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PubMed2005

Sleepiness in professional drivers: effect of age and time of day.

The effect of age and time of day on objective and subjective sleepiness in professional drivers was investigated during a simulated driving task. Thirty-six young and middle-aged professional males drivers, free from any sleep disorder, took part in two simulated driving sessions; one carried out in the afternoon (between 2 and 4 p.m.) the other in the evening (between 11 p.m. and 1 a.m.). Half of each age group drove in a low traffic condition while the second half drove in a heavy traffic condition. Throughout the driving task, subjects' electroencephalogram and Karolinska sleepiness scale (KSS) scores were recorded. Visual analog scales measuring alertness and sleepiness levels were also completed before and after the driving. After each session, subjects filled out the NASA-TLX questionnaire and were asked if they had felt sleepy during the driving. Young professional drivers presented a significant decrease in alertness (raise of the spectral power in the alpha band) in the low traffic condition and a strong propensity to sleep during the evening test in contrast to middle-aged professional drivers.

Adult↗

PubMed2004

Comparison of a dual-phase fluoride toothpaste containing calcium, phosphate, and sodium bicarbonate with a regular fluoride toothpaste on calculus formation.

This clinical study compared the effect on dental calculus formation of a dual-phase fluoride dentifrice containing sodium bicarbonate, calcium, and phosphate with that of a regular dentifrice using a short-term clinical model in which calculus formation was facilitated. A total of 87 adult volunteers completed this study, which was a double-blind, parallel-group design, consisting of 2-week pretrial and trial periods separated by a washout period. A partial-mouth technique was used wherein the lower anterior teeth were protected from brushing by a custom-fitted toothshield, which doubled as an applicator for an undiluted dentifrice, twice daily. Calculus was measured on the labial/lingual surfaces of six lower anterior teeth by the Volpe-Manhold Index (V-MI). Subjects used a non-tartar-control dentifrice during the pretrial period to determine calculus formation rates, and these V-MI scores were used as baseline data for random allocation to either a control or test product for the trial period. Subjects who were accepted into the study, based on existing tartar deposits, readily formed calculus during the pretrial period using the toothshield method. During the trial period, subjects who were assigned the test dentifrice had comparable amounts of calculus accumulation to those who used the control dentifrice. However, subjects in the test dentifrice group had significantly lower (16%) calculus scores on lingual surfaces than those in the control group. Intragroup comparisons of V-MI data from the pretrial period with those from the trial period provided similar overall results to the comparisons between groups. This study demonstrated that a dual-phase baking soda dentifrice containing calcium and phosphate did not increase calculus accumulation relative to a regular dentifrice when used by adults with a propensity for developing calculus.

Adult↗

PubMed2002

Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol.

RATIONALE: Extrapyramidal symptoms (EPS) are common with conventional antipsychotics. Clozapine and other novel antipsychotic substances with lower in vitro affinity for dopamine-2 (D(2)) receptors have a lower propensity to induce EPS. OBJECTIVE: We investigated whether striatal D(2) receptor occupancy predicted the occurrence of EPS with atypical antipsychotics and the typical neuroleptic haloperidol. METHODS: [(123)I]Iodobenzamide (IBZM) and single photon emission tomography (SPECT) were used to quantify receptor occupancy in 71 patients treated with antipsychotics. EPS were rated according to the Simpson-Angus scale (SAS). EPS were deemed clinically relevant, if the SAS score was > or = 5 and/or anticholinergic medication was required. Patients received atypical antipsychotic monotherapy for at least 14 days with amisulpride ( n=2), clozapine ( n=6), haloperidol ( n=10), olanzapine ( n=6), quetiapine ( n=4), risperidone ( n=14), sertindole ( n=13), or zotepine ( n=16). RESULTS: The striatal D(2) receptor occupancy ranged from < 20% to almost saturation. The lowest occupancy was seen with quetiapine and clozapine, the highest with haloperidol. Twenty-two of 71 patients (29%) experienced clinically relevant EPS. These patients displayed significantly higher mean striatal D(2) receptor occupancy (77%) than those without EPS (61%; P=0.002). We found a positive correlation between the percentage of striatal D(2) receptor occupancy and the SAS score ( r=0.28; P=0.02), despite 18 of these patients receiving anticholinergics, thus lowering their SAS score. CONCLUSIONS: Striatal D(2) receptor occupancy as measured with [(123)I]IBZM and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. In vivo imaging of brain receptors with SPECT may provide a useful clinical tool to titrate doses individually and avoid motor side effects in patients treated with novel antipsychotics.

