bluuebunny/crossref_metadata_2025 huggingface dataset:
Complexity and stability revisited
Authors: Jansen Vincent A. A. , Kokkoris Giorgos D.
Published: May 2003

Since Robert May's work on random community matrices it has been known that stability tends to decrease with complexity. Recently, it was shown that this is not necessarily true in competitive ecosystems. We investigated the stability of random ecosystems and found that it can largely be predicted by simple matrix statistics such as the mean and the variance of the interaction coefficients. We use this to explain why stability can increase as well as decrease with complexity in ecological communities. We argue that the variance, and to a lesser extent the mean, of the interaction coefficients go a long way in explaining patterns in the stability of ecosystems.
Diversity in mussel beds at deep‐sea hydrothermal vents and cold seeps
Authors: Turnipseed M. , Knick K. E. , Lipcius R. N. , Dreyer J. , Van Dover C. L.
Published: May 2003

Remarkably little is known about fundamental distinctions (or similarities) between the faunas of deep‐sea hydrothermal vents and seeps. Low species richness at vents has been attributed to the transient nature of vent habitats and to toxic effects of hydrogen sulphide and heavy metals in vent effluents. Seeps are arguably more stable and more chemically benign than vents. They have also been regarded as more diverse, but until now there has not been a rigorous test of this hypothesis. We evaluated diversity indices for invertebrates associated with mussel beds at six vents and two seeps and found that invertebrate diversity was significantly higher at seeps than vents, although some vent mussel beds supported nearly the same diversity as seep mussel beds. Lower diversity at vents may be a consequence of a greater physiological barrier to invasion at vents than at seeps. Diversity was lowest where spacing between vents was greatest, suggesting that risks of extinction as a result of dispersal‐related processes may contribute to the pattern of diversity observed at vents.
Effects of parasitoid fecundity and host resistance on indirect interactions among hosts sharing a parasitoid
Authors: Heimpel George E. , Neuhauser Claudia , Hoogendoorn Marlijn
Published: May 2003

We examine the effects of fecundity‐limited attack rates and resistance of hosts to parasitism on the dynamics of two‐host–one‐parasitoid systems. We focus primarily on the situation where one parasitoid species attacks two host species that differ in their suitability for parasitism. While all eggs allocated to suitable hosts develop into adult parasitoids, some of the eggs allocated to marginal host do not develop. Marginal hosts can therefore act as a sink for parasitoid eggs. Three‐species coexistence is favoured by low levels of parasitoid fecundity and by low levels of suitability of the marginal host. Our model also produces an indirect (+, −) interaction in which the suitable host can benefit from the presence of the marginal host, but the marginal host suffers from the presence of the suitable host. The mechanism driving the indirect (+, −) interaction is egg limitation of parasitoids incurred by allocating eggs to marginal hosts.
Multi‐predator effects across life‐history stages: non‐additivity of egg‐ and larval‐stage predation in an African treefrog
Authors: Vonesh James R. , Osenberg Craig W.
Published: May 2003

The effects of multiple predators on their prey are frequently non‐additive because of interactions among predators. When prey shift habitats through ontogeny, many of their predators cannot interact directly. However, predators that occur in different habitats or feed on different prey stages may still interact through indirect effects mediated by prey traits and density. We conducted an experiment to evaluate the combined effects of arboreal egg‐stage and aquatic larval‐stage predators of the African treefrog,Hyperolius spinigularis. Egg and larval predator effects were non‐additive – moreHyperoliussurvived both predators than predicted from their independent effects. Egg‐stage predator effects on aquatic larval density and size and age at hatching reduced the effectiveness of larval‐stage predators by 70%. Our results indicate that density‐ and trait‐mediated indirect interactions can act across life‐stages and habitats, resulting in non‐additive multi‐predator effects.
Disentangling biodiversity effects on ecosystem functioning: deriving solutions to a seemingly insurmountable problem
Authors: Naeem Shahid , Wright Justin P.
Published: May 2003

Experimental investigations of the relationship between biodiversity and ecosystem functioning (BEF) directly manipulate diversity then monitor ecosystem response to the manipulation. While these studies have generally confirmed the importance of biodiversity to the functioning of ecosystems, their broader significance has been difficult to interpret. The main reasons for this difficulty concern the small scales of the experiment, a bias towards plants and grasslands, and most importantly a general lack of clarity in terms of what attributes of functional diversity (FD) were actually manipulated. We review how functional traits, functional groups, and the relationship between functional and taxonomic diversity have been used in current BEF research. Several points emerged from our review. First, it is critical to distinguish between response and effect functional traits when quantifying or manipulating FD. Second, although it is widely done, using trophic position as a functional group designator does not fit the effect‐response trait division needed in BEF research. Third, determining a general relationship between taxonomic and FD is neither necessary nor desirable in BEF research. Fourth, fundamental principles in community and biogeographical ecology that have been largely ignored in BEF research could serve to dramatically improve the scope and predictive capabilities of BEF research. We suggest that distinguishing between functional response traits and functional effect traits both in combinatorial manipulations of biodiversity and in descriptive studies of BEF could markedly improve the power of such studies. We construct a possible framework for predictive, broad‐scale BEF research that requires integrating functional, community, biogeographical, and ecosystem ecology with taxonomy.
Colonoscopic surveillance after curative colorectal resection: Results of an empirical surveillance programme
Authors: McFall M. R. , Woods W. G. A. , Miles W. F. A.
Published: May 2003

Introduction  Colonoscopic surveillance after colorectal cancer resection is widely practised despite little evidence that it improves survival. The optimum protocol for colonoscopic follow‐up after colorectal cancer resection has not yet been elucidated. We audited the outcome of an empirical colonoscopic follow‐up programme in a cohort of patients who underwent colorectal resection with a minimum of five years follow‐up to establish patterns of metachronous neoplasia and suitable surveillance intervals.

