bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of the literature on HIV infection and schizophrenia: implications for research, policy and clinical practice
Authors: Gray Richard , Brewin Elizabeth , Noak James , Wyke‐Joseph Janelle , Sonik Babita
Published: March 2003

AIDS represents one of the major public health problems of the 21st century. Men having sex with men, injecting drug use and having multiple sexual partners are well‐established risk behaviours for transmitting the HIV virus. People with schizophrenia are more likely to engage in these behaviours than the general population and as a result there is an increased prevalence of HIV infection in this group. However, many contemporary mental health policy reports fail to discuss the risk of HIV/AIDS in people with schizophrenia, and there are few specific references to sexual health promotion in these documents. People with schizophrenia should be considered an at‐risk population for HIV infection and other sexually transmitted diseases. Psychiatric research, policy and clinical practice need to develop rapidly to address this important aspect of a major public health problem.
A 50‐Hz electromagnetic field impairs sleep
Authors: ÅKERSTEDT TORBJÖRN , ARNETZ BENGT , FICCA GIANLUCA , PAULSSON LARS‐ERIK , KALLNER ANDERS
Published: March 2003

In view of reports of health problems induced by low frequency (50–60Hz) electromagnetic fields (EMF), we carried out a study in 18 healthy subjects, comparing sleep with and without exposure to a 50Hz/1μTesla electrical field. We found that the EMF condition was associated with reduced: total sleep time (TST), sleep efficiency, stages 3+4 slow wave sleep (SWS), and slow wave activity (SWA). Circulating melatonin, growth hormone, prolactin, testosterone or cortisol were not affected. The results suggest that commonly occurring low frequency electromagnetic fields may interfere with sleep.
Effects of bilateral microinjections of ibotenic acid in the thalamic reticular nucleus on delta oscillations and sleep in freely‐moving rats
Authors: Marini G. , Ceccarelli P. , Mancia M.
Published: March 2003

The thalamic reticular nucleus (NRT) consists of a large pool of GABAergic neurons located on each side on the anterior, lateral, and ventral surfaces of the dorsal thalamus. The NRT is divided up into sectors. The aim of this study was to investigate the effects of bilateral lesions of the NRT on sleep and sleep oscillations. Only the results concerning delta oscillations will be reported here. As a first step we produced stereotaxically placed electrolytic lesions. The rats presented continuous circling behavior with electroencephalographic (EEG) theta and delta activity and subsequent sudden death. To avoid disruption of the bundles of fibers that pass through the NRT to and from the cerebral cortex, we used the excitotoxic ibotenic acid. Given its high toxicity, we concentrated on the rostral pole of the NRT, which is believed to have powerful effects on the synchronization of oscillatory activity during sleep. Immediately after surgery, the rats fell into a deep sleep during which there was an increase in EEG slow‐wave activity and no spindles. On postoperative day 2, corresponding to the destruction period, the sleep/wake cycle partially recovered, but NREM sleep was quantitatively diminished and showed abnormalities (increased latency to sleep onset, sleep fragmentation, gradual elimination of the delta rhythm). It is concluded that the rostral pole of the NRT contributes to normal and pathological EEG synchronization and the organization of sleep in rats.
Daytime variations in central nervous system activation measured by a pupillographic sleepiness test
Authors: Wilhelm Barbara , Giedke Henner , Lüdtke Holger , Bittner Evelyn , Hofmann Anna , Wilhelm Helmut
Published: March 2003

Pupil size is regulated exclusively by the autonomic nervous system, and in darkness is proportional to the level of central sympathetic tone. Spontaneous pupillary movements, while at rest in darkness and quiet, were recorded for a period of 11 min, using infrared video pupillography. Thirteen young adults took part in a 30‐h experiment lasting from 08.00 h to 14.00 h on the following day. Pupillographic testing and completion of a self‐rated scale for the estimate of sleepiness were repeated every two hours. Pupillary unrest index (PUI), as a measure of pupil size instability associated with daytime sleepiness, showed the lowest values at 09.00 h, when pupil size was found to be maximal, and 23.00 h. During the course of the day, amplitude spectrum ≤0.8 Hz and PUI showed increasing values during the afternoon hours, followed by a decrease during the evening. Daytime variations in the pupillary unrest index in healthy normal subjects were found to be positively correlated with the level of alertness. These findings are similar to the daytime variations found by the MSLT (multiple sleep latency test) in young adults.
A genetic analysis of the Epworth Sleepiness Scale in 1560 World War II male veteran twins in the NAS–NRC Twin Registry
Authors: Carmelli Dorit , Bliwise Donald L. , Swan Gary E. , Reed Terry
Published: March 2003

Responses to the eight‐item Epworth Sleepiness Scale (ESS) obtained from 1560 World War II male veteran twin pairs [818 monozygotic (MZ), 742 dizygotic (DZ)] were analysed to determine the extent to which genetic influences are involved in self‐reported daytime sleepiness in the elderly. Average ESS score (± SD) in this sample was 7.1 ± 3.9, range 0–24. More than half of the twins (65%–67%) reported a moderate to high chance of falling asleep while lying down to rest; fewer than 3% admitted that this would occur while sitting and talking to someone or while stopped in traffic. Daytime sleepiness was not associated with age but was significantly and positively associated with obesity. The intraclass twin correlation on ESS scores was 0.39 in MZ pairs and 0.21 in DZ pairs (both P < 0.001). Structural equation modeling of the observed variance–covariance matrices for MZ and DZ twins estimated the heritability of ESS to be 38% (95% confidence interval 33%–44%). Environmental influences not shared by twin brothers accounted for the remaining variance in daytime sleepiness. A reasonable interpretation of the heritability of ESS in this healthy cohort of elderly male twins is a genetic susceptibility for disordered breathing during sleep.
Is there a link between subjective daytime somnolence and sickness absenteeism? A study in a working population
Authors: Philip P. , Taillard J. , Niedhammer I. , Guilleminault C. , Bioulac B.
Published: March 2003

