bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases
Authors: Arendt Mikkel , Rosenberg Raben , Foldager Leslie , Perto Gurli , Munk-Jørgensen Povl
Published: November 2005

Background

Few studies have examined samples of people with cannabis-induced psychotic symptoms.

Aims

To establish whether cannabis-induced psychotic disorders are followed by development of persistent psychotic conditions, and the timing of their onset.

Method

Data on patients treated for cannabis-induced psychotic symptoms between 1994 and 1999 were extracted from the Danish Psychiatric Central Register. Those previously treated for any psychotic symptoms were excluded. The remaining 535 patients were followed for at least 3 years. In a separate analysis, the sample was compared with people referred for schizophrenia-spectrum disorders for the first time, but who had no history of cannabis-induced psychosis.

Results

Schizophrenia-spectrum disorders were diagnosed in 44.5% of the sample. New psychotic episodes of any type were diagnosed in 77.2%. Male gender and young age were associated with increased risk. Development of schizophrenia-spectrum disorders was often delayed, and 47.1% of patients received a diagnosis more than a year after seeking treatment for a cannabis-induced psychosis. The patients developed schizophrenia at an earlier age than people in the comparison group (males, 24.6 v. 30.7 years, females, 28.9 v. 33.1 years).

Conclusions

Cannabis-induced psychotic disorders are of great clinical and prognostic importance.
Perception of facial and vocal affect by people with schizophrenia in early and late stages of illness
Authors: Kucharska-Pietura Katarzyna , David Anthony S. , Masiak Marek , Phillips Mary L.
Published: November 2005

Background

Emotion recognition impairments have been demonstrated in schizophrenia, but few studies have examined whether these reflect generalised or specific perceptual deficits or are associated with illness course.

Aims

To examine the nature of emotion recognition abnormalities in patients with schizophrenia at different stages of illness.

Method

We examined the performance of 50 in-patients with early-stage schizophrenia, 50 with chronic schizophrenia and 50 healthy controls on the Benton Facial Recognition Test, Facial Emotion Recognition Test and Voice Emotion Recognition Test.

Results

Patients with chronic schizophrenia were significantly more impaired than other groups on the emotional tasks, even after controlling for impairments in non-emotional stimuli. Individual emotion recognition accuracy for the two sensory modalities was not significantly positively correlated for either group with schizophrenia.

Conclusions

Emotion recognition deficits in schizophrenia are trait features of the disorder and increase with illness duration.
Measuring outcome priorities and preferences in people with schizophrenia
Authors: Rosenheck Robert , Stroup Scott , Keefe Richard S. E. , McEvoy Joseph , Swartz Marvin , Perkins Diana , Hsiao John , Shumway Martha , Lieberman Jeffrey
Published: November 2005

Background

Measures have not taken account of the relative importance patients place on various outcomes.

Aims

To construct and evaluate a multidimensional, preference-weighted mental health index.

Method

Each of over 1200 patients identified the relative importance of improvement in six domains: social life, energy, work, symptoms, confusion and side-effects. A mental health index was created in which measures of well-being in these six domains were weighted for their personal importance.

Results

The strongest preference was placed on reducing confusion and the least on reducing side-effects. There was no significant difference between the unweighted and preference-weighted mental health status measures and they had similar correlations with global health status measures. Patients with greater preference for functional activities such as work had less preference for medical model goals such as reducing symptoms and had less symptoms.

Conclusions

A preference-weighted mental health index demonstrated no advantage over an unweighted index.
Epidemiology of intentional self-poisoning in rural Sri Lanka
Authors: Eddleston Michael , Gunnell David , Karunaratne Ayanthi , De Silva Dhammika , Sheriff M. H. Rezvi , Buckley Nick A.
Published: November 2005

We investigated the epidemiology of intentional self-poisoning in rural Sri Lanka by prospectively recording 2189 admissions to two secondary hospitals. Many patients were young (median age 25 years), male (57%) and used pesticides (49%). Of the 198 who died, 156 were men (case fatality 12.4%) and 42 were women (4.5%). Over half of female deaths were in those under 25 years old; male deaths were spread more evenly across age groups. Oleander and paraquat caused 74% of deaths in people under 25 years old; thereafter organophosphorous pesticides caused many deaths. Although the age pattern of self-poisoning was similar to that of industrialised countries, case fatality was more than 15 times higher and the pattern of fatal self-poisoning different.
Beware the problems of centralisation. Commentary on … Mental health research system in England
Authors: Lelliott Paul
Published: November 2005

It is difficult to disagree with Chilvers & Clark that, overall, recent work to bring a more systematic approach to the organisation of mental health research in England has been a good thing. It is also necessary if mental health is to compete for research funding with other branches of healthcare. However, recent changes in the research system have not all been positive and there is a danger that the process of centralisation, which is inherent to the model they describe, will have unintended adverse consequences.
Psychiatric disorders in HIV-positive individuals in urban Uganda
Authors: Petrushkin Harry , Boardman Jed , Ovuga Emilio
Published: November 2005

Aims and Method

The study examined the prevalence of psychiatric disorders in people with HIV/AIDS attending the AIDS Support Organisation (TASO) clinic at Mulago Hospital, Kampala, Uganda and the preparedness of AIDS counsellors to deal with mental disorders. Forty-six patients were interviewed using the Mini International Psychiatric Interview to ascertain DSM–IV diagnoses. All 15 counsellors working at the clinic were interviewed.

