bluuebunny/crossref_metadata_2025 huggingface dataset:
Anorectal physiology in relation to clinical subgroups of patients with severe constipation
Authors: Karlbom U. , Lundin E. , Graf W. , Påhlman L.
Published: August 2004

Objective  The aim of this study was to evaluate anorectal physiology in relation to clinically defined subgroups of patients with idiopathic constipation and to analyse relationships between anorectal physiology and rectal evacuation.

Subjects and methods  One hundred consecutive patients with idiopathic constipation were clinically categorized as slow transit (n = 19), outlet obstruction (n = 52) and a group with mixed symptoms (n = 29). They were examined by recording anal pressures and also rectal volumes in response to stepwise increases in rectal pressure (5–60 cm H2O). The manovolumetric results were compared with 28 sex and aged matched controls. Rectal evacuation was measured by computer‐based image analysis of rectal emptying rate in defaecography.

Results  The rectal pressure thresholds for filling, urge and pain did not differ between the groups but there were proportionally more patients in the slow transit and mixed group with thresholds for filling exceeding 25 cm H2O (P = 0.04). In total, 18% of patients had impaired sensitivity which was associated with long duration of symptoms (P < 0.05). Patients with grossly impaired rectal sensitivity (filling threshold > 40 cm H2O) had impaired rectal evacuation (P < 0.05). The rectal compliance was increased in the slow transit and mixed group (P < 0.01–0.05) in the pressure interval 5–15 cm H2O. Anal resting and squeeze pressures did not differ between the groups although 7/19 in the slow transit group had values around the lower limit of controls. Slow wave frequency was lower in all patient groups (P < 0.001 vs. controls). Rectal evacuation was not related to sphincter function or to rectal compliance.

Conclusions  Clinical categorization of constipated patients defines groups where altered anorectal physiology is not uncommon. Constipation with symptoms of infrequent defaecation may be associated with impaired rectal sensitivity and increased rectal compliance whereas outlet obstruction symptoms are not clearly related to changes in anorectal physiology.
Endoscopic morphological anticipation of submucosal invasion in flat and depressed colorectal lesions: clinical implications and subtype analysis of the kudo type V pit pattern using high‐magnification‐chromoscopic colonoscopy
Authors: Hurlstone D. P. , Cross S. S. , Adam I. , Shorthouse A. J. , Brown S. , Sanders D. S. , Lobo A. J.
Published: August 2004

Objective  Focal submucosal invasive colorectal cancers (submucosa‐sm1) can be managed by endoscopic mucosal resection (EMR) as local lymph node metastasis (LNM) are rare. Lesions are usually flat, depressed or mixed. In deeper vertical submucosal invasion (sm2–3) LNM rates exceed 10–15%. EMR within this group can be complicated by perforation, noncurative resection and may leave LNM untreated. It is therefore essential to differentiate accurately focal sm1 disease from submucosal sm2/3 disease. The aim of this study was to evaluate the relationship between the invasive type V pit pattern using high‐magnification‐chromoscopic‐colonoscopy (HMCC) and submucosal invasive depth for flat and depressed colorectal lesions.

Methods  Total colonoscopy was performed by a highly selected single endoscopist using the Olympus C240Z on 850 patients between January 2001 and July 2003. Kudo type V pits were identified using 0.05% crystal violet (CV) applied directly to the lesion using a steel tipped catheter. Type V pits were graded into class V(n)A‐C as described by Nagata. Morphology was documented using the Japanese Research Society classification (JRSC). Histological sections, with reference to mucosal invasive characteristics, acquired using EMR or surgical excision were then compared with the pit pattern.

Results  Fifty‐one lesions showed a type V pit pattern. The kappa coefficient of agreement between pit the type V pit pattern and histologically confirmed submucosal invasion was 0.51 (95% CI). Following resection, 97% of lesions were correctly anticipated to have sm2 + invasion using pit type Vn(B) and Vn(C) as clinical indicators of invasive disease. Specificity was low at 50% with an accuracy of 78%.

Conclusions  The type V pit pattern is useful for the in vivo staging of submucosal invasive depth in flat and depressed colorectal lesions and is as sensitive as conventional 7.5 MHz EUS. There was a tendency to over‐stage lesions and hence the technique is limited by its low overall specificity.
Long‐term results of the antegrade continent enema procedure for constipation in adults
Authors: Lees N. P. , Hodson P. , Hill J. , Pearson R. C. , MacLennan I.
Published: August 2004

Objective  The aim of this study was to evaluate the long‐term results of the Antegrade Continent Enema (ACE) procedure for treating severe constipation in adults.

Methods  Over 10 years 37 ACE conduits were created in 32 patients (median age 35 years, 26 women) with constipation caused by slow transit, obstructed defaecation or both. Conduits were created from the appendix (n = 20, 54%), ileum (n = 10, 27%), neoappendix caecostomy (n = 5, 14%) or colon (n = 2, 5%). Clinical records were retrospectively reviewed to determine outcome.