A number of studies have highlighted the increasing incidence and financial cost of sleep‐related disorders in the general population, but little research has been carried out on the impact of subjective daytime somnolence on health status. The existence of a survey of the health of employees of the French National Gas and Electricity Board has allowed us to investigate this question and measure the link between subjective daytime somnolence and sickness absenteeism, used here as a general health indicator. In order to evaluate the quality of sleep over the previous 3 months, a questionnaire was given to each participant. The association between subjective daytime somnolence and absence as a result of sickness was explored using the data of sickness absenteeism provided by the company’s social security department during a 12‐month follow‐up period. Of our 1105 subjects, 6.7% reported severe subjective daytime somnolence of 3 days or more a week and 30% of our study population had at least one spell of sickness absence during the 12‐month period of follow‐up. A strong association was observed between subjective daytime somnolence and sickness absence, which remained significant even after adjustment for potential confounding variables (age, sex, employment grade, sleep symptoms and self‐reported diseases). The odds‐ratio for absence as a result of sickness during the follow‐up period associated with subjective daytime somnolence of 3 days or more a week was 2.2 (95% CI: 1.3–3.8). Employees suffering from severe subjective daytime somnolence lose more working days for health reasons than their more alert colleagues. This may have long‐term implications for employees’ health.
Transient total sleep loss in cerebral Whipple's disease: a longitudinal study
Authors: Voderholzer Ulrich , Riemann Dieter , Gann Horst , Hornyak Magdolna , Juengling Freimut , Schumacher Martin , Reincke Martin , Von Herbay Axel , Nishino Seiji , Mignot Emmanuel , Berger Mathias , Lieb Klaus
Published: March 2003

A case with transient, almost complete sleep loss caused by cerebral manifestation of Whipple's disease (WD) is presented. Cerebral WD is rare and in most cases occurs after gastrointestinal infection. In our case, a progressive and finally almost complete sleep loss was the initial and predominant symptom. Polysomnographic studies in several consecutive nights and over 24 h showed a total abolition of the sleep–wake cycle with nocturnal sleep duration of less than 15 min. Endocrine tests revealed hypothalamic dysfunction with flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin. Cerebrospinal fluid (CSF) hypocretin was reduced. [18F]Deoxyglucose positron emission tomography (FDG‐PET) revealed hypermetabolic areas in cortical and subcortical areas including the brainstem, which might explain sleep pathology and vertical gaze palsy. In the course of treatment with antibiotics and additional carbamazepine for 1 year, insomnia slowly and gradually improved. Endocrine investigations at 1‐year follow‐up showed persistent flattening of circadian rhythmicity. The FDG‐PET indicated normalized metabolism in distinct regions of the brain stem which paralleled restoration of sleep length. The extent of sleep disruption in this case of organic insomnia was similar to cases of familial fatal insomnia, but was at least partially reversible with treatment.
The role of thromboxane A2 in regulating porcine basilar arterial tone
Authors: Miyamoto A. , Nakamoto T. , Matsuoka Y. , Ishiguro S. , Nishio A.
Published: March 2003

The aim of the present study was to clarify the participation of endogenous arachidonic acid (AA) metabolites in regulating porcine basilar, coronary, pulmonary and mesenteric arterial tones in vitro. A cyclooxygenase inhibitor, indomethacin, relaxed basilar artery but not other arteries examined. Quinacrine (a phospholipase A2 inhibitor), OKY‐046 (a thromboxane (TX) A2 synthetase inhibitor) and ONO‐3708 (a TXA2/prostaglandin H2 receptor antagonist) produced relaxation in basilar arteries with intact endothelium. Nordihydroguaiaretic acid (a lipoxygenase inhibitor) had no effect on the tone. The amount of TXB2 (a stable metabolite of TXA2) spontaneously released from porcine basilar arteries was 6–10 fold more than those from other arteries. Indomethacin and OKY‐046 mostly inhibited the production of TXB2. Endothelial denudation decreased indomethacin‐induced relaxation and the amount of TXB2. These results suggest that a vasoconstricting substance(s) is released from endothelial cells and possibly smooth muscle cells in porcine basilar arteries in vitro. The main constricting substance is proposed to be TXA2. On the other hand, several arteries from peripheral vascular beds did not release this vasoconstricting substance.
Mepivacaine: its pharmacological effects and their relationship to analytical findings in the horse
Authors: Harkins  , Karpiesiuk  , Woods  , Lehner  , Mundy  , Rees  , Dirikolu  , Bass  , Carter  , Boyles  , Tobin
Published: March 2003

Mepivacaine is a local anaesthetic drug that is widely used in equine medicine and is classified by the Association of Racing Commissioners International (ARCI) as a Class 2 foreign substance that may cause regulators to impose significant penalties if residues are identified in post‐race urine samples. Therefore, an analytical/pharmacological database was developed for this agent and its metabolites. Using an abaxial sesamoid local anaesthetic model, it was determined that the highest no‐effect dose (HNED) for its local anaesthetic effect was 2 mg. Using enzyme‐linked immunosorbent assay (ELISA) screening, it was determined that subcutaneous (s.c.) administration of the HNED of mepivacaine to eight horses yielded a peak urinary concentration of apparent mepivacaine of 63 ng/mL 2 h after injection.

