bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural history of nicotine withdrawal
Authors: Shiffman Saul , Patten Christi , Gwaltney Chad , Paty Jean , Gnys Maryann , Kassel Jon , Hickcox Mary , Waters Andrew , Balabanis Mark
Published: November 2006

Aims  To examine the natural history of nicotine withdrawal and individual differences associated with withdrawal duration and severity.

Design and Setting  Prospective study of withdrawal symptoms among smokers who quit for at least 24 hours. Participants used Ecological Momentary Assessment to monitor symptoms in their natural environment using an Electronic Diary (ED).

Participants  A total of 214 cigarette smokers (59% female, 92% Caucasian).

Intervention  All participants received a clinic‐based, behavioral, group cessation intervention. Severity and duration of withdrawal was not addressed explicitly in treatment.

Measurements  Participants were ‘beeped’ by the ED approximately five times/day to complete affect assessments (negative affect, arousal, attention disturbance, restlessness), and daily assessments of sleep disturbance (at waking) and of cognitive performance (each evening) for a week prior to quitting and for up to 21 days after quitting. Withdrawal was considered resolved when withdrawal scores returned to baseline levels for at least 2 consecutive days.

Findings  All symptoms returned to baseline levels within 10 days of quitting. All variables except arousal and sleep disturbance showed change over time. No robust predictors of individual differences in withdrawal responses emerged.

Conclusions  The time‐course of withdrawal may be shorter than previously reported. The natural history of nicotine withdrawal may have implications for theories of withdrawal and smoking relapse and for smoking cessation treatment.
Linking opioid‐dependent hospital patients to drug treatment: health care use and costs 6 months after randomization
Authors: Barnett Paul G. , Masson Carmen L. , Sorensen James L. , Wong Wynnie , Hall Sharon
Published: November 2006

Aims  To conduct an economic evaluation of the first 6 months' trial of treatment vouchers and case management for opioid‐dependent hospital patients.

Design  Randomized clinical trial and evaluation of administrative data.

Setting  Emergency department, wound clinic, in‐patient units and methadone clinic in a large urban public hospital.

Participants  The study randomized 126 opioid‐dependent drug users seeking medical care.

Interventions  Participants were randomized among four groups. These received vouchers for 6 months of methadone treatment, 6 months of case management, both these interventions, or usual care.

Findings  During the first 6 months of this study, 90% of those randomized to vouchers alone enrolled in methadone maintenance, significantly more than the 44% enrollment in those randomized to case management without vouchers (P < 0.001). The direct costs of substance abuse treatment, including case management, was $4040 for those who received vouchers, $4177 for those assigned to case management and $5277 for those who received the combination of both interventions. After 3 months, the vouchers alone group used less heroin than the case management alone group. The difference was not significant at 6 months. There were no significant differences in other health care costs in the 6 months following randomization.

Conclusion  Vouchers were slightly more effective but no more costly than case management during the initial 6 months of the study. Vouchers were as effective and less costly than the combination of case management and vouchers. The finding that vouchers dominate is tempered by the possibility that case management may lower medical care costs.
C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option
Authors: Longhurst H J , Carr S , Khair K
Published: November 2006

Economic and political factors have led to the increased use of home therapy programmes for patients who have traditionally been treated in hospital. Many patients with hereditary angioedema (HAE) experience intermittent severe attacks that affect their quality of life and may be life-threatening. These attacks are treated with C1-inhibitor concentrate which, for most patients, is infused at the local hospital. Home therapy programmes for HAE are currently being established. This paper reviews the extent of use of these programmes and summarizes the advantages and potential disadvantages of the concept so far.
Decreasing shrimp (Pandalus borealis) sizes off Newfoundland and Labrador – environment or fishing?
Authors: KOELLER P. A. , FUENTES‐YACO C. , PLATT T.
Published: November 2006

During the 1990s, carapace length statistics including minimum size caught (Lmin), mean male and female lengths, size at sex transition (L50) and maximum size (Lmax) of northern shrimp (Pandalus borealis) decreased in commercial and survey catches off Newfoundland and Labrador. Decreased growth rates caused by decreases in per‐capita food availability due to large population increases, exacerbated by increased metabolic demands from higher water temperatures in the mid‐1990s, appear to be the main cause of the size decrease. Fishing could have had an accelerating effect on environmentally driven decreases in shrimp growth and size by ‘cropping’ the largest shrimp from the population. The greatest decreases in shrimp size occurred in Hudson Strait and the adjacent northern shelf, the area which also has the highest densities and largest shrimp. We hypothesize that the greater size decrease here resulted from decreased primary production from decreased nutrient flux into the euphotic zone, caused by increased atmospheric warming, freshwater runoff and stratification during the warming trend of the 1990s.
Climatic oscillations and tuna catch rates in the Indian Ocean: a wavelet approach to time series analysis
Authors: MÉNARD F. , MARSAC F. , BELLIER E. , CAZELLES B.
Published: November 2006

