bluuebunny/crossref_metadata_2025 huggingface dataset:
A critical comparison of drug therapies in currently used therapeutic strategies for variceal haemorrhage
Authors: Nevens F.
Published: August 2004

Vasoactive drugs are safe and easy to administer, and universal treatment is the first‐line approach for all patients with suspected variceal bleeding. There are strong arguments that the combination of vasoactive drugs, started as soon as possible, and endotherapy later on is the best therapeutic option, particularly in cases of ongoing bleeding at the time of endoscopy. The main action of vasoactive drugs is to reduce variceal pressure. This can be achieved by diminishing the variceal blood flow and/or by increasing resistance to variceal blood flow inside the varices. Changes in variceal pressure parallel changes in portal pressure. Drugs for the treatment of variceal bleeding can therefore be assessed by measuring the changes in portal pressure, azygos blood flow and variceal pressure. Vasoactive drugs can be divided into two categories: terlipressin (Glypressin®), and somatostatin and its analogues, especially octreotide. Terlipressin significantly reduces portal and variceal pressure and azygos flow, is superior to placebo in the control of variceal haemorrhage and improves mortality. It is beneficial when combined with sclerotherapy. It also has the advantage that it might preserve renal function, one of the most important factors affecting the outcome of cirrhosis. As such, terlipressin is the most potent of the various vasoactive drugs. Somatostatin significantly reduces portal and variceal pressure and azygos flow, is superior to placebo in controlling variceal haemorrhage, and improves the success of sclerotherapy. The effect of octreotide is well established for preventing the increase in portal pressure after a meal (similar to blood in the intestines) though the effect of ocreotide on variceal pressure is controversial.
Hepatorenal syndrome – definitions and diagnosis
Authors: Moreau R. , Lebrec D.
Published: August 2004

Hepatorenal syndrome (HRS) is a severe complication of cirrhosis that develops in the final phase of the disease. Two types of HRS exist. Type 1 is defined by a rapid reduction of renal function and in type 2 HRS the reduction of renal function is slowly progressive. Type 1 HRS is diagnosed when the serum creatinine level increases by more than 50% of the baseline value to above 133 µmol/L. According to the International Ascites Club, HRS is defined by the presence of five criteria: (1) severe cirrhosis; (2) glomerular hypofiltration; (3) no other functional or organic causes; (4) failure of plasma volume expansion; (5) no proteinuria. Additional diagnostic criteria may be present. The diagnosis of HRS may be difficult in patients with severe cirrhosis. Other types of acute renal failure may occur. For example, ischaemic or toxic tubular necrosis or sepsis may cause renal failure in these patients. Furthermore, uncontrolled HRS may lead to ischaemic tubular necrosis; thus, these patients must be managed as soon as possible in an intensive care unit.
Pathogenesis and pathophysiology of hepatorenal syndrome – is there scope for prevention?
Authors: Møller S. , Henriksen J. H.
Published: August 2004

The hepatorenal syndrome (HRS) is a functional impairment of the kidneys in chronic liver disease caused by a circulatory failure. The prognosis is poor, particularly with type 1 HRS, but also type 2, and only liver transplantation is of lasting benefit. However, recent research into the pathophysiology of ascites and HRS has stimulated new enthusiasm in their prevention and treatment. Patients with HRS have hyperdynamic circulatory dysfunction with reduced arterial blood pressure and reduced central blood volume, owing to preferential splanchnic arterial vasodilatation. Activation of potent vasoconstricting systems, including the sympathetic nervous and renin‐angiotensin‐aldosterone systems, counteracts the arterial vasodilatation and leads to a pronounced renal vasoconstriction with renal hypoperfusion, a reduced glomerular filtration rate, and intense sodium‐water retention. Thus prevention of HRS should seek to improve liver function, limit arterial hypotension and central hypovolaemia, and reduce renal vasoconstriction and the renal and interstitial pressures. Portal pressure can be reduced with β‐adrenergic blockers and transjugular intrahepatic portosystemic shunt (TIPS). Precipitating events, like infections, bleeding, and postparacentesis circulatory syndrome, should be treated to avoid further circulatory failure. Improvement in arterial blood pressure and central hypovolaemia can be achieved with vasoconstrictors, such as terlipressin (Glypressin®), and plasma expanders such as human albumin. In the future endothelins, adenosine antagonists, long‐acting vasoconstrictors, and antileukotriene drugs may play a role in preventing and treating HRS.
Anesthetic implications of Leigh's syndrome
Authors: Shear Torin , Tobias Joseph D.
Published: August 2004

Leigh's syndrome (LS) is a mitochondrial disorder characterized by progressive neurodegenerative changes with loss of developmental milestones, abnormalities of central control of respiration, and metabolic derangements. The primary genetic defect involves the respiratory chain complex and pyruvate dehydrogenase complex resulting in abnormal mitochondrial function and defective oxidative phosphorylation. While most patients have respiratory and neurological impairment, involvement of the cardiovascular and musculoskeletal systems may also occur. The authors present the use of spinal anesthesia for muscle biopsy in a 19 month old with LS and review the potential anesthetic implications of this syndrome.
Transanal endoscopic microsurgery: clinical and functional results
Authors: Dafnis G. , Påhlman L. , Raab Y. , Gustafsson U.‐M. , Graf W.
Published: August 2004

Objective  Transanal endoscopic microsurgery (TEM) has become increasingly common in the management of rectal adenomas and also in selected cases of rectal carcinomas. The aim of this study was to assess the results in a consecutive series of patients after introducing the TEM technique.