Adolescent↗

PubMed2004

Sleep pressure score: a new index of sleep disruption in snoring children.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS), as measured by objective criteria, is infrequent in snoring children despite a high prevalence of EDS-related behavioral manifestations. We hypothesized that sleep architecture and arousal indexes may be altered relative to the severity of sleep-disordered breathing (SDB). DESIGN: Retrospective and prospective study. SETTING: Questionnaires were distributed through sleep clinic or school program; polysomnograms were performed at Kosair Children's Hospital in Louisville, Kentucky. PARTICIPANTS: To examine this issue, 182 children with SDB, 163 children with primary snoring, and 214 control children with a mean age of 6.9 +/- 2.6 years underwent polysomnographic evaluation in the laboratory. MEASUREMENTS AND RESULTS: Significant increases in slow-wave sleep (percentage of total sleep time) and decreases in rapid eye movement sleep (percentage of total sleep time) occurred in the SDB group (P < .0001). Spontaneous and respiratory arousal indexes and the apnea-hypopnea index (AHI) displayed negative and positive correlations, respectively, suggesting reciprocal interactions. Based on these observations, a sleep pressure score (SPS) was derived as a surrogate numeric measure for disrupted sleep homeostasis. The SPS exhibited linear increases relative to AHI, reaching a plateau at an AHI of 30 to 40 per hour of total sleep time. Furthermore, SPS values were significantly higher among African American and obese children (P < .0001). CONCLUSIONS: Sleep architecture is not preserved in children with SDB. An algorithm allowing for calculation of sleep propensity and disturbed sleep homeostasis in children who snore is proposed and may be of practical value in the assessment of sleepiness.

Body Mass Index↗

PubMed2000

Colorectal cancer follow-up: a reassessment of empirical evidence on effectiveness.

Colorectal cancer is an important cause of death in the Western world, with a propensity of cancer recurrence even after resection with curative intent. Active follow-up has been advocated as a means to detect cancer recurrence at an earlier stage and thereby improve the survival of colorectal cancer patients. The present study assesses published evidence on the effectiveness of follow-up. Articles were obtained from a 20-year Medline search and from cross-references between articles. Articles were included, scored for quality, and extracted by explicit criteria. Regression analysis and chi-squared analysis was performed to assess (1) whether detection of recurrence at earlier asymptomatic disease stage leads to better post-treatment prognosis, and (2) whether active follow-up does improve overall (quality adjusted) survival, as compared to symptom-guided care only. The relationship between disease stage of recurrence (symptoms, number and size) and survival was analysed from 42 articles, 10 of which provided adequate data. Absence of symptoms and small number of recurrence were significantly related to better survival, smaller size insignificantly so. The potential of active follow-up seemed related to a marginally better outcome, larger gains being found in lower quality studies. Available data do suggest that survival gains vary between 0.5 and 2%, 1% seeming to be a best estimate of overall survival gain. Neither the notion that earlier detection of recurrences does significantly improve outcome, nor the hope that active follow-up provides a statistically and clinically significant gain in (quality adjusted) survival, are so far supported by adequate evidence. Colorectal cancer follow-up still fails to meet the criteria for evidence based medicine.

Chi-Square Distribution↗

PubMed2004

A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia.