The major identified metabolite recovered from equine urine after dosing with mepivacaine is 3‐hydroxymepivacaine. Therefore, 3‐hydroxymepivacaine was synthesized, purified and characterized, and a quantitative mass spectrometric method was developed for this metabolite as isolated from horse urine. Following subcutaneous injection of the HNED of mepivacaine, the concentration of 3‐hydroxymepivacaine recovered from horse urine reached a peak of about 64.6 ng/mL at 4 h after administration as measured by GC/MS.

The concentration of mepivacaine or its metabolites after administration of a HNED dose are detectable by mass spectral techniques. Within the limits of this research, the study suggests that recovery of concentrations less than about 65 ng/mL of 3‐hydroxymepivacaine from post‐race urine samples may not be associated with a recent LA effect of mepivacaine.
Molecular and pharmacological characterization of the canine brainstem alpha‐2A adrenergic receptor
Authors: Schwartz  , Jones  , Hedden  , Clark
Published: March 2003

This study characterizes the α2‐adrenergic receptors present in canine brainstem. Radioligand binding and reverse transcriptase‐polymerase chain reaction (RT‐PCR) experiments were performed in canine brainstem to identify the receptors present and determine the pharmacological properties of these receptors. The pKi values derived from radioligand competition curves for a number of adrenergic receptor agents at the four α2‐adrenergic receptor subtypes were compared to the canine brainstem. The pKi values at the canine brainstem α2‐adrenergic receptor were consistent with the presence of the α2A‐adrenergic receptor. To determine whether the canine brainstem expressed the message for the α2A‐adrenergic receptor, RT‐PCR was performed with specific primers for the four subtypes of α2‐adrenergic receptors. In the canine brainstem, only the primers corresponding to a region in the human α2A‐adrenergic receptor produced a PCR product. No bands were detected in the canine brainstem lanes with the α2B‐, α2C‐, or α2D‐receptor primers. These data suggest that the canine brainstem contains the α2A‐adrenergic receptor.
The impact of acute phase response on the plasma clearance of antipyrine, theophylline, phenytoin and nifedipine in rabbits
Authors: Saitoh T. , Kokue E. , Shimoda M.
Published: March 2003

The impact of acute phase response (APR) on the plasma clearances of antipyrine, theophylline, phenytoin and nifedipine was studied using 50 female rabbits. APR was induced by a bolus intramuscular injection of Escherichia coli lipopolysaccharide (LPS, 50 μg/kg). No abnormal findings, other than an increase in rectal body temperature and the plasma concentration of interleukin‐6 (IL‐6), were observed in the LPS‐treated animals. Twenty‐four hours after LPS injection, the pharmacokinetic parameters of the four drugs were obtained following intravenous administrations of antipyrine (7 mg/kg), theophylline (5 mg/kg), phenytoin (10 mg/kg) and nifedipine (1 mg/kg). Total body clearances of antipyrine, theophylline, phenytoin and nifedipine in LPS‐treated rabbits decreased, and terminal elimination half‐life and the mean residence time of these drugs increased compared with those in the control rabbits. The apparent volume of distribution for phenytoin and nifedipine increased after the LPS injection, although the binding percentage of the drugs with plasma protein did not change. These results suggested that APR appears to decrease the plasma clearances of these drugs in rabbits, which may be due to the suppression of the activity of cytochrome P450 enzymes.
Changes in serum thyroxine and thyroid‐stimulating hormone concentrations in epileptic dogs receiving phenobarbital for one year
Authors: GASKILL C.L. , BURTON S.A. , GELENS H.C.J. , IHLE S.L. , MILLER J.B. , SHAW D.H. , BRIMACOMBE M.B. , CRIBB A.E.
Published: March 2003

A multicentric prospective study was conducted to monitor the effect of phenobarbital on serum total thyroxine (T4) and thyroid‐stimulating hormone (TSH) concentrations in epileptic dogs. Serum T4 concentrations were determined for 22 epileptic dogs prior to initiation of phenobarbital therapy (time 0), and 3 weeks, 6 months, and 12 months after the start of phenobarbital. Median T4 concentration was significantly lower at 3 weeks and 6 months compared to time 0. Thirty‐two percent of dogs had T4 concentrations below the reference range at 6 and 12 months. Nineteen of the 22 dogs had serum TSH concentrations determined at all sampling times. A significant upward trend in median TSH concentration was found. No associations were found between T4 concentration, dose of phenobarbital, or serum phenobarbital concentration. No signs of overt hypothyroidism were evident in dogs with low T4, with one exception. TSH stimulation tests were performed on six of seven dogs with low T4 concentrations at 12 months, and all but one had normal responses.

In conclusion, phenobarbital therapy decreased serum T4 concentration but did not appear to cause clinical signs of hypothyroidism. Serum TSH concentrations and TSH stimulation tests suggest that the hypothalamic‐pituitary‐thyroid axis is functioning appropriately.
Absorption, tissue distribution and excretion of flumequine and oxolinic acid in corkwing wrasse (Symphodus melops) following a single intraperitoneal injection or bath treatment
Authors: Samuelsen O. B. , Ervik A.
Published: March 2003