Results  After a median follow up of 36 (range 13–140) months, 28 (88%) required at least one further procedure on a primary conduit, including reversal in 19 (59%). Five patients had a second conduit fashioned, two successfully. Conduit type and constipation cause did not significantly influence the rates of ACE reversal or major revision. Ileal conduits were associated with fewer minor revision procedures for stenosis (1 in 7 patients) than appendix conduits (21 in 20 patients). There was one (3%) serious complication. Satisfactory ACE function was ultimately achieved in 47% of patients, at last follow up. After ACE reversal, 9 (28%) patients underwent formation of an end stoma and 3 patients had a colectomy.

Conclusions  Revision procedures are common, but approximately half of patients can expect satisfactory long‐term ACE function. ACE conduit reversal does not preclude subsequent alternative surgical strategies to treat this difficult condition.
Fibrin glue in the management of anal fistulae
Authors: Hammond T. M. , Grahn M. F. , Lunniss P. J.
Published: August 2004

Objective  Fibrin glue has been used as a sphincter sparing approach for the treatment of anal fistulae for two decades. However, there is uncertainty about its short and long‐term efficacy. The objective of this review was to ascertain the role of fibrin glue in the management of anal fistulae, including assessment of recurrence rates, continence disturbance and other complications.

Methods  We searched Medline (January 1966 to February 2004), the Cochrane database, and EMBASE using the terms anal fistulae, fistula‐in‐ano, and fibrin glue. Relevant papers from the reference lists of these articles and from the authors' personal collections were also reviewed. A systematic review of all articles relating to the use of fibrin glue in the treatment of anal fistulae was performed. This included 19 studies. Reviewers performed data extraction independently. Outcomes evaluated included recurrence rates, continence disturbance, septic complications, adverse drug reactions, and duration of follow‐up. Heterogeneity of the clinical trials made direct comparisons difficult and meta‐analysis impossible.

Results  The success rates reported in published studies range from 0% to 100%. Differences in patient selection (including fistula aetiology and type), treatment protocols, and follow‐up duration may contribute to such diverse results.

Conclusions  Fibrin glue is simple to use, has a minimal morbidity and should not affect later treatment options in the event of its failure. It is therefore theoretically attractive as a first line treatment in the management of those types of anal fistula in which it has been shown to work. However, further research into ‘biological’ glues is merited and these subject to randomised controlled study.
Face‐memory and emotion: associations with major depression in children and adolescents
Authors: Pine Daniel S. , Lissek Shmuel , Klein Rachel G. , Mannuzza Salvatore , Moulton John L. , Guardino Mary , Woldehawariat Girma
Published: August 2004

Background:  Studies in adults with major depressive disorder (MDD) document abnormalities in both memory and face‐emotion processing. The current study used a novel face‐memory task to test the hypothesis that adolescent MDD is associated with a deficit in memory for face‐emotions. The study also examines the relationship between parental MDD and memory performance in offspring.

Methods:  Subjects were 152 offspring (ages 9–19) of adults with either MDD, anxiety disorders, both MDD and anxiety, or no disorder. Parents and offspring were assessed for mental disorders. Collection of face‐memory data was blind to offspring and parent diagnosis. A computerized task was developed that required rating of facial photographs depicting ‘happy,’‘fearful,’ or ‘angry’ emotions followed by a memory recall test. Recall accuracy was examined as a function of face‐emotion type.

Results:  Age and gender independently predicted memory, with better recall in older and female subjects. Controlling for age and gender, offspring with a history of MDD (n = 19) demonstrated significant deficits in memory selectively for fearful faces, but not happy or angry faces. Parental MDD was not associated with face‐memory accuracy.

Discussion:  This study found an association between MDD in childhood or adolescence and perturbed encoding of fearful faces. MDD in young individuals may predispose to subtle anomalies in a neural circuit encompassing the amygdala, a brain region implicated in the processing of fearful facial expressions. These findings suggest that brain imaging studies using similar face‐emotion paradigms should test whether deficits in processing of fearful faces relate to amygdala dysfunction in children and adolescents with MDD.
Do children with autism perceive second‐order relational features? The case of the Thatcher illusion
Authors: Rouse Helen , Donnelly Nick , Hadwin Julie A. , Brown Tony
Published: August 2004

Background:  This study presents two experiments that investigated whether children with autism were susceptible to the Thatcher illusion. Perception of the Thatcher illusion requires being able to compute second‐order configural relations for facial stimuli.

Method:  In both experiments children with autism were matched for non‐verbal and verbal ability with a group of children with moderate (non‐specific) mental retardation (MLD) and a group of typically developing children respectively. Participants were asked to detect the ‘unusual’ face in a two‐alternative‐forced‐choice version of the Margaret Thatcher illusion with grey‐scale (Experiment 1) and monochrome ‘Mooney’ face images (Experiment 2). In Experiment 1 participants also performed a control task where buildings had been doctored in the same way as the facial stimuli.

Results:  Children with autism were as susceptible to the Thatcher illusion as both control groups, in terms of accuracy and reaction time to make decisions about which face was unusual. Children with autism performed more accurately than children with MLD in the buildings task.

Conclusion:  Children with autism are able to compute second‐order configural features in faces and exhibit no difference in face processing, relative to appropriate control groups.
Event‐related brain potentials reveal anomalies in temporal processing of faces in autism spectrum disorder
Authors: McPartland James , Dawson Geraldine , Webb Sara J. , Panagiotides Heracles , Carver Leslie J.
Published: August 2004

Background: Individuals with autism exhibit impairments in face recognition, and neuroimaging studies have shown that individuals with autism exhibit abnormal patterns of brain activity during face processing. The current study examined the temporal characteristics of face processing in autism and their relation to behavior.

