Understanding and reducing work-related psychological distress in interns: a systematic review.

The aim of this study was to collate and evaluate studies investigating either the factors influencing work-related psychological distress in postgraduate year one (PGY1) doctors or the strategies designed to reduce it. This is a systematic review conducted in May 2014. The data sources were key databases (MEDLINE, PsycINFO and Embase) and manual searches of reference lists for relevant studies published in the last 15 years. This study is an empirical research designed either to elucidate the factors influencing work-related psychological distress in PGY1 doctors, or examine the effects of an intervention designed to reduce it. Key information was extracted into an electronic data extraction form, which incorporated elements of Murphy's model of work stress factors. A total of 21 studies was included in the review; 16 studies had examined the factors influencing work-related psychological distress, four studies had investigated strategies to reduce it, and a single study addressed both. Analysis of the findings of each individual study through the conceptual framework provided by Murphy's model revealed a discrepancy between the factors influencing work-related psychological distress and the focus of strategies designed to reduce it. Factors such as career progression and a PGY1 doctor's role within the organisation were not addressed in the interventions identified. Significant sources of psychological distress in PGY1 doctors remain overlooked by current interventions. Strategies designed to prevent or reduce psychological distress should be broad-based and grounded in both the literature exploring salient factors and existing theories of work-related stress.

Alignment: a conceptual shift from adherence.

Developing a treatment plan with a patient is one of the cornerstones of clinical medicine. The current concept of adherence, a conceptual shift away from the notion of compliance, connotes an agreement to and implementation of a plan. There are, however, myriad causes that can impinge on whether or not a treatment plan is followed through. The current clinical usage of the word 'adherence' tends to focus on the ultimate behaviour of the patient, and as such the factors acting on the behaviour may escape attention. We propose the concept of treatment 'alignment'. The term 'alignment' conveys an image of the patient and clinician in the context of a range of factors that must 'line up' to maximise the chances of a treatment plan being successfully implemented.

Ultra-high resolution array painting facilitates breakpoint sequencing.

OBJECTIVE: To describe a considerably advanced method of array painting, which allows the rapid, ultra-high resolution mapping of translocation breakpoints such that rearrangement junction fragments can be amplified directly and sequenced. METHOD: Ultra-high resolution array painting involves the hybridisation of probes generated by the amplification of small numbers of flow-sorted derivative chromosomes to oligonucleotide arrays designed to tile breakpoint regions at extremely high resolution. RESULTS AND DISCUSSION: How ultra-high resolution array painting of four balanced translocation cases rapidly and efficiently maps breakpoints to a point where junction fragments can be amplified easily and sequenced is demonstrated. With this new development, breakpoints can be mapped using just two array experiments: the first using whole-genome array painting to tiling resolution large insert clone arrays, the second using ultra-high-resolution oligonucleotide arrays targeted to the breakpoint regions. In this way, breakpoints can be mapped and then sequenced in a few weeks.

Microdissection-based high-resolution genomic array analysis of two patients with cytogenetically identical interstitial deletions of chromosome 1q but distinct clinical phenotypes.

We describe two boys with cytogenetically identical interstitial deletions in the q42.11-q42.13 region of the long arm of chromosome 1 detected by high-resolution G-banding analysis. These children share some phenotypic features but also exhibit distinct morphologic differences. We further characterized the deletions using a new technical strategy--microdissection-based high-resolution genomic array (MHGA) analysis--to define the breakpoints, genomic sizes, and gene contents of the deletions. This showed that the patients had distinguishable deletions that were adjacent but did not overlap, thus explaining the observed phenotypic differences. These results were surprising because we expected at least some degree of overlap to explain the features that were shared. MHGA can quickly give precise and detailed information about any rearrangement in the genome using as little material as a single cell. This novel strategy provides unique advantages for both clinical diagnosis and genomic research.

Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although observational studies suggest that estrogen replacement therapy (ERT) reduces cardiovascular morbidity and mortality in postmenopausal women, use of unopposed ERT for prevention of coronary heart disease in healthy postmenopausal women remains untested. OBJECTIVE: To determine the effects of unopposed ERT on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-based clinic. PATIENTS: 222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease and with low-density lipoprotein cholesterol levels of 3.37 mmol/L or greater (>/=130 mg/dL). INTERVENTION: Unopposed micronized 17beta-estradiol (1 mg/d) or placebo. All women received dietary counseling. Women received lipid-lowering medication if their low-density lipoprotein cholesterol level exceeded 4.15 mmol/L (160 mg/dL). MEASUREMENTS: The rate of change in intima-media thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms obtained at baseline and every 6 months during the 2-year trial. RESULTS: In a multivariable mixed-effects model, among women who had at least one follow-up measurement of carotid intima-media thickness (n = 199), the average rate of progression of subclinical atherosclerosis was lower in those taking unopposed estradiol than in those taking placebo (-0.0017 mm/y vs. 0.0036 mm/y); the placebo-estradiol difference between average progression rates was 0.0053 mm/y (95% CI, 0.0001 to 0.0105 mm/y) (P = 0.046). Among women who did not receive lipid-lowering medication (n = 77), the placebo-estradiol difference between average rates of progression was 0.0147 mm/y (CI, 0.0055 to 0.0240) (P = 0.002). Average rates of progression did not differ between estradiol and placebo recipients who took lipid-lowering medication (n = 122) (P > 0.2). CONCLUSIONS: Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17beta-estradiol than in women taking placebo. Reduction in the progression of subclinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications.

The Cockayne Syndrome group B gene product is involved in general genome base excision repair of 8-hydroxyguanine in DNA.

Cockayne Syndrome (CS) is a human genetic disorder with two complementation groups, CS-A and CS-B. The CSB gene product is involved in transcription-coupled repair of DNA damage but may participate in other pathways of DNA metabolism. The present study investigated the role of different conserved helicase motifs of CSB in base excision repair. Stably transformed human cell lines with site-directed CSB mutations in different motifs within its putative helicase domain were established. We find that CSB null and helicase motif V and VI mutants had greater sensitivity than wild type cells to gamma-radiation. Whole cell extracts from CSB null and motif V/VI mutants had lower activity of 8-hydroxyguanine incision in DNA than wild type cells. Also, 8-hydroxyguanine accumulated more in CSB null and motif VI mutant cells than in wild type cells after exposure to gamma-radiation. We conclude that a deficiency in general genome base excision repair of selective modified DNA base(s) might contribute to CS pathogenesis. Furthermore, whereas the disruption of helicase motifs V or VI results in a CSB phenotype, mutations in other helicase motifs do not cause this effect. The biological functions of CSB in different DNA repair pathways may be mediated by distinct functional motifs of the protein.

Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease.

OBJECTIVE: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. DESIGN: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. PATIENTS AND PARTICIPANTS: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. METHODS: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. RESULTS: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. CONCLUSIONS: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.

Improved common carotid elasticity and intima-media thickness measurements from computer analysis of sequential ultrasound frames.

B-mode ultrasound has gained popularity as a non-invasive method for direct visualization of superficial vessels. With B-mode ultrasound, arterial stiffness can be directly measured since image acquisition of the arterial wall thickness and vessel diameter can be obtained simultaneously in a dynamic fashion throughout the cardiac cycle. Recently, a method was developed to measure carotid arterial diameter and intima-media thickness (IMT) from B-mode images that utilizes computerized edge tracking-multiframe image processing that automatically measures arterial diameter and IMT in multiple sequential frames spanning several cardiac cycles. To evaluate this method, replicate B-mode common carotid artery ultrasound examinations and blood pressure measurements were obtained in 24 subjects 1-2 weeks apart. Approximately 80 sequential frames spanning two cardiac cycles were analyzed from each ultrasound examination to obtain maximum arterial diameter (D(max)), minimum arterial diameter (D(min)), and IMT using a computerized edge detection method. The intraclass correlations of D(max), D(min), and IMT were 0.97-0.99 and the mean absolute difference for these measurements were 0.03-0.11 mm. The coefficient of variation for D(max) and D(min) were 1.28 and 1.18%, respectively. The intraclass correlation for several standard arterial stiffness indices, Peterson's elastic modulus, Young's modulus, arterial distensibility, compliance, and the beta stiffness index ranged between 0.84 and 0.89. Additionally, it was determined that averaging IMT over five frames centered at D(min) reduced single frame IMT measurement variability by 27% (P=0.005) compared with IMT measured from a single frame corresponding to D(min). Comparison of the phasic relationship of D(max) and D(min) measured from the B-mode ultrasound image with the simultaneously recorded electrocardiogram (ECG) signal in the 24 subjects, provided a more accurate method of frame selection for arterial diameter extrema independent of the ECG signal. The method of computerized edge detection-sequential multiframe image processing presented in this paper represents a technological advance for image analysis of B-mode ultrasound images of common carotid arterial dimensions that is highly reproducible and directly applicable to noninvasive imaging of atherosclerosis.