The pharmacokinetic properties of the antibacterial agents oxolinic acid and flumequine were studied in corkwing wrasse (Symphodus melops) after either intraperitoneal injection or bath treatment. Following intraperitoneal administration the peak plasma concentrations (Cmax) and the time to peak plasma concentrations (Tmax) were estimated to be 2.0 μg/mL and 12 h, respectively, for oxolinic acid and 2.6 μg/mL and 12 h, respectively, for flumequine. In muscle, Cmax and Tmax were estimated to 6.7 μg/g and 12 h, respectively, for oxolinic acid with corresponding values of 8.5 μg/g and 13 h, respectively, for flumequine. In liver, Cmax and Tmax were calculated to 7.0 μg/g and 12 h, respectively, for oxolinic and 12.2 μg/g and 11 h, respectively, for flumequine. Elimination half‐lives (t1/2β) of 26, 24 and 29 h, respectively, for plasma, muscle and liver were calculated for flumequine. For oxolinic acid two distinct elimination phases were found and calculated to be 16 h (t1/2β) and 57 h (t1/2γ) in plasma, 15 and 59 h, respectively, in muscle and 20 and 72 h, respectively, in liver. Bath treatment using 150 mg/L of flumequine or 200 mg/L of oxolinic acid for 72 h resulted in flumequine concentrations of 1.0 μg/mL in plasma, 5.0 μg/g in muscle and 12.4 μg/g in liver. Corresponding values for oxolinic acid were 1.0 μg/g in plasma, 2.5 μg/g in muscle and 4.9 μg/g in liver.
The effect of soybean oil refuse powder used as vehicle on the absorption of oxolinic acid in chickens under fasting and nonfasting conditions and the correlation with in vitro dissolution
Authors: Hamamoto K. , Koike R. , Machida Y.
Published: March 2003

The effect of soybean oil refuse powder (SOR) when used as a vehicle on the absorption of oxolinic acid (OXA) powder in chicken, the dissolution profile of OXA and the correlation between in vivo and in vitro study were examined. To examine in vivo bioavailability, chickens fed or fasted were studied using a 2 × 2 crossover design. The OXA was administered OXA or OXA–SOR (1 : 9) mixture 20 mg OXA/kg. In vitro dissolution rates for OXA and OXA–SOR were measured using the paddle (PD) and the rotatory dialysis cell dissolution (PTSW) methods. Maximum plasma concentration (Cmax) and area under the curve (AUC) were significantly increased by the addition of SOR to OXA. Differences between OXA and OXA–SOR were more remarkable under fasted as compared with fed condition. In vitro dissolution rates of OXA–SOR pH 1.2, 6.5 and 7.2 as determined by the PD and the PTSW methods were increased in the presence of SOR vehicle. Differences between OXA and OXA–SOR in vitro dissolution rates were greater than in vivo bioavailability. Correlation between in vitro release (%) and in vivo absorption (%) showed good linearity (γ=0.8805–0.9999).
A pharmacokinetic study of amoxycillin in febrile beagle dogs following repeated administrations of endotoxin
Authors: Marier J.‐F. , Beaudry F. , Ducharme M. P. , Fortin D. , Moreau J.‐P. , Massé R. , Vachon P.
Published: March 2003

The pharmacokinetics of amoxycillin was studied in nine male beagle dogs under healthy and febrile conditions. In Period 1, dogs received 20 mg/kg of an oral suspension of amoxycillin. Intravenous doses of saline, 2 and 20 μg/kg of endotoxin (LPS from Escherichia coli serotype) were administered to dogs (three per group) prior to administration of 20 mg/kg of amoxycillin in Period 2. Rectal temperature and behavioral changes were recorded and blood samples were collected over 12 h for pharmacokinetic analysis. Amoxycillin was assessed in plasma using liquid chromatography coupled with mass spectrometry. Plasma concentrations were analysed using a one‐compartment model with lag‐time for absorption using an iterative two‐stage method. As compared with control groups, amoxycillin clearance decreased significantly with preliminary treatments of 2 μg/kg endotoxin (0.209 vs. 0.140 L/h kg, P < 0.05) and 20 μg/kg endotoxin (0.214 vs. 0.075 L/h kg, P < 0.05). As a result of this, the area under curve for the 2 and 20 μg/kg endotoxin groups increased significantly 100.4 vs. 149.4 μg h/mL (P < 0.05) and 99.2 vs. 277.7 μg h/mL (P < 0.05), respectively. Other drugs currently used for the treatment of fever and septic shock should be re‐evaluated using a febrile animal model to avoid improper dose administration.
Oxidative monensin metabolism and cytochrome P450 3A content and functions in liver microsomes from horses, pigs, broiler chicks, cattle and rats
Authors: Nebbia C. , Ceppa L. , Dacasto M. , Nachtmann C. , Carletti M.
Published: March 2003

The oxidative metabolism of monensin, an ionophore antibiotic extensively used in veterinary practice as a coccidiostat and a growth promoter, was studied in hepatic microsomal preparations from horses, pigs, broiler chicks, cattle and rats. As assayed by the measurement of the amount of the released formaldehyde, the rate of monensin O‐demethylation was nearly of the same order of magnitude in all species, but total monensin metabolism, which was estimated by measuring the rate of substrate disappearance by a high‐performance liquid chromatography (HPLC) method, was highest in cattle, intermediate in rats, chicks and pigs, and lowest in horses. When expressed as turnover number (nmol of metabolized monensin/min nmol cytochrome P450−1), the catalytic efficiency (chick ≫ cattle ≫ pig ≈ rat > horse) was found to correlate inversely with the well known interspecies differences in the susceptibility to the toxic effects of the ionophore, which is characterized by an oral LD50 of 2–3 mg/kg bodyweight (bw) in horses, 50–80 mg/kg bw in cattle and 200 mg/kg bw in chicks. Chick and cattle microsomes also displayed both the highest catalytic efficiency toward two P450 3A dependent substrates (erythromycin and triacetyloleandomycin) and the highest immunodetectable levels of proteins cross‐reacting with anti rat P450 3A1/2. Further studies are required to define the role played by this isoenzyme in the oxidative biotransformation of the drug in food producing species.
Comparative studies on Polyferm and Fermosorb, two oral (ferment + sorbent) – type preparations designed for therapy/prophylaxis of intestinal infections in animal neonates
Authors: Biziulevičius G. A. , Žukaitė V.
Published: March 2003