Method: High‐density event‐related brain potentials (ERPs) were recorded to images of faces, inverted faces, and objects from 9 individuals with autism spectrum disorder (15–42 years old) and 14 typical individuals (16–37 years old).

Results: With respect to a face‐sensitive ERP component (N170), individuals with autism exhibited longer N170 latencies to faces than typical individuals but comparable latencies to objects. Typical individuals exhibited longer N170 latencies to inverted as compared to upright faces, whereas individuals with autism did not show differences in N170 latency to upright versus inverted faces. Neural speed of face processing, as reflected in N170 latency, correlated with performance on a face recognition task for individuals with autism.

Conclusions: These data provide evidence for slowed neural speed of face processing in autism and highlight the role of speed of processing in face processing impairments in autism.
Online aggressor/targets, aggressors, and targets: a comparison of associated youth characteristics
Authors: Ybarra Michele L. , Mitchell Kimberly J.
Published: August 2004

Background:  While most youth report positive experiences and activities online, little is known about experiences of Internet victimization and associated correlates of youth, specifically in regards to Internet harassment.

Methods:  The Youth Internet Safety Survey is a cross‐sectional, nationally representative telephone survey of young regular Internet users in the United States. Interviews were conducted between the fall of 1999 and the spring of 2000 and examined characteristics of Internet harassment, unwanted exposure to sexual material, and sexual solicitation that had occurred on the Internet in the previous year. One thousand, five hundred and one regular Internet users between the ages of 10 and 17 years were interviewed, along with one parent or guardian. To assess the characteristics surrounding Internet harassment, four groups of youth were compared: 1) targets of aggression (having been threatened or embarrassed by someone; or feeling worried or threatened by someone's actions); 2) online aggressors (making rude or nasty comments; or harassing or embarrassing someone with whom the youth was mad at); 3) aggressor/targets (youth who report both being an aggressor as well as a target of Internet harassment); and 4) non‐harassment involved youth (being neither a target nor an aggressor online).

Results:  Of the 19% of young regular Internet users involved in online aggression, 3% were aggressor/targets, 4% reported being targets only, and 12% reported being online aggressors only. Youth aggressor/targets reported characteristics similar to conventional bully/victim youth, including many commonalities with aggressor‐only youth, and significant psychosocial challenge.

Conclusions:  Youth aggressor/targets are intense users of the Internet who view themselves as capable web users. Beyond this, however, these youth report significant psychosocial challenge, including depressive symptomatology, problem behavior, and targeting of traditional bullying. Implications for intervention are discussed.
Local Inflammation as a Mediator of Migraine and Tension‐Type Headache
Authors: Friedman Mark H.
Published: August 2004

Objective.—To demonstrate the relationship of migraine and tension‐type headache to a localized maxillary gingival inflammation.

Background.—Intraoral tenderness has been observed consistently in the most common types of primary headache disorders. The laterality and degree of tenderness is related to laterality and severity of reported symptoms, both during headache and in the interictal state.

Methods.—Bilateral posterior maxillary palpation and local temperature recordings were performed during unilateral migraine and tension‐type headache. Local anti‐inflammatory techniques, ie, local chilling and a topical anti‐inflammatory gel, were used in these tender areas in episodic migraine and tension‐type headache patients.

Results.—Ipsilateral intraoral tenderness and increased local temperature were consistently observed during unilateral migraine and tension‐type headache, suggesting local inflammation. Intraoral chilling and topical application of a nonsteroidal anti‐inflammatory drug were highly effective for the treatment of migraine and tension‐type headache, both in the acute phase and for headache prevention.

Conclusion.—These results suggest that a local intraoral inflammation may be associated with the pathogenesis of these common headaches.
Epidemiology and Symptomatology of Migraine Among School Children: Denizli Urban Area in Turkey
Authors: Zencir Mehmet , Ergin Hacer , Şahiner Türker , Kılıç İlknur , Alkış Esma , Özdel Lale , Gürses Dolunay , Ergin Ahmet
Published: August 2004

Objective.—This study was aimed at finding the prevalence, associated factors, and symptomatology of migraine among 5 to 8 grades of secondary and 9 to 11 grades of high school children (age range between 11 and 18 years old) in the Denizli urban area in the western part of Turkey.

Background.—Data from the developed countries indicate that migraine is the most common cause of recurrent headaches in children. Also, childhood migraine is sufficiently severe to prevent the half of the suffering children from carrying on their usual daily activities.

Methods.—A cross‐sectional school‐based study was conducted between May 2000 and June 2000. There were 2,490 participants selected by a multistage stratified clustered sampling procedure. A validated self‐administered questionnaire designed according to the International Headache Society criteria was given to the school children of age between 11 and 18 years.

Results.—Overall migraine prevalence was 8.8%; it was 6.7% in boys and 11.0% in girls (OR: 1.7; 95% CI: 1.3 to 2.3). Among girls, the highest prevalence (17.7%) occurred at 15 years of age, but among boys, the highest prevalence (11.9%) occurred at 16 years of age. Of children with migraine, 56.5% had a positive family history, and only 29.1% visited a doctor for headache.