Results

The total prevalence of psychiatric disorder was 82.6 (38 out of 46 patients). Depressive and anxiety disorders were common. Non-affective psychoses were present in eight patients (17.4%), bipolar affective disorder in eight (17.4%) and major depression with melancholic features in five (10.9%); 8 (13%) had current suicidal thoughts. None of the people with psychiatric disorders were receiving mental health treatment. The prevalence of disorder as estimated by the counsellors ranged from 0 to 33%. Only one counsellor had received any formal training in mental disorders and only two thought that they could deal with these if they arose. The attitudes of counsellors towards people with mental disorders were mixed, but most believed that they should be trained to provide care.

Clinical Implications

There is a need to provide additional mental health services to the TASO clinic through appropriate training of TASO counsellors to improve their awareness of psychiatric disorders, delivery of some psychological therapies and liaison with the psychiatric services at Mulago Hospital, in addition to public mental health education. The psychiatric disorders experienced by those attending the clinic might put them at greater risk of contracting HIV/AIDS.
National survey of methadone prescribing for maintenance treatment: ‘opiophobia’ among substance misuse services?
Authors: Joseph Renju , Foselpy Hamdy F.
Published: November 2005

Aims and Method

The aims of this study were to describe the characteristics of substance misuse services prescribing methadone for maintenance treatment of opioid dependence and to determine the average daily doses of methadone prescribed across England. A postal questionnaire survey of all substance misuse treatment centres in England was carried out.

Results

A total of 298 treatment centres were identified and contacted, 212 of which responded to the survey (response rate of 71%). Of these, 157 were prescribing methadone for maintenance treatment; the majority (71%) were community-based and 125 centres had doctors attached. The most common formulation of methadone prescription was oral methadone mixture (152 centres, 97%). The mean daily dose of methadone prescribed was 47 mg. Surprisingly, 37 (24%) of the respondents felt that methadone maintenance treatment should be time-limited and 21 teams (13%) stated that patients should receive only drug substitution and no psychosocial interventions.

Clinical Implications

There is currently a move among substance misuse services towards community-based treatment. In our survey, the mean daily dose of methadone prescribed was less than the dosage recommended by the Department of Health. This suggests that specialist addiction services are continuing to underprescribe heroin substitutes. The inadequate understanding of some of the respondents of the basic principles of methadone maintenance treatment also raises concerns, and highlights the need for further training and education.
Ordered thoughts on thought disorder
Authors: Rule Ashley
Published: November 2005

Aims and Method

To review and clarify the large number of psychophenomenological terms used to describe thought disorder. The most recent editions of the major psychiatric textbooks and medical dictionaries in the library of a London teaching hospital were used to compile a list of such terms. The various, often conflicting definitions were compared.

Results

There were 68 terms identified. There was significant redundancy in these terms (i.e. more terms than significantly different concepts described). Different sources gave different definitions for the same terms.

Clinical Implications

The understanding of many of the terms used to describe thought disorder is poor. This is confusing for clinicians, trainees and patients.
Regulation of two insulin granule populations within the reserve pool by distinct calcium sources
Authors: Hao Mingming , Li Xia , Rizzo Mark A. , Rocheleau Jonathan V. , Dawant Benoit M. , Piston David W.
Published: November 2005

Insulin granule trafficking is a key step of glucose-stimulated insulin secretion from pancreatic β cells. Using quantitative live cell imaging, we examined insulin granule movements within the reserve pool upon secretory stimulation in βTC3 cells. For this study, we developed a custom image analysis program that permitted automatic tracking of the individual motions of over 20,000 granules. This analysis of a large sample size enabled us to study micro-populations of granules that were not quantifiable in previous studies. While over 90% of the granules depend on Ca2+ efflux from the endoplasmic reticulum for their mobilization, a small and fast-moving population of granules responds to extracellular Ca2+ influx after depolarization of the plasma membrane. We show that this differential regulation of the two granule populations is consistent with localized Ca2+ signals, and that the cytoskeletal network is involved in both types of granule movement. The fast-moving granules are correlated temporally and spatially to the replacement of the secreted insulin granules, which supports the hypothesis that these granules are responsible for replenishing the readily releasable pool. Our study provides a model by which glucose and other secretory stimuli can regulate the readily releasable pool through the same mechanisms that regulate insulin secretion.
Calcium increases endocytotic vesicle size and accelerates membrane fission in insulin-secreting INS-1 cells
Authors: MacDonald Patrick E. , Eliasson Lena , Rorsman Patrik
Published: November 2005