Patients and methods  All 58 patients operated with TEM from January 1996 to January 1999 were evaluated in a retrospective review. Forty‐eight patients answered a clinically validated questionnaire a median of 22 months after TEM. Eighty patients who had undergone transanal excision and 12 who had undergone York Mason's procedure served as a reference group with respect to recurrence rates.

Results  The complication rate was 5% (immediate) and 14% (long‐term). The overall 30‐day mortality rate was zero. An impairment of continence was seen in 18 (37%) patients. Of these, all 18 experienced varying degree of incontinence to liquid stool, 14 also to flatus and 5 of them even to solid stool. The recurrence rate was 11% in adenomas and 14% in cancers; T1, 1 (10%) recurrence and T2, 1 (50%) recurrence. There was a correlation between operating time and impairment of continence as well as recurrence rate.

Conclusion  TEM is a safe procedure, having a low recurrence rate and an acceptable functional outcome.
‘An investigation of the nervous control of defecation’ by Denny‐Brown and Robertson: a classic paper revisited
Authors: Vilensky J. A. , Bell D. R. , Gilman S.
Published: August 2004

In 1935 two young neurologists, Derek Denny‐Brown and E. Graeme Robertson, published an article explaining the mechanisms underlying human defaecation based on a manometric study in patients with sacral root and spinal cord lesions, and normal subjects. This article is still routinely cited in studies of rectal and sphincter ani function. Unfortunately, however, the article itself is not written well, being composed of long convoluted sentences and containing 79 often indecipherable figures. Difficult‐to‐understand articles were common to the publications of Denny‐Brown, who became one of the most prominent neurologists of the twentieth century. In accord with our prior work explaining Denny‐Brown and Robertson's earlier paper on micturition, we provide here what we hope is a clear explanation of the methods and results in their study on defaecation.
Transanal endoscopic microsurgery: indications and results after 100 cases
Authors: Palma P. , Freudenberg S. , Samel S. , Post S.
Published: August 2004

Objective  Transanal endoscopic microsurgery (TEM), a minimally invasive technique has been employed in the excision of benign and well‐selected malignant rectal tumours since June 1998. We present a prospective descriptive study and analyse the currently accepted indications.

Patients and methods  Over a 4‐year period 100 patients underwent TEM for treatment of rectal tumours located between 4 and 18 cm from the anal verge.

Results  TEM was performed in 71 cases for adenomas, 20 potentially curative excisions for pre‐operative staged low‐grade carcinoma, 3 palliative procedures for advance carcinoma, 5 carcinoids and 1 solitary ulcer. The local complication rate included wound breakdown in 7 patients, three of them requiring ileostomy. Conversion to laparotomy was performed in two patients. Five adenomas recurred and were successfully treated by TEM. Of the cancers, four patients required immediate salvage therapy by means of total mesorectal excision. Three patients underwent palliative TEM procedures combined with radiotherapy. A single cancer recurrence was treated by means of abdomino‐perineal resection after radiotherapy.

Conclusions  TEM appears to be an effective method of excising benign tumours and selected T1 carcinomas of the rectum. The superior exposure of tumours higher in the rectum combined with the greater precision of excision make this minimally invasive technique an attractive surgical approach.
Parents and partners in crime: a six‐year longitudinal study on changes in supportive relationships and delinquency in adolescence and young adulthood
Authors: Meeus W. , Branje S. , Overbeek G.J.
Published: August 2004

Background:  This study sought the answer to three questions: 1. Is having an intimate partner associated with the level of delinquency? 2. Does the quality of the relationship with an intimate partner, operationalised as partner support, predict the level of delinquency? 3. Does a relationship with an intimate partner or age moderate the association between parental support and delinquency?

Method:  Data from a three‐wave, six‐year longitudinal study of 1302 adolescents and young adults, aged 12–23 at wave 1, were used.

Results:  1. Univariate latent growth curve analysis showed that, as predicted, having an intimate partner does not lead to less criminality among young adults over the age of 20. We found no support for the hypothesis among the group of 12‐ to 20‐year‐old adolescents, since the group of mid‐adolescents who consistently have a partner is more criminal than the other groups. 2. Our findings show that partner support is negatively related to criminality in both 12‐ to 20‐year‐olds and 21‐ to 23‐year‐olds. The longitudinal effect of partner support is also uni‐directional: partner support T1 certainly has an impact on criminality T3, but the reverse is not true. In both groups the influence of partner support is also greater than that of parental support. 3. Having an intimate partner moderates the association between parental support and delinquency, but in an age‐specific manner. Parental support has no bearing on criminality when adolescents and young adults continuously have an intimate partner. Parental support does, however, cause a reduction in the level of criminality in adolescents and young adults who have never had a partner and adolescents who only have a partner at time 3.

Conclusions:  We interpret our results in terms of shifts in the relational system: if an adolescent finds a partner, that partner takes over the role of the parents in reducing criminality; if not, the parents remain important in doing so.
No Exit: An Evaluation of Measures of Physician Attrition
Authors: Rittenhouse Diane R. , Mertz Elizabeth , Keane Dennis , Grumbach Kevin
Published: August 2004

Objective. To validate physicians' self‐reported intentions to leave clinical practice and the American Medical Association (AMA) Masterfile practice status variable as measures of physician attrition, and to determine predictors of intention to leave, and actual departure from, clinical practice.

Data Sources. Survey of specialist physicians in urban California (1998); the AMA Physician Masterfile (2001); and direct ascertainment of physician practice status (2001).