We analysed the influence of climatic oscillations [based on the Indian Oscillation Index (IOI)] on monthly catch rates of two tropical tuna species in the equatorial Indian Ocean. We carried out wavelet analysis, an efficient method of time series analysis to study non‐stationary data. Catch per unit of effort (CPUE) of bigeye tuna was computed from Japanese longline statistics from 1955 to 2002 in the equatorial Indian Ocean and CPUE of yellowfin tuna was derived from industrial purse seine statistics from 1984 to 2003 in the Western Indian Ocean. Wavelet analyses allowed us to quantify both the pattern of variability in the time series and non‐stationary associations between tuna and climatic signals. Phase analyses were carried out to investigate dependency between the two signals. We reported strong associations between tuna and climate series for the 4‐ and 5‐yr periodic modes, i.e. the periodic band of the El Niño Southern Oscillation signal propagation in the Indian Ocean. These associations were non‐stationary, evidenced from 1970 to 1990 for bigeye, and from 1984 to 1991 and then from 1993 to 2001 for yellowfin. Warm episodes (low negative IOI values) matched increases of longline catch rates of bigeye during the 1970–1990 time frame, whereas the strong 1997–1998 warm event matched a decrease of purse seine catch rates of yellowfin. We discussed these results in terms of changes in catchability for purse seine and longline.
The effects of glucocorticoid therapy on the inflammatory and Dendritic cells in muscular dystrophies
Authors: Hussein Mahmoud R. , Hamed Sherifa A. , Mostafa Mohammed G. , Abu‐Dief Eman E. , Kamel Nageh Fouly , Kandil Mahmoud R.
Published: November 2006

Various clinical trials have documented the therapeutic benefit of glucocorticoids (GCs) in enhancing muscle strength and slowing disease progression of Duchenne and Becker muscular dystrophies (DMD/BMD). We hypothesized that GCs may have relevance to the differential anti‐inflammatory effect on mononuclear inflammatory cells (MICs) and Dendritic cells (DCs) infiltrating the dystrophic muscles. In this prospective study, two muscle biopsies were obtained (before and after 6‐month prednisone therapy) from 30 patients with dystrophies (DMD = 18; BMD = 6; and limb girdle muscular dystrophies (LGMD) = 6). MICs and DCs infiltrating the muscles were examined using mouse monoclonal antibodies and immunoperoxidase staining methods. Muscle strength was evaluated monthly by manual testing, motor ability and timed tests. Prednisone therapy was associated with: (i) functional improvement of overall motor disability, in upper limbs of DMD (P < 0.001) and BMD (P < 0.01) and lower limbs of DMD (P < 0.001) and BMD (P < 0.05); (ii) histological improvement such as fibre size variation (DMD, P < 0.01; BMD, P < 0.05), internalization of nuclei (DMD, P < 0.05), degeneration and necrosis (DMD and BMD, P < 0.01), regeneration (DMD, P < 0.001; BMD, P < 0.01) and endomysial connective tissue proliferation (DMD, P < 0.01; BMD, P < 0.05) and (iii) reduction of total MICs (P < 0.01) and DCs (P < 0.01). There was a positive correlation between the degree of improvement in overall motor disability and reduction of DCs numbers (In upper limbs; r = 0.638, P < 0.01 for DMD and r = 0.725, P < 0.01 for BMD, in Lower limbs; r = 0.547, P < 0.05 for DMD and r = 0.576, P < 0.05 for BMD). Such improvements and changes of MICs/DCs were absent in LGMD. In DMD/BMD, prednisone therapeutic effect was associated with reduced MICs and DCs numbers. Whether this therapeutic effect reflects targeting of the deleterious immune response produced by these cells mandates further investigations.
Immunological hormone atrophy by gonadotropin‐based drug
Authors: Li Jun , Zhang Jinkun
Published: November 2006

Luteinizing hormone releasing hormone–Pseudomonas aeruginosa exotoxin A (LHRH–PE40) and sequence‐modified LHRH–PE40 (mLHRH–PE40) are two anti‐tumour drugs developed by fusing either native or modified LHRH with the same PE40. This study was designed to evaluate their toxicity on the male genital tract. Male rats were treated intravenously or intraperitoneally with either LHRH–PE40 or mLHRH–PE40 on alternate days for 12 weeks. Serum and testes were examined to detect anti‐LHRH, anti‐LHRH–PE40 or anti‐mLHRH–PE40 using an ELISA assay, testosterone level was measured by radioimmunoassay, and testicular morphology was evaluated. Rats receiving LHRH–PE40 intraperitoneal injections had higher anti‐LHRH antibody titres, lower serum testosterone concentration and remarkable testicular atrophy, whereas those administrated with intravenous injections of either LHRH–PE40 or mLHRH‐PE40 demonstrated no such changes. We concluded that the testicular atrophy can be attributed to higher titre of anti‐LHRH antibodies, which was affected by both drug delivery and the LHRH motif of the chimeric protein.
What is a role of haeme oxygenase‐1 in psoriasis? Current concepts of pathogenesis
Authors: Wojas‐Pelc Anna , Marcinkiewicz Janusz
Published: November 2006