In many cells, endocytotic membrane retrieval is accelerated by Ca2+. The effect of Ca2+ on single endocytotic vesicles and fission pore kinetics was examined by measuring capacitance and conductance changes in small membrane patches of insulin-secreting INS-1 cells. In intact cells, elevation of Ca2+ by glucose stimulation induced a 1.8-fold increase in membrane internalisation. This surprisingly resulted from an increased unitary capacitance of endocytotic vesicles whereas the frequency of endocytosis was unaltered. This effect of glucose was prevented by inhibition of L- or R-type Ca2+ channels. Extracellular (pipette) Ca2+ was found to regulate endocytotic vesicle capacitance in a bimodal manner. Vesicle capacitance was increased at intermediate Ca2+ (2.6 mM), but not at high Ca2+ (10 mM). Similar results were obtained upon direct application of 100 nM and 0.5 mM Ca2+ to the intracellular surface of inside-out excised membrane patches, and in these experiments the increase in vesicle capacitance was prevented by the calcineurin inhibitor deltamethrin. Endocytotic fission pore kinetics were accelerated by Ca2+ in both the intact cells and isolated membrane patches; however, the effect in this case was neither bimodal nor deltamethrin sensitive. Membrane retrieval can therefore be upregulated by a Ca2+-dependent increase in endocytotic vesicle size and acceleration of membrane fission in insulin-secreting INS-1 cells.
Consequences of loss of PINCH2 expression in mice
Authors: Stanchi Fabio , Bordoy Randi , Kudlacek Oliver , Braun Attila , Pfeifer Alexander , Moser Markus , Fässler Reinhard
Published: November 2005

PINCH2 belongs, together with PINCH1, to a new family of focal adhesion proteins, the members of which are composed of five LIM domains. PINCH1 and PINCH2 interact, through their first LIM domain, with the integrin-linked kinase and thereby link integrins with several signal transduction pathways. Despite their high similarity, it has been shown that PINCH1 and PINCH2 could exert distinct functions during cell spreading and cell survival. To investigate the function of PINCH2 in vivo, we deleted PINCH2 in mouse using the loxP/Cre system. In contrast to the PINCH1-deficient mice, which die at the peri-implantation stage, PINCH2-null mice are viable, fertile and show no overt phenotype. Histological analysis of tissues that express high levels of PINCH2 such as bladder and kidney revealed no apparent abnormalities, but showed a significant upregulation of PINCH1, suggesting that the two PINCH proteins may have, at least in part, overlapping function in vivo. To further test this possibility, we established PINCH1-null mouse embryonic fibroblasts, which express neither PINCH1 nor PINCH2. We found that in fibroblasts with a PINCH1/2-null background, PINCH2 is able to rescue the spreading and adhesion defects of mutant fibroblasts to the same extent as PINCH1. Furthermore, we show that the LIM1 domain only of either PINCH1 or PINCH2 can prevent ILK degradation despite their failure to localize to focal adhesions. Altogether these results suggest that PINCH1 and PINCH2 share overlapping functions and operate dependently and independently of their subcellular localization.
Histone acetylation increases chromatin accessibility
Authors: Görisch Sabine M. , Wachsmuth Malte , Tóth Katalin Fejes , Lichter Peter , Rippe Karsten
Published: November 2005

In eukaryotes, the interaction of DNA with proteins and supramolecular complexes involved in gene expression is controlled by the dynamic organization of chromatin inasmuch as it defines the DNA accessibility. Here, the nuclear distribution of microinjected fluorescein-labeled dextrans of 42 kDa to 2.5 MDa molecular mass was used to characterize the chromatin accessibility in dependence on histone acetylation. Measurements of the fluorescein-dextran sizes were combined with an image correlation spectroscopy analysis, and three different interphase chromatin condensation states with apparent pore sizes of 16-20 nm, 36-56 nm and 60-100 nm were identified. A reversible change of the chromatin conformation to a uniform 60-100 nm pore size distribution was observed upon increased histone acetylation. This result identifies histone acetylation as a central factor in the dynamic regulation of chromatin accessibility during interphase. In mitotic chromosomes, the chromatin exclusion limit was 10-20 nm and independent of the histone acetylation state.
Paxillin is essential for PTP-PEST-dependent regulation of cell spreading and motility: a role for paxillin kinase linker
Authors: Jamieson Jennifer S. , Tumbarello David A. , Hallé Maxime , Brown Michael C. , Tremblay Michel L. , Turner Christopher E.
Published: November 2005

The tyrosine phosphatase PTP-PEST has been implicated in the regulation of cell spreading and migration through dephosphorylation of focal adhesion proteins and inhibition of Rac GTPase activity. The focal adhesion adaptor protein paxillin is also necessary for normal cell migration and binds directly to PTP-PEST. In this study, we have utilized PTP-PEST–/– and paxillin–/– fibroblasts to demonstrate that paxillin is essential for PTP-PEST inhibition of cell spreading and membrane protrusion as well as inhibition of adhesion-induced Rac activation. Furthermore, we show that paxillin-binding is necessary for PTP-PEST stimulation of cell migration. Mutation analysis indicates that PTP-PEST function involves binding to the paxillin C-terminal LIM domains, and signaling through the tyrosine 31 and 118 phosphorylation sites, as well as the LD4 motif of the paxillin N-terminus. Using `substrate trapping' approaches and immunoprecipitation, we show that the ARF GAP paxillin kinase linker PKL/GIT2, a paxillin LD4 binding partner, is a substrate for PTP-PEST. Additionally, the PKL-paxillin interaction was necessary for PTP-PEST inhibition of cell spreading. These data provide mechanistic insight into how the paxillin-PTP-PEST interaction contributes to integrin signaling events associated with the spatiotemporal regulation of key modulators of the cytoskeleton and cell motility machinery.
Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells
Authors: Gouzi Jean Y. , Moog-Lutz Christel , Vigny Marc , Brunet-de Carvalho Nicole
Published: November 2005