Efficacy of two lipid-lowering treatments on quantitative coronary angiographic endpoints.

This study contrasts the sensitivity of four quantitative coronary angiography (QCA) measures (percent diameter stenosis [%S], minimum lumen diameter, average segment diameter, and percent involvement) in detecting 2-year treatment effects of two lipid-lowering therapies and reports on the longitudinal pattern after 4 years of treatment on the primary QCA trial endpoint (%S) for all, mild/moderate (<50%S), and severe lesions (> or =50%S). Patient cohorts were followed up from two randomized, placebo-controlled clinical trials of lipid-lowering therapies-colestipol/niacin in the Cholesterol Lowering Atherosclerosis Study (CLAS) and lovastatin in the Monitored Atherosclerosis Regression Study (MARS). Identical QCA methodology was used. In CLAS, the largest 2-year treatment effect size (=0.60) was noted for %S. In MARS, equivalent 2-year effect sizes (=0.15) were noted for three QCA measures. The largest 2-year effect size in %S was found in CLAS for mild/moderate lesions (=0.55) and in MARS for severe lesions (=0.31). Treatment in CLAS led to regression of disease in the first 2 years; treatment in MARS slowed progression of disease in the first 2 years and led to regression of disease after 4 years. Colestipol/niacin reduced progression of mild/moderate and severe lesions over the first 2 years of therapy; lovastatin reduced the progression of severe lesions over the last 2 years of therapy. We conclude that reducing the progression of atherosclerosis is not a simple proposition; maximal therapy for reducing and stabilizing atherosclerosis most likely will result from the selection of agents targeted at specific lesions.

Molecular characterization of an acidic region deletion mutant of Cockayne syndrome group B protein.

Cockayne syndrome (CS) is a human genetic disorder characterized by post-natal growth failure, neurological abnormalities and premature aging. CS cells exhibit high sensitivity to UV light, delayed RNA synthesis recovery after UV irradiation and defective transcription-coupled repair (TCR). Two genetic complementation groups of CS have been identified, designated CS-A and CS-B. The CSB gene encodes a helicase domain and a highly acidic region N-terminal to the helicase domain. This study describes the genetic characterization of a CSB mutant allele encoding a full deletion of the acidic region. We have tested its ability to complement the sensitivity of UV61, the hamster homolog of human CS-B cells, to UV and the genotoxic agent N-acetoxy-2-acetylaminofluorene (NA-AAF). Deleting 39 consecutive amino acids, of which approximately 60% are negatively charged, did not impact on the ability of the protein to complement the sensitive phenotype of UV61 cells to either UV or NA-AAF. Our data indicate that the highly acidic region of CSB is not essential for the TCR and general genome repair pathways of UV- and NA-AAF-induced DNA lesions.

Correlations between measures of atherosclerosis change using carotid ultrasonography and coronary angiography.

Few studies have examined the correlation between change in carotid artery intima-media thickness (IMT) and change in coronary artery disease. In the Cholesterol Lowering Atherosclerosis Study, current nonsmoking men with coronary artery disease were randomized to colestipol-niacin or placebo. Among 133 subjects with baseline and on-trial coronary angiography and carotid ultrasonography, colestipol-niacin treatment significantly reduced progression of atherosclerosis by both end point measures (2-year average change in percent diameter stenosis by coronary angiography and rate of change in carotid IMT). Significant correlations between change in common carotid artery IMT and quantitative coronary angiographic measures of change were evident over all coronary artery lesions, and in mild/moderate (<50% diameter stenosis), but not severe (>/=50% diameter stenosis) coronary artery lesions. In mild/moderate lesions, correlations with change in common carotid IMT were: percent diameter stenosis (r=0.28, P=0.002), minimum lumen diameter (r=-0.28, P=0.002), and vessel edge roughness (r=0.25, P=0.003). While measures obtained by carotid ultrasonography and coronary angiography are correlated, they each assess different aspects of atherosclerosis change.