Study Design. Physicians' intention to leave clinical practice by 2001 (self‐reported in 1998) was tested as a measure of each physician's actual practice status in 2001 (directly ascertained). Physician practice status according to the 2001 AMA Masterfile was also tested as a measure of physicians' actual practice status in 2001. Multivariate regression was used to predict both physicians' intentions to leave clinical practice and their actual departure.

Data Collection/Extraction Methods. AMA Masterfile data on 2001 practice status were obtained for 967 of 968 physician respondents to the 1998 survey. Actual practice status for 2001 was directly ascertained for 957.

Principal Findings. The sensitivity of Masterfile practice status as a measure of actual departure from clinical practice was 9.0 percent, and the positive predictive value was 52.9 percent. Allowing for a two‐year reporting lag did not change this substantially. Self‐reported intention to leave clinical practice had a sensitivity of 73.3 percent and a positive predictive value of 35.4 percent as a measure of actual departure from practice. The strongest predictor of both intention to leave clinical practice and actual departure from practice was older age. Physician dissatisfaction had a strong association (OR=5.6) with intention to leave clinical practice, but was not associated with actual departure from practice.

Conclusions. Our findings call into question the accuracy of both AMA Masterfile data and physicians' self‐reported intentions to leave as measures of physician attrition from clinical practice. Research using these measures should be interpreted with caution. Self‐reported intention to leave practice may be more of a proxy for dissatisfaction than an accurate predictor of actual behavior.
The Effect of HMOs on the Inpatient Utilization of Medicare Beneficiaries
Authors: Dhanani Nasreen , O'Leary June F. , Keeler Emmett , Bamezai Anil , Melnick Glenn
Published: August 2004

Objective. To determine the effect of joining HMOs (health maintenance organizations) on the inpatient utilization of Medicare beneficiaries.

Data Sources. We linked enrollment data on Medicare beneficiaries to patient discharge data from the California Office of Statewide Health Planning and Development (OSHPD) for 1991–1995.

Design and Sample. A quasi‐experimental design comparing inpatient utilization before and after switching from fee‐for‐service (FFS) to Medicare HMOs; with comparison groups of continuous FFS and HMO beneficiaries to adjust for aging and secular trends. The sample consisted of 124,111 Medicare beneficiaries who switched from FFS to HMOs in 1992 and 1993, and random samples of 108,966 continuous FFS beneficiaries and 18,276 continuous HMO enrollees yielding 1,227,105 person‐year observations over five years.

Main Outcomes Measure. Total inpatient days per thousand per year.

Principal Findings. When beneficiaries joined a group/staff HMO, their total days per year were 18 percent lower (95 percent confidence interval, 15–22 percent) than if the beneficiaries had remained in FFS. Total days per year were reduced less for beneficiaries joining an IPA (independent practice association) HMO (11 percent; 95 percent confidence interval, 4–19 percent). Medicare group/staff and IPA‐model HMO enrollees had roughly 60 percent of the inpatient days per thousand beneficiaries in 1995 as did FFS beneficiaries (976 and 928 versus 1,679 days per thousand, respectively). In the group/staff model HMOs, our analysis suggests that managed care practices accounted for 214 days of this difference, and the remaining 489 days (70 percent) were due to favorable selection. In IPA HMOs, managed care practices appear to account for only 115 days, with 636 days (85 percent) due to selection.

Conclusions. Through the mid‐nineties, Medicare HMOs in California were able to reduce inpatient utilization beyond that attributable to the high level of favorable selection, but the reduction varied by type of HMO.
Perfectionists' Appraisal of Daily Hassles and Chronic Headache
Authors: Bottos Shauna , Dewey Deborah
Published: August 2004

Objective.—To investigate the relationships between daily hassles, perfectionism, and the experience of chronic headache among university students.

Background.—Headaches are very common among university students. It has been found that a higher number of hassles reported by students is associated with an increase in headache activity. It has also been suggested that individuals higher in perfectionism appraise more situations as hassles, and that this dispositional characteristic may constitute a risk factor for the experience of chronic headaches.

Methods.—A total of 291 university students completed three questionnaires: (1) the Headache Assessment Questionnaire that was utilized to obtain information on headache occurrence and its features, (2) the Brief College Student Hassles Scale, and (3) the Multidimensional Perfectionism Scale.

Results.—A total of 18 students (6.2%) met the 2004 IHS criteria for chronic headaches, 179 (61.5%) met the criteria for frequent headaches, and 69 (23.7%) met the criteria for infrequent headaches. Students with chronic headaches reported significantly more stress, as measured by daily hassles. They also exhibited higher levels of perfectionism. The number of hassles reported was a significant predictor of headache frequency, intensity, and duration. Analyses also revealed that perfectionism was a significant predictor of headache frequency and intensity.

Conclusions.—The present study indicates that there is a relationship between perfectionism and chronic headache in university students, with those higher in perfectionism experiencing more frequent headaches. This investigation confirmed the relationship between daily hassles and chronic headache in this population. The results also suggest that perfectionists may generate their own stress through their tendency to appraise more situations as hassles. This, in turn, may explain their tendency to experience chronic headaches.
Botulinum Neurotoxin Type A in the Preventive Treatment of Refractory Headache: A Review of 100 Consecutive Cases
Authors: Tepper Stewart J. , Bigal Marcelo E. , Sheftell Fred D. , Rapoport Alan M.
Published: August 2004

Objectives.—To review the efficacy of botulinum neurotoxin type A (BoNT‐A) in the preventive treatment of refractory headache.