BACKGROUND: While the atypical antipsychotics should ultimately reduce the prevalence of tardive dyskinesia, it is likely to remain a significant clinical problem for a long time to come. No strategy has clearly emerged as the treatment of choice for tardive dyskinesia. Atypical antipsychotics have reduced propensities for producing acute extrapyramidal symptoms (EPS) and possibly tardive dyskinesia and may be effective in treating patients with established tardive dyskinesia. METHOD: This 12-month, randomized, investigator-blinded study compared the efficacy of quetiapine (N = 22) and haloperidol (N = 23) in treating patients with DSM-IV schizophrenia or schizoaffective disorder and established tardive dyskinesia. Dyskinesia was assessed using the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale scores and the Clinical Global Impression (CGI) dyskinesia scores. Other EPS, weight, serum prolactin level, and glycosylated hemoglobin level were also assessed. Subjects were enrolled in the study between April 2000 and March 2002. RESULTS: Mean endpoint doses were 400 mg/day of quetiapine and 8.5 mg/day of haloperidol. Compared with the haloperidol group, the quetiapine group showed significantly greater improvements in ESRS dyskinesia (6 and 9 months [p or= 50% symptom reduction) was greater with quetiapine than haloperidol (64% [9/14] and 37% [6/16] at 6 months; 55% [6/11] and 28% [4/14] at 12 months). Other EPS decreased significantly with quetiapine at 3 (p =.01), 6 (p =.01), and 9 (p =.002) months. Serum prolactin levels decreased with quetiapine but increased with haloperidol, differing significantly between the groups at endpoint (p =.005). No significant changes in weight or glucose metabolism were recorded in either group. CONCLUSION: Quetiapine effectively reduces the severity of tardive dyskinesia and is well tolerated in patients with established tardive dyskinesia.

Adult↗

PubMed1983

A simple technique for assessing the propensity for crystallization of calcium oxalate and brushite in urine from the increment in oxalate or calcium necessary to elicit precipitation.

In an effort to develop a simple and reliable method with which to assess the propensity for spontaneous nucleation of calcium oxalate and brushite in urine, the permissible increment of oxalate and calcium was calculated. This represented the additional amount of oxalate or calcium that could be added to urine in three hours before spontaneous precipitation of calcium oxalate or brushite was initiated. The permissible increment of oxalate inversely correlated (P less than 0.001) with the formation-product ratio-activity-product ratio discriminant score of calcium oxalate, which was previously shown to reflect a quantitative measure of the likelihood for spontaneous nucleation. Similarly, the permissible increment of calcium inversely correlated (P less than 0.001) with the formation-product ratio-activity-product ratio discriminant score of brushite. The permissible increments in oxalate and calcium were significantly lower (P less than 0.001) in patients with renal stones than in control subjects. Moreover, treatment with thiazides, allopurinol, sodium cellulose phosphate, orthophosphate, and diphosphonate significantly raised the permissible increment of oxalate in patients with stones. Thus, the permissible increment was reliable in discriminating "stone-forming" from control urine and in assessing response to treatment.

Calcium↗

PubMed1999

Neurophysiologic predictors of treatment response to fluoxetine in major depression.

Treatment with antidepressants is marked by heterogeneity of response; predicting individual response to any given agent remains problematic. Neuroimaging studies suggest that response is accompanied by physiologic changes in cerebral energy utilization, but have not provided useful markers at pretreatment baseline. Using quantitative EEG (QEEG) techniques, we investigated pretreatment neurophysiologic features to identify responders and non-responders to fluoxetine. In a double-masked study, 24 adult subjects with current major depression of the unipolar type were studied over 8 weeks while receiving fluoxetine (20 mg QD) or placebo. Neurophysiology was assessed with QEEG cordance, a measure reflecting cerebral energy utilization. Response was determined with rating scales and clinical interview. Subjects were divided into discordant and concordant groups based upon the number of electrodes exhibiting discordance. The concordant group had a more robust response than the discordant group, judged by lower final Hamilton Depression (HAM-D) mean score (8.0+/-7.5 vs. 19.6+/-4.7, P = 0.01) and final Beck Depression Inventory (BDI) mean score (14.0+/-9.4 vs. 27.8+/-3.7, P = 0.015), and by faster reduction in symptoms (HAM-D: 14.0+/-5.0 vs. 23.8+/-4.1, P = 0.004 at 1 week). Groups did not differ on pretreatment clinical or historical features. Response to placebo was not predicted by this physiologic measure. We conclude that cordance distinguishes depressed adults who will respond to treatment with fluoxetine from those who will not. This measure detects a propensity to respond to fluoxetine and may indicate a more general responsiveness to antidepressants.