Serial quantitative coronary angiography and coronary events.

BACKGROUND: Although assessment of progression of atherosclerosis by quantitative coronary angiography (QCA) is used as a surrogate for coronary events, no validation study has compared the several QCA measures used. METHODS AND RESULTS: The Cholesterol Lowering Atherosclerosis Study was a clinical trial testing the efficacy of colestipol-niacin on the progression of coronary atherosclerosis. Baseline/2-year coronary angiograms were obtained on 156 men with prior coronary artery bypass graft surgery. Changes in percent diameter stenosis and minimum lumen diameter (both measured in coronary lesions and segments) and coronary segment measures of average diameter, percent involvement, and vessel edge roughness were measured by QCA. Coronary events ascertained over 12 years of follow-up included myocardial infarction (MI), coronary death, and coronary artery revascularizations. Proportional hazards models evaluated the relation between QCA change measures and coronary events. Changes in percent diameter stenosis and minimum lumen diameter of coronary artery lesions were significantly related to the risk of MI/coronary death. All QCA measures were significantly related to the risk of any coronary event. Relative risks for each QCA measure were of similar magnitude when estimated separately within each treatment group. Change in minimum lumen diameter of lesions was the only measure independently associated with the risk of coronary events. CONCLUSIONS: All QCA measures of progression of coronary artery disease were related to all coronary events (including revascularizations). Only QCA measures of lesion progression were related to MI/coronary death. QCA measures of lesion change may be better surrogate end points for "hard" coronary events than measures of change in coronary segments.

Role of the ATPase domain of the Cockayne syndrome group B protein in UV induced apoptosis.

Cockayne syndrome (CS) is a human autosomal recessive disorder characterized by many neurological and developmental abnormalities. CS cells are defective in the transcription coupled repair (TCR) pathway that removes DNA damage from the transcribed strand of active genes. The individuals suffering from CS do not generally develop cancer but show increased neurodegeneration. Two genetic complementation groups (CS-A and CS-B) have been identified. The lack of cancer formation in CS may be due to selective elimination of cells containing DNA damage by a suicidal pathway. In this study, we have evaluated the role of the CSB gene in UV induced apoptosis in human and hamster cells. The hamster cell line UV61 carries a mutation in the homolog of the human CSB gene. We show that both human CS-B and hamster UV61 cells display increased apoptotic response following UV exposure compared with normal cells. The increased sensitivity of UV61 cells to apoptosis is complemented by the transfection of the wild type human CSB gene. In order to determine which functional domain of the CSB gene participates in the apoptotic pathway, we constructed stable cell lines with different CSB domain disruptions. UV61 cells were stably transfected with the human CSB cDNA containing a point mutation in the highly conserved glutamic acid residue in ATPase motif II. This cell line (UV61/ pc3.1-CSBE646Q) showed the same increased apoptosis as the UV61 cells. In contrast, cells containing a deletion in the acidic domain at the N-terminal end of the CSB protein had no effect on apoptosis. This indicates that the integrity of the ATPase domain of CSB protein is critical for preventing the UV induced apoptotic pathway. In primary human CS-B cells, the induction and stabilization of the p53 protein seems to correlate with their increased apoptotic potential. In contrast, no change in the level of either p53 or activation of mdm2 protein by p53 was observed in hamster UV61 cells after UV exposure. This suggests that the CSB dependent apoptotic pathway can occur independently of the transactivation potential of p53 in hamster cells.

The ATPase domain but not the acidic region of Cockayne syndrome group B gene product is essential for DNA repair.

