The murine cytomegalovirus chemokine homolog, m131/129, is a determinant of viral pathogenicity

Chemokines are important mediators of the early inflammatory response to infection and modify a wide range of host immune responses. Functional homologs of cellular chemokines have been identified in a number of herpesviruses, suggesting that the subversion of the host chemokine response contributes to the pathogenesis of these viruses. Transcriptional and reverse transcription-PCR analyses demonstrated that the murine cytomegalovirus (MCMV) chemokine homolog, m131, was spliced at the 3' end to the adjacent downstream open reading frame, m129, resulting in a predicted product of 31 kDa, which is significantly larger than most known chemokines. The in vivo impact of m131/129 was investigated by comparing the replication of MCMV mutants having m131/129 deleted (Delta m131/129) with that of wild-type (wt) MCMV. Our studies demonstrate that both wt and Delta m131/129 viruses replicated to equivalent levels during the first 2 to 3 days following in vivo infection. However, histological studies demonstrated that the early inflammatory response elicited by Delta m131/129 was reduced compared with that of wt MCMV. Furthermore, the Delta m131/129 mutants failed to establish a high-titer infection in the salivary glands, These results suggest that m131/129 possesses proinflammatory properties in vivo and is important for the dissemination of MCMV to or infection of the salivary gland. Notably, the Delta m131/129 mutants were cleared more rapidly from the spleen and liver during acute infection compared with wt MCMV. The accelerated clearance of the mutants was dependent on NK cells and cells of the CD4(+) CD8(+) phenotype. These data suggest that m131/129 may also contribute to virus mechanisms of immune system evasion during early infection, possibly through the interference of NK cells and T cells.

Stalagmite evidence for the onset of the Last Interglacial in southern Europe at 129+/- 1 ka

Multi-proxy data from an Italian stalagmite constrain the commencement of full Last Interglacial conditions in southern Europe at 129 +/- 1 ka, consistent with absolutely dated records currently available from both hemispheres. The post-glacial transition towards warmer and wetter conditions commenced at 134 +/- 2 ka. Oxygen isotope evidence suggests this was interrupted briefly at 130 +/- 2 ka, an event probably related to the 'Termination II pause' associated with Heinrich Event 11. For most of the stalagmite, the pattern of delta(18)O variation mimics the air temperature record from the Vostok ice core, especially through marine isotope stage 5. There is no obvious evidence for substantial 'early interglacial' warming.

Long-term disability after first-ever stroke and related prognostic factors in the Perth Community Stroke Study, 1989-1990

Background and Purpose-Few reliable estimates of the long-term functional outcome after stroke are available. This population-based study aimed to describe disability, dependency, and related independent prognostic factors at 5 years after,a first-ever stroke in patients in Perth, Western Australia. Methods-All individuals with a suspected acute stroke who were resident in a geographically defined region (population, 138 708) of Perth, Western Australia, were registered prospectively and assessed according to standardized diagnostic criteria over a period of 18 months in 1989 to 1990. Patients were followed up prospectively at 4 and 12 months and 5 years after the index event. Results-There were 370 cases of first-ever stroke, and 277 patients survived to 30 days. Of these early survivors, 152 (55%) were alive at 5 years, and among those who were neither institutionalized (n=146) nor disabled (n=129) at the time of their stroke, 21 (14%) were institutionalized in a nursing home, and 47 (36%) were disabled. The most important predictors of death or disability at 5 years were increasing age, baseline disability defined by a Barthel Index score of <20/20 (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.7 to 14), moderate hemiparesis (OR, 2.7. 95% CI, 1.1 to 6.2), severe hemiparesis (OR, 4.5; 95% CI, 1.1 to 19), and recurrent stroke (OR, 9.4; 95% CI, 3.0 to 30). A low level of activity before the stroke was a significant predictor of institutionalization, and subsequent recurrent stroke was a consistent, independent predictor of institutionalization, disability, and death or institutionalization, increasing the odds of each of these 3 adverse outcomes by 5- to 15-fold. Conclusions-Among 30-day survivors of first-ever stroke, about half survive 5 years; of survivors, one third remain disabled, and I in 7 are in permanent institutional care. The major modifiable predictors of poor long-term outcome are a low level of activity before the stroke and subsequent recurrent stroke. Efforts to increase physical activity among the elderly and to prevent recurrent stroke in survivors of a first stroke are likely to reduce the long-term burden of cerebrovascular disease.