Methods  The colonoscopic records, biopsy results and follow‐up details of patients diagnosed with colorectal cancer between June1990 and June1996 were reviewed. The number and type of metachronous neoplastic lesions diagnosed was recorded. Rates of development of new neoplasms were estimated by calculating the time from operation to their first discovery. Factors predictive of further development of polyps or cancer were sought. Results were compared to published reports of intensive follow‐up programmes.

Results  Seven hundred and ninety‐eight patients underwent colorectal resection with curative intent during the study period. 226 patients had one or more follow‐up colonoscopies (mean time post resection 48.8 months). In total 352 colonoscopies, encompassing 1437 patient years of surveillance, were performed. Nine metachronous cancers in eight patients, five of which were asymptomatic were diagnosed by colonoscopy at a mean of 63 months. Three asymptomatic recurrences were diagnosed but all were inoperable. 70 (31%) patients had adenomatous polyps diagnosed after a mean time from operation of 34 months for simple adenomatous polyps and 21 months for those with advanced features. Patients with multiple polyps or advanced polyps at the initial colonoscopy were more likely to form subsequent polyps. Only 5.8% of patients with a single adenoma or a normal colon formed an advanced adenoma over the next 36 months of surveillance.

Conclusion  The results of an empirical colonoscopic follow‐up programme compared favourably to the results of the intensive programmes reported in the literature. Most patients are at very low risk of developing significant colonic pathology over the first five years after resection. Colonoscopic surveillance intervals need not be less than five years unless the patient has multiple adenomas or advanced adenomas at the first colonoscopy. Three yearly surveillance intervals are most probably adequate in these individuals.
Rectal endosonography can distinguish benign rectal lesions from invasive early rectal cancers
Authors: Starck M. , Bohe M. , Simanaitis M. , Valentin L.
Published: May 2003

Objective To determine whether an experienced ultrasound examiner, using good ultrasound equipment with high multifrequency probes, can discriminate between a high grade or low grade dysplastic adenoma (pT0) and very early invasive rectal cancers (pT1).

Subjects and methods Sixty consecutive patients with clinically possibly pT0 or pT1 rectal tumours referred for transanal local excision underwent endorectal ultrasound examination. Lesions where the endorectal ultrasound image showed the mucosal layer to be expanded but the submucosal layer to be intact (uT0) were considered to represent a low grade or high grade dysplasia adenoma (pT0). An irregularity or disruption of the submucosal layer (uT1) was considered to characterize early invasive rectal cancers (pT1). The ultrasound staging was compared with the histological staging made on the basis of the diagnoses in the excised specimens.

Results The histopathological diagnoses were: invasive rectal cancer (n = 18, 10 pT1, 4 pT2, 4 pT3 cancers); high grade dysplastic adenoma (n = 21); low grade dysplastic adenoma (n = 18); non adenomatous benign lesions (n = 3). Endorectal ultrasound incorrectly classified two of the invasive cancers (both pT1 tumours) as noninvasive lesions. Five of 42 pT0 tumours were overstaged as uT1 tumours. Overstaging was more common in patients who had undergone a previous excision and in tumours with peritumoral inflammation and desmoplastic reaction. The sensitivity of endorectal ultrasound with regard to invasive cancer was 89% (16/18), specificity 88% (37/42), positive predictive value 76% (16/21), negative predictive value 95% (37/39), and accuracy 88% (53/60). Among pT0 and pT1 tumours, the corresponding figures were 80% (8/10), 88% (37/42), 62% (8/13), 95% (37/39), and 87% (45/52).

Conclusion Endorectal ultrasound can distinguish between noninvasive lesions and invasive rectal cancers clinically of stage pT0 or pT1.
Caecal‐diverticulitis: A rare differential diagnosis for right‐sided lower abdominal pain
Authors: Junge K. , Marx A. , Peiper Ch. , Klosterhalfen B. , Schumpelick V.
Published: May 2003

Objective There are several differential diagnoses for acute abdominal discomfort with pain referred to the right lower quadrant region. The objective of this report is to outline our experience with diverticulitis of the caecum, which is a rare condition that is particularly difficult to diagnose correctly pre‐operatively.

Methods A retrospective analysis of acute diverticulitis of the caecum was performed over the period from January 1992 to December 2000 within the Surgical Department of the RWTH Aachen, Germany. The progress of each patient was assessed by interviewing the patient and by telephone contact with the patient's general practitioner.

Results Seven patients with isolated infective diverticulitis of the caecum were encountered in the course of this study. In five of these cases, the pre‐operative diagnosis was either unclear or incorrect. Four patients underwent surgery for suspected appendicitis. In one patient, the diverticulitis was diagnosed during laparoscopic surgery undertaken for presumed adnexal disease. Intestinal continuity was restored in all cases. The postoperative course was uneventful.