Adult↗

PubMed2005

ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis.

The International Conference on Harmonization (ICH) stems from the initiative of three major world partners (Japan, USA, European Community) who composed a mutually accepted body of regulations concerning the safety, quality and efficacy requirements that new medicines have to meet in order to receive market approval. Documents on non-clinical safety pharmacology already composed by this organisation include two guidelines: the S7A adopted in 2000 and, its companion, the S7B guideline, in a draft form since 2001. The S7A guideline deals with general principles and recommendations on safety pharmacology studies designed to protect healthy volunteers and patients from potential drug-induced adverse reactions. The S7B recommends a general non-clinical testing strategy for determining the propensity of non-cardiovascular pharmaceuticals to delay ventricular repolarisation, an effect that at times progresses into life-threatening ventricular arrhythmia. In the most recent version of this document (June 2004), the strategy proposes experimental assays and a critical examination of other pertinent information for applying an 'evidence of risk' label to a compound. Regrettably, the guideline fails to deal satisfactorily with a number of crucial issues such as scoring the evidence of risk and the clinical consequences of such scoring. However, in the latter case, the S7B relies on the new ICH guideline E14 which is currently in preparation. E14 is the clinical counterpart of the S7B guideline which states that non-clinical data are a poor predictor of drug-induced repolarisation delay in humans. The present contribution summarises and assesses salient aspects of the S7A guideline as its founding principles are also applicable to the S7B guideline. The differences in strategies proposed by the various existing drafts of the latter document are critically examined together with some unresolved, crucial problems. The need for extending the objective of the S7B document to characterise the full electrophysiological profile of new pharmaceuticals is argued as this approach would more extensively assess the non-clinical cardiac safety of a drug. Finally, in order to overcome present difficulties in arriving at the definitive version of the S7B guideline, the Expert Working Group could reflect on the introduction of the S7B guideline recommendations in the S7A document, as originally intended, or on postponing the adoption of an harmonized text until the availability of novel scientific data allows solving presently contentious aspects of this and the E14 guidelines.

Arrhythmias, Cardiac↗

PubMedDate not supplied

The point on myelodysplastic syndromes.

The Myelodysplastic Syndromes (MDS) are heterogeneous borderline diseases, with propensity to transform into acute leukemia. Some paradoxes need more attention either in experimental and clinical approach: the clonal proliferation, involving all the hematopoietic lines, but associated with a relatively long evolution which ends not always into acute leukemia; involvement of cytokines, but a poor therapeutical response to anti-cytokine therapy; the surprisingly good effect of the "differentiating "drugs in vitro and the poor response in vivo. The prognostic scores according to cytological, histological and genetic criteria, and the therapeutical approach are discussed.

Humans↗

PubMed1999

Quality-of-Life Assessment in Patients with Lesions of the Cranial Base.

Lesions of the cranial base have a propensity to affect physical, mental and social well-being of the patient. Cranial Base surgeons have a duty to go beyond the standard outcome measures of survival and morbidity in presenting the results of surgery for lessions of the cranial base. This paper reviews the fundamental features of quality of life outcome measures as applied to the field of skull base surgery.The author reviews the The Glasgow Outcome Scale, the Karnofsky Score, Spitzer Quality of Life Index, the Sickness Impact Profile, the Rand 36 (MOS-SF 36), the FACT G health-related quality of life scale and the University of Washington Quality of Life Scale for their use in the field cranial base surgery.Major advances in cranial base surgery will be facilitated by the use of scientifically sound and practical health-related quality of life outcome measures.

Journal Article↗

PubMed2004

Hazardous drinking and relationship violence perpetration and victimization in women arrested for domestic violence.