Program sustainability of a community-based intervention to prevent falls among older Australians

Multi-strategy interventions have been demonstrated to prevent falls among older people, but studies have not explored their sustainability. This paper investigates program sustainability of Stay on Your Feet (SOYF), an Australian multi-strategy falls prevention program (1992-1996) that achieved a significant reduction in falls-related hospital admissions. A series of surveys assessed recall, involvement and current falls prevention activities, 5 years post-SOYF in multiple original SOYF stakeholder groups within the study area [general practitioners (GPs), pharmacists, community health (CH) staff shire councils (SCs) and access committees (ACs)]. Focus groups explored possible behavioural changes in the target group. Surveys were mailed, except to CH staff and ACs. who participated in guided group sessions and were contacted via the telephone, respectively. Response rates were: GPs. 67% (139/209); pharmacists, 79% (53/67); CH staff, 63% (129/204); SCs, 90% (9/10); ACs, 80% (8/10). There were 73 older people in eight focus groups. Of 117 GPs who were practising during SOYF 80% recalled SOYF and 74% of these reported an influence on their practice. Of 46 pharmacists operating a business during SOYF, 45% had heard of SOYF and 79% of these reported being 'somewhat' influenced. Of 76 community health staff (59%) in the area at that time, 99% had heard of SOYF and 82% reported involvement. Four SCs retained a SOYF resource, but none thought current activities were related. Seven ACs reported involvement, but no activities were sustained. Thirty-five focus group participants (48%) remembered SOYF and reported a variety of SOYF-initiated behaviour changes. Program sustainability was clearly demonstrated among health practitioners. Further research is required to assess long-term effect sustainability.

Promoting physical activity to older adults: a preliminary evaluation of three general practice-based strategies

The aim of this study was to explore the feasibility of an exercise scientist (ES) working in general practice to promote physical activity (PA) to 55 to 70 year old adults. Participants were randomised into one of three groups: either brief verbal and written advice from a general practitioner (GP) (G1, N=9); or individualised counselling and follow-up telephone calls from an ES, either with (G3, N=8) or without a pedometer (G2, N=11). PA levels were assessed at week 1, after the 12-wk intervention and again at 24 weeks. After the 12-wk intervention, the average increase in PA was 116 (SD=237) min/wk; N=28, p < 0.001. Although there were no statistically significant between-group differences, the average increases in PA among G2 and G3 participants were 195 (SD=207) and 138 (SD=315) min/wk respectively, compared with no change (0.36, SD=157) in G1. After 24 weeks, average PA levels remained 56 (SD=129) min/wk higher than in week 1. The small numbers of participants in this feasibility study limit the power to detect significant differences between groups, but it would appear that individualised counselling and follow-up contact from an ES, with or without a pedometer, can result in substantial changes in PA levels. A larger study is now planned to confirm these findings.

Timing and duration of the last interglacial inferred from high resolution U-series chronology of stalagmite growth in Southern Hemisphere

High-precision Th-230-U-238 ages for a stalagmite from Newdegate Cave in southern Tasmania, Australia define a rare record of precipitation between 100 and 155 ka before the present. The fastest stalagmite growth occurred between 129.2 +/- 1.6 and 122.1 +/- 2.0 ka (similar to 61.5 mm/ka), coinciding with a time of prolific coral growth from Western Australia (128-122 ka). This is the first high-resolution continental record in the Southern Hemisphere that can be compared and correlated with the marine record. Such correlation shows that in southern Australia the onset of full interglacial sea level and the initiation of highest precipitation on land were synchronous. The stalagmite growth rate between 129.2 and 142.2 ka (similar to 5.9 mm/ka) was lower than that between 142.2 and 154.5 ka (similar to 18.7 mm/ka), implying drier conditions during the Penultimate Deglaciation, despite rising temperature and sea level. This asymmetrical precipitation pattern is caused by latitudinal movement of subtropical highs and an associated Westerly circulation, in response to a changing Equator-to-Pole temperature gradient. Both marine and continental records in Australia strongly suggest that the insolation maximum between 126 and 128 ka at 65 degreesN was directly responsible for the maintenance of full Last Interglacial conditions, although the triggers that initiated Penultimate Deglaciation (at similar to 142 ka) remain unsolved. (C) 2001 Elsevier Science B.V. All rights reserved.

Solid-state NMR structure determination of melittin in a lipid environment

Solid-state C-13 NMR spectroscopy was used to investigate the three-dimensional structure of melittin as lyophilized powder and in ditetradecylphosphatidylcholine (DTPC) membranes. The distance between specifically labeled carbons in analogs [1-C-13]Gly3-[2-C-13]Ala4, [1-C-13]Gly3-[2-C-13]Leu6, [1-C-13]Leu13-[2-C-13]Ala15, [2-C-13]Leu13-[1-C-13]Ala15, and [1-C-13]Leu13-[2-C-13]Leu16 was measured by rotational resonance. As expected, the internuclear distances measured in [1-C-13]Gly3-[2-C-13]Ala4 and [1-C-13]Gly3-[2-C-13]Leu6 were consistent with alpha -helical structure in the N-terminus irrespective of environment. The Internuclear distances measured in [1-C-13]Leu13-[2-C-13]Ala15, [2-C-13]Leu13-[1-C-13]Ala15, and [1-C-13]Leu13-[2-C-13]Leu16 revealed, via molecular modeling, some dependence upon environment for conformation in the region of the bend in helical structure induced by Pro14. A slightly larger interhelical angle between the N- and C-terminal helices was indicated for peptide in dry or hydrated gel state DTPC (139 degrees -145 degrees) than in lyophilized powder (121 degrees -139 degrees) or crystals (129 degrees). The angle, however, is not as great as deduced for melittin in aligned bilayers of DTPC in the liquid-crystalline state (similar to 160 degrees) (R. Smith, F. Separovic, T. J. Milne, A. Whittaker, F. M. Bennett, B. A. Cornell, and A. Makriyannis, 1994, J. Mol, Biol 241:456-466). The study illustrates the utility of rotational resonance in determining local structure within peptide-lipid complexes.