Conclusion.—Migraine is a common health problem among school children in Denizli urban area and it often goes underdiagnosed.
Validity and Reliability of the Turkish Migraine Disability Assessment (MIDAS) Questionnaire
Authors: Ertaş Mustafa , Siva Aksel , Dalkara Turgay , Uzuner Nevzat , Dora Babür , İnan Levent , İdiman Fethi , Sarica Yakup , Selçuki Deniz , Şirin Hadiye , Oğuzhanoğlu Atilla , İrkeç Ceyla , Özmenoğlu Mehmet , Özbenli Taner , Öztürk Musa , Saip Sabahattin , Neyal Münife , Zarifoğlu Mehmet , MIDAS group Turkish
Published: August 2004

Objectives.—The aim of this study is to assess the comprehensibility, internal consistency, patient‐physician reliability, test‐retest reliability, and validity of Turkish version of Migraine Disability Assessment (MIDAS) questionnaire in patients with headache.

Background.—MIDAS questionnaire has been developed by Stewart et al and shown to be reliable and valid to determine the degree of disability caused by migraine.

Design and Methods.—This study was designed as a national multicenter study to demonstrate the reliability and validity of Turkish version of MIDAS questionnaire. Patients applying to 17 Neurology Clinics in Turkey were evaluated at the baseline (visit 1), week 4 (visit 2), and week 12 (visit 3) visits in terms of disease severity and comprehensibility, internal consistency, test‐retest reliability, and validity of MIDAS. Since the severity of the disease has been found to change significantly at visit 2 compared to visit 1, test‐retest reliability was assessed using the MIDAS scores of a subgroup of patients whose disease severity remained unchanged (up to ±3 days difference in the number of days with headache between visits 1 and 2).

Results.—A total of 306 patients (86.2% female, mean age: 35.0 ± 9.8 years) were enrolled into the study. A total of 65.7%, 77.5%, 82.0% of patients reported that “they had fully understood the MIDAS questionnaire” in visits 1, 2, and 3, respectively. A highly positive correlation was found between physician and patient and the applied total MIDAS scores in all three visits (Spearman correlation coefficients were R= 0.87, 0.83, and 0.90, respectively, P < .001). Internal consistency of MIDAS was assessed using Cronbach's α and was found at acceptable (>0.7) or excellent (>0.8) levels in both patient and physician applied MIDAS scores, respectively. Total MIDAS score showed good test‐retest reliability (R= 0.68). Both the number of days with headache and the total MIDAS scores were positively correlated at all visits with correlation coefficients between 0.47 and 0.63. There was also a moderate degree of correlation (R= 0.54) between the total MIDAS score at week 12 and the number of days with headache at visit 2 + visit 3, which quantify headache‐related disability over a 3‐month period similar to MIDAS questionnaire.

Conclusion.—These findings demonstrated that the Turkish translation is equivalent to the English version of MIDAS in terms of internal consistency, test‐retest reliability, and validity. Physicians can reliably use the Turkish translation of the MIDAS questionnaire in defining the severity of illness and its treatment strategy when applied as a self‐administered report by migraine patients themselves.
Complete but Transient Relief of Chronic Cluster Headache With Mycophenolate Mofetil
Authors: Rozen Todd D.
Published: August 2004

Chronic cluster headache is one of the most disabling of all neurologic conditions. New effective therapies for refractory chronic cluster headache are needed. The unique sensitivity of most cluster headache patients to corticosteroid treatment suggests that steroid‐sparing immunosuppressive drugs may show benefit as cluster headache preventives. A patient is presented who had complete but transient relief of chronic cluster headache with mycophenolate mofetil.
Hemicrania Continua: A Third Case in Which Attacks Alternate Sides
Authors: Newman Lawrence C. , Spears Roderick C. , Lay Christine L.
Published: August 2004

Hemicrania continua (HC) is an uncommon, primary headache disorder characterized by a continuous unilateral headache of moderate intensity with superimposed exacerbations of more severe pain. HC exists in two temporal subtypes, a continuous form in which headaches persist continuously without remission periods, and a less common remitting form in which bouts of continuous headaches are separated by pain‐free remissions. There have been more than 100 prior reports of HC; in the majority of which the headache is strictly unilateral and without side shift. We now report the third patient in whom headaches alternated sides during different attacks.
Different Perspectives on the Practice of Leadership
Authors: Fairholm Matthew R.
Published: August 2004

Public administrators need not only practical and intellectual permission to exercise leadership, but also a practical and intellectual understanding of what leadership actually is. Much has emerged in the public administration literature and practice about the need for and legitimacy of public managers exerting leadership in their work, complementing the traditional functions of organizational management and policy implementation. Calling on the experiences and ideas of practitioners, this article offers an empirical understanding—both descriptive and prescriptive—of what leadership actually looks like as it is practiced by public managers. It uncovers five leadership perspectives (ranging from leadership as equivalent to scientific management, to leadership being a whole‐soul or spiritual endeavor) held by public managers and discusses their implications for public administration. It legitimizes the notion that leadership is a crucial part of public administration and offers public managers the chance to improve or enhance those legitimate leadership activities.
Measuring Accountability for Results in Interagency Collaboratives
Authors: Page Stephen
Published: August 2004