Conclusions Right‐sided caecal diverticulitis is rare in comparison to diverticulitis of the sigmoid or descending colon. Nevertheless, it should be actively considered in the differential diagnosis of patients with acute tenderness in the right lower abdominal region.
Safety of primary anastomosis in emergency colo‐rectal surgery
Authors: Zorcolo L. , Covotta L. , Carlomagno N. , Bartolo D. C. C.
Published: May 2003

Background  The surgical management of left‐sided large bowel emergency patients remains controversial. There has been an increasing trend towards primary reconstructive surgery. The main dilemma remains appropriate patient selection for primary anastomosis.

Methods  The records of 323 patients who presented as acute emergencies and underwent surgery between January 1990 and December 2000 for left‐sided colorectal cancer and diverticular disease were reviewed, to compare the outcome of resection and primary anastomosis with Hartmann's procedure. Patients were stratified into 3 groups according to whether the presentation was with localized or generalized peritonitis, or with obstruction.

Results  Resection and anastomosis was carried out in 176 (55.7%) patients with a 30‐day mortality of 5.7%. Anastomotic dehiscence occurred in 9 (5.1%) patients, with no difference between the three groups. Wound sepsis occurred in 8 (4.5%) patients, and the median hospital stay was 13 days.

Hartmann's resection was associated with a higher incidence of systemic and surgical morbidity (39.5% and 24.3%, respectively).

The mortality rates in those selected for primary anastomosis (5.7%) compared favourably with those undergoing Hartmann's resections (20.4%) (P < 0.001).

Conclusion  Emergency primary anastomosis in left‐sided disease can be performed with a low morbidity and mortality in selected patients, even in the presence of a free perforation with diffuse peritonitis. Patients selected for staged resection, were those with major comorbid disease.
The rhomboid flap for pilonidal disease
Authors: Arumugam P. J. , Chandrasekaran T. V. , Morgan A. R. , Beynon J. , Carr N. D.
Published: May 2003

Introduction  There have been many surgical techniques described for the treatment of pilonidal sinuses. Recurrent disease causes significant morbidity particularly with time from work.

Aim  To assess the rhomboid flap's role in promoting one‐stage primary healing in pilonidal disease and to evaluate the morbidity and recurrence.

Methods  Fifty‐three patients were prospectively recruited of which 27 had previous multiple abscess formation requiring surgical drainage from their pilonidal disease, although none had acute disease at the time of surgery. By using the transposition flap, we were able to obliterate the natal cleft and therefore the rolling action of the buttocks between the cleft in these patients and thereby remove one of the factors involved in pilonidal disease. Hospital stay, healing time, wound infection, wound breakdown and recurrence were noted.

Results  There were 47 males and 6 females with a median age of 28 years (range 16–64 years). Median follow‐up was 24 months (range 3–36 months). Post‐operative morbidity involved superficial wound infection in 7 (13%) which settled with out‐patient dressings. There were four recurrences (7%), two occurred between the flap and the anal canal, and the other two in the flap margin needing intervention. All the patients healed their wounds and the median healing time was 14 days.

Conclusion  As this condition affects a predominantly young population causing significant time off from work, we feel that the Rhomboid Flap is useful for difficult cases in that it allows early return to full activity and does not necessitate prolonged postoperative care.
Anorectal function following low anterior resection
Authors: Rasmussen O. O. , Petersen I. K. , Christiansen J.
Published: May 2003

Introduction Rectal function following rectal resection for carcinoma was studied in 43 patients.

Methods Sixteen women and 27 men with a median age of 66 years (range 41–79 years) were included. Twenty‐three patients had a diverting ileostomy at the time of resection. Eight patients had a 6‐cm colonic J‐pouch. Ten patients had anastomotic leakage including two patients without diverting ileostomy. One patient had pre‐operative radiation with 25 Gy. The patients were studied at a median 12 months (range 3–30) after rectal resection. Distance from anal verge to the anastomosis was a median 7 cm (range 3–12 cm). Clinical data, anal manometry and rectal compliance were analysed.

Results Stool frequency was 3 per day (range 1–10). Twenty‐two (51%) patients were continent, 11 (26%) were incontinent for flatus, and 10 (23%) were incontinent for faeces (three for liquid and seven for solid stool). Fourteen (33%) patients had constipation, two of whom also had incontinence for solid or liquid stool. The level of the anastomosis for patients with postoperative constipation was 5 cm (range 3–12 cm), while it was 7 cm (range 3–10 cm) for nonconstipated patients (NS). Anal manometry was normal. Rectal compliance was lower in patients with incontinence for liquid or solid faeces than in patients with flatus incontinence only (P < 0.01), and rectal volume tolerability was lower in incontinent patients compared with continent patients (P < 0.05). The rectoanal reflex was present in 31 (72%) patients. There was a negative correlation between maximal rectal volume and stool frequency and between level of the anastomosis and degree of incontinence. Age did not affect functional outcome.

Conclusion Many patients had a poor functional result following low anterior resection. One in four suffered from incontinence to liquid or solid faeces and one third of the patients experienced constipation. A low level of anastomosis tended to increase stool frequency and carried a higher risk of incontinence. Patients with faecal incontinence tended to have lower rectal compliance and volume tolerability than patients who were continent, while there was no difference in anal pressures.
A prospective randomized trial of diltiazem and glyceryltrinitrate ointment in the treatment of chronic anal fissure
Authors: Bielecki K. , Kolodziejczak M.
Published: May 2003

Objective The aim of this study was to compare prospectively diltiazem with GTN ointment in the treatment of anal fissure.