Polyferm and Fermosorb are oral acid resistant antimicrobial enzyme preparations designed specifically for therapy/prophylaxis of intestinal infections in animal neonates. Both are authorized for use throughout the former Soviet Union, but until now only Fermosorb is being applied on a large scale. The comparative studies on these two preparations, described in this paper, were carried out in order to find differences between the preparations. Characteristics that were compared included stability of the preparations in acidic environment as well as in storage (in vitro studies), and their efficacy for the treatment and prophylaxis of colibacillosis in newborn calves (in vivo studies). Results of in vitro studies revealed that proteolytic enzymes of Polyferm (as well as lytic enzymes of Fermosorb) were suitably (and in a very similar magnitude) protected from the influence of the acidic environment. The complete enzyme activity retention period in storage at room temperature of Polyferm and Fermosorb was equally high (5 years). In vivo studies performed on 2000 calves revealed that both preparations were highly effective and, although the efficacy of Polyferm was a bit lower than that of Fermosorb (93.6% vs. 95.0%, 94.6% vs. 95.8% for therapy and prophylaxis of colibacillosis, respectively), no statistically significant differences in the number of Polyferm vs. Fermosorb cured/protected animals were found. It is concluded that there were no reasons, other than the lack of supportive advertising materials, that might impede the utility of Polyferm.
Pharmacological characterization of α1‐adrenoceptor subtypes in the bovine tail artery
Authors: Ioudina M. V. , Dyer D. C.
Published: March 2003

Ioudina, M. V., Dyer, D. C. Pharmacological characterization of α1‐adrenoceptor subtypes in the bovine tail artery. J. vet. Pharmacol. Therap. 25, 363–369.

The purpose of this study was to identify the α1‐adrenoreceptor subtypes present in the bovine tail artery which mediate contractions to adrenergic agonists. A61603, an α1A‐selective agonist, was more potent compared with norepinephrine and phenylephrine. The pKA value of A61603 was 6.93 ± 0.19 μM (n=6). Antagonists, BMY 7378, WB 4101 and 5‐methylurapidil, caused a parallel shift to the right of the concentration–response curve to A61603 with pA2 values of 6.62, 9.27 and 8.86, respectively. Prazosin, BMY 7378 and WB 4101 inhibited phenylephrine induced contraction with pA2 values of 9.47, 7.17 and 9.73, respectively. The pA2 values obtained for 5‐methylurapidil, WB 4101, BMY 7378 and prazosin against α1‐adrenoceptor agonists were significantly correlated with pKi values (Zhu, Zhang & Han, 1997, Eur. J. Pharmacol.329, 55–61) for the cloned α1a‐adrenoceptor but not with the cloned α1b‐ or α1d‐adrenoceptor. BMY 7378, a selective α1D‐adrenoceptor antagonist, was significantly more potent against the nonsubtype selective agonist phenylephrine than to A61603. Chloroethylclonidine (50 μM for 10 min) did not affect contractile responses to A61603, but caused a significant inhibition of contractile responses to phenylephrine. In conclusion, it appears that α1A‐ and α1D‐adrenoceptors play a role in adrenergic mediated contraction in the bovine tail artery.
Composition of peripheral blood lymphocyte populations during different stages of chronic infection with hepatitis B virus
Authors: Sing G. , Butterworth L. , Chen X. , Bryant A. , Cooksley G.
Published: March 2003

To characterize the immunological populations associated with different stages of chronic infection with hepatitis B virus (HBV), we performed flow cytometric analyses on the peripheral blood leucocytes of 29 patients with various forms of chronic hepatitis B. The clinical spectrum of the patients ranged from asymptomatic infections, in the presence of high virus production, to intermittent or recurrent exacerbations of liver injury alternating with relatively normal liver function. Patients with partial resolution of disease who experienced an initial acute flare followed by prolonged seroconversion showed decreased percentages of CD3+ cells during the seroconversion phase when levels of serum alanine transferase (ALT) had normalized. These CD3+ cells were predominantly CD4+ cells bearing the αβ+ T‐cell receptor (TCR). In addition, we saw an increase in CD4+ and CD8+ cells bearing the γδTCR in those patients who had seroconverted. No significant differences were seen between any of the groups with respect to percentage of cells with a naive (CD45RA) or memory (CD45RO) phenotype, or of cells displaying the activation markers CD38, HLA‐DR or CD57. Longitudinal analyses of 15 patients failed to show any consistent pattern of changes in the immunophenotypic profile during acute flares and their resolution. Our results indicate that the turnover of circulating T lymphocytes during the apparent quiescent phase of chronic infections is higher than that during acute exacerbations, suggesting an active immunosurveillance role of T‐cell subpopulations in maintaining low virus levels during seroconversion.
Are all Type I human interferons equivalent?
Authors: Foster G. R. , Finter N. B.
Published: March 2003

