaecation as the end of the period of ileus.

Postoperative ileus lasted significantly longer in the LT group (first flatus after 3.0 [3.0–4.0] days) compared with the LS (1.0 [1.0–2.0] days) and EA (1.0 [1.0–3.0] days) groups. Urinary nitrate excretion increased significantly in the LT and EA groups during the first 24 h after surgery (from 797.0 [214.0–810.0] and 551.5 [438.3–1215.8] to 2079.0 [889.0–4644.0] and 1102.5 [315.3–1238.0] μmol/24 h, median [IQR]), but normalized before the end of postoperative ileus. Plasma levels of nitrate were unchanged after surgery, whereas CRP levels were significantly increased in all groups (LT > LS=EA).

In the first 24 h following surgery, urinary nitrate excretion is increased, suggesting increased endogeneous synthesis of NO postoperatively. As no correlation was found between urinary nitrate excretion and duration of postoperative ileus, we conclude that assessment of nitrate has no value in predicting clinical outcome after surgery.
Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea‐pig small intestine
Authors: Shahbazian  , Holzer
Published: March 2003

The tachykinin NK1 receptor agonist substance P methyl ester (SPOME) impedes intestinal peristalsis by releasing nitric oxide (NO) from inhibitory motor neurones. Since NK1 receptor agonists differ in their receptor interaction, we set out to compare a range of NK1 receptor agonists including SPOME, septide and GR‐73 632 in their effects on propulsive peristalsis and circular muscle activity in the guinea‐pig isolated small intestine. SPOME (100–300 n
M) inhibited peristalsis by a rise of the pressure threshold at which peristaltic waves were triggered, whereas septide and GR‐73 632 (30–300 n
M) interrupted peristalsis by causing circular muscle spasms. Separate experiments showed that all three NK1 receptor agonists caused contraction of the circular muscle, which was enhanced by the NO synthase inhibitor NG‐nitro‐
L‐arginine methyl ester (300 μM) and the P2X purinoceptor antagonist suramin (300 μM). In contrast, tetrodotoxin (300 n
M) augmented the contractile effect of septide and GR‐73 632 but not that of SPOME. It is concluded that the motor response to NK1 receptor agonists involves release of NO and adenosine triphosphate from inhibitory motor neurones. However, the NK1 receptor agonists differ in the mechanism by which they cause inhibitory transmitter release, which corresponds to differences in their antiperistaltic action.
Effect of mucosal anaesthesia on oropharyngeal swallowing
Authors: Ertekin C. , Kiylioglu N. , Tarlaci S. , Keskin A. , Aydogdu I.
Published: March 2003

The effect of the topical anaesthesia of the oropharyngeal mucosae was studied in order to evaluate the role of the mucosal sensory receptors on the oropharyngeal swallowing in 12 adult volunteers. Laryngeal vertical movements were detected by a piezoelectric sensor and electromyography of the submental muscle complex were simultaneously recorded. All subjects were instructed to swallow doses of water, gradually increasing in quantity from 3–20 mL and any recurrence of the signals related to swallowing within 8 s was accepted as a sign of dysphagia and its limit value measured. Before the topical anaesthesia of the oropharyngeal mucosae by xylocaine puffs; the dysphagia limit was never observed with less than 20 mL water. During topical mucosal anaesthesia lasting 4–6 min among the subjects, the dysphagia limit was less than 20 mL water and the recurrence of swallows two or more times was mainly recorded with 3–5 mL water. Five of the subjects demonstrated the clinical and electrophysiological signs of laryngeal aspiration at the earlier period of the topical anaesthesia. It is concluded that the sensory inputs from the mucosal receptors are important to trigger voluntary swallowing and their absence or dysfunction may contribute to oropharyngeal dysphagia and laryngeal aspiration.
Altered electrical activity in colonic smooth muscle cells from dystrophic (mdx) mice
Authors: Serio R. , Bonvissuto F. , Mulè F.
Published: March 2003

Because the colon from dystrophic (mdx) mice shows an altered motor pattern, probably due to neural disorders, our aim was to examine the electrophysiological properties of muscle cells and the functionality of nitrergic transmission in circular muscle from normal and mdx colon. Normal colonic cells (resting membrane potential [RMP] about −50 mV) showed spontaneous hyperpolarizations (inhibitory junction potentials; IJPs) and cyclic slow depolarizations were sometimes recorded. Mdx colon had a depolarized RMP (about –36 mV) and spontaneous IJPs, but the cyclic activity was never observed. In the normal colon, Nω‐nitro‐

L‐arginine methyl ester (

L‐NAME) induced depolarization and abolished the cyclic activity. In the mdx colon,

L‐NAME caused a slight depolarization. Both preparations displayed the same value of RMP in the presence of

L‐NAME. In normals, neural stimulation induced nonadrenergic, noncholinergic IJPs composed of fast hyperpolarizations followed by a nitrergic slow hyperpolarization, selectively abolished by