This article examines the intersection of two types of innovations that are increasingly common in public administration—accountability for results and interagency collaboration. Recent scholarship suggests four approaches that collaborators can use to increase their accountability for results. The article proposes measures of these four approaches to assess a collaborative's capacity for accountability, and uses them to compare the accountability of human services collaboratives in 10 states. The findings indicate that collaboratives tend to use the four approaches together with one another. In combination, the various approaches may help collaborators manage their stake holders' expectations about their actions and accomplishments. Further research is needed to determine whether a collaborative's capacity for accountability for results actually correlates with improvements in outcomes.
Crossing the Great Divide: Dilemmas of U.K. Voluntary‐Sector Leaders Who Move into Government
Authors: Little Amanda
Published: August 2004

Evidence suggests the boundaries between the U.K. government and the voluntary sector are blurring because of an increasing emphasis on partnership between the two. One symptom of this changing relationship–or a contributing cause of it–is the practice of recruiting senior managers from the voluntary sector into government service. The intention is that these managers should play a significant role in formulating and implementing government strategy with regard to the voluntary sector and in other policy areas where voluntary‐sector organizations are seen as key players. This article addresses the issues that voluntary‐sector leaders face when they move into government–to what extent are they insiders, outsiders, or critical friends, and to whom? It concludes that the madness of the government machine is more than the sum of its parts: people, policy, and process.
New medication treatment options for bipolar disorders
Authors: Ketter T. A. , Wang P. W. , Nowakowska C. , Marsh W. K.
Published: August 2004

Objective:  To assess new treatment options for bipolar disorders.

Method:  Controlled studies of new treatments for bipolar disorders were identified by computerized searches and reviews of scientific meeting proceedings, and were compiled by drug category.

Results:  Two main categories of medications, newer anticonvulsants and newer antipsychotics, are yielding emerging new treatment options for bipolar disorders. Newer anticonvulsants have diverse psychotropic profiles, and although not generally effective for acute mania, may have utility for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or acute bipolar depression), or for comorbid conditions (e.g. gabapentin for anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or migraine, and zonisamide for obesity). In contrast, newer antipsychotics generally appear effective for acute mania, and some may ultimately prove effective in acute depression (e.g. olanzapine combined with fluoxetine, quetiapine) and maintenance (e.g. olanzapine).

Conclusion:  Emerging research is yielding new treatment options for bipolar disorders and comorbid conditions.
Scale matters: the need for a Bipolar Depression Rating Scale (BDRS)
Authors: Berk M. , Malhi G. S. , Mitchell P. B. , Cahill C. M. , Carman A. C. , Hadzi‐Pavlovic D. , Hawkins M. T. , Tohen M.
Published: August 2004

Objective:  To briefly review the clinical and biological distinctions between unipolar and bipolar depression critiquing in particular currently available depression rating scales and discuss the need for a new observer‐rated scale tailored to bipolar depression.

Method:  Relevant literature pertaining to the symptomatic differences between bipolar disorder and unipolar disorder as well as their measurement using existing assessment scales was identified by computerized searches and reviews of scientific journals known to the authors.

Results:  Bipolar depression is distinct from unipolar depression in terms of phenomenology and clinical characteristics. These distinguishing features can be used to identify bipolarity in patients that present with recurrent depressive episodes. This is important because current self‐report and observer‐rated scales are optimized for unipolar depression, and hence limited in their ability to accurately assess bipolar depression.

Conclusion:  The development of a specific bipolar depression rating scale will improve the assessment of bipolar depression in both research and clinical settings and assist the development of better treatments and interventions.
Bipolaroids: functional imaging in bipolar disorder
Authors: Malhi G. S. , Lagopoulos J. , Owen A. M. , Yatham L. N.
Published: August 2004

Objective:  To evaluate the literature pertaining to the use of functional magnetic resonance imaging (fMRI) in bipolar disorder research.

Method:  A search for papers published in English in journals from 1984 onwards was conducted using MedLine and EMBASE with the following terms: functional neuroimaging or fMRI and depression or bipolar disorder. In addition, retrieved papers and literature known to the authors was also scrutinized for further relevant reports.

Results:  The research findings from 26 articles are tabulated and the results from 10 articles dealing specifically with bipolar disorder are discussed in detail.

Conclusion:  fMRI is a useful tool for investigating bipolar disorder. Preliminary studies point to trait and state abnormalities involving structures known to be associated with the generation and modulation of emotion. The patterns of fMRI activation are different to those found in healthy subjects and patients with major depression. FMRI studies are likely to provide valuable insights into the pathophysiology of bipolar disorder.
Lithium treatment in Aarhus: contributions and controversies through half a century
Authors: Vestergaard Per
Published: August 2004

In 1954 the first of several hundred publications on the use of lithium for treatment of affective disorders, lithium's unwanted effects, and its pharmacology was authored at the Aarhus University Psychiatric Hospital, the majority with Professor, now emeritus, Mogens Schou playing the principal part. The early part of this long series of papers highlights the pharmacology of lithium with its renal excretion, low therapeutic index, and ensuing risk of intoxication, the prophylactic effect not only against manic episodes but also the depressive ones and finally the long‐term renal structural and functional impairment.