Patients and methods Of 43 outpatients with chronic anal fissure, 22 patients were randomized to topical diltiazem (2%) ointment and 21 patients to glyceryltrinitrate (GTN) (0.5%) ointment twice daily for 8 weeks. During the course of treatment each patient was seen three times. Side‐effects and healing were recorded.

Results Healing occurred in 19 of 22 patients treated with diltiazem and 18 of 21 patients were cured with GTN (P = 0.95). Those who were treated with nitroglycerin ointment developed headache and dizzness developed after GTN in 33.3% of cases while no patient had any side‐effects after diltiazem.

Conclusions Diltiazem and glyceryltrinitrate (GTN) were equally effective in healing anal fissure but the former resulted in fewer side‐effects.
The correlation between quality of life and functional outcome in ulcerative colitis patients after proctocolectomy ileal pouch anal anastomosis
Authors: Carmon E. , Keidar A. , Ravid A. , Goldman G. , Rabau M.
Published: May 2003

Objective  The aim of this study was to evaluate functional outcome and quality of life (QOL) in patients undergoing proctocolectomy ileal pouch anal anastomosis (IPAA), to assess the correlation between functional outcome and QOL, and to identify factors influencing functional outcome and QOL in these patients.

Background  IPAA is now considered the procedure of choice for ulcerative colitis. Functional outcome and QOL are important factors in evaluating operative outcome.

Methods  All patients with UC who had undergone IPAA at our institute during the period 1990–2001 were included. QOL and functional outcome were evaluated by mailed questionnaires. QOL was scored using the Short Form 36 (SF‐36). Global Assessment of Function Scale was used to evaluate functional outcome.

Results  Data were obtained in 77 of 99 patients (78%), with the median age of 38 years. Median follow up time was 4.25 years. The QOL in patients after pelvic pouch procedure was excellent, with scores equal to published norms for the Israeli general population in most scales. Functional outcome and QOL scores correlated strongly (r > 0.5; P < 0.0001) in all dimensions. Older age was associated with lower scores in both functional outcome and QOL scales (P < 0.0001).

Conclusions  This study demonstrates a strong association between functional outcome and QOL in patients after IPAA. These patients, however, have a QOL that is comparable with the general population. Age at time of surgery strongly influences both functional outcome and QOL. This finding has to be taken into consideration in pre‐operative counseling.
Pathological staging of epidermoid anal carcinoma for the new era
Authors: Hill J. , Meadows H. , Haboubi N. , Talbot I. C. , Northover J. M. A.
Published: May 2003

Chemoradiotherapy is the standard treatment for most patients with epidermoid anal cancer. Pre‐treatment staging is based on size for T1‐T3 lesions and clinical and radiological assessment of adjacent organ invasion for T4 lesions. For patients with residual or recurrent carcinoma, anorectal excision offers the best chance of oncological salvage. Pathological staging systems for anorectal excision specimens were validated at the time when surgical treatment was first line therapy. A validated staging system is necessary for salvage surgical excision specimens following an attempt to cure by radiotherapy and chemotherapy for the purpose of prognosis and further treatment planning.
Synaptically released zinc: neuromodulator and toxin
Authors: Frederickson C. J.
Published: May 2003

In addition to its familiar role as a component of metalloproteins, zinc is also sequestered in the presynaptic vesicles in ‘zinc‐containing’ neurons. The best‐established physiological role of synaptically released zinc is the tonic modulation of brain excitability through modulation of amino acid receptors; prominent pathological effects include acceleration of plaque deposition in Alzheimer's disease and exacerbation of excitotoxic neuron injury. Synaptically released zinc functions as a conventional synaptic neurotransmitter or neuromodulator being released into the cleft then recycled into the postsynaptic neurons during synaptic events, functioning analogously to calcium in this regard, as a transmembrane neural signal. To stimulate comparisons of zinc signals with calcium signals, we have compiled a list of the important parameters of calcium signals and zinc signals. More speculatively, we hypothesize that zinc signals may loosely mimic phosphate signals in the sense that signal zinc ions may commonly bind to proteins in a lasting manner, as a result changing their structure and function.
Zinc‐enriched neurons
Authors: Danscher G. , Stoltenberg M.
Published: May 2003

Zinc‐enriched (ZEN) neurons are a complex group of neurons that are abundant in telencephalic structures, but present in all parts of the CNS including cerebellum and spinal cord. A ZEN neuron is characterized by containing a pool of synaptic vesicles that hold zinc ions and have zinc transporter molecules (ZnT3) in their membranes. Most likely all ZEN neurons in cerebrum are glutaminergic. However, ZEN terminals displaying an inhibitory morphology have recently been found in lamprey and mouse spinal cord and cerebellum. The functions of the vesicular pool of zinc ions are not fully characterized, but it has been suggested that zinc ions: (1) make peptides/proteins osmotic invisible and facilitate protein/peptide transport; (2) bind to certain postsynaptic receptors like NMDA and GABAA and influence the membrane potential; (3) flow into the postsynaptic neurons by specific or unspecific channels; (4) if released in excess into the intercellular space, cause damage to membrane proteins and/or flood into neurons equipped with zinc transporters or zinc gates.
Routes of Zn2+ entry in ischemia
Authors: Weiss J. H.
Published: May 2003