The skin is constantly exposed to endogenous and environmental pro‐oxidant agents, which lead to harmful generation of reactive oxygen species (ROS). Healthy skin, being a potential target for oxidative stress, is equipped with a large number of defence mechanisms including antioxidant systems. This protection can be corrupted by an imbalance between ROS and antioxidants with pathological level of oxidants prevailing. There is a great body of evidence indicating that some inflammatory skin diseases, such as psoriasis, are mediated by oxidative stress. Keratinocytes of normal skin, the primary target for pro‐oxidant agents, show strong expression of ROS‐detoxifying enzymes. In addition, normal keratinocytes express haeme oxygenase (HO), an enzyme which might be involved in the protection of cells against oxidative stress. HO (inducible HO‐1, constitutive HO‐2 and HO‐3) is the rate‐limiting enzyme in haeme catabolism, which leads to the generation of biliverdin, iron, and carbon monoxide. HO‐1 is a stress‐responsive protein whose expression is induced by various oxidative agents. HO‐1 is known for its cytoprotective, antioxidant and anti‐inflammatory properties. Interestingly, a strong overexpression of HO‐1 was observed in psoriatic skin. However, the role of HO‐1 in psoriasis remains unclear. In this review, we will discuss some current concepts concerning pathogenesis of psoriasis and the contribution of HO‐1 in skin inflammation to show the relationships between HO‐1, ROS and cytokine network in psoriatic skin. We will try to answer a question whether enhanced HO‐1 expression in keratinocytes results in beneficial or detrimental effect on the development and severity of psoriatic lesions.
Chondroitin AC lyase activity is related to virulence of fish pathogenic Flavobacterium columnare
Authors: Suomalainen L‐R , Tiirola M , Valtonen E T
Published: November 2006

The virulence of eight Flavobacterium columnare strains was studied to find correlations between several virulence‐related factors and virulence. Virulence was tested in vivo using rainbow trout, Oncorhynchus mykiss (Walbaum). Suggested virulence‐related factors such as production of the degradative enzyme chondroitin lyase, plasmid occurrence and adhesion capability were studied in vitro. Infection with the four most virulent strains resulted in 95–100% mortality within 114 h. Chondroitin lyase activity was found to be significantly related to the virulence of the strains at 25 °C and it was also shown to be temperature‐dependent, being higher at 25 °C than at 20 °C. Virulence was not plasmid associated. The adhesion capability of the strains in vitro varied substantially when tested on crude mucus‐coated slides and no statistical relationship between adhesion and virulence was found using this method.
σE‐dependent small RNAs of Salmonella respond to membrane stress by accelerating global omp mRNA decay
Authors: Papenfort Kai , Pfeiffer Verena , Mika Franziska , Lucchini Sacha , Hinton Jay C. D. , Vogel Jörg
Published: November 2006

The bacterial envelope stress response (ESR) is triggered by the accumulation of misfolded outer membrane proteins (OMPs) upon envelope damage or excessive OMP synthesis, and is mediated by the alternative sigma factor, σE. Activation of the σE pathway causes a rapid downregulation of major omp mRNAs, which prevents further build‐up of unassembled OMPs and liberates the translocation and folding apparatus under conditions that require envelope remodelling. The factors that facilitate the rapid removal of the unusually stable omp mRNAs in the ESR were previously unknown. We report that in Salmonella the ESR relies upon two highly conserved, σE‐controlled small non‐coding RNAs, RybB and MicA. By using a transcriptomic approach and kinetic analyses of target mRNA decay in vivo, RybB was identified as the factor that selectively accelerates the decay of multiple major omp mRNAs upon induction of the ESR, while MicA is proposed to facilitate rapid decay of the single ompA mRNA. In unstressed bacterial cells, the two σE‐dependent small RNAs function within a surveillance loop to maintain envelope homeostasis and to achieve autoregulation of σE.
Obliquity‐dominated glacio‐eustatic sea level change in the early Oligocene: evidence from the shallow marine siliciclastic Rupelian stratotype (Boom Formation, Belgium)
Authors: Abels Hemmo A. , Simaeys Stefaan Van , Hilgen Frits J. , Man Ellen De , Vandenberghe Noël
Published: November 2006

Our results prove that glacio‐eustatic sea level oscillations in the early Oligocene were dominantly obliquity controlled with additional influence of the ∼100‐ and 405‐kyr eccentricity cycles. This was derived from spectral analysis of resistivity records from an extended downhole section of the Boom Clay succession in Belgium, that reveals a prevailing obliquity control on the laterally persistent metre‐scale alternations of shallow marine silt‐ and claystones in the Rupelian historical stratotype succession. These direct measurements of sea level variations in a shallow marine setting corroborate that variations with similar frequencies in benthonic oxygen isotope records from the open ocean indeed reflect, at least partly, ice volume change. A very tentative astronomical tuning has been established for the Boom Clay succession which awaits future confirmation with the addition of more accurate age calibration points.
Efficacy of artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia
Authors: Denis Mey Bouth , Tsuyuoka Reiko , Lim Pharath , Lindegardh Niklas , Yi Poravuth , Top Sophoan Narann , Socheat Duong , Fandeur Thierry , Annerberg Anna , Christophel Eva Maria , Ringwald Pascal
Published: November 2006

Objective  To determine the efficacy of artemether–lumefantrine malaria treatment, as an alternative to artesunate + mefloquine, which is becoming ineffective in some areas of the Thai–Cambodian border.

Methods  Two studies were conducted to monitor the efficacy of artemether–lumefantrine in Sampov Lun referral hospital, Battambang Province, in 2002 and 2003, and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison. The studies were performed according to the WHO standardized protocol with a follow‐up of 28 days. The therapeutic efficacy tests were complemented with in vitro tests and in 2003, with the measurement of lumefantrine plasma concentration at day 7 for the patients treated with artemether–lumefantrine.