The Type I interferons are a family of closely related cytokines that have antiviral and immunostimulatory properties. There has been prolonged debate regarding the different interferon‐α subtypes: with some authorities suggest that the different interferons have essentially similar properties but others argue that there are significant differences between them. Recent work has shown that the various interferon‐α subtypes can interact with the interferon receptor components in different ways and can activate a number of different signalling pathways. Recent studies on the immunomodulatory properties of the Type I interferons indicate that there are profound differences between the subtypes. The clinical significance of all these differences remains to be determined.
Incidence and clinical significance of hepatitis B virus precore gene translation initiation mutations in e antigen‐negative patients
Authors: Laras A. , Koskinas J. , Avgidis K. , Hadziyannis S. J.
Published: March 2003

Hepatitis Be antigen (HBeAg)‐negative chronic hepatitis B (CHB) is associated with hepatitis B virus (HBV) variants harbouring changes in the precore region. Most commonly, a G to A point mutation at nucleotide 1896 (m1896) creates a novel translation stop codon that prevents HBeAg production. In the Mediterranean region the m1896 mutation prevails in greater than 98% of HBeAg‐negative CHB patients. In this study the prevalence of additional mutations in the precore region was investigated among patients with chronic HBV infection. Precore sequences were determined by sequencing serum HBV DNA amplified by polymerase chain reaction (PCR) with primers flanking the precore/core region. Thirty‐one HBeAg‐negative and five HBeAg‐positive individuals were studied. All HBeAg‐negative patients (100%) harboured the m1896 mutation and 20 (64.5%) also had a G to A mutation at nucleotide 1899 (m1899). Additional mutations affecting the translation initiation of the precore gene were found in seven (22.5%) patients, all with active liver disease, five of whom had episodes of HBV reactivation. HBeAg‐positive patients had no mutations in these positions and neither did any of the five HBeAg‐negative patients with normal levels of liver enzymes, representing the healthy carrier state of HBV infection. Serial sample analysis from one patient revealed that the initiation codon mutation developed following HBeAg seroconversion and the appearance of m1896. During periods of high HBV replication, the ratio of mutant to wild‐type ATG was found to increase in parallel with HBV DNA levels. These data show that a significant proportion of HBeAg‐negative patients who already harbour the 1896 stop codon mutation may subsequently develop precore translation initiation mutations, which appear to be associated with enhanced HBV replication and severe liver disease.
Characterization of small hepatitis B surface antigen epitopes involved in binding to human annexin V
Authors: De Meyer S. , Depla E. , Maertens G. , Soumillion A. , Yap S. H.
Published: March 2003

Previously, we have shown that small hepatitis B surface antigen (SHBsAg) binds specifically to human annexin V (hAV) and that hAV plays a key role in the initial steps of hepatitis B virus (HBV) infection. We have also demonstrated the spontaneous development of anti‐idiotypic antibodies (antibodies to HBsAg Ab2) in rabbits immunized with hAV. As Ab2 is able to inhibit the binding of hAV to SHBsAg, Ab2 might contain epitope(s) mimicking a region of hAV for binding to SHBsAg. Identification of this epitope will therefore reveal a SHBsAg sequence involved in hAV binding. Using a panel of synthetic peptides covering the region of SHBsAg located on the outer surface of the virus, binding studies showed that the region incorporating amino acids (aa) 125–131 of SHBsAg is important for binding to Ab2 and consequently also for binding to hAV. Further experiments revealed that not only this region, but also the region incorporating aa 158–169, is involved in the binding of SHBsAg to hAV. As these regions are located in the structural vicinity according to the topological model of HBsAg proposed by Chen et al., our findings suggest that these regions are parts of a conformational epitope of SHBsAg for binding to hAV. Because of the crucial role of hAV in HBV infection, further studies on the HBsAg epitopes for hAV binding may lead to the development of a new generation of vaccines or molecules for prevention and for treatment of patients with chronic hepatitis B.
Hepatitis C viral quasispecies
Authors: GÃ³mez J. , Martell M. , Quer J. , Cabot B. , Esteban J. I.
Published: March 2003

Analysing significant numbers of cDNA clones of the hepatitis C virus (HCV) from single isolates provides unquestionable proof that the viral genome cannot be defined by a single sequence, but rather by a population of variant sequences closely related to one another. This way of organizing the genetic information is referred to as quasispecies. Throughout HCV infection, the number and composition of the variants in the viral population keeps changing owing to environmental influences, resulting in a virus that is constantly redefining itself both genetically and phenotypically. Therefore, the virus has often been investigated in population terms. Many clinical studies have tried to unravel, through the parameters that characterize the HCV quasispecies, prognostic markers of the disease and its response to treatment. Other investigations have focused on discovering how the virus and host interact during chronic infection. The consensus sequence, the rate of fixation of mutations and the complexity of the viral population are useful parameters for describing the viral population behaviour and its interaction with the host. In addition to sequencing, several other methods, based on electrophoretic mobility, have been used to study these parameters, such as temperature gradient‐gel electrophoresis, single‐strand conformation polymorphism and gel‐shift analysis. The viral region examined, the source of clinical specimen, as well as the methodology employed, will be decisive in interpreting the information obtained.
Hepatitis B surface antigen variants in vaccinees, blood donors and an interferon‐treated patient
Authors: Seddigh‐Tonekaboni S. , Lim W. L. , Young B. , Hou J.‐L. , Waters J. , Luo K.‐X. , Thomas H. C. , Karayiannis P.
Published: March 2003