Background.—Even after receiving expert care, some patients with refractory headache continue to have high disability and persistent headaches.

Methods.—Clinical records and headache calendars of 100 patients fulfilling the following inclusion criteria were reviewed: (1) age from 18 to 65 years; (2) primary headache with previous failure of at least four preventive treatments; and (3) have received BoNT‐A and have been followed for at least 6 months after the BoNT‐A injections. BoNT‐A (100 units) was diluted in 4‐cc normal saline. The muscles injected included some or all of the following: frontalis, temporalis, corrugator, procerus, occipitalis, semispinalis, splenius capitis, trapezius, cervical paraspinalis, and sternocleidomastoid. Migraine‐related disability was assessed using the Migraine Disability Assessment (MIDAS) questionnaire.

Results.—There was a statistically significant reduction of the frequency of headache days 1 month after BoNT‐A was administered (14.2 vs 28.2 days at the baseline, P < .001), which was maintained through the 3 months of study; similarly, a significant reduction in the headache index (22.3 vs 40.3, P < .001) and number of severe days with headache per month (2.6 vs 7.4, P < .001) were found at 1 month and maintained through the 3 months of study. MIDAS scores were reduced from 34.5 at baseline to 15.9 at 3 months (P < .001). A similar pattern was found in those overusing versus nonoverusing acute medication, though the response was more dramatic in the nonoverusing subgroup.

Conclusion.—BoNT‐A may play a role in the preventive treatment of refractory headache. A significant number of patients showed decrease in clinically important measurements of their headaches as well as reduced headache‐related disability with this treatment. Prospective, controlled studies must be considered for severely disabled, refractory patients.
Mechanism of Action of Botulinum Toxin Type A in Migraine Prevention: A Pilot Study
Authors: Smuts Johan A. , Schultz Donovan , Barnard Adri
Published: August 2004

Objective.—The main objective of this study is to determine whether change in migraine frequency is correlated with a denervation pattern of the corrugator muscle after local botulinum toxin type A injections.

Background.—Recent studies suggest botulinum toxin type A is effective in preventing migraine. Relaxation of the corrugator muscle may be one of multiple targets of botulinum toxin type A in relieving migraine pain.

Methods.—The pretreatment amplitude of the compound muscle action potential (CMAP) was obtained in 10 patients with a migraine frequency of two to six attacks per month following stimulation of the temporal branch of the facial nerve. Patients were subsequently injected with 20 units of botulinum toxin type A at predefined sites in the procerus and corrugator muscles. CMAP was obtained on days 7, 30, 60, and 90 after injection. Migraine frequency, as reported in headache diaries, was compared with the amplitudes obtained.

Results.—A 50% decrease in CMAP was demonstrated in the total group by day 7. Maximal decline of CMAP was observed by day 30, and was sustained at day 60. Migraine frequency declined by 50% or more in 7 of 10 patients by day 60. Migraine response to botulinum toxin type A treatment did not correlate with the denervation pattern.

Conclusion.—Relaxation of the corrugator muscles is not solely responsible for the pain relief in migraine patients treated with botulinum toxin type A.
Tolosa‐Hunt Syndrome Due to Actinomycosis of the Cavernous Sinus: The Infectious Hypothesis Revisited
Authors: Mandrioli Jessica , Frank Giorgio , Sola Patrizia , Ernesta Leone Maria , Guaraldi Giovanni , Guaraldi Pietro , Collina Guido , Roncaroli Federico , Cortelli Pietro
Published: August 2004

Background.—The Tolosa‐Hunt syndrome is characterized by ophthalmoplegia with unilateral severe retro‐orbital pain associated to a granulomatous inflammatory process occupying the cavernous sinus or the superior orbital fissure. The etiology is unknown and diagnosis is based upon a clinical response to steroid treatment and exclusion of neoplasm, trauma, aneurysms, infectious, and inflammatory diseases.

Case description.—A 43‐year‐old man was admitted because of a 1‐week history of acute onset left‐sided retro‐orbital pain, followed by left sixth cranial nerve palsy. Magnetic resonance imaging was normal and Tolosa‐Hunt syndrome was suspected. Steroid treatment controlled pain with recovery of ophthalmoplegia. Four months later, when a good response to treatment was still present, brain magnetic resonance imaging revealed a lesion enlarging the left cavernous sinus, isointense with the gray matter on T1‐weighted sequences, hypointense on T2‐weighted images, and with homogeneous enhancement after gadolinium injection. Two months later, ocular pain and sixth cranial nerve palsy recurred and new brain magnetic resonance imaging showed an extension of the tissue occupying the left cavernous sinus, over the sella, to the right cavernous sinus, making possible an endoscopic transphenoidal biopsy.

Results.—Histopathological study revealed a granulomatous aspecific inflammation containing actinomycetes colonies. The patient was treated with intravenous penicillin G followed by amoxicillin per os, with improvement of pain and ophthalmoplegia. A control magnetic resonance imaging 1 month after therapy showed a consistent reduction of the enlarged cavernous sinus, and 3 months later neurological examination and brain magnetic resonance imaging were completely normal.