Results  A total of 190 patients were included: 55 were treated with artemether–lumefantrine in 2002 (AL2002), 80 with artemether–lumefantrine and food supplementation in 2003 (AL2003) and 55 with artesunate + mefloquine in 2003 (AM2003). With the per‐protocol analysis, the cure rate was 71.1% in study AL2002, 86.5% in study AL2003 and 92.4% in study AM2003. All the data were PCR corrected. The artemether–lumefantrine cure rate was unexpectedly low in 2002, but it increased with food supplementation in 2003. There was a significant difference (P = 0.02) in lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases. In vitro susceptibility to lumefantrine was reduced for isolates sampled from patients presenting with treatment failure, but the difference was not statistically different from isolates sampled from patients who were successfully treated.

Conclusion  Treatment failure cases of artemether–lumefantrine are most probably because of low levels of lumefantrine blood concentration. Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to lumefantrine is present in the region.
Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment
Authors: Haglund Mattias , Sjöbeck Martin , Englund Elisabet
Published: November 2006

Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer’s disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non‐focal white matter disease (WMD) in AD. This report is a pathological follow‐up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.
Age‐related changes in histogram pattern of anterior horn cells in human cervical spinal cord
Authors: Anamizu Yorito , Seichi Atsushi , Tsuzuki Nobuyuki , Nakamura Kozo
Published: November 2006

The purpose of the present study was to clarify age‐related changes in histograms of spinal anterior horn cells. The study examined Rexed lamina IX of the C7 spinal cord segment in 22 men who had died of non‐spinal disease (age range, 0–85 years). First, we confirmed that the size of nucleoli exhibited a linear relationship to the diameter of spinal anterior horn cells by preparing histograms of nucleoli. Second, this formula was used to create histograms of cervical anterior horn cells. Results were as follows: (i) diameter of nucleoli ranged from 2.0 µm to 6.0 µm; (ii) in each subject, no changes were seen in histogram patterns among ventral, intermediate, dorsal and overall sections; (iii) at ≤ 20 years of age, histograms displayed a single peak for the diameter of nucleoli at about 4.0–4.5 µm; (iv) at 21–60 years of age, histograms displayed two peaks, at about 3.5–4.0 µm and 5.0–5.5 µm; and (v) at 61–85 years of age, histograms displayed a single peak at about 5.0–5.5 µm.
Corticobasal degeneration as cause of progressive non‐fluent aphasia: Clinical, radiological and pathological study of an autopsy case
Authors: Takao Masaki , Tsuchiya Kuniaki , Mimura Masaru , Momoshima Suketaka , Kondo Hiromi , Akiyama Haruhiko , Suzuki Norihiro , Mihara Ban , Takagi Yasuyuki , Koto Atsuo
Published: November 2006

A Japanese male developed gradual loss of spontaneous speech at age 60. Three years later meaningful speech had deteriorated to the point that it had become restricted to monotonous utterances. Neuropsychological examination at age 62 showed that he had severe non‐fluent aphasia. A brain MRI demonstrated mild cortical atrophy with ischemic lesions in the cerebral white matter. He was diagnosed as having primary progressive aphasia. At age 63, he was admitted to the hospital to reevaluate the neurological condition. Neurologic examination showed severe non‐fluent aphasia, hyperreflexia, snout and sucking reflexes. No alien hand was observed. He was able to walk, dress, wash himself and use chopsticks as well as name real objects. At age 65, 99mTc‐hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO‐SPECT) revealed diffuse cerebral hypoperfusion that was particularly prominent in the left frontal lobe. An MRI showed progressive cortical atrophy with the definite atrophy of the left paracentral gyrus. The hippocampal formation and putamen were also atrophic. He died of pneumonia at age 67. The brain weighed 810 g with atrophy of the frontal lobe, globus pallidus, enlargement of the lateral ventricles and depigmentation of the substantia nigra. Microscopic examination showed severe neuronal loss and gliosis in the cerebral cortex, globus pallidus interna and substantia nigra. Ballooned neurons were observed in the cerebral cortex. Gallyas‐Braak method revealed numerous astrocytic plaques and argentophilic threads in the cerebrum. Clinical diagnosis of corticobasal degeneration sometimes is difficult in individuals with atypical clinical presentations. More exact clinical and radiological criteria may warrant a diagnosis of corticobasal degeneration.
Light and GABAA receptor activation alter Period mRNA levels in the SCN of diurnal Nile grass rats
Authors: Novak Colleen M. , Ehlen J. Christopher , Paul Ketema N. , Fukuhara Chiaki , Albers H. Elliott
Published: November 2006