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed in specific areas of the developing central and peripheral nervous systems. We previously demonstrated that a membrane-bound and constitutively active form of the ALK protein tyrosine kinase (PTK) domain induced the neuron-like differentiation of PC12 cells through specific activation of the mitogen-activated protein kinase (MAP kinase) pathway. Its PTK domain had been originally identified in a nucleo-cytosolic and constitutively active transforming protein, NPM-ALK. Downstream targets involved in oncogenic proliferation and survival processes have been proposed to include phospholipase Cγ (PLCγ), phosphoinositide 3-kinase (PI 3-kinase)/AKT, STAT 3/5 and Src. We therefore postulated that activation of specific signaling pathways leading to differentiation or proliferation can be differently controlled depending on the subcellular localization of ALK PTK domain. To increase knowledge of its physiological role in the nervous system, we focused in the present study on the influence of its subcellular localization on neuronal differentiation. To achieve this goal, we characterized biological responses and transduction pathways in PC12 cells elicited by various constructs encoding membrane-bound (through transmembrane or myristyl sequences) or cytosolic ALK-derived proteins. In order to control the activation of their PTK domain, we used an inducible dimerization system. Here, we demonstrate that membrane attachment of the ALK PTK domain, in PC12 cells, is crucial for initiation of neurite outgrowth and proliferation arrest through a decrease of DNA synthesis. Furthermore, we show that this differentiation process relies on specific and sustained activation of ERK 1/2 proteins. By contrast, activation of the cytosolic form of this domain fails to induce MAP kinase activation and cell differentiation but promotes a PI 3-kinase/AKT-dependant PC12 cell proliferation. These data indicate that subcellular localization of the ALK PTK domain was a determinant for the control and specificity of downstream transduction cascades and was crucial for deciding the fate to which the neuronal cell will be committed.
Pulmonary thromboembolism in Klippel–Trenaunay–Weber syndrome – should all cases be anticoagulated?
Authors: Bagul N B , Pathak R , Garg N K , Platts A , Baker D M
Published: November 2005

Klippel–Trenaunay–Weber syndrome (KTWS) is a congenital disorder characterized by a triad of varicose veins and venous malformation involving one or more extremities, cutaneous haemangioma, and hypertrophy of soft tissue and bone. The syndrome is rare and it usually presents as varicose veins or cutaneous naevi. We report a patient with KTWS who developed superficial thrombophlebitis in her varicose veins and died from a pulmonary embolism. To optimize management it is important to recognize the syndrome, and the patient should ideally be referred for multidisciplinary vascular care and all such patients should be anticoagulated in the long term.
Ultrasound-guided foam sclerotherapy in the treatment of varicose veins: tips and tricks
Authors: de Zeeuw R , Toonder I M , Wittens C H A , Loots M A M
Published: November 2005

Objective: Ultrasound-guided foam sclerotherapy has become an accepted technique in the treatment of varicose veins. Compared with liquid sclerotherapy, foam is a much more powerful tool in the hands of an experienced practitioner. The introduction of consensus statements on foam sclerotherapy enhances its efficacy. This report will provide clinical tips and tricks during ultrasound-guided foam sclerotherapy.

Methods: In general, consensus statements do not include practical tips and tricks to facilitate ultrasound-guided foam sclerotherapy itself. Experiences acquired during ultrasound-guided foam sclerotherapy sessions in our clinical practice can enhance the power of this treatment, which may be useful for colleagues in their everyday clinical practice.

Conclusion: This report presents useful tips and tricks, which may contribute to effective ultrasound-guided foam sclerotherapy.
Audit of varicose vein surgery: the patients' perspective
Authors: Sains P S , Reddy K M , Jones H J S , Derodra J K
Published: November 2005

Objectives: Varicose veins cause varying symptoms and post-surgical patient dissatisfaction is not uncommon. We aimed to identify patients' reasons for having surgery and sought to identify measures for improvement.

Methods: A postal questionnaire was sent to patients. The patients' preoperative symptoms and postoperative satisfaction were enquired upon. Replies were cross-referenced to the operation notes.

Results: Three hundred and thirty-five patients completed the questionnaire. The consultant carried out 73% of operations, with 27% being carried out by trainees. In all, 41% of patients were very satisfied with surgery, 39% were satisfied, 17% were dissatisfied and 4% were very dissatisfied. In those whose operation was carried out by a consultant, 18% were dissatisfied as compared with 31% of those operated on by a trainee.

Conclusion: The vast majority of patients are satisfied with varicose vein surgery and there are modifiable factors such as grade of surgeon and supervision, which can influence the outcome and satisfaction.
Endoscope-assisted management of primary varicose veins below the knee
Authors: Lin S-D , Lin T-M , Lee S-S , Yang Y-L , Sun I-F , Lai C-S
Published: November 2005

Objective: Primary varicose veins below the knee were managed with the assistance of endoscopic surgery in 240 limbs (235 cases).