L‐NAME. In the mdx colon the evoked IJPs were composed only of the initial fast hyperpolarization, the nitrergic component being absent. The hyperpolarization to sodium nitroprusside was not significantly different in both preparations. We conclude that the colon from animals lacking in dystrophin displays different electrophysiological features because of an impairment of nitric oxide function.
Endogenous nitric oxide release modulates the direction and frequency of colonic migrating motor complexes in the isolated mouse colon
Authors: Powell A. K. , Bywater R. A. R.
Published: March 2003

Spontaneous colonic migrating motor complexes (CMMCs) were recorded from circular muscle at three sites along the isolated mouse colon. The interval between CMMCs was decreased from ∼3 min in control solution, by ∼55% in a nitric oxide synthase (NOS) inhibitor, N‐nitro‐L‐arginine (L‐NNA; 100 μmol L–1). This was associated with a shift in migration direction of CMMCs, such that CMMCs migrated in an oral direction. Application of the endogenous substrate for NOS, L‐arginine, at a low concentration used to mimic plasma concentration (134 μmol L–1), or a high concentration (5 mmol L–1) suppressed CMMCs (for at least 15 min) which were replaced by high frequency (10–15 min–1), short duration (half width ∼1.5 s) contractions of variable amplitudes (largest in the proximal region) until CMMCs resumed. CMMCs remained in the presence of D‐arginine (134 μmol L–1 and 5 mmol L–1). Apamin (250 nmol L–1) did not alter the interval between CMMCs, however, additional nonmigrating contractions were observed between the CMMCs in the distal region. In addition to its effects on smooth muscle tone, NO, but not apamin‐sensitive channels, plays an important role in suppressing the frequency of migrating contractions in the isolated mouse colon. Consideration should be given to the inclusion of L‐arginine, in in vitro experiments where there may be spontaneous activity in NOS containing neurones.
Manometric abnormalities of the oesophagus in patients with Parkinson’s disease
Authors: Castell J. A. , Johnston B. T. , Colcher A. , Li Q. , Gideon R. M. , Castell D. O.
Published: March 2003

Dysphagia in Parkinson’s disease (PD) is known to correlate with abnormalities of oropharyngeal function. Oesophageal abnormalities have not been previously demonstrated to correlate with dysphagia. The aim of the study was to determine if motor dysfunction of the oesophageal body correlates with dysphagia or disease severity in PD. Twenty‐two patients with PD were assessed for the severity of their dysphagia (scale of 1–7) and severity of PD (Hoehn and Yahr scale 1–4). All underwent oesophageal manometry. Dysphagia was present daily in 10 patients (45%). Parkinson’s disease was graded as severe (Hoehn and Yahr >=3) in eight (36%) patients. Oesophageal manometry was abnormal in 16 (73%) patients. Thirteen patients had either complete aperistalsis or multiple simultaneous contractions (diffuse oesophageal spasm). These findings were significantly more common in patients with daily dysphagia (90% vs. 33%; P < 0.005), and were not related to duration or severity of PD. We conclude that the presence of aperistalsis or multiple simultaneous contractions in the oesophagus does correlate with dysphagia and is independent of PD severity or duration. This may reflect selective involvement of either the dorsal motor nucleus of the vagus or the oesophageal myenteric plexus.
Immunoreactivity of Hu proteins facilitates identification of myenteric neurones in guinea‐pig small intestine
Authors: LIN Z. , GAO N. , HU H‐Z. , LIU S. , GAO C. , KIM G. , REN J. , XIA Y. , PECK O. C. , WOOD J. D.
Published: March 2003

Hu proteins, together with neurone‐specific enolase (NSE), protein gene product 9.5 (PGP‐9.5), microtubule‐associated protein‐2 (MAP‐2) and tubulin beta III isoform, were evaluated immunohistochemically as neuronal markers in whole‐mount preparations and cultures obtained from the myenteric plexus of guinea‐pig small intestine. Anti‐Hu immunostaining marked the ganglion cell somas and nuclei without staining of the neuronal processes in the whole‐mounts and cultures. The ganglion cell bodies were not obscured by staining of multiple neuronal fibres and this facilitated accurate counting of the neurones. MAP2 immunostaining also provided clear images of individual neurones in both whole mounts and cultures. Immunoreactivity for NSE, PGP‐9.5 and tubulin beta III isoform provided sharp images of the ganglion cells in culture, but not in whole‐mount preparations. Strong staining of the neuronal processes in the whole‐mount preparations obscured the profiles of the ganglion cell bodies to such an extent that accurate counting of the total neuronal population was compromised. Anti‐Hu immunostaining was judged to be an acceptable method for obtaining reliable estimates of total numbers of myenteric neurones in relation to other specific histochemical properties such as histamine binding.
Influences of pelvic floor structures and sacral innervation on the response to distension of the cat rectum
Authors: Mathis C. , Schikowski A. , Thewißen M. , Ross H‐G. , Crowell M. D. , Enck P.
Published: March 2003