We examined Period (Per) mRNA rhythms in the suprachiasmatic nucleus (SCN) of a diurnal rodent and assessed how phase‐shifting stimuli acutely affect SCN Per mRNA using semiquantitative in situ hybridization. First, Per1 and Per2 varied rhythmically in the SCN over the course of one circadian cycle in constant darkness: Per1 mRNA was highest in the early to mid‐subjective day, while Per2 mRNA levels peaked in the late subjective day. Second, acute light exposure in the early subjective night significantly increased both Per1 and Per2 mRNA. Third, Per2 but not Per1 levels decreased 1 and 2 h after injection of the γ‐aminobutyric acid (GABA)A receptor agonist muscimol into the SCN during the subjective day. Fourth, muscimol also reduced the light‐induced Per2 in the early subjective night, but Per1 induction by light was not significantly affected. Consistent with previous studies, these data demonstrate that diurnal and nocturnal animals show very similar daily patterns of Per mRNA and light‐induced Per increases in the SCN. As with light, muscimol alters circadian phase, and daytime phase alterations induced by muscimol are associated with significant decreases in Per2 mRNA. In diurnal animals, muscimol‐induced decreases in Per are associated with phase delays rather than advances. The direction of the daytime phase shift may be determined by the relative suppression of Per1 vs. Per2 in SCN cells. As in nocturnal animals, changes in Per1 and Per2 mRNA by photic and non‐photic stimuli appear to be associated with circadian phase alteration.
Second‐by‐second measurement of acetylcholine release in prefrontal cortex
Authors: Bruno John P. , Gash Clelland , Martin Brad , Zmarowski Amy , Pomerleau Francois , Burmeister Jason , Huettl Peter , Gerhardt Greg A.
Published: November 2006

Microdialysis has been widely used to measure acetylcholine (ACh) release in vivo and has provided important insights into the regulation of cholinergic transmission. However, microdialysis can be constrained by limited spatial and temporal resolution. The present experiments utilize a microelectrode array (MEA) to rapidly measure ACh release and clearance in anaesthetized rats. The array electrochemically detects, on a second‐by‐second basis, changes in current selectively produced by the hydrolysis of ACh to choline (Ch) and the subsequent oxidation of choline and hydrogen peroxidase (H2O2) at the electrode surface. In vitro calibration of the microelectrode revealed linear responses to ACh (R2 = 0.9998), limit of detection of 0.08 µm, and signal‐to‐noise ratio of 3.0. The electrode was unresponsive to ascorbic acid (AA), dopamine (DA), or norepinephrine (NE) interferents. In vivo experiments were conducted in prefrontal cortex (PFC) of anaesthetized rats. Pressure ejections of ACh (10 mm; 40 nL) through an adjoining micropipette produced a rapid rise in current, reaching maximum amplitude in ∼1.0 s and cleared by 80% within 4–11 s. Endogenously released ACh, following local depolarization with KCl (70 mm; 40, 160 nL), was detected at values as low as 0.05 µm. These signals were volume‐dependent and cleared within 4–12 s. Finally, nicotine (1.0 mm, 80 nL) stimulated ACh signals. Nicotine‐induced signals reflected the hydrolysis of ACh by endogenous acetylcholinesterase (AChE) as inhibition of the enzyme following perfusion with neostigmine (10 µm) attenuated the signal (40–94%). Collectively, these data validate a novel method for rapidly measuring cholinergic transmission in vivo with a spatial and temporal resolution that far exceeds conventional microdialysis.
Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol‐delivery form of lidocaine‐prilocaine for treating premature ejaculation
Authors: Dinsmore Wallace W. , Hackett Geoffrey , Goldmeier David , Waldinger Marcel , Dean John , Wright Patrick , Callander Michael , Wylie Kevan , Novak Claire , Keywood Charlotte , Heath Patricia , Wyllie Michael
Published: November 2006

OBJECTIVE

To evaluate, in a phase II study, the efficacy and safety of a topical eutectic mixture for premature ejaculation (TEMPE), a metered‐dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine, as a treatment for PE.

PATIENTS AND METHODS

Men with PE (Diagnostic and Statistical Manual‐IV definition) aged 18–75 years were randomized into a double‐blind, placebo‐controlled study in the UK and the Netherlands. Efficacy variables included the mean change in intravaginal ejaculatory latency time (IELT) from baseline and the proportion of patients who achieved an IELT of ≥ 4, ≥ 3 or ≥ 2 min on two occasions, and the effect of TEMPE on the index of ejaculatory control (IEC) and sexual quality‐of‐life (SQoL) scores of patients and their partners. Safety and adverse event data were also collected.

Fifty‐four patients were randomized and received study treatment.

RESULTS

The observed mean change in IELT from baseline to the end of the treatment period was 3.8 min in the TEMPE group and 0.7 min in the placebo group, and when adjusted for baseline and centre was 2.4 times higher in the TEMPE than the placebo group (P < 0.01). The efficacy of TEMPE in increasing IELT was further supported by positive trends in the other efficacy endpoints. The proportion of men who had an IELT time ≥ 2, ≥ 3 or ≥ 4 min on two occasions after treatment was 11/20 (55%), 8/20 (40%) and 5/25 (20%) in the TEMPE group, and 8/23 (35%), 3/23 (13%) and 3/23 (13%) in the placebo group, respectively, although these differences were not statistically significant. Improvements in IEC and SQoL (male and female) scores also showed trends towards greater efficacy for TEMPE than placebo. In all, 35 of 42 (83%) patients considered the spray easy to use. Mild to moderate local numbness occurred in three (12%) of the TEMPE‐treated patients but did not lead to discontinuation.