Methods: Patients were classified into five clinico-anatomic types according to associated normal veins involved in the varicosities. All procedures were limited to below the knee. With the superior illumination and magnified monitor view offered by the endoscope, all the varicosities and the incompetent perforating veins were dissected, clipped, divided and removed through one or more access incisions (2.5–3.0 cm in length). However, the normal veins were preserved, including the long saphenous vein.

Results: The mean number of incisions in each limb of all patients was 1.86. As there were no residual varicosities or incompetent perforating veins, there was little possibility of recurrence. In the follow-up of 218 limbs, recurrence occurred in only two limbs.

Conclusion: Endoscope-assisted surgery is a good alternative for management of primary varicose veins below the knee, resulting in low recurrence and aesthetically acceptable surgical scarring.
Retrospective study of radiologically confirmed hospital-acquired venous thromboembolic disease
Authors: Carrim Z I , Ruckley C V , Boyd J , Sutherland M , Murchison J T
Published: November 2005

Objective: To study hospital-acquired venous thromboembolic disease (HAVTED) and the relationship between its incidence and compliance with thromboprophylaxis protocols.

Methods: For the past eight years, specialty-specific protocols for VTE prophylaxis have been in operation throughout this hospital. Patients developing radiologically proven VTE either as inpatients or within 12 weeks of discharge were identified from a register. Patients were categorized according to risk as per the Scottish Intercollegiate Guidelines Network (SIGN) guidelines. The use of pharmacological prophylaxis for VTE was recorded.

Results: Over a period of 24 months, 98 patients had radiologically proven HAVTED. Of 44 categorized as high risk, 17 (39%) had received prophylaxis. Corresponding figures for 50 at medium risk and four at low risk were 16 (32%) and three (75%), respectively. The overall incidence of HAVTED averaged two per 1000 inpatient discharges varying between 0.2 in General Medicine and 6.6 in Trauma Orthopaedics. The mean additional cost of treating a case of HAVTED was estimated at £3,000.

Conclusion:Audit of radiological investigations of VTE showed that 18% of all cases were hospital acquired. A hospital policy of thromboprophylaxis may reduce but does not eliminate HAVTED. A substantial proportion of patients with HAVTED had not received prophylaxis. The possibility of a further reduction in incidence of HAVTED with potential saving in morbidity, mortality and cost is highlighted. The implementation and efficacy of thromboprophylaxis protocols should be monitored.
Hepatotoxicity Associated with Acarbose Therapy
Authors: Hsiao Shu-Hwa , Liao Li-Hsiang , Cheng Pin-Nan , Wu Ta-Jen
Published: November 2005

Objective:

To report a case of acarbose-induced hepatotoxicity and compare other reported cases from the literature.

Case Summary:

A 57-year-old woman with type 2 diabetes mellitus for about 10 years had been treated with insulin glargine 20 units/day since December 19, 2002. Acarbose 100 mg 3-times-daily add-on therapy for inadequate glycemic control was started on June 5, 2003. Six months later, the woman complained of gastrointestinal discomfort; the acarbose dose was decreased to 50 mg 3 times daily thereafter. Laboratory examination later revealed alanine aminotransferase (ALT) 640 U/L (upper reference value 55). To elucidate the possibilities of adverse reactions caused by concurrent use of nutritional supplements and medication, we discontinued propolis extract, Ginkgo biloba, placeta extract, and estrogen. Although no remarkable symptoms were noted thereafter, the abnormal ALT values persisted, and no definite viral or autoimmune etiologies were identified. Acarbose was discontinued in August 2004; aspartate aminotransferase and ALT values returned to normal in October 2004.

Discussion:

In addition to ruling out other possible etiologic factors, we assessed the probability of acarbose-induced hepatotoxicity by observing the close time relationship between drug administration and the development of signs and symptoms, as well as the close time relationship between drug withdrawal and the normalization of abnormal liver function test values. An objective causality assessment revealed that an adverse drug reaction was probable as determined by both the Naranjo probability scale and the Roussel Uclaf Causality Assessment Method score.

Conclusions:

Although acarbose-induced hepatotoxicity appears to be uncommon, diabetic patients receiving long-term acarbose therapy should be closely monitored for this adverse effect.
Blood Pressure and Heart Rate Effects Following a Single Dose of Bitter Orange
Authors: Bui Linda T , Nguyen DiemThuy T , Ambrose Peter J
Published: November 2005

Background:

The ingredients of numerous “ephedra-free” dietary supplements used for weight loss include bitter orange, which contains sympathomimetic alkaloids such as synephrine. Due to the similarity in chemical structure to ephedrine and the potential sympathomimetic effects of synephrine, it is hypothesized that bitter orange may increase blood pressure (BP) and heart rate (HR).

Objective:

To determine the effects on BP and HR after a single dose of bitter orange in healthy adults.

Methods:

In a prospective, randomized, double-blind, placebo-controlled, crossover study, 15 young, healthy, adult subjects received either a single dose of Nature's Way Bitter Orange—a 900 mg dietary supplement extract standardized to 6% synephrine—or matching placebo, with a one week washout period. Systolic BP (SBP), diastolic BP (DBP), and HR were measured at baseline and every hour for 6 hours after administration.