Conclusions.—The present case suggests that the International Classification of Headache Disorders (2nd edition) definition of Tolosa‐Hunt syndrome does not reflect the complexity of the syndrome and that some cases of secondary painful ophthalmoplegias can fit the criteria for the primary form. Since the biopsy can only rarely be performed, we agree with other authors that clinical and radiological follow‐up should be performed for at least 2 years. Moreover, we propose that in patients with painful ophthalmoplegia having transient response to steroid therapy, a trial with antibiotic therapy should be taken into account.
The Reform Bubble Bursts
Authors: Roberts Alasdair
Published: August 2004

Books reviewed in this article:

Columbia Accident Investigation Board, Report, Volume One
Strategies for improving treatment of bipolar disorder: integration of measurement and management
Authors: Sachs G. S.
Published: August 2004

Objective:  Bipolar disorder is a common and complex condition associated with high rates of disability and high health care costs. The aim of this article is to provide an overview of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD).

Method:  The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD) was conceived in response to an NIMH request for proposals to study the effectiveness of treatments for Bipolar Disorder. Aspects of this program have been adapted and enriched for presentation in this paper.

Result:  Designed for implementation in routine practice across a variety of settings, STEP‐BD offers a disease management program in which standardized assessments are linked to critical decision points in clinical management pathways.

Conclusion:  This paper describes strategies used in STEP‐BD to improve the treatment of Bipolar disorder: a simple conceptual model, which integrates assessments and management, and several specialized elements, used in the STEP‐BD assessment package.
Psychological interventions in bipolar disorder: From wishful thinking to an evidence‐based approach
Authors: Vieta E. , Colom F.
Published: August 2004

Objective:  We aimed to examine the historical and current relevance of psychosocial approaches to bipolar illness by conducting a systematic review of prospective studies assessing the effectiveness of psychological interventions for bipolar disorder.

Method:  A systematic literature search was conducted using EMBASE, MedLine and PsychLIT and reference sections of papers were scrutinized for further relevant reports. Only four trials met the criteria of a prospective study and achieved the necessary methodological standards.

Results:  The studies showed benefits for patients in terms of relapse prevention and the reduction of hospitalization rates. Psychoeducation (delivered in groups or as part of a family intervention) and cognitive behavioural therapy were also found to be effective prophylactic treatments for bipolar disorder in medicated patients. Other interventions do not appear to be supported by sufficient evidence.

Conclusion:  Psychological approaches, and particularly psychoeducation and cognitive‐behavioural therapies, are evidence‐based prophylactic therapies for bipolar patients receiving pharmacotherapy. They should be used as adjuncts to medication where possible in the prevention of bipolar disorder.
Vasomotor responses to decreased venous return: effects of cardiac deafferentation in humans
Authors: Weisbrod Cara J. , Arnolda Leonard F. , McKitrick Douglas J. , O'Driscoll Gerard , Potter Kathleen , Green Daniel J.
Published: August 2004

We compared haemodynamic and peripheral vasomotor responses to lower body negative pressure (LBNP) in cardiac transplant recipients who had undergone bicaval anastomoses, involving right atrial deafferentation (−RA), and the conventional procedure in which some atrial baroreceptor afferents remain intact (+RA). We measured mean forearm blood flow (FBF) responses using Doppler/ultrasound during three randomised trials involving 0 (baseline), −20 and −40 mmHg LBNP in 15 transplant recipients (9 −RA, 6 +RA) and in eight healthy matched controls. A significant effect of LBNP on FBF existed between control and transplant groups (P < 0.05; two‐way ANOVA). Mild LBNP (−20 mmHg), significantly decreased FBF by 29.7 ± 10.0% relative to baseline in +RA subjects (P < 0.05), whereas the 17.7 ± 10.3% decrease in −RA subjects was not significant. In response to −40 mmHg LBNP, FBF significantly decreased in control (42.4 ± 4.6%, P < 0.05) and +RA subjects (33.3 ± 11.4%, P < 0.05) with no significant change in the −RA group. The response of systolic blood pressure (SBP) to −40 mmHg significantly differed between groups (P < 0.05): −RA subjects decreased significantly (P < 0.05) whilst the decrease in SBP in +RA subjects did not achieve significance and control subjects exhibited an increase. The heart rate increase from baseline to −40 mmHg was significantly attenuated in −RA relative to controls and the +RA group (P < 0.05). The present study demonstrates that atrial deafferentation impairs reflex vasomotor control of the circulation in response to low‐ and high‐level LBNP, indicating that atrial deafferentation may contribute to abnormal arterial pressure regulation.
Proteinase‐activated receptor 2 activation modulates guinea‐pig mesenteric lymphatic vessel pacemaker potential and contractile activity
Authors: Chan Alice K. , Vergnolle Nathalie , Hollenberg Morley D. , Weid Pierre‐Yves von der
Published: August 2004