CONCLUSION

Topical treatment with TEMPE produced a statistically and clinically significant increase in IELT compared with placebo, and resulted in positive trends in ejaculatory control and SQoL. TEMPE was considered easy to use and was well tolerated. The data support the conduct of further large‐scale studies to establish the utility of TEMPE as a first‐line treatment for PE.
Some Results on the Control of the False Discovery Rate under Dependence
Authors: FARCOMENI ALESSIO
Published: November 2006

Abstract.  Controlling the false discovery rate (FDR) is a powerful approach to multiple testing, with procedures developed with applications in many areas. Dependence among the test statistics is a common problem, and many attempts have been made to extend the procedures. In this paper, we show that a certain degree of dependence is allowed among the test statistics, when the number of tests is large, with no need for any correction. We then suggest a way to conservatively estimate the proportion of false nulls, both under dependence and independence, and discuss the advantages of using such estimators when controlling the FDR.
Inflammation associated with implants with different surface types
Authors: Pongnarisorn Nuchjaree J. , Gemmell Erica , Tan Albert E. S. , Henry Patrick J. , Marshall Roderick I. , Seymour Gregory J.
Published: November 2006

Objectives: The aim of this study was to determine the nature of the inflammatory infiltrate associated with different transmucosal implant surfaces in dogs.

Methods: Three experimental and one control single‐stage implants were randomly placed on each side of the jaw in eight dogs. The transmucosal portion of the test implants consisted of an acid‐etched surface (type A), a machined surface with a circumferential groove (type C) and a surface prepared by mild anodic oxidation (type D). The control was a standard machined surface (type B). In order to determine the response to the different surfaces, plaque control was carried out twice weekly following placement of the implants for the entire period of the experiment. At 6 months, gingival biopsies and plaque samples were obtained. The area of inflammatory infiltrate and the nature of the infiltrating cell types were determined using immunohistology. Real‐time polymerase chain reaction was used to identify putative periodontal pathogens.

Results: Inflammatory infiltrates were associated with all implant surfaces and were commonly found subepithelially and perivascularly. T cells were the predominant infiltrating cell type in all lesions, associated with the different surfaces. In all lesions the CD4 : CD8 ratio was approximately 2 : 1. Statistical analysis showed that the type C surface (machined surface with a groove) had significantly larger inflammatory infiltrates than the type B surface (machined surface without a groove; P<0.05). No statistically significant differences were found with respect to the size of the inflammatory infiltrates or in terms of the nature of infiltrating cells. However, despite the intensive plaque control regime, plaque was present on all implant surfaces at the time of biopsy 6 months after placement. All implants had similar numbers of Tannerella forsythia, Fusobacterium nucleatum and Porphyromonas gingivalis. Actinobacillus actinomycetemcomitans, was not detected in any sample.

Conclusions: These results suggest that the development of inflammation associated with implants is independent of surface type, but is nevertheless associated with the presence of plaque. The different surfaces had no influence on the nature of the infiltrate, with T cells being the predominant cell type in all lesions. Finally, the different implant surface types seemed not to influence the peri‐implant microbiota. However, the presence of the circumferential groove tended to be associated with larger infiltrates. Whether this is due to increased plaque accumulation remains to be determined.
Review article: the risks of oesophageal acid exposure ‐ from minimal mucosal changes to malignancy
Authors: HUNT R. H.
Published: November 2006

Gastro‐oesophageal reflux disease is very common and presents with a spectrum of symptoms with or without oesophageal damage. Gastro‐oesophageal reflux disease has an adverse impact on quality of life, especially in those with nocturnal symptoms.

Prolonged exposure of the oesophageal mucosa to acidic gastric contents with pepsin and bile increases the risk of oesophageal mucosal injury. The frequency and severity of symptoms and oesophagitis correlate with the frequency, severity and duration of acid exposure, particularly at night‐time.

This study reviews the mechanisms and evidence for acid‐induced symptoms and oesophageal injury, from superficial mucosal injury to Barrett's oesophagus and the long‐term risk of oesophageal adenocarcinoma.

Optimizing the choice and dose regimen of proton‐pump inhibitor is essential for treating gastro‐oesophageal reflux disease, and nocturnal acid control is important in preventing complicated gastro‐oesophageal reflux disease.
Review article: a conceptual model for the relationship of nocturnal acidity and extra‐oesophageal manifestations of gastro‐oesophageal reflux disease ‐ where are we now?
Authors: SHAKER R.
Published: November 2006

A number of extra‐oesophageal abnormalities ranging from otolaryngologic disorders and dysphonia to non‐cardiac chest pain and sleep disturbances have been attributed to gastro‐oesophageal reflux disease. A significant degree of uncertainty and confusion continues to exist with regard to the pathogenesis, diagnosis and treatment of these conditions.

The following conceptual model could be proposed for the pathogenesis of the extra‐oesophageal manifestations of gastro‐oesophageal reflux disease and, consequently, the likely response to therapy.

This model suggests that these disorders are, in fact, multifactorial and that the contributions of refluxed gastric contents comprise only part of the pathogenesis. In the case of asthma, for example, factors that influence airway resistance and symptom production include basal airway resistance, intra‐oesophageal events, such as acid reflux‐stimulating vagal afferent fibres and inducing further airway changes, and extra‐oesophageal, allergic and other pulmonary factors that can influence airway resistance. This model allows for different degrees of influence from these three main contributors. In this model, if gastro‐oesophageal reflux disease‐related events contribute minimally to the changes in airway resistance compared with other factors, treating gastro‐oesophageal acid reflux would result in minimal or no change in symptoms and vice versa.