Variants of hepatitis B virus (HBV), with amino acid substitutions in the major antigenic ‘a’ determinant of hepatitis B surface antigen (HBsAg), have been described mainly in vaccinated children. In the present study in addition to vaccinated children, we have investigated Chinese blood donors positive for anti‐HBc alone, and a patient with continuing liver disease after interferon‐induced seroconversion to anti‐HBs. Variants were detected in two of four children with break‐through infections. One child had a double mutation (P142S and G145R) and the other a G145A substitution. Three of seven anti‐HBc positive Chinese blood donors had a T131I substitution, whilst the interferon‐treated patient had a treble amino acid substitution (P142S, G145R and N146D). The present results indicate that HBsAg variants may exist in individuals other than vaccinated children.
Viral hepatitis and primates: historical and molecular analysis of human and nonhuman primate hepatitis A, B, and the GB‐related viruses
Authors: Robertson Betty H.
Published: March 2003

The hepatitis viruses have long been assumed to be highly host‐specific, with infection of other nonhuman primates occurring due to inoculation with, or exposure to, human viruses. This paradigm has slowly changed over the last 10 years, as mounting data has revealed nonhuman primate equivalents of hepatitis A virus, hepatitis B virus, and the hepatitis C‐related viruses GBV‐C and GBV‐A. This review summarizes the historical and molecular information for each of these groups and highlights the impact of these nonhuman primate hepatitis viruses on our understanding of the evolution of each of these viruses.
Expression of the hepatitis C virus structural proteins in mammalian cells induces morphology similar to that in natural infection
Authors: Greive S. J. , Webb R. I. , Mackenzie J. M. , Gowans E. J.
Published: March 2003

Like many positive‐strand RNA viruses, replication of the hepatitis C virus (HCV) is associated with cytoplasmic membrane rearrangements. However, it is unclear which HCV proteins induce these ultrastructural features. This work examined the morphological changes induced by expression of the HCV structural proteins, core, E1 and E2, expressed from a Semliki Forest Virus (SFV) recombinant RNA replicon. Electron microscopy of cells expressing these proteins showed cytoplasmic vacuoles containing membranous and electron‐dense material that were distinct from the type I cytoplasmic vacuoles induced during SFV replicon replication. Immunogold labelling showed that the core and E2 proteins localized to the external and internal membranes of these vacuoles, but at times were also associated with some of the internal amorphous material. Dual immunogold labelling with antibodies raised against the core protein and against an endoplasmic reticulum (ER)‐resident protein (protein disulphide isomerase) showed that the HCV‐induced vacuoles were associated with ER‐labelled membranes. This report has identified an association between the HCV core and E2 proteins with induced cytoplasmic vacuoles which are morphologically similar to those observed in HCV‐infected liver tissue, suggesting that the HCV structural proteins may be responsible for the induction of these vacuoles during HCV replication in vivo.
Antiviral treatment responses in patients with chronic hepatitis C virus infection evaluated by a third generation anti‐hepatitis C virus assay
Authors: Tung H.‐D. , Lu S.‐N. , Lee C.‐M. , Wang J.‐H. , Chen T.‐M. , Hung C.‐H. , Huang W.‐S. , Changchien C.‐S.
Published: March 2003

summary. Antibodies to hepatitis C virus (HCV) may decrease or disappear after viral clearance in treated or spontaneously resolved infection. We evaluated the usefulness of serial antibody assays in predicting the antiviral treatment responses. One hundred and four chronic hepatitis C patients who received 24 weeks of interferon and ribavirin combination therapy were assayed with a third generation enzyme immunoassay anti‐HCV. The mean titre of anti‐HCV decreased by more than 50% (from 89.5 ± 10.8 to 43.6 ± 17.5) at 48 weeks post‐treatment in patients with a sustained virological response, while in nonsustained virological responders and nonresponders, the titres remained over 85% of the pretreatment level at 48 weeks post‐treatment. There was a divergence of anti‐HCV titres between sustained and nonsustained virological responders during 6–9 months. By using the ratio of 9‐month to 6‐month titres as an index and receiver operator characteristic curve analysis with the cut‐off point set at 90%, we could differentiate sustained virological responders from nonsustained virological responders with a sensitivity and specificity of 91.7% and 90.9%, respectively, 3 months after treatment. The titre of this third generation anti‐HCV decreased progressively in sustained virological responders and this assay may be used to monitor and predict antiviral treatment responses.
The rate of fibrosis progression is an independent predictor of the response to antiviral therapy in chronic hepatitis C
Authors: Myers R. P. , Patel K. , Pianko S. , Poynard T. , McHutchison J. G.
Published: March 2003

summary. The response to antiviral therapy and the rate of fibrosis progression in chronic hepatitis C virus (HCV) infection are related to common factors, including age and gender. The aim of this study was to evaluate the relationship between the rate of fibrosis progression and the sustained virologic response (SVR) to interferon (IFN)‐based treatment. A total of 332 patients treated for chronic HCV infection were evaluated. Using multivariate logistic regression analysis, the impact of the rate of fibrosis progression (defined as the stage of liver fibrosis according to the Metavir system/duration of infection) on the rate of SVR (negative HCV RNA at least 6 months following the end of treatment), was determined. The median age of the patients was 44 (range 25–77) years, 64% were male, and 66% were infected with genotypes 1, 4, 5 or 6. The median rate of fibrosis progression was 0.083 (range 0–2) Metavir units/year; 158 patients (48%) had F2–F4 fibrosis. After a median of 48 (range 2–126) weeks of therapy (IFN, n=190; IFN and ribavirin, n=96; pegylated IFN, n=20; pegylated IFN and ribavirin, n=26), 93 patients (28%) achieved an SVR. In univariate analysis, the rate of SVR was higher in slow [< 0.083 Metavir units/year (n=162)] than rapid progressors [≥ 0.083 Metavir units/year (n=170)] (35%vs 22%, P=0.01). After controlling for age, gender, genotype, viral load, and treatment regimen and duration, the rate of fibrosis progression remained an independent predictor of SVR (slow vs rapid progressors, OR 2.74; 95% CI 1.27–5.92; P=0.01). Hence the rate of fibrosis progression is an independent predictor of SVR to IFN‐based therapy in patients with chronic hepatitis C. This additional factor should be considered in economic models evaluating this condition.
A review of the status and decline in abundance of the Irish Hare (Lepus timidus hibernicus) in Northern Ireland
Authors: Dingerkus S. K. , Montgomery W. I.
Published: March 2003