Results:

SBP after bitter orange was significantly increased versus placebo at hours 1–5 (p < 0.0001); the peak difference was 7.3 ± 4.6 mm Hg. Although the baseline DBP was higher than after administration of both placebo and bitter orange, DBP after bitter orange was significantly increased versus placebo at hours 4 and 5 (p ≤ 0.02); the peak difference was 2.6 ± 3.8 mm Hg. HR was significantly increased after bitter orange versus placebo for hours 2–5 (p < 0.01); the peak difference was 4.2 ± 4.5 beats/min.

Conclusions:

SBP, DBP, and HR were higher for up to 5 hours after a single dose of bitter orange versus placebo in young, healthy adults.
Mechanism of Signal Amplification in the Olfactory Sensory Cilia
Authors: Takeuchi Hiroko , Kurahashi Takashi
Published: November 2005

Molecular mechanisms underlying olfactory signal amplification were investigated by monitoring cAMP dynamics in the intact sensory cilia. We saw that [cAMP]iincreased superlinearly with time during odorant stimuli for >1 s. This time course was remarkably different from that obtained with the rapid quench method previously applied to thein vitropreparation, in which [cAMP]ichange has been reported to be transient. The superlinear increase of [cAMP]iwas attributable to a gradual increase of cAMP production rate that was consistent with the thermodynamical interaction model between elemental molecules, as has been revealed on the rod photoreceptor cell. It thus seems likely that the fundamental mechanism for molecular interactions between olfactory transduction elements is similar to that of the rod. In olfaction, however, cAMP production was extremely small (∼200,000 molecules/s/cell at the maximum), in contrast to the cGMP hydrolysis in the rod (250,000 molecules/photon). The observed numbers indicate that the olfactory receptor cell has lower amplification at the enzymatic cascade. Seemingly, such low amplification is a disadvantage for the signal transduction, but this unique mechanism would be essential to reduce the loss of ATP that is broadly used for the activities of cells. Apparently, transduction by a smaller number of second-messenger formations would be achieved by the fine ciliary structure that has a high surface-volume ratio. In addition, it is speculated that this low amplification at their enzymatic processes may be the reason why the olfactory receptor cell has acquired high amplification at the final stage of transduction channels, using Ca2+as a third messenger.
Fear Conditioning following Unilateral Temporal Lobectomy: Dissociation of Conditioned Startle Potentiation and Autonomic Learning
Authors: Weike Almut I. , Hamm Alfons O. , Schupp Harald T. , Runge Uwe , Schroeder Henry W. S. , Kessler Christof
Published: November 2005

The present study investigated fear-potentiated startle and autonomic learning in brain-lesioned patients in a classical fear-conditioning paradigm. Startle blink and skin conductance responses of 30 patients who underwent unilateral temporal lobectomy because of drug-resistant epilepsy were compared with those of 32 healthy controls. As expected, temporal lobectomy patients showed a general impairment in fear conditioning relative to controls. This impairment did not differ with respect to the affected hemisphere. Moreover, while fear-conditioned startle potentiation in healthy controls was independent of contingency awareness, skin conductance discrimination was only observed for those participants who correctly recognized the stimulus contingencies. Patients who acquired a declarative memory of the contingencies also showed intact skin conductance discrimination but failed to exhibit fear-potentiated startle. The present findings support a two-levels-of-learning account of human fear conditioning and also demonstrate that the amygdala is crucially involved in fear learning.
In VivoCircadian Function of Casein Kinase 2 Phosphorylation Sites inDrosophilaPERIOD
Authors: Lin Jui-Ming , Schroeder Analyne , Allada Ravi
Published: November 2005

Phosphorylation plays a key role in the precise timing of circadian clocks. Daily rhythms of phosphorylation of theDrosophilacircadian clock component PERIOD (PER) were first described more than a decade ago, yet little is known about their phosphorylation sites and their function in circadian behavior. Here we show that serines 151 and 153 in PER are required for robustin vitrophosphorylation by the casein kinase 2 (CK2) holoenzyme, a cytoplasmic kinase shown to be involved in circadian rhythms. Mutation of these sites in transgenic flies results in significant period lengthening of behavioral rhythms, altered PER rhythms, and delayed PER nuclear localization in circadian pacemaker neurons. In many respects, mutation of these phosphorylation sites phenocopies mutation of the catalytic subunit of CK2. We propose that CK2 phosphorylation at these sites triggers PER nuclear localization.
Modulation of Synaptic Plasticity by Physiological Activation of M1Muscarinic Acetylcholine Receptors in the Mouse Hippocampus
Authors: Shinoe Toru , Matsui Minoru , Taketo Makoto M. , Manabe Toshiya
Published: November 2005

The muscarinic acetylcholine receptor (mAChR) has been considered one of the neurotransmitter receptors regulating hippocampal synaptic plasticity, which likely plays a critical role in learning and memory. In previous studies, however, muscarinic agonists were used at relatively high concentrations, and the subtype selectivity of muscarinic antagonists was not satisfactory. Thus, it remains to be answered whether physiological levels of ACh are involved in the regulation of synaptic plasticity and which mAChR subtypes are responsible for such effects. We found in this study that a low concentration (50 nm) of carbachol enhanced long-term potentiation (LTP) of excitatory synaptic transmission in mouse hippocampal slices. Notably, this enhancing effect was abolished in M1mAChR knock-out (KO) but not in M3mAChR KO mice, although LTP itself was intact in both mutant mice. Furthermore, we found that repetitive stimulation in the stratum oriens, which presumably triggered the release of endogenous ACh from cholinergic terminals, could enhance LTP in wild-type mice but not in M1mAChR KO mice. These results suggest that physiologically released ACh from cholinergic fibers modulates hippocampal synaptic plasticity through the postsynaptic M1mAChR activation.
Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice
Authors: Stalder Anna K. , Ermini Florian , Bondolfi Luca , Krenger Werner , Burbach Guido J. , Deller Thomas , Coomaraswamy Janaky , Staufenbiel Matthias , Landmann Regine , Jucker Mathias
Published: November 2005