Population pharmacokinetics of lamotrigine

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided spare data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (TM) (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

Shoot control of hypernodulation and aberrant root formation in the har1-1 mutant of Lotus japonicus

The har1-1 mutant of Lotus japonicus B-129-S9 Gifu is characterized by two phenotypes: greater than normal nodulation (hypernodulation) and significantly inhibited root growth in the presence of its microsymbiont Mesorhizobium loti strain NZP2235. We demonstrate that the two traits co-segregate, suggesting a single genetic alteration involving developmental pleiotropy. A cross between the mutant and genotype Funakura (with wild-type root and nodule morphology) demonstrated Mendelian recessive segregation of both phenotypes (root and nodule) in 216 F2 individuals. Using DNA-amplification fingerprinting polymorphisms in Gifu har1-1 and Funakura, the mutant locus was positioned between two markers at about 7 and 13 cM distance. Reciprocal hypocotyl grafting of shoots and roots showed that the hypernodulation and reduced root phenotypes are both predominantly controlled by the shoot.

Longitudinal study of veterinarians from entry to the veterinary course to ten years after graduation: career paths

Objective To map out the career paths of veterinarians during their first 10 years after graduation, and to determine if this could have been predicted at entry to the veterinary course. Design Longitudinal study of students who started their course at The University of Queensland in 1985 and 1986, and who completed questionnaires in their first and fifth year as students, and in their second, sixth and eleventh year as veterinarians. Methods Data from 129 (96%) questionnaires completed during the eleventh year after graduation were coded numerically then analysed, together with data from previous questionnaires, with SAS System 7 for Windows 95. Results Ten years after they graduated, 80% were doing veterinary work, 60% were in private practice, 40% in small animal practice and 18% in mixed practice. The equivalent of 25% of the working time of all females was taken up by family duties. When part-time work was taken into account, veterinary work constituted the equivalent of 66% of the group working full-time. That 66% consisted of 52% on small animals, 7% on horses, 6% on cattle/sheep and 1% on pigs/poultry. Those who had grown up on farms with animals were twice as likely to be working with farm animals as were those from other backgrounds. Forecasts made on entry to the veterinary course were of no value in predicting who would remain in mixed practice. Conclusions Fewer than one-fifth of graduates were in mixed practice after 10 years, but the number was higher for those who grew up on farms with animals. Forecasts that may be made at interview before entry to the course were of little value in predicting the likelihood of remaining in mixed veterinary practice.

Longitudinal study of veterinarians from entry to the veterinary course to 10 years after graduation: attitudes to work, career and profession

Objective To describe the attitudes of veterinarians to their work, career and profession during the 10 years after graduation. Design Longitudinal study of students who started their course at The University of Queensland in 1985 and 1986, and who completed questionnaires in their first and fifth year as students, and after one, five and 10 years as veterinarians. Methods Data from 129 (96%) questionnaires completed after 10 years as a veterinarian were coded numerically then analysed, together with data from previous questionnaires, with SAS System 7 for Windows 95. Results After 10 years, almost all respondents were either very glad they had done the veterinary course (57%) or generally glad, though with some misgivings (37%). Despite this, only 55% would definitely become a veterinarian if they 'had to do it over again'. The responses for about one-third were different from those given five years earlier. The views of many were related to the level of support and encouragement received in their first job after graduation. There were 42% who were working less than half-time as veterinarians, and their main reasons were, in order, raising children, long hours of work, attitudes of bosses and clients, and poor pay. A majority was concerned about the ethics and competence of some colleagues, and almost all believed that consideration of costs must influence the type of treatment animals receive. Conclusions Most veterinarians were glad to have done the veterinary course, but for about one-quarter their career had not lived up to expectations and almost half would not do it again in another incarnation. Stress, hours of work, difficulties in balancing personal life with career and low income were important concerns for many. Low income may contribute to the low number of males entering the veterinary profession.

A randomised controlled trial of methadone maintenance treatment versus wait list control in an Australian prison system

Objectives: The aim was to determine whether methadone maintenance treatment reduced heroin use, syringe sharing and HIV or hepatitis C incidence among prisoners. Methods: All eligible prisoners seeking drug treatment were randomised to methadone or a waitlist control group from 1997 to 1998 and followed up after 4 months. Heroin use was measured by hair analysis and self report; drugs used and injected and syringe sharing were measured by self report. Hepatitis C and HIV incidence was measured by serology. Results: Of 593 eligible prisoners, 382 (64%) were randomised to MMT (n = 191) or control (n = 191). 129 treated and 124 control subjects were followed up at 5 months. Heroin use was significantly lower among treated than control subjects at follow up. Treated subjects reported lower levels of drug injection and syringe sharing at follow up. There was no difference in HIV or hepatitis C incidence. Conclusions: Consideration should be given to the introduction of prison methadone programs particular where community based programs exist. (C) 2003 Elsevier Ireland Ltd. All rights reserved.