Abstract
 
The contributions to the rectal response to distension of the pelvic floor structures surrounding the rectum and of the sacral spinal innervation have never been studied. Using paralysed intercollicularly decerebrate, anaesthesia‐free cats, we studied pressure–volume relationships during slow ramp distensions of the rectum. Results obtained from animals with intact pelvic cavities were compared with those following mobilization of the rectum from the pelvic floor musculature. To assess the influences of spinal outflow and afferent input, rectal pressure–volume relationships were measured in the mobilized rectum following bilateral sequential transection of the spinal roots S1 to S3, first dorsal, then ventral. Isolation of the rectum from the pelvic floor structures resulted in a decrease in balloon volume in the lower range of distension pressure but did not affect volumes at higher pressures. The only afferent effect was seen after sectioning of dorsal roots S1, which resulted in a decrease in balloon volume. The only efferent effect was seen after sectioning of ventral roots S3, which decreased balloon volume further. In conclusion, the rectal response to distension depends on the properties of the rectal wall. It may be influenced by somatic inputs, inputs from the myenteric nervous plexus, and from the parasympathetic and sympathetic nervous systems. Afferent inputs and spinal autonomic reflexes may decrease the tone of the rectal musculature during distension.
Sensory–motor responses to volume‐controlled duodenal distension
Authors: Gao C. , Petersen P. , Liu W. , Arendt‐Nielsen L. , Drewes A. M. , Gregersen H.
Published: March 2003

Abstract
 Visceral perception and secondary peristalsis evoked by distension of the duodenum were studied in 10 healthy volunteers. An impedance planimetric probe for cross‐sectional area (CSA) measurements inside a balloon and with three pressure channels was used. Balloon distensions were performed in the fed state with or without the administration of the antimuscarinic drug butylscopolamine. A modified questionnaire was used to assess the nonpainful and painful sensations. The total tension (Ttotal) and the passive tension (Tpassive) were determined from the distensions without and with the administration of butylscopolamine, respectively. The active tension (Tactive) was Ttotal – Tpassive. The stepwise balloon distensions induced the first sensation at a volume of 33 ± 3 mL. After administration of butylscopolamine the first sensation appeared at 42 ± 1 mL. The perception score (PS) revealed an approximately linear increase as function of volume, CSA, pressure and tension after the first sensation. Butylscopolamine resulted in significant changes in PS score as function of volume, CSA and strain, but not as a function of pressure and tension. The frequency of the secondary peristalsis increased to the highest value (8.2 ± 0.8 contractions min−1) at a volume of 21 mL. Butylscopolamine almost abolished the distension‐evoked motility. Ttotaland Tpassiveincreased nonlinearly as a function of volume, whereas Tactiveincreased up to a distension volume of 33 mL and then decreased at higher volumes. Hence, the conventional length–tension diagrams as known from studies of smooth muscle strips in vitro can be reproduced in the human duodenum in vivo. This new way of studying intestinal sensation and motility may prove to have both basic and clinical importance as both passive tissue structures and the sensorimotor function are tested.
Spontaneous mechanical activity and evoked responses in isolated gastric preparations from normal and dystrophic (mdx) mice
Authors: Mulè F. , Serio R.
Published: March 2003

Abstract  This study examined whether alterations of the spontaneous and evoked mechanical activity are present in the stomach of the mdx mouse, the animal model for Duchenne muscular dystrophy. The gastric mechanical activity from whole‐organ of normal and mdx mice was recorded in vitro as changes of intraluminal pressure. All gastric preparations developed spontaneous tone and phasic contractions, although the tone of the mdx preparations was significantly greater. Atropine reduced the tone of the two preparations by the same degree. N

‐nitro‐
l
‐arginine methyl ester (
l
‐NAME) significantly increased the tone and spontaneous contractions only in the stomach from normal animals, but did not affect on the mdx preparations. Effects of
l
‐NAME on tone and contractility were preserved in the presence of tetrodotoxin. In both types of tissues electrical field stimulation (EFS) induced a biphasic response: cholinergic contraction followed by slow relaxation. In nonadrenergic noncholinergic conditions, EFS induced a rapid relaxation followed by a slow component in both types of tissues.
l
‐NAME abolished the rapid component, reduced the slow component and unmasked tachychinergic contractions. No significant difference was found in evoked responses. The enteric neurotransmission is preserved in mdx gastric preparations, although alterations in the ongoing production of nitric oxide are present.
REVIEW: tau protein pathology in Alzheimer’s disease and related disorders
Authors: Tolnay  , Probst
Published: March 2003