The significance of the peripheral immune system in Alzheimer's disease pathogenesis remains controversial. To study the CNS invasion of hematopoietic cells in the course of cerebral amyloidosis, we used a green fluorescence protein (GFP)-bone marrow chimeric amyloid precursor protein transgenic mouse model (APP23 mice). No difference in the number of GFP-positive invading cells was observed between young APP23 mice and nontransgenic control mice. In contrast, in aged, amyloid-depositing APP23 mice, a significant increase in the number of invading ameboid-like GFP-positive cells was found compared with age-matched nontransgenic control mice. Interestingly, independent of the time after transplantation, only a subpopulation of amyloid deposits was surrounded by invading cells. This suggests that not all amyloid plaques are a target for invading cells or, alternatively, all amyloid plaques attract invading cells but only for a limited time, possibly at an early stage of plaque evolution. Immunological and ultrastructural phenotyping revealed that macrophages and T-cells accounted for a significant portion of these ameboid-like invading cells. Macrophages did not show evidence of amyloid phagocytosis at the electron microscopic level, and no obvious signs for T-cell-mediated inflammation or neurodegeneration were observed. The observation that hematopoietic cells invade the brain in response to cerebral amyloidosis may hold an unrecognized therapeutic potential.
Functional Organization of a Schwann Cell Enhancer
Authors: Denarier Eric , Forghani Reza , Farhadi Hooman F. , Dib Samar , Dionne Nancy , Friedman Hana C. , Lepage Pierre , Hudson Thomas J. , Drouin Régen , Peterson Alan
Published: November 2005

Myelin basic protein (MBP) gene expression is conferred in oligodendrocytes and Schwann cells by different upstream enhancers. In Schwann cells, expression is controlled by a 422 bp enhancer lying -9 kb from the gene. We show here that it contains 22 mammalian conserved motifs ≥6 bp. To investigate their functional significance, different combinations of wild-type or mutated motifs were introduced into reporter constructs that were inserted in single copy at a common hypoxanthine phosphoribosyltransferase docking site in embryonic stem cells. Lines of transgenic mice were derived, and the subsequent qualitative and quantitative expression phenotypes were compared at different stages of maturation. In the enhancer core, seven contiguous motifs cooperate to confer Schwann cell specificity while different combinations of flanking motifs engage, at different stages of Schwann cell maturation, to modulate expression level. Mutation of a Krox-20 binding site reduces the level of reporter expression, whereas mutation of a potential Sox element silences reporter expression. This potential Sox motif was also found conserved in other Schwann cell enhancers, suggesting that it contributes widely to regulatory function. These results demonstrate a close relationship between phylogenetic footprints and regulatory function and suggest a general model of enhancer organization. Finally, this investigation demonstrates thatin vivofunctional analysis, supported by controlled transgenesis, can be a robust complement to molecular and bioinformatics approaches to regulatory mechanisms.
Overexpression of the Epidermal Growth Factor Receptor Confers Migratory Properties to Nonmigratory Postnatal Neural Progenitors
Authors: Aguirre Adan , Rizvi Tilat A. , Ratner Nancy , Gallo Vittorio
Published: November 2005

Approaches to successful cell transplantation therapies for the injured brain involve selecting the appropriate neural progenitor type and optimizing the efficiency of the cell engraftment. Here we show that epidermal growth factor receptor (EGFR) expression enhances postnatal neural progenitor migrationin vitroandin vivo. Migratory NG2-expressing (NG2+) progenitor cells of the postnatal subventricular zone (SVZ) express higher EGFR levels than nonmigratory, cortical NG2+cells. The higher endogenous EGFR expression in SVZ NG2+cells is causally related with their migratory potentialin vitroas well asin vivoafter cell engraftment. EGFR overexpression in cortical NG2+cells by transient transfection converted these cells to a migratory phenotypein vitroandin vivo. Finally, cortical NG2+cells purified from a transgenic mouse in which the EGFR is overexpressed under the CNP promoter exhibited enhanced migratory capability. These findings reveal a new role for EGFR in the postnatal brain and open new avenues to optimize cell engraftment for brain repair.
Calcium- and Metabolic State-Dependent Modulation of the Voltage-Dependent Kv2.1 Channel Regulates Neuronal Excitability in Response to Ischemia
Authors: Misonou Hiroaki , Mohapatra Durga P. , Menegola Milena , Trimmer James S.
Published: November 2005