Synaptic release of Zn2+ and its translocation into postsynaptic hippocampal pyramidal neurons may contribute to their degeneration in epilepsy or ischemia. Culture studies have revealed that of the three major routes of divalent cation entry [NMDA channels, voltage sensitive Ca2+ channels (VSCC) and Ca‐A/K channels], Ca‐A/K channels exhibit the highest permeability to exogenously applied Zn2+. Until recently, there has been little information about routes through which synaptically released Zn2+ enters postsynaptic neurons. In a recent study employing mouse hippocampal slice preparations subjected to brief oxygen and glucose deprivation (OGD), we found a Ca‐A/K channel antagonist, but not combined NMDA and VSCC antagonism, to attenuate both Zn2+ accumulation in CA3 and CA1 pyramidal neurons and their subsequent injury. While overall Zn2+ accumulation appears to reflect a combination of translocation and release from intracellular stores, present results suggest that Zn2+ influx through Ca‐A/K channels may play a critical role in Zn2+ dependent ischemic injury.
Zn2+, mitochondria and neuronal injury
Authors: Sensi S. L.
Published: May 2003

Zn2+ critically contributes to the neural injury observed in epilepsy and transient global ischaemia. Mechanisms by which Zn2+ exerts its potent neurotoxic effects are still largely unknown. We have recently suggested that an important factor could be Zn2+ dependent disruption of mitochondrial function. As in the case of Ca2+, neuronal mitochondria take up Zn2+ to restore Zn2+i homeostasis. However, mitochondrial Zn2+ sequestration leads to potent mitochondrial dysfunction with prolonged loss of mitochondrial membrane potential and free radicals generation. Intriguingly, in direct comparison to Ca2+, Zn2+ seems to induce these effects with a considerably greater degree of potency. These injurious, and likely necrotic, effects are particularly evident upon large (micromolar) Zn2+i rises. Conversely, submicromolar [Zn2+]i increases promote release of pro‐apoptotic factors, suggesting that different degrees of cytosolic [Zn2+]i rises might activate distinct injurious pathways.
Platelet‐activating factor: role in long‐term potentiation and in brain damage
Authors: Francescangeli E. , Nardicchi V. , Macchioni L. , Goracci G.
Published: May 2003

Brain platelet‐activating factor (PAF) is a lipid mediator involved in neurotransmission and in LTP. It has been reported that the induction of LTP by high frequency stimulation increases the activity of the enzymes responsible for its synthesis by a still unknown mechanism (1). One of the two biosynthetic pathways is Ca2+‐dependent and transforms a membrane ether phospholipid into PAF by a sequence of two reactions being the first one, catalyzed by a phospholipase A2 (PLA2), rate limiting. Overproduction of PAF, taking place in pathological conditions, contributes to brain damage. Various PLA2s are present in brain tissue and, particularly, sPLA2‐IIA is very likely involved in the production of PAF as its expression increases in pathological conditions. Recently, we have found the release of sPLA2‐IIA from rat brain cortex mitochondria and its association with nuclear membranes, which might be an intracellular target for the enzyme.
2‐Arachidonoylglycerol, an endogenous cannabinoid receptor ligand in the nervous tissue
Authors: Waku K. , Sugiura T.
Published: May 2003

2‐Arachidonoylglycerol (2‐AG) is a unique molecular species of monoacylglycerol identified as an endogenous cannabinoid receptor ligand by us and Mechoulam and co‐workers (1). We found that 2‐AG possesses binding activity toward the cannabinoid receptor in rat brain. We also found that 2‐AG induces transient elevation of the intracellular Ca2+ concentration in NG108‐15 cells. The response induced by 2‐AG was blocked by pretreatment of cells with a cannabinoid CB1 receptor‐specific antagonist SR141716A, indicating that CB1 receptor is involved in the response. Based on the results of structure–activity relationship experiments, we concluded that the cannabinoid CB1 receptor in the nervous system is originally and primary a 2‐AG receptor. 2‐AG was produced and released from nervous tissues following various types of stimulation through enhanced breakdown of arachidonic acid‐containing phospholipids such as inositol phospholipids. Physiological and pathophysiological roles of 2‐AG in the nervous system will be discussed.
Sphingoid mediators in brain function and dysfunction
Authors: Riboni L. , Anelli V. , Bassi R. , Giussani P. , Viani P. , Tettamanti G.
Published: May 2003

Over the past decade, ceramide and sphingosine‐1‐phosphate have emerged as crucial mediators in many cells including those from the nervous system. In brain cells various stimuli, ranging from growth factors and differentiating agents, to oxidative stress and cytotoxic drugs, regulate one or more of the enzymes of sphingolipid metabolism. This results in the variation of cell sphingoids, which in turn act as mediators in regulating growth, differentiation and fate. Emerging data also indicate that sphingosine‐1‐phosphate can be released from brain cells and acts as intercellular mediator, after interaction with specific EDG receptors. The importance of sphingoid mediators in brain has been reinforced by recent findings implicating them in physiological processes as well as in the pathogenesis of brain diseases, including degenerative disorders and cancers. Evidence is accumulating that the manipulation of sphingolipid metabolism in brain cells will offer novel potential targets for therapeutic intervention in brain dysfunctions.
Phosphoinositides kinases in brain aging and amyloid beta neurotoxicity
Authors: Strosznajder J. B.
Published: May 2003