At present, as it is difficult to identify prospectively those patients in whom reflux comprises the main pathological factor, and who might therefore respond to acid suppression, a trial of empiric proton‐pump inhibitor therapy with reflux precautionary measures seems appropriate and has been suggested by some expert panels.
Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea
Authors: Foster Glen E. , Poulin Marc J. , Hanly Patrick J.
Published: November 2006

Obstructive sleep apnoea (OSA) has been implicated as a risk factor for the development of hypertension, stroke and myocardial infarction. The main cause of cardiovascular and cerebrovascular disease in OSA is thought to be exposure to intermittent hypoxia, which can lead to oxidative stress, inflammation, atherosclerosis, endothelial dysfunction and hypertension. These proposed mechanisms have been drawn from basic research in animal and human models of intermittent hypoxia in addition to clinical investigation of patients with OSA. This review outlines the association between OSA and vascular disease, describes basic mechanisms that may be responsible for this association and compares the results from studies of OSA subjects with those in experimental models of intermittent hypoxia.
Kinetics of calcium spikes in rat cardiac myocytes
Authors: Zahradníková Alexandra , Poláková Eva , Zahradník Ivan , Zahradníková Alexandra
Published: November 2006

The local calcium release flux signals (calcium spikes) evoked by membrane depolarization were recorded at high temporal resolution (2000 lines s−1) in isolated ventricular myocytes of male rats, using combination of scanning confocal microscopy and the patch‐clamp technique. The kinetic properties of calcium spikes were investigated. The time course of calcium spike activation could be described reliably by a model with higher‐order (n= 3) kinetics, but not by a first‐order exponential process. A model of calcium spike with calcium release termination coupled to its activation was preferential to a model with the release termination independent of its activation. Three fluorescent calcium dyes (OG‐5N, fluo‐3, and fluo‐4) were compared for calcium spike measurements. Experimental measurements as well as simulations showed that the occurrence and latency of calcium spikes could be measured faithfully with all indicators, while the kinetics of calcium spikes was reliably traced only with OG‐5N. Calcium spikes evoked by a step depolarization from −50 to 0 mV commenced with a mean latency of 4.1 ± 0.2 ms and peaked 6.7 ± 0.2 ms later. Their full amplitudes were normally distributed. The activation time constant of calcium spikes was 3.1 ± 0.1 ms, and the time constant of termination was 5.5 ± 0.2 ms. A negative correlation was observed between the observed amplitude of calcium spikes and their time constant of activation, but there was no correlation between their observed amplitude and time constant of termination, in agreement with the concept of steep calcium‐dependent activation and fateful inactivation of calcium release flux.
Enhanced macroscopic desensitization shapes the response of α4 subtype‐containing GABAA receptors to synaptic and extrasynaptic GABA
Authors: Lagrange Andre H. , Botzolakis Emmanuel J. , Macdonald Robert L.
Published: November 2006

Up‐regulation of the GABAA receptor α4 subunit subtype has been consistently shown in multiple animal models of chronic epilepsy. This isoform is expressed in both thalamus and hippocampus and is likely to play a significant role in regulating corticothalamic and hippocampal rhythms. However, little is known about its physiological properties, thus limiting understanding of the role of α4 subtype‐containing GABAA receptors in normal and abnormal physiology. We used rapid GABA application to recombinant GABAA receptors expressed in HEK293T cells to compare the macroscopic kinetic properties of α4β3γ2L receptors to those of the more widely distributed α1β3γ2L receptors. These receptor currents had similar peak current amplitudes and GABA EC50 values. However, α4β3γ2L currents activated more slowly when exposed to submaximal GABA concentrations, had more fast desensitization (τ= 15–100 ms), and had less residual current during long GABA applications. In addition, α4β3γ2L currents deactivated more slowly than α1β3γ2L currents. Peak currents evoked by repetitive, brief GABA applications were more strongly attenuated for α4β3γ2L currents than α1β3γ2L currents. Moreover, the time required to recover from desensitization was prolonged in α4β3γ2L currents compared to α1β3γ2L currents. We also found that exposure to prolonged low levels of GABA, similar to those that might be present in the extrasynaptic space, greatly suppressed the response of α4β3γ2L currents to higher concentrations of GABA, while α1β3γ2L currents were less affected by exposure to low levels of GABA. Taken together, these data suggest that α4β3γ2L receptors have unique kinetic properties that limit the range of GABA applications to which they can respond maximally. While similar to α1β3γ2L receptors in their ability to respond to brief and low frequency synaptic inputs, α4β3γ2L receptors are less efficacious when exposed to prolonged tonic GABA or during repetitive stimulation, as may occur during learning and seizures.
Response variability of marmoset parvocellular neurons
Authors: Victor J. D. , Blessing E. M. , Forte J. D. , Buzás P. , Martin P. R.
Published: November 2006