Abundant neurofibrillary lesions made of hyperphosphorylated microtubule‐associated protein tau constitute one of the defining neuropathological features of Alzheimer’s disease. However, tau containing filamentous inclusions in neurones and/or glial cells also define a number of other neurodegenerative disorders clinically characterized by dementia and/or motor syndromes. All these disorders, therefore, are grouped under the generic term of tauopathies. In the first part of this review we outline the morphological and biochemical features of some major tauopathies, e.g. Alzheimer’s disease, argyrophilic grain disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. The impact of the recent finding of tau gene mutations in familial frontotemporal dementia and parkinsonism linked to chromosome 17 on other tauopathies is discussed in the second part. The review closes with a look towards a new understanding of neurodegenerative disorders characterized by filamentous nerve cell inclusions. The recent identification of the major protein component of their respective inclusions led to a surprising convergence of seemingly unrelated disorders. The new findings now allow us to classify neurodegenerative disorders with filamentous nerve cell inclusions into four main categories: (i) the tauopathies; (ii) the α‐synucleinopathies; (iii) the polyglutamine disorders; and (iv) the iquitin disorders’. Within the proposed classification scheme, tauopathies constitute the most frequent type of disorder.
Expression of caspase‐3 in brains from paediatric patients with HIV‐1 encephalitis
Authors: James  , Sharer  , Zhang  , Wang  , Epstein  , Reed  , Gelbard
Published: March 2003

Apoptosis of neurones, macrophages, and microglia occurs in the brains of paediatric patients with human immunodeficiency virus (HIV) type 1 encephalitis, which is often associated with pre‐mortem neurological disease (progressive encephalopathy). We have previously reported that TUNEL‐positive neurones in brain tissue from paediatric patients with HIV type 1 encephalitis and progressive encephalopathy are strikingly devoid of the pro‐apoptotic gene product Bax, in marked contrast to brain‐resident macrophages and microglia. Using immunocytochemical methods, the present study demonstrate that neurones in patients with HIV type 1 encephalitis and progressive encephalopathy, as well as macrophages and microglia, but not astrocytes, overexpress caspase‐3, a pro‐apoptotic enzyme that is proteolytically activated downstream of Bax–Bcl‐2 dysregulation. Co‐localization of neuronal cytoplasmic caspase‐3 and nuclear TUNEL staining, a marker for fragmented DNA, was also infrequently observed in brain tissue from patients with HIV type 1 encephalitis and progressive encephalopathy. These findings suggest that vulnerable neurones in brain tissue from patients with HIV virus type 1 encephalitis and progressive encephalopathy undergo apoptosis by a mechanism that involves upregulation of caspase‐3 in a pathway that is independent of Bax–Bcl‐2 dysregulation. Furthermore, caspase‐3 upregulation in apoptotic neurones likely occurs prior to DNA fragmentation.
Phosphorylated c‐MYC expression in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration
Authors: Ferrer I. , Blanco R. , Carmona M. , Puig B.
Published: March 2003

Phosphorylated c‐Myc (c‐Myc‐P) expression has been examined by immunohistochemistry, using an antibody that recognizes phosphorylated c‐Myc at Thr58 and Ser62, in the brains of Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and age‐matched control cases, as well as in human medulloblastomas and central neuroblastomas. Strong c‐Myc‐P immunoreactivity was seen in dystrophic neurites and neurones with neurofibrillary tangles in AD, and in neurones and glial cells bearing abnormal tau deposits in PiD, PSP and CBD. Previous studies have shown active Ras and increased mitogen‐activated protein kinase (MAPK/ERK) expression in neurones and glial cells with abnormal tau deposition in AD and other tauopathies. Since MAPKs phosphorylate c‐Myc at Thr58 and Ser62, these observations implicate the Ras/MAP kinase pathway in c‐Myc phosphorylation and accumulation in AD and other tauopathies. Previous studies have also shown activation of cell cycle associated proteins in neuronal death. The present results have shown colocalization of nuclear c‐Myc‐P and active, cleaved caspase‐3, a major executioner of apoptosis, in medulloblastomas and central neuroblastomas, thus suggesting phosphorylated c‐Myc expression in caspase‐3‐dependent apoptosis of tumour cells. However, no evidence of caspase‐3 activation has been observed in neurones and glial cells with strong phosphorylated c‐Myc immunoreactivity in AD, PiD, PSP and CBD. Therefore, it is not clear that the activation of the Ras/MAPK/c‐Myc subprogramme leads to neuronal death in AD and other tauopathies.
Association of APOE polymorphisms and pathological features in traumatic brain injury
Authors: Smith C. , Graham D. I. , Murray L. , Nicoll J. A. R.
Published: March 2003

Introduction:  Previous studies have found that polymorphisms of the apolipoprotein E gene (APOE) influences the outcome from head injury, with possession of APOE ε4 being associated with an unfavourable outcome (Teasdale et al. Lancet 1997; 350: 1069–1071). In this study we correlated the pathological features of traumatic brain injury with the presence or absence of APOE ε4.

Materials and methods:  During the 13‐year period 1987–99, 238 brains were examined from cases of traumatic brain injury (TBI) in the Department of Neuropathology, Glasgow. APOE genotype was determined by PCR. For each case a number of pathological features were recorded ‘blind’ to the APOE ε4 status.