Phosphatidylinositol 4‐kinase (PI‐4K) and phosphatidylinositol‐monophosphate 5‐kinase (PIP‐5K) are responsible for the synthesis of PIP and phosphatidylinositol‐(4,5)bisphosphate (PIP2) the substrates for phospholipase C (PLC). PIP2 is a preferential substrate for phosphatidylinositol‐3kinase (PI‐3K) regulator(s) of cytoskeleton function and cell survival. In this study modulation of phosphoinositides kinases by G protein, brain aging, amyloid beta (AB) 1‐42 and apolipoprotein E4 (ApoE4) was investigated. Our data indicate that aging affected phosphorylation of endogenous PIP but had no effect on PI‐4K and PIP‐5K in synaptic plasma membrane from brain cortex and hippocampus. AB 1‐42 and ApoE4 decrease by 50% PI‐4K and ApoE4 additionally inhibits PIP‐5K. The results with wortmanin suggest that AB 1‐42 and ApoE4 affected also PI‐3K. Our data indicate that AB peptides through arachidonic acid and free radicals decrease PI‐4K and PI‐3K activity and alter polyphosphoinositides synthesis and signaling.
Immune mechanisms in pain control
Authors: Stein C.
Published: May 2003

Pain inhibition can be induced by immune‐derived opioids interacting with opioid receptors on peripheral sensory nerves. These receptors are up‐regulated in inflammation (1). Opioid peptides are synthesised in circulating immune cells which migrate to injured tissue. This is orchestrated by selectins and other adhesion molecules located on immunocytes and on vascular endothelium (2). In response to releasing stimuli the opioids are secreted, activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur in the periphery and are devoid of central side‐effects such as respiratory depression, sedation, dysphoria or dependence. Targeting of immune cells containing opioids to injured tissues is a novel concept of pain control and opens potential new therapeutic approaches.
Synaptic plasticity in chronic pain
Authors: Zieglgänsberger W.
Published: May 2003

Chronic pain syndromes are characterized by altered neuronal excitability in the pain matrix. These long‐term changes most commonly require alterations in gene expression. Immediate‐early genes (IEGs) are thought to participate as third messengers in the late phase of the stimulus transcription cascade in neurons of the pain matrix. The ability to rapidly acquire and store memory of aversive events is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement the resulting behavioral response of the organism will gradually diminish to be finally extinct. The cellular mechanisms of extinction are largely unknown. The endogenous cannabinoid system plays a central role in the extinction of aversive memories. We proposed that endocannabinoids facilitate extinction of aversive memories via their selective inhibitory effects on GABAergic networks in the amygdala (1).
Endocannabinoids, a novel target in pain treatment
Authors: Azad S. C.
Published: May 2003

Cannabinoids display a variety of central effects including analgesia, control of spasticity and influence of emotional states. Activation of the brain‐type cannabinoid receptor CB1 inhibits the adenylyl cyclase‐protein kinase A‐pathway and modulates calcium and potassium conductances. CB1 is widely distributed throughout the central nervous system. Among other brain regions, CB1 is highly expressed in the amygdala, which is important for the control of emotional behavior including anxiety and pain perception. In a recent investigation using auditory fear‐conditioning tests, we showed that the endogenous cannabinoid system in the amygdala is crucially involved in the extinction of aversive memories. Using electrophysiological techniques, we also found that endogenous and exogenously applied cannabinoids play a major role in the modulation of both, synaptic transmission and plasticity in this brain region. Our behavioral and electrophysiological results indicate that the endogenous cannabinoid system may represent a novel target in the treatment of chronic pain.
Opioids in neuropathic pain
Authors: Przewłocki R.
Published: May 2003

Neuropathic pain in human appears not to be opioid‐resistant but only reduced sensitivity to systemic opioids is observed in this condition. We studied the contribution of central and peripheral mu‐opioid receptors to the antinociception in rats with a spinal nerve ligation‐induced neuropathy. Results of the present study indicate that both spinal and peripheral opioid receptors may contribute to the opioid‐induced antinociception in the neuropathy. Further, mu‐opioid peptide ligands (DAMGO and endomorphins) are more effective than opioid alkaloids in relieving of neuropathic pain. Moreover, reduction of the mu‐opioid antinociceptive potency appears to be due to the fact that nerve injury reduced expression of mu‐opioid receptors in the spinal ganglia. Identification of the molecular mechanisms involved may be of importance to the understanding of the molecular mechanism of opioid action in neuropathic pain, as well as to the development of better and more effective treatment of neuropathic pain in humans.
Can umbilical cord blood‐derived progenitors behave like neural cells after exposure to neurogenic signals?
Authors: Zigova T. , Sanberg P. R.
Published: May 2003

Previous studies have suggested that human umbilical cord blood (HUCB) may serve as a rich source of hematopoietic and nonhematopoietic stem cells and that conditions exist that can coax hematopoietic cells to express neural characteristics. In our laboratory, these cells were tested for several models of neurodegenerative diseases and spinal cord injuries. Through a series of transplantation studies we have begun to uncover the properties of HUCB‐derived cells in neuropoietic regions of the neonatal (1) and aging rodent brain. The systematic application of phenotyping approaches to characterize survival, migratory potential and morphologic properties of the differentiated HUCB progeny within normal/unaffected brain will serve as a base for understanding the potential effect of these cells in the diseased brain.