OBJECTIVE: Research has shown that women who perpetrate partner violence or are victims of partner violence are more likely than comparison groups to have alcohol problems. The present study represents the largest sample collected to date of women arrested for domestic violence and court referred to batterer intervention programs. The aim of this study is to compare hazardous and nonhazardous drinking women on violence perpetration and victimization and to examine whether group differences in these variables are attributable to women's drinking, their general propensity for violence, their partners' drinking, or a combination of these factors. METHODS: We recruited 103 women who were arrested for domestic violence and divided the sample into groups of hazardous drinkers (HD) and nonhazardous drinkers (NHD). We administered multiple measures of substance use and problems and assessed the women's relationship aggression, use of general violence and their relationship partners' substance use. RESULTS: Relative to the NHD group, the HD group scored higher on violence perpetration (physical assault, psychological abuse, sexual abuse, injuries) and violence victimization (physical assault). In addition, the HD group scored higher than the NHD group on general violence perpetration and partner alcohol and drug problems. Results from regression analyses indicated that women's drinking, women's general violence, and partner drinking all contributed to some form of violence perpetration or victimization; women's hazardous drinking group status was particularly important in the prediction of physical assault perpetration and victimization. CONCLUSIONS: The results of the study suggest that substance use and problems should be assessed routinely as part of violence intervention programs for women and that intervention programs would be improved by offering adjunct or integrated alcohol treatment.

Adult↗

PubMed2000

Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS?

BACKGROUND: Administration of novel, versus classic, antipsychotic agents to patients suffering from psychosis is associated both with moderately better scores on cognitive tests, and with fewer extrapyramidal symptoms (EPS). Because improved motor functioning may enable better performance on some components of cognitive test batteries, and because the advantages of the novel antipsychotics on cognitive performance are not very large, it is sometimes difficult to discern if improvement in a given cognitive task is due to a direct effect of the novel antipsychotic drug, or is secondary to the novel drug's decreased propensity to induce EPS. In an attempt to distinguish between these two possibilities, the present study examined the ability of patients suffering from schizophrenia receiving classic, versus novel antipsychotics, to perform a computerized visuo-motor test (VMT). VMT assesses planning capabilities, attention and executive functions known to be impaired in schizophrenia, which are suggested to be affected by novel antipsychotics. METHODS: Seventy-six patients suffering from schizophrenia or schizophreniform disorder, receiving haloperidol (23 patients, mean dose 10.01+/-6.1mg/day), olanzapine (26 patients, mean dose 10.56 +/- 4.9 mg/day) or risperidone (27 patients, mean dose 4.35 +/- 1.7 mg/day) were assessed for EPS using the parkinsonian subscale of the Extrapyramidal Symptom Rating Subscale (ESRS), and with the VMT. RESULTS: Cognitive functioning as measured by the VMT was better for patients receiving risperidone or olanzapine, compared with those receiving haloperidol (F=6.636, df=2,67, P=0. 002), while the patients receiving haloperidol or risperidone suffered from more severe EPS compared with the patients receiving olanzapine (F=3.996, df=2,71, P=0.023). DISCUSSION: Although the patients receiving risperidone suffered from EPS similar in severity to the EPS of the patients receiving haloperidol, their performance on a task involving visuo-motor and attentional skills was similar to that of the patients receiving olanzapine. This finding implies that there is a dissociation between the antipsychotic drug's ability to affect cognitive functioning, and EPS. This dissociation indirectly suggests that the advantages offered by novel antipsychotics on cognitive performance are a direct effect, rather than being entirely mediated by improved movement abilities.

Adolescent↗

PubMed1999

Patterned library analysis: a method for the quantitative assessment of hypotheses concerning the determinants of protein structure.

Site-directed mutagenesis and combinatorial libraries are powerful tools for providing information about the relationship between protein sequence and structure. Here we report two extensions that expand the utility of combinatorial mutagenesis for the quantitative assessment of hypotheses about the determinants of protein structure. First, we show that resin-splitting technology, which allows the construction of arbitrarily complex libraries of degenerate oligonucleotides, can be used to construct more complex protein libraries for hypothesis testing than can be constructed from oligonucleotides limited to degenerate codons. Second, using eglin c as a model protein, we show that regression analysis of activity scores from library data can be used to assess the relative contributions to the specific activity of the amino acids that were varied in the library. The regression parameters derived from the analysis of a 455-member sample from a library wherein four solvent-exposed sites in an alpha-helix can contain any of nine different amino acids are highly correlated (P < 0.0001, R(2) = 0. 97) to the relative helix propensities for those amino acids, as estimated by a variety of biophysical and computational techniques.