Cockayne syndrome (CS) is a human genetic disorder characterized by UV sensitivity, developmental abnormalities, and premature aging. Two of the genes involved, CSA and CSB, are required for transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes certain lesions rapidly and efficiently from the transcribed strand of active genes. CS proteins have also been implicated in the recovery of transcription after certain types of DNA damage such as those lesions induced by UV light. In this study, site-directed mutations have been introduced to the human CSB gene to investigate the functional significance of the conserved ATPase domain and of a highly acidic region of the protein. The CSB mutant alleles were tested for genetic complementation of UV-sensitive phenotypes in the human CS-B homologue of hamster UV61. In addition, the CSB mutant alleles were tested for their ability to complement the sensitivity of UV61 cells to the carcinogen 4-nitroquinoline-1-oxide (4-NQO), which introduces bulky DNA adducts repaired by global genome repair. Point mutation of a highly conserved glutamic acid residue in ATPase motif II abolished the ability of CSB protein to complement the UV-sensitive phenotypes of survival, RNA synthesis recovery, and gene-specific repair. These data indicate that the integrity of the ATPase domain is critical for CSB function in vivo. Likewise, the CSB ATPase point mutant failed to confer cellular resistance to 4-NQO, suggesting that ATP hydrolysis is required for CSB function in a TCR-independent pathway. On the contrary, a large deletion of the acidic region of CSB protein did not impair the genetic function in the processing of either UV- or 4-NQO-induced DNA damage. Thus the acidic region of CSB is likely to be dispensable for DNA repair, whereas the ATPase domain is essential for CSB function in both TCR-dependent and -independent pathways.

In vitro reactions of butadiene monoxide with single- and double-stranded DNA: characterization and quantitation of several purine and pyrimidine adducts.

We have previously shown that butadiene monoxide (BM), the primary metabolite of 1,3-butadiene, reacted with nucleosides to form alkylation products that exhibited different rates of formation and different stabilities under in vitro physiological conditions. In the present study, BM was reacted with single-stranded (ss) and double-stranded (ds) calf thymus DNA and the alkylation products were characterized after enzymatic hydrolysis of the DNA. The primary products were regioisomeric N-7-guanine adducts. N-3-(2-hydroxy-3-buten-1-yl)adenine and N-3-(1-hydroxy-3-buten-2-yl)adenine, which were depurinated from the DNA more rapidly than the N-7-guanine adducts, were also formed. In addition, N6-(2-hydroxy-3-buten-1-yl)deoxyadenosine and N6-(1-hydroxy-3-buten-2-yl)deoxyadenosine were detected and evidence was obtained that these adducts were formed by Dimroth rearrangement of the corresponding N-1-deoxyadenosine adducts, not while in the DNA, but following the release of the N-1-alkylated nucleosides by enzymatic hydrolysis. N-3-(2-hydroxy-3-buten-1-yl)deoxyuridine adducts, which were apparently formed subsequent to deamination reactions of the corresponding deoxycytidine adducts, were also detected and were stable in the DNA. Adduct formation was linearly dependent upon BM concentration (10-1000 mM), with adduct ratios being similar at the various BM concentrations. At a high BM concentration (750 mM), the adducts were formed in a linear fashion for up to 8 h in both ssDNA and dsDNA. However, the rates of formation of the N-3-deoxyuridine and N6-deoxyadenosine adducts increased 10- to 20-fold in ssDNA versus dsDNA, whereas the N-7-guanine adducts increased only slightly, presumably due to differences in hydrogen bonding in ssDNA versus dsDNA. These results may contribute to a better understanding of the molecular mechanisms of mutagenesis and carcinogenesis of both BM and its parent compound, 1,3-butadiene.

Onset of adolescent eating disorders: population based cohort study over 3 years.

OBJECTIVE: To study the predictors of new eating disorders in an adolescent cohort. DESIGN: Cohort study over 3 years with six waves. SUBJECTS: Students, initially aged 14-15 years, from 44 secondary schools in the state of Victoria, Australia. OUTCOME MEASURES: Weight (kg), height (cm), dieting (adolescent dieting scale), psychiatric morbidity (revised clinical interview schedule), and eating disorder (branched eating disorders test). Eating disorder (partial syndrome) was defined when a subject met two criteria for either anorexia nervosa or bulimia nervosa according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). RESULTS: At the start of the study, 3.3% (29/888) of female subjects and 0.3% (2/811) of male subjects had partial syndromes of eating disorders. The rate of development of new eating disorder per 1000 person years of observation was 21.8 in female subjects and 6.0 in male subjects. Female subjects who dieted at a severe level were 18 times more likely to develop an eating disorder than those who did not diet, and female subjects who dieted at a moderate level were five times more likely to develop an eating disorder than those who did not diet. Psychiatric morbidity predicted the onset of eating disorder independently of dieting status so that those subjects in the highest morbidity category had an almost sevenfold increased risk of developing an eating disorder. After adjustment for earlier dieting and psychiatric morbidity, body mass index, extent of exercise, and sex were not predictive of new eating disorders. CONCLUSIONS: Dieting is the most important predictor of new eating disorders. Differences in the incidence of eating disorders between sexes were largely accounted for by the high rates of earlier dieting and psychiatric morbidity in the female subjects. In adolescents, controlling weight by exercise rather than diet restriction seems to carry less risk of development of eating disorders.