Acknowledgements:  Supported in part by R01 6155039 (TZ). HUCB cells were obtained from Saneron CCEL Therapeutics, Inc. and BioWhittaker, Inc.
Neural stem cells: plasticity and therapeutic potential
Authors: Bottai D.
Published: May 2003

The adult brain retains neural stem cells (NSC). At least two evidences support this notion; firstly primary precursors within the central nervous system (CNS) germinal zone continue to produce neuron and glia throughout an animal life; second, cells from adult brain with the properties of NCS can be grown in vitro in presence of mitogens. NSCs are multipotential precursors that grow and self‐renew in culture in response to growth factors for extensive time. It has recently been argued that NSCs undergo rapid transformation in vitro. Our recent data, which describe the systematic investigation of the functional properties of NSCs upon long‐term culturing shown that NSCs do not display any sign of transformations neither at early nor at late culture stages; moreover the self‐renewal capacity of NSCs does not change over time. I will then show how we can confirm previous findings showing how NSCs do possess the ability to give rise to non‐neural‐derivatives, i.e. mesodermal cells. Finally, I will illustrate the lack of any tumorigenic potential of NSCs and their striking capacity for engraftment in the CNS.
Differentiation of human neuronal progenitor cells via novel integrative nuclear FGFR1 signaling pathway
Authors: Stachowiak M. K.
Published: May 2003

Activation of cAMP signaling pathway, along with its transcriptional factor CREB and coactivator CBP, are key determinants of neuronal differentiation. Our studies have revealed an integrative nuclear FGFR1 signaling (INFS) pathway by which extracellular signals and cAMP induce differentiation of proliferating fetal brain‐ or cord blood‐derived neuronal progenitor cells. Upon cell stimulation, FGF receptor‐1 (FGFR1) is released from ER membranes into the cytosol and translocates to cell nucleus where it blocks cell proliferation and induces neuronal differentiation. FGFR1 associates with the active nuclear centers of RNA synthesis and processing and activates structurally distinct neural‐specific genes and CBP. Our findings indicate that (1) INFS mediates activation of multigene program for neuronal growth/differentiation, and (2) FGFR1 serves as a nuclear matrix‐attached scaffold on which multifunctional protein complexes are dynamically assembled causing a coordinated local RNA pol II regulation and chromatin remodeling.
Grafting dopamine neurons in Parkinson's disease: do stem cells have a role in the future?
Authors: Li J.‐Y. , Brundin P.
Published: May 2003

Parkinson's disease (PD) patients display motor symptoms, e.g. tremor, rigidity and bradykinesia, largely due to a dramatic loss of dopaminergic neurons in the substantia nigra. Grafts of human embryonic dopamine neurons can survive in the striatum and reduce several of the motor symptoms. Several lines of evidence suggest that a crucial threshold of surviving dopaminergic neurons must be exceeded for the grafts to become functional and relieve symptoms. A relatively small number of operations have been performed so far. The major obstacle to large clinical trials has been that tissue from large numbers of donor embryos is needed for each patient. Thus, there is definitely a need for alternative sources of donor tissue for grafting in PD. Clearly various forms of stem cells are interesting options. This presentation will focus the possible future use of embryonic stem cells and bone marrow stem cells as donor tissue for transplantation in PD.
Neurotrophic factors in diabetic neuropathy
Authors: Tomlinson D. R. , Burnand R. C. , Price S. A.
Published: May 2003

Dysfunctional switches in neuronal phenotype are at the root of diabetic neuropathy and many aspects of neuronal phenotype are maintained by neurotrophic influences. Thus the failure of these and their mediating signals are fundamental to understanding and controlling the condition. In experimental diabetes, failure of the C fiber phenotype is secondary to reduced neurotrophic regulation by nerve growth factor (NGF). We have performed gene array profiling to identify candidate genes for other neurotrophic factors. This reveals sonic hedgehog as a neurotrophic regulator, with the capacity to maintain nerve conduction velocity in the normal range and to maintain normal gene expression for a range of influential candidate genes. As all known targets for sonic hedgehog are transcription dependent, this implicates impaired gene expression, rather than disturbed physiology, in the nerve conduction defects of diabetes and suggest the most successful method of prevention of the condition.
Oxidative stress in the pathogenesis of experimental diabetic neuropathy
Authors: Low P. A. , Schmeichel A. , Schmelzer J. D. , Kishi M.
Published: May 2003

We evaluated the effects of chronic hyperglycemia on L5 DRG neurons. Experimental diabetic neuropathy (EDN) was induced by streptozotocin. We studied peripheral nerve after 1, 3, 12 months of diabetes. A conduction deficit was present from the first month and persisted over 12 months, affecting mainly sensory fibers. 8‐Hydroxy‐deoxyguanosine labeling was significantly increased at all time points in DRG neurons, indicating oxidative injury. Caspase‐3 labeling was increased at all three time‐points, indicating commitment to the efferent limb of the apoptotic pathway. Apoptosis was confirmed by a significant increase in the percent of neurons undergoing apoptosis (TUNEL staining) at 1 month (8%), 3 months (7%) and 12 months (11%). Morphometry of DRG showed a selective loss (42%) of the largest neurons. These findings support the concept that oxidative stress leads to oxidative injury of DRG neurons, with mitochondrium as a specific target, leading to apoptosis and a predominantly sensory neuropathy.
Vascular changes in animal models of diabetic neuropathy
Authors: Cameron N. E. , Cotter M. A.
Published: May 2003