Amino Acids↗

PubMed2002

The Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales: II. Predicting psychophysiological response pattens.

This study evaluated the predictive value of a newly developed measure of the propensity for sexual inhibition and excitation; the Sexual Inhibition Sexual Excitation Scales (SIS/SES). Sexual, cardiovascular, and startle responses were measured in a group of 40 sexually functional men during the presentation of threatening and nonthreatening erotic films. Two levels of performance demand were created and two films were combined with a distraction task. Participants were assigned to high and low groups for each of the three SIS/SES scales. As predicted, men with high SES scores showed generally higher sexual responses. High and low SIS1 groups did not differ in their responses. Men with high and low SIS2 scores did not differ in their responses to nonthreatening stimuli; however, low SIS2 men showed greater genital response to the threatening stimuli. The findings provide support for the value of the SIS/SES scales in predicting sexual responses.

Adult↗

PubMed2004

The early snail acquires the learning. Comparison of scores for conditioned taste aversion between morning and afternoon.

The pond snail Lymnaea stagnalis acquires conditioned taste aversion (CTA) and maintains its memory for more than a month. Snails in our laboratory were cultured at 20 degrees C on a 12:12 light-dark cycle (light from 7 am to 7 pm). To examine the hours during which snails acquire CTA effectively, we trained some snails in the morning and others in the afternoon, and then compared their scores. CTA developed in both cases, but scores were significantly better in the morning than in the afternoon. To elucidate the cause of this difference in scores, we observed the voluntary activity of snails and found the circadian rhythm reflected in the snails' free-movement distances; distances at the circadian time 0-12 (daytime) were significantly longer than those at the circadian time 12-24 (nighttime). This rhythm was kept up for at least 3 days, even in constant darkness. In conclusion, L. stagnalis should be trained in the morning to acquire associative learning, possibly because of its greater propensity to roam about at that time as opposed to the afternoon.

Afferent Pathways↗

PubMed1999

Aortic medial changes associated with bicuspid aortic valve: myth or reality?

OBJECTIVE: To determine whether aortic medial changes are more severe in patients who require aortic valve replacement of congenitally bicuspid aortic valves (BAV) than in patients who require replacement of tricuspid aortic valves and acquired valvular disease (AVD). DESIGN: Aortas from autopsies of 14 patients with BAV and 25 with AVD were histologically assessed by two 'blinded' cardiovascular pathologists and analyzed independently with computer-aided morphometry. The aortic valves were examined for valvular fibrosis and calcification. SETTING: The patient population was from a tertiary-care facility. PATIENTS: Patients were selected by retrospective review of autopsy records for patient deaths after aortic valve replacement, over the period 1984 to 1995. RESULTS: There were no significant differences in age (P=0.89), sex (P=0.94), prevalence of systemic arterial hypertension (P=0.37), valvular degenerative changes (P=0.10 and P=1.0) or heart weights (P=0.60) between the two groups. Histological scores for aortic medial degenerative changes including elastic fragmentation, fibrosis and medionecrosis were not statistically different between the groups. However, morphometry demonstrated less elastic tissue in patients with BAV (P=0.003). CONCLUSION: Routine microscopy shows no significant difference in the degree of aortic medial degenerative changes between patients with BAV and AVD. However, morphometry shows less elastic tissue in the aortas of BAV patients. This may explain the anecdotal increase in aortic fragility and propensity for aortic dissection in these patients.

Aged↗

PubMed2004

Multigenic control of hepatic iron loading in a murine model of hemochromatosis.

BACKGROUND & AIMS: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading. METHODS: To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers. RESULTS: We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism. CONCLUSIONS: Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.

Animals↗