Lymphatic vessels rhythmically constrict to avoid fluid and protein accumulation in the interstitial space. This activity is critical during inflammation to prevent excessive oedema. Lymphatic pumping is intrinsic to the smooth muscle in the vessel wall and is due to the spontaneous occurrence of action potentials, the pacemaker of which is proposed to be spontaneous transient depolarizations (STDs). This function is highly susceptible to the fluid load and modulated by chemical agents, amongst which inflammatory mediators are important players. Activation of proteinase‐activated receptors (PARs) has been involved in inflammation and affects vascular smooth muscle tone. The present study aims to investigate the role of PAR2, a member of the PAR family, in lymphatic vessel pumping. RT‐PCR experiments revealed that PAR2 message is present in lymphatic vessels of the guinea‐pig mesentery. Agonists of PAR2 such as trypsin and the activating peptide, SLIGRL‐NH2, caused a decrease in the contractile activity of intraluminally perfused lymphatic vessels. Moreover, intracellular microelectrode recordings from isolated vessels revealed that PAR2 activation hyperpolarized the lymphatic smooth muscle membrane potential and altered STD amplitude and frequency. The decreases in constriction frequency and STD activity as well as the hyperpolarization were dependent on a functional endothelium, not affected by NO synthase or guanylyl‐cyclase inhibition, but mimicked by PGE2 and iloprost and blocked by indomethacin (10 μm) and glibenclamide (1 μm). These results show that PAR2 activation alters guinea‐pig lymphatic vessel contractile and electrical activity via the production of endothelium‐derived cyclo‐oxygenase metabolites.
Search for Low-Mass Exoplanets by Gravitational Microlensing at High Magnification
Authors: Abe F. , Bennett D. P. , Bond I. A. , Eguchi S. , Furuta Y. , Hearnshaw J. B. , Kamiya K. , Kilmartin P. M. , Kurata Y. , Masuda K. , Matsubara Y. , Muraki Y. , Noda S. , Okajima K. , Rakich A. , Rattenbury N. J. , Sako T. , Sekiguchi T. , Sullivan D. J. , Sumi T. , Tristram P. J. , Yanagisawa T. , Yock P. C. M. , Gal-Yam A. , Lipkin Y. , Maoz D. , Ofek E. O. , Udalski A. , Szewczyk O. , ZÌebrunÌ K. , SoszynÌski I. , SzymanÌski M. K. , Kubiak M. , PietrzynÌski G. , Wyrzykowski L.
Published: August 2004

Observations of the gravitational microlensing event MOA 2003-BLG-32/OGLE 2003-BLG-219 are presented, for which the peak magnification was over 500, the highest yet reported. Continuous observations around the peak enabled a sensitive search for planets orbiting the lens star. No planets were detected. Planets 1.3 times heavier than Earth were excluded from more than 50% of the projected annular region from approximately 2.3 to 3.6 astronomical units surrounding the lens star, Uranus-mass planets were excluded from 0.9 to 8.7 astronomical units, and planets 1.3 times heavier than Saturn were excluded from 0.2 to 60 astronomical units. These are the largest regions of sensitivity yet achieved in searches for extrasolar planets orbiting any star.
Ceacam1a−/−Mice Are Completely Resistant to Infection by Murine Coronavirus Mouse Hepatitis Virus A59
Authors: Hemmila Erin , Turbide Claire , Olson Melanie , Jothy Serge , Holmes Kathryn V. , Beauchemin Nicole
Published: August 2004

CEACAM1a glycoproteins are members of the immunoglobulin (Ig) superfamily and the carcinoembryonic antigen family. Isoforms expressing either two or four alternatively spliced Ig-like domains in mice have been found in a number of epithelial, endothelial, or hematopoietic tissues. CEACAM1a functions as an intercellular adhesion molecule, an angiogenic factor, and a tumor cell growth inhibitor. Moreover, the mouse and human CEACAM1a proteins are targets of viral or bacterial pathogens, respectively, including the murine coronavirus mouse hepatitis virus (MHV),Haemophilus influenzae,Neisseria gonorrhoeae, andNeisseria meningitidis, as well asMoraxella catarrhalisin humans. We have shown that targeted disruption of theCeacam1a(MHVR) gene resulting in a partial ablation of the protein in mice (p/p mice) led to reduced susceptibility to MHV-A59 infection of the modified mice in the BALB/c background. We have now engineered and produced aCeacam1a−/−mouse that exhibits complete ablation of the CEACAM1a protein in every tissue where it is normally expressed. We report that 3-week-oldCeacam1a−/−mice in the C57BL/6 genetic background are fully resistant to MHV-A59 infection by both intranasal and intracerebral routes. Whereas virus-inoculated wild-type +/+ C57BL/6 mice showed profound liver damage and spinal cord demyelination under these conditions,Ceacam1a−/−mice displayed normal livers and spinal cords. Virus was recovered from liver and spinal cord tissues of +/+ mice but not of −/− mice. These results indicate that CEACAM1a is the sole receptor for MHV-A59 in both liver and brain and that its deletion from the mouse renders the mouse completely resistant to infection by this virus.
Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis
Authors: Fantuzzi Laura , Purificato Cristina , Donato Karim , Belardelli Filippo , Gessani Sandra
Published: August 2004

Dendritic cells (DCs) play a crucial role in bridging innate and acquired immune responses to pathogens. In human immunodeficiency virus type 1 (HIV-1) infection, immature DCs (iDCs) are also main targets for HIV-1 at the mucosal level. In this study, we evaluated the effects of HIV-1-DC interactions on the maturation and functional activity of these cells. Exposure of human monocyte-derived iDCs to either aldrithiol-2-inactivated HIV-1 or gp120 led to an upmodulation of activation markers indicative of functional maturation. Despite their phenotype, these cells retained antigen uptake capacity and showed an impaired ability to secrete cytokines or chemokines and to induce T-cell proliferation. Although gp120 did not interfere with DC differentiation, the capacity of these cells to produce interleukin-12 (IL-12) upon maturation was markedly reduced. Likewise, iDCs stimulated by classical maturation factors in the presence of gp120 lacked allostimulatory capacity and did not produce IL-12, in spite of their phenotype typical of activated DCs. Exogenous addition of IL-12 restores the allostimulatory capacity of gp120-exposed DCs. The finding that gp120 induces abnormal maturation of DCs linked to profound suppression of their activities unravels a novel mechanism by which HIV can lead to immune dysfunction in AIDS patients.
Herpesvirus Ateles Tio Can Replace Herpesvirus Saimiri StpC and Tip Oncoproteins in Growth Transformation of Monkey and Human T Cells
Authors: Albrecht Jens-Christian , Biesinger Brigitte , Müller-Fleckenstein Ingrid , Lengenfelder Doris , Schmidt Monika , Fleckenstein Bernhard , Ensser Armin
Published: August 2004