Results:  Of the 238 cases examined, 83 (35%) had the APOE ε4 allele, while 155 (65%) did not. Possession of APOE ε4 was associated with a greater incidence of severe hypoxic brain damage (ε4+ 54%, ε4– 42%) and with a greater incidence of moderate or severe contusion index (ε4+ 42%, ε4– 30%). No significant differences were noted between the other pathological features examined.

Conclusions:  Possession of APOE ε4 is associated with a greater incidence of moderate/severe contusional injury and severe hypoxic brain damage in fatal cases of TBI. This may be relevant to the relatively poor outcome from TBI in patients with an APOE ε4 allele identified in clinical studies.
Muscle fibrillin deficiency associated with Marfan's syndrome myopathy
Authors: Behan W. M. H. , Longman C. , Petty R. K. H. , Boxer M. , Foskett P. , Harriman D. G. F.
Published: March 2003

Introduction:  Marfan's syndrome (MFS) is the commonest inherited disorder of connective tissue. It is defined by major features in the cardiovascular, skeletal and ocular systems, and minor features in the integument and lungs. Patients who fulfil the diagnostic criteria have a mutation in the fibrillin (FBN1) gene, which encodes a major glycoprotein in the microfibrillar system, including in perimysium and endomysium. Muscle involvement, although in the original description, has not been mentioned at all recently.

Materials and methods:  We studied a family with MFS in whom myopathy led to respiratory failure. Genetic analyses on venous blood and immunohistochemical studies of muscle biopsies were carried out.

Results:  Single stranded conformational polymorphism screening of all exons of the FBN1 gene revealed a C4621 T base change in exon 37. This was predicted to result in the production of a truncated form of FBN1. Immunohistochemical studies showed conspicuous abnormalities in endomysial and perimysial fibrillin.

Conclusion:  This is the first demonstration of fibrillin deficiency in muscle in MFS and its implications for biomechanical function are discussed.
The role of the cysteine proteinase cathepsin S in astrocytoma invasion
Authors: Gibson D. , Flannery T. , Mulligan K. , Mirakhur M. , McCormick D.
Published: March 2003

Introduction:  Local tumour invasion gives rise to recurrence after surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Extracellular proteolytic enzymes including cysteine proteinases have been implicated in facilitating tumour cell invasion. The current study was designed to characterize the expression of the cysteine proteinase, cathepsin S and investigate its potential role in the invasive process.

Materials and methods:  Expression of cathepsin S was investigated in astrocytoma biopsies by immunohistochemistry and in astrocytoma cultures by immunocytochemistry and the reverse transcription polymerase chain reaction. Cathepsin S activity assays were also performed on in vitro and in vivo samples. An in vitro Matrigel invasion assay was used to evaluate the effect of selective cathepsin S inactivation, by the inhibitor LHVS, on glioblastoma cell invasion.

Results:  Cathepsin S immunostaining was restricted to tumour cells in vivo. Cathepsin S transcript, protein and activity were observed within astrocytoma cells in vitro. Extracellular cathepsin S activity was about five‐fold higher in cultures from grade IV tumours than in lower grades. Inhibition of cathepsin S with 0.01 µm LHVS significantly inhibited in vitro invasion of the glioblastoma cell line U251 mg by 50% (P < 0.0001).

Conclusions:  It has been demonstrated for the first time that cathepsin S is expressed and secreted by astrocytoma cells and plays a role in astrocytoma invasion, and is therefore a potential therapeutic target.
Deposition of tau in the brain in Alzheimer's disease is related to the amount of Aβ40 but not Aβ42(43) deposits and the presence of apolipoprotein E ε4 allele
Authors: Mann D. M. A. , Thaker U. , McDonagh A. M. , Lendon C. L.
Published: March 2003

Introduction:  Alzheimer's disease (AD) is characterized by the widespread deposition of amyloid β protein (Aβ) in the form of extracellular plaques and the intracellular accumulation of pathological aggregates of the microtubule associated protein, tau, in the form of neurofibrillary tangles and neuropil threads. We have investigated relationships between the amount of plaque amyloid and tau deposition in brain in sporadic AD and the affect of apolipoprotein E (APOE) genotype on tau load.

Material and methods:  Wax sections of frontal cortex from 109 cases of late onset AD were immunostained using AT8 antibody to detect deposition of pathological tau proteins. The amount of tau, and Aβ as Aβ40 and Aβ42(43), was quantified by image analysis. The APOE genotype was determined by standard methods.

Results:  The amount of tau within frontal cortex correlated inversely with patient age but not duration of illness suggesting a more aggressive ‘spread’ of disease into frontal lobes by time of death in younger patients. Tau load correlated (P < 0.001) with Aβ40 but not Aβ42(43) levels, and was also greater in patients with APOE ε4 allele than those without, increasing in line with ε4 allele copy number.