The Northern Ireland Hare Survey documented the distribution of the Irish Hare (Lepus timidus hibernicus). Historical game bag records and other, more contemporary,

records of hare distribution were examined. These data indicate how numbers of L.

t. hibernicus may have changed over the last 140 years. The results of the Northern

Ireland Hare Survey suggested that L. t. hibernicus was widespread throughout

Northern Ireland. Current average densities are no more than 0.65 hares/km2.

Game bag records indicate that hare densities may have been much higher in the past,

with a maximum of 138 hares/km2 recorded on Crom Estate, Co. Fermanagh,

in 1864. Evidence from hare distribution recorded during the Northern Ireland Rabbit

Survey indicates that hare numbers declined between 1984 and 1994. Evidence from

all sources suggests that L. t. hibernicus has declined in abundance substantially,

with present total population estimates for Northern Ireland ranging from 8250 to

21 000 individuals. Flushing data indicate that rushes and hedgerows are important

diurnal resting areas for hares. While the principal reason for the decline in numbers

of L. t. hibernicus in Northern Ireland is not clear, more species‐rich pasture and provision of areas of cover, such as rushes, may arrest further declines, or indeed promote numbers of hares, particularly in lowland areas.
Age structure of overwintered face fly populations estimated by pteridine concentrations and ovarian dynamics
Authors: Krafsur E. S. , Rosales A. L. , Kim Y.
Published: March 2003

Abstract.Pteridines in the head capsules of face flies, Musca autumnalis DeGeer, were measured spectrofluorometrically to provide estimates of age. The flies also were dissected to determine ovarian development and fat body hypertrophy. Physiological ages in terms of degree‐day accumulations were estimated among late autumn, winter, and early spring face flies. The reproductive history of eight overwintered face fly populations near Ames, Iowa, U.S.A., suggested that each had behaved as a single cohort, maturing their eggs and ovipositing according to a simple heat unit model. 83.8 ± 16.4 degree‐days above a 12° threshold (DD > 12°) were estimated to elapse between 1 January and the date at which 50% of overwintered cohorts had oviposited. Pteridine deposits indicated that diapausing females in late autumn had acquired a mean 96 ± 36 DD > 9.8° and the males 135 ± 39 DD > 9.8°. Soon after emergence from hibernaculae, females were average physiological ages of 135 ± 25 DD > 9.8° and the males were 152 ± 28 DD > 9.8°. Mean physiological age of overwintered females was 155 ± 37 DD > 9.8° compared with 110 ± 38 DD > 9.8° among parous flies in summer. Overwintered males in spring were an average 175 ± 41 DD > 9.8° compared with 144 ± 65 DD > 9.8° among summer flies.
Associations of Phlebotomus orientalis and other sandflies with vegetation types in the eastern Sudan focus of kala‐azar
Authors: Elnaiem D. A. , Hassan H. K. , Ward R. D.
Published: March 2003

Abundances of Phlebotomus orientalis, P. papatasi (Diptera: Psychodidae) and other sandflies were investigated in relation to different types of vegetation associated with endemic foci of visceral leishmaniasis (kala‐azar) in eastern Sudan. Sandfly collection sites were in Umsalala Village (Galabat Province) and Dinder National Park (Dinder Province). Sandfly species found in the area were P. orientalis, P. papatasi, Sergentomyia africana, S. antennata, S. clydei, S. schwetzi and S. squamipleuris. Among the types of trees in the Dinder area, P. orientalis was more abundant in forests dominated by Acacia seyal than where Combretum kordofanum, Balanites aegyptiaca, Hyphaena thaibaica or Ziziphus spinachristi were the dominant trees. At Umsalala, P. papatasi was more abundant in the village than at any site with dense vegetation, but P. orientalis was uncommon. Sergentomyia spp. were distributed fairly evenly amongst most types of vegetation investigated at both localities. The ecological distribution of sandflies and epidemiology of kala‐azar in Sudan are discussed with emphasis on the association of P. orientalis with A. seyal woodlands.
Evolution and structural organisation of mitochondrial DNA control region of myiasis‐causing flies
Authors: Lessinger A. C. , Azeredo‐Espin A. M. L.
Published: March 2003

This study reports the molecular characterization of the mtDNA control region (called the A + T‐rich region in insects) of five dipteran species which cause myiasis: Cochliomyia hominivorax Coquerel, Cochliomyia macellaria Fabricius, Chrysomya megacephala Fabricius, Lucilia eximia Wiedemann (Diptera: Calliphoridae) and Dermatobia hominis Linnaeus Jr (Diptera: Oestridae). The control region in these species varies in length from 1000 to 1600 bp. Two structural domains with specific evolutionary patterns were identified. These were (1) conserved sequence blocks containing primary sequence motifs, including dinucleotide pyrimidine‐purine series and long T‐stretches, located at the 5′ end adjacent to the tRNAIle gene and (2) a hypervariable domain at the 3′ end characterized by increased nucleotide divergence and size variation. A high frequency of A↔T transversions at nucleotide substitution level indicated directional mutation pressure. The phylogenetic usefulness of the insect control region is discussed.