A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms.

OBJECTIVE: To investigate whether a combination treatment of regular-release levodopa (rr-L-dopa) and sustained-release levodopa (sr-L-dopa) compared with monotherapy of rr-L-dopa improves sleep quality and reduces periodic limb movements (PLM) in patients with restless legs syndrome (RLS) and problems with maintaining sleep. BACKGROUND: Reappearance of RLS symptoms during the second half of the night while being treated with rr-L-dopa is a common problem in the treatment of sleep disturbances caused by RLS. METHODS: A randomized, controlled, double-blind crossover trial was undertaken. Eligible patients fulfilled the diagnostic criteria of the International RLS Study Group, and met an actigraphically confirmed higher number of PLM per hour time in bed (PLM index) during the second half compared with the first half of the night under treatment with rr-L-dopa. During the crossover periods the patients received 100 to 200 mg rr-L-dopa plus either placebo or 100 to 200 mg sr-L-dopa at bedtime for 4 weeks each period. RESULTS: Thirty patients with RLS (11 men and 19 women) were assessed by actigraphy and subjective sleep quality, and showed a significant improvement in PLM index (p < 0.0001), in "time in bed without movements" (p < 0.0001), and in subjective sleep quality (p < 0.001). Eight of 30 patients reported an altered pattern of RLS symptoms, characterized by a time shift of RLS symptoms into the afternoon or evening, five of these during monotherapy with rr-L-dopa. CONCLUSIONS: A combination therapy of rr-L-dopa and sr-L-dopa is better than monotherapy with rr-L-dopa in reducing the frequency of PLM and problems maintaining sleep, even in patients who are severely affected.

Stories for a humanistic medicine.

In this first article for the feature Humanism and Medicine, Rita Charon introduces an excerpt from Richard Selzer's introduction to his latest book, The Doctor Stories. In her introductory and concluding comments, Charon contemplates the role of stories in medicine and how both truth and healing can be found in both listening to and telling stories. In the excerpt presented, surgeon and writer Selzer muses on his twin crafts. As a writer, Selzer can fully appreciate that which he witnesses in his life as a doctor. His ruminations on his own dual citizenship suggests that all doctors, perhaps, can deepen their commitment to medicine, to their patients, and to themselves by strengthening their capacity to behold their patients and to grasp their predicaments. Selzer also traces his origins and, by implication, projects his future. As practicing physicians and medical educators, readers of Academic medicine might be inspired to do the same.

Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial.

OBJECTIVE: To investigate the efficacy and safety of levodopa plus benserazide in the treatment of restless legs syndrome (RLS), in terms of the frequency of periodic limb movements (PLMs), objective and subjective criteria of sleep, onset of action, and withdrawal effects. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, crossover trial, with two 4-week treatment periods. SETTING: Outpatient units of three specialist centers in Germany. PATIENTS: Eligible patients had to fulfill the diagnostic criteria of the International RLS Study Group and have sleep disturbances and PLMs during sleep shown on polysomnography at screening. Thirty-five patients were recruited, of whom 32 (13 men, 19 women) completed the study. INTERVENTIONS: Patients received a single dose of standard-release levodopa/benserazide 100/25 mg or placebo at bedtime each night for 4 weeks, before crossing over to receive the alternative treatment for a further 4 weeks; the dose could be doubled if required. The average dosages were 159 +/- 31 mg of levodopa and 1.56 +/- 0.29 capsules of placebo. RESULTS: Levodopa/benserazide significantly reduced the number of PLMs per hour (p<0.0001), increased the time in bed without limb movements (p<0.0001), and improved subjective quality of sleep (p=0.0004). The onset of action was rapid after the first dose, and full efficacy was achieved within the first few days of therapy; these improvements disappeared immediately when treatment was discontinued. Levodopa/benserazide treatment was well tolerated and safe. CONCLUSIONS: Levodopa/benserazide is effective and safe in the treatment of RLS. Objective and subjective measures of sleep improved rapidly after the first dose. RLS symptoms recurred immediately after treatment was discontinued.