Conclusions:  Results suggest that tau deposition in late onset AD is favoured in the presence of APOE ε4 allele and when Aβ40 levels are high, the latter also being associated with ε4 allele. Aβ40 is preferentially present in cored plaques where microglial cells are frequent. The amount of tau deposited in the brain in AD may therefore reflect the extent of local neuroinflammatory changes.
Quantitative evidence for continuing axonal pathology after optic nerve stretch‐injury
Authors: Domleo A. , McColl G. , Graham D. I. , Maxwell W.
Published: March 2003

Introduction:  Stretch‐injury to the optic nerve of the guinea‐pig results in cytoskeletal pathology. We tested the hypothesis that post‐traumatic changes may continue up to 1 week after injury.

Material and methods:  Six animals were injured under controlled conditions. Under terminal anaesthesia, three controls and three animals were killed at 24 h or 1 week. Unbiased stereological analysis of the axonal cytoskeleton was undertaken.

Results:  At 4 h, 20% of nerve fibres are injured (Jafari et al. J Neurotrauma 1998; 15: 955). In the present study, no evidence for a change in the proportion of injured nerve fibres at longer survivals was obtained. At 24 h, three types of injured fibre occur: (i) some are compacted as at 4 h; (ii) some, termed ‘degenerating’, show loss/increased spacing between neurofilaments and microtubules (P = 0.005); and (iii) in some, empty myelin figures occur. At 7 days, both degenerating fibres and empty myelin figures are increased (P = 0.032).

Conclusions:  These results demonstrate that injured nerve fibres undergo secondary axotomy between 4 and 24 h and there are increased numbers of degenerating fibres at 7 days. However, not all injured fibres undergo axotomy between 4 and 24 h, because, at 7 days fibres undergoing axotomy are present.
Squamous cell carcinoma: a rare complication of dermoid cysts
Authors: Ashkan K. , Wilkins P. , Marsh H.
Published: March 2003

Introduction:  Dermoid cysts constitute 0.3% of all brain tumours. Carcinomatous differentiation has been described only in a handful of cases.

Material and methods:  A 44‐year‐old‐man presented with a several‐year history of headaches and a 5‐week history of progressive visual deterioration in the left eye. Clinical examination confirmed a normal visual acuity but an impaired left visual field. A magnetic resonance imaging scan showed a lesion in the left paraclinoid area compressing the ipsilateral optic nerve. Signal characteristics of the lesion were consistent with a dermoid or epidermoid cyst. At operation, the lesion was thought to be typical of a dermoid cyst and a near‐complete excision was achieved leaving behind parts adherent to the optic nerve. Histology showed invasive squamous cell carcinoma arising within the dermoid tumour. Postoperatively the patient received radiotherapy.

Results:  The patient's clinical condition initially stabilized. At 15 months follow up, however, there was clinical and radiological evidence of tumour progression and he died 1 year later.

Conclusion:  Squamous cell carcinoma may rarely arise from an intracranial dermoid tumour. This may hinder total excision of the lesion and confounds the prognosis.
White matter pathology in Alzheimer's disease and vascular dementia: quantification by amyloid‐β precursor protein immunocytochemistry
Authors: Teahan O. , Slade J. Y. , Perry R. H. , Ballard C. G. , Kalaria R. N.
Published: March 2003

Alzheimer's disease (AD) and vascular dementia (VaD) are two of the common dementias in the elderly. Imaging studies have demonstrated white matter changes of vascular etiology to occur in both disorders. While there have increased efforts to differentiate white matter pathology by quantitative magentic resonance imaging in these disorders there is no clear consensus. We assessed white matter lesions in brains of the first 100 demented patients who came to autopsy from our prospectively evaluated series. We examined the extent of axonal pathology by conventional methods including LFB for myelin, and amyloid‐β precursor protein (AβPP) immunocytochemistry with antibodies to 22C11. AβPP has recently been used to examine axonal injury in head trauma. Our results indicated AβPP reactive accumulation along white matter tracts in the temporal cortex encompassing the hippocampal formation to be common. The highest reactivity was evident in tissue from VaD subjects compared with that from AD or dementia with Lewy bodies (DLB). Compared with conventional myelin stains, AβPP immunocytochemistry was more sensitive to visualize subtle changes. We suggest AβPP immunocytochemistry is a useful index to assess ischaemic white matter lesions to differentiate dementias.