Later papers present the problems related to lithium's lower effectiveness in routine clinical use, the problems of non‐adherence, the dose effect relationships, and the problems inherent to establishing effective treatment service delivery.

The present priority of the Aarhus lithium group is the simple large scale pragmatic effectiveness studies in which, together with domestic and foreign collaborators, we compare the long‐term effectiveness of lithium with new promising drugs with mood stabilizing properties.

The story of treatment with lithium in aarhus highlights important steps in the development of effective and comprehensive treatments for bipolar patients.
Quantal release of ATP from clusters of PC12 cells
Authors: Fabbro Alessandra , Skorinkin Andrei , Grandolfo Micaela , Nistri Andrea , Giniatullin Rashid
Published: August 2004

Although ATP is important for intercellular communication, little is known about the mechanism of endogenous ATP release due to a dearth of suitable models. Using PC12 cells known to express the P2X2 subtype of ATP receptors and to store ATP with catecholamines inside dense‐core vesicles, we found that clusters of PC12 cells cultured for 3–7 days generated small transient inward currents (STICs) after an inward current elicited by exogenous ATP. The amplitude of STICs in individual cells correlated with the peak amplitude of ATP‐induced currents. STICs appeared as asynchronous responses (approximately 20 pA average amplitude) for 1–20 s and were investigated with a combination of patch clamping, Ca2+ imaging, biochemistry and electron microscopy. Comparable STICs were produced by focal KCl pulses and were dependent on extracellular Ca2+. STICs were abolished by the P2X antagonist PPADS and potentiated by Zn2+, suggesting they were mediated by P2X2 receptor activation. The highest probability of observing STICs was after the peak of intracellular Ca2+ increase caused by KCl. Biochemical measurements indicated that KCl application induced a significant release of ATP from PC12 cells. Electron microscopy studies showed narrow clefts without ‘synaptic‐like’ densities between clustered cells. Our data suggest that STICs were caused by quantal release of endogenous ATP by depolarized PC12 cells in close juxtaposition to the recorded cell. Thus, STICs may be a new experimental model to characterize the physiology of vesicular release of ATP and to study the kinetics and pharmacology of P2X2 receptor‐mediated quantal currents.
Excitability changes in human forearm corticospinal projections and spinal reflex pathways during rhythmic voluntary movement of the opposite limb
Authors: Carson R. G. , Riek S. , Mackey D. C. , Meichenbaum D. P. , Willms K. , Forner M. , Byblow W. D.
Published: August 2004

Rhythmic movements brought about by the contraction of muscles on one side of the body give rise to phase‐locked changes in the excitability of the homologous motor pathways of the opposite limb. Such crossed facilitation should favour patterns of  bimanual coordination in which homologous muscles are engaged simultaneously, and disrupt those in which the muscles are activated in an alternating fashion. In order to examine these issues, we obtained responses to transcranial magnetic stimulation (TMS), to stimulation of the cervicomedullary junction (cervicomedullary‐evoked potentials, CMEPs), to peripheral nerve stimulation (H‐reflexes and f‐waves), and elicited stretch reflexes in the relaxed right flexor carpi radialis (FCR) muscle during rhythmic (2 Hz) flexion and extension movements of the opposite (left) wrist. The potentials evoked by TMS in right FCR were potentiated during the phases of movement in which the left FCR was most strongly engaged. In contrast, CMEPs were unaffected by the movements of the opposite limb. These results suggest that there was systematic variation of the excitability of the motor cortex ipsilateral to the moving limb. H‐reflexes and stretch reflexes recorded in right FCR were modulated in phase with the activation of left FCR. As the f‐waves did not vary in corresponding fashion, it appears that the phasic modulation of the H‐reflex was mediated by presynaptic inhibition of Ia afferents. The observation that both H‐reflexes and f‐waves were depressed markedly during movements of the opposite indicates that there may also have been postsynaptic inhibition or disfacilitation of the largest motor units. Our findings indicate that the patterned modulation of excitability in motor pathways that occurs during rhythmic movements of the opposite limb is mediated primarily by interhemispheric interactions between cortical motor areas.
Preconditioning of skeletal muscle against contraction‐induced damage: the role of adaptations to oxidants in mice
Authors: McArdle F. , Spiers S. , Aldemir H. , Vasilaki A. , Beaver A. , Iwanejko L. , McArdle A. , Jackson M. J.
Published: August 2004