Ischemic stroke is often accompanied by neuronal hyperexcitability (i.e., seizures), which aggravates brain damage. Therefore, suppressing stroke-induced hyperexcitability and associated excitoxicity is a major focus of treatment for ischemic insults. Both ATP-dependent and Ca2+-activated K+channels have been implicated in protective mechanisms to suppress ischemia-induced hyperexcitability. Here we provide evidence that the localization and function of Kv2.1, the major somatodendritic delayed rectifier voltage-dependent K+channel in central neurons, is regulated by hypoxia/ischemia-induced changes in metabolic state and intracellular Ca2+levels. Hypoxia/ischemia in rat brain induced a dramatic dephosphorylation of Kv2.1 and the translocation of surface Kv2.1 from clusters to a uniform localization. In cultured rat hippocampal neurons, chemical ischemia (CI) elicited a similar dephosphorylation and translocation of Kv2.1. These events were reversible and were mediated by Ca2+release from intracellular stores and calcineurin-mediated Kv2.1 dephosphorylation. CI also induced a hyperpolarizing shift in the voltage-dependent activation of neuronal delayed rectifier currents (IK), leading to enhancedIKand suppressed neuronal excitability. TheIKblocker tetraethylammonium reversed the ischemia-induced suppression of excitability and aggravated ischemic neuronal damage. Our results show that Kv2.1 can act as a novel Ca2+- and metabolic state-sensitive K+channel and suggest that dynamic modulation ofIK/Kv2.1 in response to hypoxia/ischemia suppresses neuronal excitability and could confer neuroprotection in response to brief ischemic insults.
Gap-Junctional Coupling and Absolute Sensitivity of Photoreceptors in Macaque Retina
Authors: Hornstein Eric P. , Verweij Jan , Li Peter H. , Schnapf Julie L.
Published: November 2005

We investigated gap-junctional coupling of rods and cones in macaque retina. Cone voltage responses evoked by light absorption in neighboring rods were briefer and smaller than responses recorded in the rods themselves. Rod detection thresholds, calculated from noise and response amplitude histograms, closely matched the threshold for an ideal detector limited by quantal fluctuations in the stimulus. Surprisingly, cone thresholds were only approximately two times higher. Amplitude fluctuations in cones could be explained by a Poisson distribution of photoisomerizations within a pool of seven or more coupled rods. Neurobiotin coupling between rods and cones was consistent with our electrical recordings, with approximately six rods labeled per injected cone. The spatial distribution of tracer-coupled rods matched the light-evoked cone receptive field. The gap junction inhibitor carbenoxolone abolished both electrical and tracer coupling. Amplitude fluctuations in most rods were accounted for by the expected rate of light absorption in their outer segments. The fluctuations in some rods, however, were consistent with a summation pool of up to six rods. When single rods were injected with Neurobiotin, up to 10 rods were labeled. Rod-rod and rod-cone electrical coupling is expected to extend the range of scotopic vision by circumventing saturation at the rod to rod-bipolar cell synapse; however, because coupling also renders the rod synapse less effective at separating out photon signals from dark noise, coupling is expected to elevate the absolute threshold of dark-adapted observers.
Cholinergic Modulation of Appetite-Related Synapses in Mouse Lateral Hypothalamic Slice
Authors: Jo Young-Hwan , Wiedl Denise , Role Lorna W.
Published: November 2005

Nicotine administration reduces appetite and alters feeding patterns; a major deterrent to smoking cessation is hyperphagia and resultant weight gain. We demonstrate here that lateral hypothalamic (LH) circuits involving melanin-concentrating hormone (MCH) neurons are subject to cholinergic modulation that may be related to the effects of nicotine on appetite control. Cholinergic input to the perifornical LH area of the mouse is confirmed by examination of immunostaining for vesicular acetylcholine (ACh) transporter (VAT) in conjunction with antibodies to MCH and the vesicular GABA transporter (vGABAT). vAChT-positive neurons border the LH, and VAT-positive projections are detected throughout the perifornical area. MCH-positive dendrites appear studded with vGABAT-positive contacts, consistent with recordings of GABAergic inputs to LH/MCH neurons identified by their location, morphology, electrophysiological profile, and MCH expression. Activation of presynaptic nicotinic ACh receptors (nAChRs) enhances GABAergic transmission. GABAergic transmission is potentiated by (1) direct nicotine application, (2) increasing local ACh concentration, and (3) stimulation of cholinergic projections. Based on pharmacological studies and comparisons of wild-type versus α7 nAChR subunit mutant mice, we propose that α7*-nAChRs are required for the modulation of GABAergic inputs in LH. Prenatal exposure to nicotine elicits a persistent elevation of GABAergic transmission in the LH of postnatal pups. Furthermore, GABAergic inputs to LH of prenatal nicotine-exposed pups are insensitive to subsequent nicotine challenge. Our studies support the hypothesis that nicotine administration or elevated cholinergic tone enhance inhibition of perifonical LH/MCH neurons via activation of presynaptic α7*-nAChRs.
Vascular Remodeling versus Amyloid β-Induced Oxidative Stress in the Cerebrovascular Dysfunctions Associated with Alzheimer's Disease
Authors: Tong Xin-Kang , Nicolakakis Nektaria , Kocharyan Ara , Hamel Edith
Published: November 2005

The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-β1 (TGF+). Age-related impairments and theirin vitroreversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+mice but had no effect in those of TGF+mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.