Acknowledgements:  Supported by the MRC (UK), Alzheimer's Research Trust (UK) and Alzheimer's Association (USA).
Involvement of precerebellar nuclei in multiple system atrophy
Authors: Braak H. , Rüb U. , Del Tredici K.
Published: March 2003

H. Braak, U. Rüb and K. Del Tredici (2003)Neuropathology and Applied Neurobiology29,60–76  Involvement of precerebellar nuclei in multiple system atrophy

In this semiquantitative study based on 26post‐mortemcases, we describe the involvement of precerebellar nuclei in multiple system atrophy (MSA), a progressive degenerative disorder of the human central nervous system characterized by abnormal, argyrophilic and α‐synuclein immunopositive intracellular inclusions within selectively vulnerable oligodendrocytes and nerve cells. The Campbell‐Switzer silver‐pyridine technique with α‐synuclein immunoreactions using 100‐µm thick sections is recommended over more conventional methods, thereby permitting visualization of the pertinent lesions in greater detail and facilitatingpost‐mortemdiagnosis of MSA specimens. Affected oligodendrocytes occur in specific fibre tracts and grey matters, with most pathology being observed in projections from the precerebellar nuclei to the cerebellum (ponto‐cerebellar, olivo‐cerebellar, reticulo‐cerebellar tracts) and in descending/ascending fibre tracts of the motor system (cortico‐pontine, cortico‐bulbar, cortico‐spinal, spino‐reticular, spino‐olivary, spino‐cerebellar tracts). Three types of abnormal intraneuronal aggregations occur: (i) a loosely woven network within the cell nucleus; (ii) a latticework accumulating in peripheral portions of the cell body; and (iii) irregularly outlined patches of compact, intensely argyrophilic material usually located within deposits of lipofuscin granules. Counter‐staining for the presence of extraneuronal lipofuscin can aid neuropathologists in the recognition of lost existent neurones in MSA. Neurones with inclusion bodies occur in the inferior olivary nuclear complex, lateral reticular nucleus, external cuneate nucleus, conterminal nucleus, interfascicular nucleus, nucleus of Roller, dorsal paramedian reticular nucleus, subventricular nucleus, arcuate nucleus, pontobulbar body and pontine grey. The lateral reticular nucleus and accessory nuclei of the inferior olive sustain the most damage and reveal prominent neuronal loss, followed by the pontobulbar body and arcuate nucleus. The uniformly bilateral damage and, in some cases, even obliteration of the nuclei studied, supply additional evidence for the pathoanatomical substrata of the cerebellar dysfunction that reportedly emerges in the clinical course of MSA.
Traditional nutritional and surgical practices and their effects on the growth of infants in south‐west Ethiopia
Authors: Asefa Makonnen , Hewison Jenny , Drewett Robert
Published: March 2003

A 1‐year birth cohort of 1563 infants was seen bi‐monthly for the first year of life. They comprised all identified infants born in Jimma town, south‐west Ethiopia, in the year starting 1 Meskren 1985 in the Ethiopian calendar (11 September 1992). Growth in infancy is poor in this town, as it is in Ethiopia more generally: mean z‐scores for both weight and length were more than 1.5 SD below the median of the NCHS/WHO reference population by 1 year of age, and infant mortality was 115/1000. In this paper we examine the weight gain of singletons in relation to background variables and to traditional nutritional and surgical practices in the families.

   Confirming work in other areas, sanitation, water supply, the income of the family and the mother's literacy were important determinants of weight gain. Almost all the infants were initially breast fed, and about 80% were still breast fed at 1 year. Many were also given cows’ milk from 4 months onwards. Breast feeding had beneficial effects up to 8 months of age, and cows’milk had beneficial effects after 6 months of age. Supplementary feeds of solids and semi‐solids were given at appropriate ages, but had no detectable benefit. Water was given inappropriately early, but did no detectable harm.

   Episodes of diarrhoea, fever or persistent cough each reduced weight gain. Catch‐up in weight then took up to 8 months, probably because of the poor nutritional quality of supplementary feeds. The incidences of local traditional operations in the first year were: circumcision 63% in males and 4% in females, uvulectomy 35% and the extraction of milk teeth 38%. Although circumcision had no detectable adverse effect on weight, uvulectomy and milk teeth extraction both reduced weight gain.
A lower rate of preterm birth after clotrimazole therapy during pregnancy
Authors: Czeizel  , Rockenbauer
Published: March 2003

Topical or vaginal clotrimazole treatment during pregnancy was evaluated in the large population‐based control data set of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–92. The database comprised 32 804 control non‐malformed newborn infants, 7.7% of whom were born to mothers who had received clotrimazole treatment during pregnancy. An increase in mean gestational age among exposed vs. unexposed was found. It is postulated that the use of clotrimazole during pregnancy reduced significantly the proportion of preterm births because of the effective treatment of genital infections caused by candidiasis in pregnant women.
The influence of parental age on the risk of Wilms’ tumour
Authors: Sharpe  , Franco  , De Camargo  , Lopes  , Barreto  , Johnsson  , Mauad
Published: March 2003