This study concerns the properties of neurons carrying signals for colour vision in primates. We investigated the variability of responses of individual parvocellular lateral geniculate neurons of dichromatic and trichromatic marmosets to drifting sinusoidal luminance and chromatic gratings. Response variability was quantified by the cycle‐to‐cycle variation in Fourier components of the response. Averaged across the population, the variability at low contrasts was greater than predicted by a Poisson process, and at high contrasts the responses were approximately 40% more variable than responses at low contrasts. The contrast‐dependent increase in variability was nevertheless below that expected from the increase in firing rate. Variability falls below the Poisson prediction at high contrast, and intrinsic variability of the spike train decreases as contrast increases. Thus, while deeply modulated responses in parvocellular cells have a larger absolute variability than weakly modulated ones, they have a more favourable signal: noise ratio than predicted by a Poisson process. Similar results were obtained from a small sample of magnocellular and koniocellular (‘blue‐on’) neurons. For parvocellular neurons with pronounced colour opponency, chromatic responses were, on average, less variable (10–15%, p < 0.01) than luminance responses of equal magnitude. Conversely, non‐opponent parvocellular neurons showed the opposite tendency. This is consistent with a supra‐additive noise source prior to combination of cone signals. In summary, though variability of parvocellular neurons is largely independent of the way in which they combine cone signals, the noise characteristics of retinal circuitry may augment specialization of parvocellular neurons to signal luminance or chromatic contrast.
Interactions between pairs of transcranial magnetic stimuli over the human left dorsal premotor cortex differ from those seen in primary motor cortex
Authors: Koch Giacomo , Franca Michele , Mochizuki Hitoshi , Marconi Barbara , Caltagirone Carlo , Rothwell John C.
Published: November 2006

A single TMS pulse (110% resting motor threshold, RMT) to the left dorsal premotor cortex (PMd) (CS2) suppresses the amplitude of motor evoked potentials (MEPs) from a test pulse (TS) over the right motor cortex (M1), and facilitates MEPs from the left motor cortex. We probed how this interaction was changed by a prior conditioning pulse over PMd (CS1) using a paired pulse TMS design. In the main experiments, the intensity of CS1 was 80% RMT. Basal suppression of right M1 was removed when CS1–CS2 was 1 ms or 5 ms with a similar tendency at 15 ms. Basal facilitation of left M1 was suppressed at CS1–CS2 of 5 ms. A similar time course was seen if CS2 was increased to 100% RMT, but there was no significant effect if CS1 was 70% RMT. Preconditioning PMd with continuous or intermittent theta burst repetitive TMS (cTBS, iTBS) abolished the basal CS2–TS interaction between premotor and motor cortices. Finally, if very short interstimulus intervals between CS1 and CS2 were explored to detect interactions similar to I‐wave facilitation in M1, we found that the basal suppression of right M1 was abolished at CS1–CS2 intervals of 1.8 and 2.8 ms. We suggest that paired pulse TMS may be capable of investigating properties of intrinsic circuits in PMd and that their properties differ from those in the nearby M1. Paired TMS may be a useful method of studying the excitability of intrinsic circuits in non‐primary areas of the motor system.
Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy
Authors: Alvarez Bernardo V. , Johnson Danielle E. , Sowah Daniel , Soliman Daniel , Light Peter E. , Xia Ying , Karmazyn Morris , Casey Joseph R.
Published: November 2006

Hypertrophic cardiomyocyte growth contributes substantially to the progression of heart failure. Activation of the plasma membrane Na+–H+ exchanger (NHE1) and Cl−–HCO3− exchanger (AE3) has emerged as a central point in the hypertrophic cascade. Both NHE1 and AE3 bind carbonic anhydrase (CA), which activates their transport flux, by providing H+ and HCO3−, their respective transport substrates. We examined the contribution of CA activity to the hypertrophic response of cultured neonatal and adult rodent cardiomyocytes. Phenylephrine (PE) increased cell size by 37 ± 2% and increased expression of the hypertrophic marker, atrial natriuretic factor mRNA, twofold in cultured neonatal rat cardiomyocytes. Cell size was also increased in adult cardiomyocytes subjected to angiotensin II or PE treatment. These effects were associated with increased expression of cytosolic CAII protein and the membrane‐anchored isoform, CAIV. The membrane‐permeant CA inhibitor, 6‐ethoxyzolamide (ETZ), both prevented and reversed PE‐induced hypertrophy in a concentration‐dependent manner in neonate cardiomyocytes (IC50= 18 μm). ETZ and the related CA inhibitor methazolamide prevented hypertrophy in adult cardiomyocytes. In addition, ETZ inhibited transport activity of NHE1 and the AE isoform, AE3, with respective EC50 values of 1.2 ± 0.3 μm and 2.7 ± 0.3 μm. PE significantly increased neonatal cardiomyocyte Ca2+ transient frequency from 0.33 ± 0.4 Hz to 0.77 ± 0.04 Hz following 24 h treatment; these Ca2+‐handling abnormalities were completely prevented by ETZ (0.28 ± 0.07 Hz). Our study demonstrates a novel role for CA in mediating the hypertrophic response of cardiac myocytes to PE and suggests that CA inhibition represents an effective therapeutic approach towards mitigation of the hypertrophic phenotype.
Formation of a Nematic Fluid at High Fields in Sr
3
Ru
2
O
7
Authors: Borzi R. A. , Grigera S. A. , Farrell J. , Perry R. S. , Lister S. J. S. , Lee S. L. , Tennant D. A. , Maeno Y. , Mackenzie A. P.
Published: November 2006

In principle, a complex assembly of strongly interacting electrons can self-organize into a wide variety of collective states, but relatively few such states have been identified in practice. We report that, in the close vicinity of a metamagnetic quantum critical point, high-purity strontium ruthenate Sr
3
Ru
2
O
7
possesses a large magnetoresistive anisotropy, consistent with the existence of an electronic nematic fluid. We discuss a striking phenomenological similarity between our observations and those made in high-purity two-dimensional electron fluids in gallium arsenide devices.