Herpesvirus saimiri group C strains are capable of transforming human and simian T-lymphocyte populations to permanent antigen-independent growth. Two viral oncoproteins, StpC and Tip, that are encoded by a single bicistronic mRNA, act in concert to mediate this phenotype. A closely related New World monkey herpesvirus, herpesvirus ateles, transcribes a single spliced mRNA at an equivalent genome locus. The encoded protein, Tio, has sequence homologies to both StpC and Tip. We inserted the
tio
sequence of herpesvirus ateles strain 73 into a recombinant herpesvirus saimiri C488 lacking its own
stpC
/
tip
oncogene. Simian as well as human T lymphocytes were growth transformed by the chimeric Tio-expressing viruses. Thus, a single herpesvirus protein appears to be responsible for the oncogenic effects of herpesvirus ateles.
Fitness Analyses of Vesicular Stomatitis Strains with Rearranged Genomes Reveal Replicative Disadvantages
Authors: Novella Isabel S. , Ball L. Andrew , Wertz Gail W.
Published: August 2004

Gene expression of the nonsegmented negative-strand RNA viruses is determined by the position of each gene relative to that the single 3′ promoter. The general order of genes among all of the viruses of the order
Mononegavirales
is highly conserved. In previous work we generated recombinant viruses in which the order of the three central genes of the prototypical rhabdovirus, vesicular stomatitis virus, was rearranged to all six possible permutations. While some of these viruses replicated less well than the wild type when assayed by single-step growth analyses in BSC-1 cells, others replicated as well or slightly better. In the work reported here, we used competition assays to compare the fitness of the viruses with alternative gene orders to that of the wild-type (wt) virus. We found that the relative fitness of these recombinant viruses depended on the multiplicity of infection (MOI) but not on the population size. However, during competitions at low MOI, when complementation cannot compensate for the defects of the populations with rearranged genomes, the virus with the wt gene order was always the most fit.
Coxsackievirus B4 Infection of Human Fetal Thymus Cells
Authors: Brilot Fabienne , Geenen Vincent , Hober Didier , Stoddart Cheryl A.
Published: August 2004

The infection of human fetal thymus organ cultures (FTOC) with coxsackievirus B4 E2 (CVB4 E2) was investigated. Both positive- and negative-strand viral RNA were detected by real-time quantitative reverse transcription-PCR (RT-PCR) in CVB4 E2-infected FTOC, which supported high yields of virus production (∼10650% tissue culture infective doses/ml), and in flow-sorted thymocyte populations for 7 days after inoculation. Cortical CD4+CD8+thymocytes were found to be the principal targets of infection. Inoculation of human FTOC with CVB4 E2 led to a marked and progressive depletion of immature thymocytes (CD4+CD8+cells) with no enhancement of Annexin V-positive cells. CVB4 E2 replication caused significant major histocompatibility complex (MHC) class I upregulation on these cells. MHC class I upregulation was correlated with positive- and negative-strand RNA quantitative detection and the release of infectious particles. In addition, chloroquine treatment of FTOC and single-thymocyte suspensions suggested that MHC class I upregulation on thymocytes was the result of direct infection rather than caused by production of soluble factors such as alpha interferon. Thus, CVB4 E2 can infect human fetal thymocytes, which subsequently results in quantitative and qualitative abnormalities of these cells.
Major and Minor Capsid Proteins of Human Polyomavirus JC Cooperatively Accumulate to Nuclear Domain 10 for Assembly into Virions
Authors: Shishido-Hara Yukiko , Ichinose Shizuko , Higuchi Kayoko , Hara Yoshinobu , Yasui Kotaro
Published: August 2004

The human polyomavirus JC (JCV) replicates in the nuclei of infected cells. Here we report that JCV virions are efficiently assembled at nuclear domain 10 (ND10), which is also known as promyelocytic leukemia (PML) nuclear bodies. The major capsid protein VP1, the minor capsid proteins VP2 and VP3, and a regulatory protein called agnoprotein were coexpressed from a polycistronic expression vector in COS-7 cells. We found that VP1 accumulated to distinct subnuclear domains in the presence of VP2/VP3 and agnoprotein, while VP1 expressed alone was distributed both in the cytoplasm and in the nucleus. Mutation analysis revealed that discrete intranuclear accumulation of VP1 requires the presence of either VP2 or VP3. However, VP2 or VP3 expressed in the absence of VP1 showed diffuse, not discrete, nuclear localization. The C-terminal sequence of VP2/VP3 contains two basic regions, GPNKKKRRK (cluster 1) and KRRSRSSRS (cluster 2). The deletion of cluster 2 abolished the accumulation of VP1 to distinct subnuclear domains. Deletion of the C-terminal 34 residues of VP2/VP3, including both cluster 1 and cluster 2, caused VP1 to localize both in the cytoplasm and in the nucleus. Using immunoelectron microscopy of cells that coexpressed VP1, VP2/VP3, and agnoprotein, we detected the assembly of virus-like particles in discrete locations along the inner nuclear periphery. Both in oligodendrocytes of the human brain and in transfected cells, discrete nuclear domains for VP1 accumulation were identified as ND10, which contains the PML protein. These results indicate that major and minor capsid proteins cooperatively accumulate in ND10, where they are efficiently assembled into virions.
The detection of circulating breast cancer cells in blood
Authors: Gilbey A M , Burnett D , Coleman R E , Holen I
Published: August 2004