The Brazilian Wilms’ Tumour Study Group carried out a hospital‐based multicentre case–control study of potential risk factors for the disease between April 1987 and January 1989. The parents of 109 cases of Wilms’ tumour (WT) were interviewed when they were admitted to hospital for diagnosis and treatment. Also interviewed were the parents of two controls per case, matched for age, sex and interviewer, who were admitted to the same or nearby hospitals for treatment of non‐neoplastic conditions. Odds ratios adjusted for family income and parental education were calculated by conditional logistic regression. Among cases diagnosed before 25 months of age there was a marked gradient of increasing risk of WT with increasing maternal age at the time of the child’s birth. There was no increased risk for cases diagnosed after 25 months of age. The effects of paternal age were less marked. Possible explanations for these results are discussed.
Pre‐eclampsia disrupts the normal relationship between serum leptin concentrations and adiposity in pregnant women
Authors: Williams  , Havel  , Schwartz  , Leisenring  , King  , Zingheim  , Zebelman  , Luthy
Published: March 2003

The adipocyte hormone, leptin, is secreted in proportion to adipose mass and is implicated in the regulation of energy balance via its central actions on food intake and sympathetic nervous system activity. The placenta was also shown recently to be a possible source of leptin in pregnant women, raising the possibility that the normal relationship between leptin and adiposity may be altered in pre‐eclampsia. We therefore sought to assess the extent to which maternal second trimester serum leptin concentrations differed for women who would subsequently develop pre‐eclampsia and those who would remain normotensive. This nested case–control study population comprised 38 women with pregnancy‐induced hypertension and proteinuria (pre‐eclampsia) and 192 normotensive women. Multiple least‐squares regression procedures were used to assess the independent relationship between leptin concentrations and risk of pre‐eclampsia. Serum leptin concentrations, measured by radioimmunoassay, were highly correlated with maternal pre‐pregnancy and second trimester body mass index (r = 0.71 and r = 0.74 respectively; P < 0.001 for both) among normotensive women, and to a lesser extent among women who developed pre‐eclampsia (r = 0.29 and r = 0.42; P = 0.09 and 0.02 respectively). Among women with a pre‐pregnancy body mass index of  25 kg/m2, pre‐eclampsia cases compared with controls had higher mean second trimester leptin con‐centrations after adjustment for confounding factors. In contrast, pre‐eclampsia cases had lower mean leptin concentrations than controls for those women with a pre‐pregnancy body mass index above 25 kg/m2. Other factors in addition to the level of adiposity may therefore influence serum leptin concentrations in pre‐eclamptic pregnant women. Our results suggest the possibility that leptin, like several other placentally derived substances (e.g. steroid hormones, eicosanoids and cytokines), may be involved in the pathogenesis of pre‐eclampsia. Further work is needed to confirm our findings and to assess the metabolic importance and determinants of leptin concentrations in uncomplicated and pre‐eclamptic pregnancies.
How effective is antenatal care in preventing maternal mortality and serious morbidity? An overview of the evidence
Authors: Carroli G. , Rooney C. , Villar J.
Published: March 2003

This is an overview of evidence of the effectiveness of antenatal care in relation to maternal mortality and serious morbidity, focused in particular on developing countries. It concentrates on the major causes of maternal mortality, and traces their antecedent morbidities and risk factors in pregnancy. It also includes interventions aimed at preventing, detecting or treating any stage along this pathway during pregnancy. This is an updated and expanded version of a review first published by the World Health Organization (WHO) in 1992. The scientific evidence from randomised controlled trials and other types of intervention or observational study on the effectiveness of these interventions is reviewed critically. The sources and quality of available data, and possible biases in their collection or interpretation are considered. As in other areas of maternal health, good‐quality evidence is scarce and, just as in many aspects of health care generally, there are interventions in current practice that have not been subjected to rigorous evaluation. A table of antenatal interventions of proven effectiveness in conditions that can lead to maternal mortality or serious morbidity is presented. Interventions for which there is some promising evidence, short of proof, of effectiveness are explored, and the outstanding questions formulated. These are presented in a series of tables with suggestions about the types of study needed to answer them.
Operative delivery during labour: trends and predictive factors
Authors: Roberts Christine L. , Algert Charles S. , Carnegie Michelle , Peat Brian
Published: March 2003

Summary

Monitoring operative delivery trends provides the opportunity to consider whether changes are in a direction that will achieve the best outcomes for mothers and their infants. The aims of this study were to identify trends in and predictors of operative delivery (forceps, vacuum or caesarean) among women who have labour; and to determine trends in the operative methods used. The study was based on 616 303 live, singleton, term births delivered between 1990 and 1997 in New South Wales, Australia. There was no change in the annual percentage of women who experienced labour and 20% had an operative birth during labour. The vacuum to forceps ratio declined from 1 : 6 in 1990 to 1 : 1 in 1997. Among women with labour, caesareans increased from 6.4% to 7.8%. For primiparae, the factors predictive of operative delivery (epidural analgesia, age > 34 years, induced or augmented labour and private care) did not change over time. A predictive model for multiparae did not have adequate fit, indicating the importance of data on prior birth history. Studies of trends in operative deliveries are most useful and consistent with decision making when interventions before the onset of labour and during labour are analysed separately. Furthermore, the vacuum:forceps ratio provides a useful tool for comparative analyses.