Adaptations of skeletal muscle following exercise are accompanied by changes in gene expression, which can result in protection against subsequent potentially damaging exercise. One cellular signal activating these adaptations may be an increased production of reactive oxygen and nitrogen species (ROS). The aim of this study was to examine the effect of a short period of non‐damaging contractions on the subsequent susceptibility of muscle to contraction‐induced damage and to examine the changes in gene expression that occur following the initial contraction protocol. Comparisons with changes in gene expression in cultured myotubes following treatment with a non‐damaging concentration of hydrogen peroxide (H2O2) were used to identify redox‐sensitive genes whose expression may be modified by the increased ROS production during contractions. Hindlimb muscles of mice were subjected to a preconditioning, non‐damaging isometric contraction protocol in vivo. After 4 or 12 h, extensor digitorum longus (EDL) and soleus muscles were removed and subjected to a (normally) damaging contraction protocol in vitro. Muscles were also analysed for changes in gene expression induced by the preconditioning protocol using cDNA expression techniques. In a parallel study, C2C12 myotubes were treated with a non‐damaging concentration (100 μm) of H2O2 and, at 4 and 12 h following treatment, myotubes were treated with a damaging concentration of H2O2 (2 mm). Myotubes were analysed for changes in gene expression at 4 h following treatment with 100 μm H2O2 alone. Data demonstrate that a prior period of non‐damaging contractile activity resulted in significant protection of EDL and soleus muscles against a normally damaging contraction protocol 4 h later. This protection was associated with significant changes in gene expression. Prior treatment of myotubes with a non‐damaging concentration of H2O2 also resulted in significant protection against a damaging treatment, 4 and 12 h later. Comparison of changes in gene expression in both studies identified haem oxygenase‐1 as the sole gene showing increased expression during adaptation in both instances suggesting that activation of this gene results from the increased ROS production during contractile activity and that it may play a role in protection of muscle cells against subsequent exposure to damaging activity.
Rho‐kinase inhibition and electromechanical coupling in rat and guinea‐pig ureter smooth muscle: Ca2+‐dependent and ‐independent mechanisms
Authors: Shabir S. , Borisova L. , Wray Susan , Burdyga T.
Published: August 2004

Recent data have shown Ca2+‐dependent activation of Rho‐kinase by sustained depolarization of arterial smooth muscle. Visceral smooth muscles, however, contract phasically in response to action potentials and it is unclear whether Ca2+‐dependent or ‐independent Rho‐kinase activation occurs. We have therefore investigated this, under physiologically relevant conditions, in intact ureter. Action potentials, ionic currents, Ca2+ transients, myosin light chain (MLC) phosphorylation and phasic contraction evoked by action potentials in guinea‐pig and rat ureter were investigated. In rat, but not guinea‐pig ureter, three Rho‐kinase inhibitors, Y‐27632, HA‐1077 and H‐1152, significantly decreased phasic contractions and Ca2+ transients. Voltage‐ and current‐clamp data showed that Rho‐kinase inhibition reduced the plateau component of the action potential, inhibited Ca2+‐channels and, indirectly, Ca2+‐activated Cl− channels. The Ca2+ channel agonist Bay K8644 could reverse these effects. The K+ channel blocker TEA could also reverse the inhibitory effect of Y‐27632 on the action potential and Ca2+ transient. Ca2+ transients and inward current, activated by carbachol‐induced sarcoplasmic reticulum Ca2+release, were not affected by Rho‐kinase inhibition. Rho‐kinase inhibition produced a Ca2+‐independent increase in the relaxation rate of contraction, associated with acceleration of MLC dephosphorylation, which was sensitive to calyculin A. These data show for the first time that: (1) Rho‐kinase has major effects on Ca2+ signalling associated with the action potential, (2) this effect is species dependent and (3) Rho‐kinase controls relaxation of phasic contraction of myogenic origin. Thus Rho‐kinase can modulate phasic smooth muscle in the absence of agonist, and the mechanisms are both Ca2+‐dependent, involving ion channels, and Ca2+‐independent, involving MLC phosphorylation activity.
Decavanadate modulates gating of TRPM4 cation channels
Authors: Nilius Bernd , Prenen Jean , Janssens Annelies , Voets Thomas , Droogmans Guy
Published: August 2004

We have tested the effects of decavanadate (DV), a compound known to interfere with ATP binding in ATP‐dependent transport proteins, on TRPM4, a Ca2+‐activated, voltage‐dependent monovalent cation channel, whose activity is potently blocked by intracellular ATP4−. Application of micromolar Ca2+ concentrations to the cytoplasmic side of inside‐out patches led to immediate current activation followed by rapid current decay, which can be explained by an at least 30‐fold decreased apparent affinity for Ca2+. Subsequent application of DV (10 μm) strongly affected the voltage‐dependent gating of the channel, resulting in large sustained currents over the voltage range between −180 and +140 mV. The effect of DV was half‐maximal at a concentration of 1.9 μm. The Ca2+‐ and voltage‐dependent gating of the channel was well described by a sequential kinetic scheme in which Ca2+ binding precedes voltage‐dependent gating. The effects of DV could be explained by an action on the voltage‐dependent closing step. Surprisingly, DV did not antagonize the effect of ATP4− on TRPM4, but caused a nearly 10‐fold increase in the sensitivity of the ATP4− block. TRPM5, which is the most homologous channel to TRPM4, was not modulated by DV. The effect of DV was lost in a TRPM4 chimera in which the C‐terminus was substituted with that of TRPM5. Deletion of a cluster in the C‐terminus of TRPM4 containing positively charged amino acid residues with a high homology to part of the decavanadate binding site in SERCA pumps, completely abolished the DV effect but also accelerated desensitization. Deletion of a similar site in the N‐terminus had no effects on DV responses. These results indicate that the C‐terminus of TRPM4 is critically involved in mediating the DV effects. In conclusion, decavanadate modulates TRPM4, but not TRPM5, by inhibiting voltage‐dependent closure of the channel.
Jejunal afferent nerve sensitivity in wild‐type and TRPV1 knockout mice
Authors: Rong Weifang , Hillsley Kirk , Davis John B. , Hicks Gareth , Winchester Wendy J. , Grundy David
Published: August 2004