At present, sampling of the lymph nodes or bone marrow for the detection of regions of metastatic disease in patients with breast cancer can only be undertaken at the time of initial diagnosis and surgery. However, the sampling of these tissues and the methods used are inaccurate, time consuming, and cannot be used for easy routine screening to determine disease recurrence and response to treatment. Because of the problems encountered with current methods and tissues sampled at the time of breast cancer diagnosis, this review discusses the urgent requirement for and potential development of a quick, simple, and accurate diagnostic test utilising the haematogenous system, a source of circulating tumour cells in patients with breast cancer, and highly sensitive molecular biological techniques, such as reverse transcription polymerase chain reaction. In addition, this review also highlights potential problems that may be encountered and should be avoided when devising such a test.
Colonic IgA producing cells and macrophages are reduced in recurrent and non-recurrentClostridiumdifficileassociated diarrhoea
Authors: Johal S S , Lambert C P , Hammond J , James P D , Borriello S P , Mahida Y R
Published: August 2004

Background:InClostridium difficileassociated diarrhoea (CDAD), histological changes in the colonic mucosa range from minimal inflammation to pseudomembranous colitis (PMC). The disease also recurs in a considerable proportion of patients.

Aim:To investigate mucosal immune system cells in colonic biopsies of patients with CDAD.

Methods:Colonic biopsies were obtained from 12 control patients with diarrhoea, six patients with CDAD and minimal inflammation, and 10 patients with CDAD with pseudomembranous colitis (samples obtained from areas with and without inflammatory exudate). Immunohistochemical studies were performed using antibodies to T cells (CD3), macrophages (CD68), B/plasma cells (CD79α), and to IgA, IgM, and IgG. Labelled cells in lamina propria were quantified.

Results:In contrast to T cells, there were significant reductions in B/plasma cell and macrophage counts in all biopsies from patients with CDAD compared with controls (p<0.001). Studies using anti-immunoglobulin antibodies showed significant reductions in IgA producing cells in CDAD biopsies (p<0.05), with the greatest reduction in samples from patients with PMC. In contrast, there was a significant increase (p<0.05) in IgG producing cells in CDAD biopsies. Only patients with PMC relapsed. In these patients, B/plasma cell and IgA producing cell counts (in biopsies with and without inflammatory exudates) were significantly lower (p<0.01) in mucosal samples from those who subsequently relapsed (five) than those who did not.

Conclusions:A selective reduction in mucosal IgA producing cells and macrophages is associated with colonic disease inC difficileinfected patients. Severe reduction in colonic IgA producing cells may predispose to recurrence of CDAD.
Lobaria pulmonaria abundance as an indicator of macrolichen diversity in Interior CedarHemlock forests of east-central British Columbia
Authors: Campbell Jocelyn , Fredeen Arthur L
Published: August 2004

Orographic precipitation over interior mountains has resulted in the formation of the inland temperate rainforest, where certain stands are potentially antique and support a rich flora of epiphytic macrolichens. We documented macrolichen diversity across three age-classes in forests of the Interior CedarHemlock biogeoclimatic zone (i.e., ICHwk3 subzone) east of Prince George, British Columbia. Our objectives were to report changes in lichen communities with stand age, identify potential indicators of antiquity, and investigate the functional role of dominant species in the ecosystem. We identified 41 taxa, including 4 alectorioid lichens, 21 foliose chlorolichens, and 16 old-growth-associated chlorolichens and cyanolichens. Older forests supported more species than young or mature forests. The abundance of Lobaria pulmonaria (L.) Hoffm. was strongly correlated with this increase in diversity and may therefore be an appropriate indicator of stand age in the ICH. The increase in L. pulmonaria and other N2-fixing cyanolichens with stand age may have significant implications for forest nitrogen budgets in the interior of British Columbia, where atmospheric nitrogen deposition is relatively low and biological N2 fixation accounts for nearly all of the nitrogen lost to forest harvesting. We hope that this greater understanding of lichen ecology across age-classes will promote sustainable stewardship of the remaining old-growth forests of inland British Columbia.Key words: macrolichen diversity, Interior CedarHemlock zone, Lobaria pulmonaria, indicator species, cyanolichens, stand age.
Leaf fall in white birch (Betula pubescens) is independent of leaf asymmetry
Authors: Kozlov Mikhail V
Published: August 2004

Developmental instability, reflected by high fluctuating asymmetry, frequently indicates low fitness of an organism. However, it remains unknown whether in modular organisms, like plants, asymmetry is linked with performance at the level of individual metamers. To explore within-tree relationships between fluctuating asymmetry and leaf longevity, each third day between 22 August and 10 October 2001, leaves were collected under two large trees of white birch (Betula pubescens Ehrh.). The date of leaf fall (a proxy of leaf life-span) was not linked with either leaf asymmetry or damage imposed by chewing insects. Similarly, leaves collected under 10 birches at the end of leaf fall in 2002 demonstrated the same asymmetry as leaves collected at the beginning of leaf fall. These results suggest that leaf longevity in white birch is independent of leaf asymmetry.Key words: leaf longevity, fluctuating asymmetry, within-tree variation.