Blood flow to neural tissues is reduced by diabetes. For peripheral nerve and ganglia, this occurs within a week of diabetes induction in experimental rat models. Some of the metabolic changes in diabetes target blood vessels, including vasa nervorum, resulting in attenuation of endothelial vasodilatory mechanisms based on nitric oxide, endothelium‐derived hyperpolarizing factor, and prostanoids. Moreover, there is increased production of and reactivity to some vasoconstrictors, particularly angiotensin II and endothelin‐1. Impaired vasa nervorum blood flow leads to endoneurial hypoxia, which causes or contributes of function defects affecting both large and small caliber nerve fibers. Intervention with vasodilator treatments corrects many diabetic neural deficits without affecting the hyperglycemic state, including reduced motor and sensory conduction velocity, elevated resistance to hypoxic conduction failure, impaired regeneration following nerve damage, aspects of hyperalgesia and allodynia, and autonomic dysfunction.
Interactions between hyperglycemia‐induced metabolic abnormalities and vascular factors in experimental diabetic neuropathy
Authors: Cotter M. A. , Cameron N. E.
Published: May 2003

Metabolic and vascular changes in diabetes conspire to cause nervous system dysfunction, which is particularly apparent for peripheral nerves. Hyperglycemia and hyperlipidemia give rise to numerous metabolic changes including, elevated polyol pathway flux, oxidative stress, formation of advanced glycation and lipoxidation end products, increased protein kinase C activity, and impaired essential fatty acid utilization. These disturbances interact to target neurons and their vascular supply. Experiments employing joint therapeutic approaches have revealed synergistic interactions between some of these mechanisms for both large and small caliber nerve fibers. Successful drug combinations conferring 5–10‐fold increases in efficacy include protein kinase C inhibitors and antioxidants, statins and angiotensin receptor antagonists, and antioxidants and essential fatty acids. This could provide a potentially important advantage for the treatment of diabetic neuropathy.
Therapy with antioxidants in human diabetic neuropathy
Authors: Ziegler D.
Published: May 2003

Increased oxidative stress has been implicated in the pathogenesis of diabetic polyneuropathy (DPN). Antioxidant treatment with alpha‐lipoic acid (ALA) has been shown to prevent or ameliorate experimental diabetic neuropathy, providing the rationale for treatment in humans. A recent meta‐analysis including four controlled clinical trials provided evidence that treatment with ALA (600 mg/day i.v.) over 3 weeks is safe and significantly improves both neuropathic symptoms and deficits to a clinically meaningful degree in patients with symptomatic DPN. Moreover, oral treatment for 4–7 months tends to ameliorate neuropathic deficits and cardiac autonomic neuropathy. Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of this drug. Based on these findings, a pivotal long‐term multicenter trial of oral treatment with ALA (NATHAN 1 Study) is under way aimed at slowing the progression of DPN.
PKC is involved in arachidonic acid‐induced choline acetyltransferase activity in spinal cord neurons
Authors: Chalimoniuk M. , Pederson W. A. , Mattson M. P. , Toborek M.
Published: May 2003

Arachidonic acid (AA) may affect cholinergic neuronal circuits in spinal cord. To test this hypothesis, activity of choline acetyltransferase (ChAT) was studied in cultured spinal cord neurons treated with AA (0.1–10 mm). AA increased ChAT activity in dose‐ and time‐dependent manners. These effects were mimicked by exposure to PMA but inhibited by a coexposure to PKC inhibitors. AA‐mediated increase in ChAT activity also was prevented by treatments with EGTA, indicating the role of calcium. In contrast, cotreatments with 7‐nitroindazole, sodium vanadate, and N‐acetyl‐cysteine had no influence on AA‐induced changes in ChAT activity. These results indicate that the AA‐evoked increase in ChAT activity in spinal cord neurons is mediated by PKC, most likely, at the post‐transcriptional level.

Acknowledgements: Supported by grants from KSCHIRT and Philip Morris Research Program.
Developmental pattern of synapsin I expression in mouse somatosensory cortex
Authors: Liguz‐Lecznar M. , Nowicka D. , Skangiel‐Kramska J.
Published: May 2003

Synapsin I is a member of a synapsin family which are phosphoproteins associated with synaptic vesicles. It is thought to be involved in neuronal development and plasticity. We have shown the existence of two distinct patterns of synapsin I immunostaining in adult mice primary somatosensory cortex (SI). The first consisted of small, dispersed immunoreactive puncta in neuropil. The second is confined to the perikarya and proximal dendrites of the specific class of neurons present in layers IV and VI of SI, probably reflecting the expression of a novel isoform of synapsin I. The aim of this study was to examine the developmental pattern of synapsin I expression in mouse SI cortex. Using immunocytochemistry and Western blot analysis we found that this unique pattern of synapsin I expression in SI appeared between the 2nd and 3rd postnatal week and probably coincides with the increase in the number of synaptic contacts and the development of inhibitory circuits in SI.

Acknowledgement: Supported by KBN grant no. 3P04C 008 22.