The aim of this study was to investigate the contribution of the TRPV1 receptor to jejunal afferent sensitivity in the murine intestine. Multiunit activity was recorded in vitro from mesenteric afferents supplying segments of mouse jejunum taken from wild‐type (WT) and TRPV1 knockout (TRPV1−/−) animals. In WT preparations, ramp distension of the gut (up to 60 mmHg) produced biphasic changes in afferent activity so the pressure–response curve had an initial rapid increase in afferent discharge followed by a second phase of slower increase in activity. Afferent response to distension was significantly lower in TRPV1−/− than in WT mice. Single‐unit analysis revealed three functional types of afferent fibres: (1) low‐threshold fibres (2) wide dynamic range fibres and (3) high‐threshold fibres. There was a marked downward shift of the pressure–response curve for wide dynamic range fibres in the TRPV1−/− mice as compared to the WT controls. The afferent response to intraluminal hydrochloric acid (20 mm) was also attenuated in the TRPV1−/− mice. In contrast, the response to bath application of bradykinin (1 μm, 3 ml) was not significantly different between the two groups. The TRPV1 antagonist capsazepine (10 μm) significantly attenuated the nerve responses to distension, intraluminal acid and bradykinin, as well as the spontaneous discharge in WT mice. The WT jejunal afferents responded to capsaicin with rapid increases in afferent activity, whereas TRPV1−/− afferents were not at all sensitive to capsaicin. Previous evidence indicates that TRPV1 is not mechanosensitive, so the results of the present study suggest that activation of TRPV1 may sensitize small intestinal afferent neurones.
A transiently expressed SK current sustains and modulates action potential activity in immature mouse inner hair cells
Authors: Marcotti Walter , Johnson Stuart L. , Kros Corné J.
Published: August 2004

From just after birth, mouse inner hair cells (IHCs) expressed a Ca2+‐activated K+ current that was reduced by intracellular BAPTA at concentrations ≥ 1 mm. The block of this current by nifedipine suggests the direct involvement of Cav1.3 Ca2+ channels in its activation. On the basis of its high sensitivity to apamin (KD 360 pm) it was identified as a small‐conductance Ca2+‐activated K+ current (SK), probably SK2. A similar current was also found in outer hair cells (OHCs) from the beginning of the second postnatal week. In both cell types the appearance of the SK current coincided with their becoming responsive to acetylcholine (ACh), the main efferent neurotransmitter in the cochlea. The effect of ACh on IHCs was abolished when they were simultaneously superfused with strychnine, consistent with the presence of nicotinic ACh receptors (nAChRs). Extracellular Ca2+ either potentiated or blocked the nAChR current depending on its concentration, as previously reported for the recombinant α9α10 nAChR. Outward currents activated by ACh were reduced by blocking the SK current with apamin or by preventing SK current activation with intracellular BAPTA (≥ 10 mm). The endogenous mobile Ca2+ buffer concentration was estimated to be equivalent to about 1 mm BAPTA, suggesting that in physiological conditions the SK channel is significantly activated by Ca2+ influx through both Cav1.3 Ca2+ channels and α9α10 nAChRs. Current clamp experiments showed that in IHCs the SK current is required for sustaining a train of action potentials and also modulates their frequency when activated by ACh.
Soma-Germ Line Competition for Lipid Phosphate Uptake Regulates Germ Cell Migration and Survival
Authors: Renault A. D. , Sigal Y. J. , Morris A. J. , Lehmann R.
Published: August 2004

Lipid phosphates can act as signaling molecules to influence cell division, apoptosis, and migration.
wunen
and
wunen2
encode
Drosophila
lipid phosphate phosphohydrolases, integral membrane enzymes that dephosphorylate extracellular lipid phosphates.
wun
and
wun2
act redundantly in somatic tissues to repel migrating germ cells, although the mechanism by which germ cells respond is unclear. Here, we report that
wun2
also functions in germ cells, enabling them to perceive the
wun/wun2
–related signal from the soma. Upon Wun2 expression, cultured insect cells dephosphorylate and internalize exogenously supplied lipid phosphate. We propose that
Drosophila
germ cell migration and survival are controlled by competition for hydrolysis of a lipid phosphate between germ cells and soma.
Best Practice No 179
Authors: Ellis I O , Humphreys S , Michell M , Pinder S E , Wells C A , Zakhour H D
Published: August 2004

Non-operative diagnosis has become the norm in breast disease assessment and, until relatively recently, fine needle aspiration cytology has been the sampling method of choice. The introduction of automated core biopsy guns in the mid 1990s led to the additional introduction of core biopsy in assessment units. This paper presents a summary of the guidance on handling and routine reporting of breast needle core biopsy specimens in the context of breast disease multidisciplinary assessment. This guidance has been produced by the UK National Coordinating Committee for Breast Screening Pathology and is endorsed by the European Commission working group on breast screening pathology.