Associations of Arthritis-Attributable Interference with Routine Life Activities: A Modifiable Source of Compromised Quality-of-Life.

OBJECTIVE: Arthritis patients experience the impact of disease beyond routinely assessed clinical measures. We characterized arthritis-attributable interference in four important routine life domains: 1) recreation/leisure/hobbies; 2) household chores; 3) errands/shopping; and 4) social activities. METHODS: Participants were from the Arthritis Conditions Health Effects Survey (2005-2006), a cross-sectional survey of noninstitutionalized US adults 45 years or older with doctor-diagnosed arthritis (n = 1793). We estimated the prevalence of "a lot" of arthritis-attributable interference and quantified the associations between sociodemographic, clinical, and psychological characteristics and "a lot" of arthritis-attributable interference (vs "a little" or "none") in each domain using prevalence ratios (PRs) in multivariable (MV)-adjusted logistic regression models. RESULTS: An estimated 1 in 5 to 1 in 4 adults with arthritis reported "a lot" of arthritis-attributable interference in recreation/leisure/hobbies (27%), household chores (25%), errands/shopping (22%), and social activities (18%). The highest prevalence of "a lot" of arthritis-attributable interference was for those unable to work/disabled or reporting severe arthritis symptoms (pain, stiffness, fatigue), anxiety, depression, or no/low confidence in ability to manage arthritis, across domains. In MV-adjusted models, those unable to work/disabled, currently seeing a doctor, or reporting fair/poor self-rated health, severe joint pain, anxiety, or no/low confidence in ability to manage arthritis were more likely to report arthritis-attributable interference than their respective counterparts. Magnitudes varied by domain but were consistently strongest for those unable to work/disabled (MV PR range = 1.8-2.5) and with fair/poor health (MV PR range = 1.7-2.7). CONCLUSION: Many characteristics associated with arthritis-attributable interference in routine life activities are potentially modifiable, suggesting unmet need for use of existing evidence-based interventions that address these characteristics and reduce interferences to improve quality of life.

The association between asymptomatic hyperuricemia and knee osteoarthritis: data from the third National Health and Nutrition Examination Survey.

OBJECTIVE: In vitro and clinical studies suggest that urate may contribute to osteoarthritis (OA) risk. We tested the associations between hyperuricemia and knee OA, and examined the role of obesity, using a cross-sectional, nationally representative dataset. METHOD: National Health and Nutrition Examination Survey (NHANES) III used a multistage, stratified probability cluster design to select USA civilians from 1988 to 1994. Using NHANES III we studied adults >60 years, with or without hyperuricemia (serum urate > 6.8 mg/dL), excluding individuals with gout (i.e., limiting to asymptomatic hyperuricemia (AH)). Radiographic knee OA (RKOA) was defined as Kellgren-Lawrence grade ≥ 2 in any knee, and symptomatic radiographic knee osteoarthritis (RKOA) (sRKOA) was defined as RKOA plus knee pain (most days for 6 weeks) in the same knee. RESULTS: AH prevalence was 17.9% (confidence interval (CI) 15.3-20.5). RKOA prevalence was 37.7% overall (CI 35.0-40.3), and was 44.0% for AH vs 36.3% for normouricemic adults (p = 0.056). symptomatic radiographic knee osteoarthritis (sRKOA) was more prevalent in AH vs normouricemic adults (17.4% vs 10.9%, p = 0.046). In multivariate models adjusting for obesity, model-based associations between AH and knee OA were attenuated (for RKOA, prevalence ratio (PR) = 1.14, 95% CI 0.95, 1.36; for sRKOA, PR = 1.40, 95% CI 0.98, 2.01). In stratified multivariate analyses, AH was associated with sRKOA in adults without obesity (PR = 1.66, 95% CI 1.02, 2.71) but not adults with obesity (PR = 1.21, 95% CI 0.66, 2.23). CONCLUSIONS: Among adults aged 60 or older, AH is associated with knee OA risk that is more apparent in adults without obesity.

The pharmacodynamic effects of combined administration of flibanserin and alcohol.

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

Annual incidence rates of hip symptoms and three hip OA outcomes from a U.S. population-based cohort study: the Johnston County Osteoarthritis Project.

OBJECTIVE: Estimate annual incidence rates (IRs) of hip symptoms and three osteoarthritis (OA) outcomes (radiographic, symptomatic, and severe radiographic) overall and by race, sociodemographic characteristics, and hip OA risk factors. DESIGN: Analyze baseline (1991-1997) and first follow-up (1999-2003) data (n = 1446) from the Johnston County Osteoarthritis Project, a population-based, prospective study of adults ≥45 years in North Carolina. Hip symptoms were pain, aching, and/or stiffness on most days, or groin pain. Radiographic and severe radiographic OA were Kellgren-Lawrence (KL) grades ≥2 and ≥3, respectively. Symptomatic OA was radiographic OA with symptoms in the same hip. Sociodemographics were age, gender, race, highest attained education, and annual household income. Hip OA risk factors were self-reported body mass index (BMI) at age 18 years, clinically measured BMI at baseline, and history of hip injury. RESULTS: Annual IRs (median = 5.5 years follow-up) were 37, 23, 13, and 2.9 per 1000 person-years for hip symptoms, and radiographic, symptomatic, and severe radiographic hip OA, respectively. We found low IRs of radiographic and symptomatic hip OA among African Americans and high IRs of hip symptoms among the obese and the very poor. Across outcomes, IRs were highest for those with hip injury. CONCLUSION: No prior studies have reported IRs of hip symptoms; IRs of radiographic and severe radiographic hip OA were similar to, and the IR of symptomatic hip OA was higher than, previous estimates. Prevention efforts should target low socioeconomic status (SES) populations and obese adults; interventions for hip OA and hip symptoms are imperative for those with hip injuries.

Meeting physical activity guidelines and the risk of incident knee osteoarthritis: a population-based prospective cohort study.

OBJECTIVE: Knee osteoarthritis (OA) is a leading cause of disability and joint pain. Although other risk factors of knee OA have been identified, how physical activity affects incident knee OA remains unclear. METHODS: Using data from the first (1999-2004) and second (2005-2010) followup periods of the Johnston County Osteoarthritis Project study, we tested the association between meeting physical activity guidelines and incident knee outcomes among 1,522 adults ages ≥45 years. The median followup time was 6.5 years (range 4.0-10.2 years). Physical activity at baseline (moderate-equivalent physical activity minutes/week) was calculated using the Minnesota Leisure Time Physical Activity questionnaire. Incident knee radiographic OA (ROA) was defined as the development of Kellgren/Lawrence grade ≥2 in a knee at followup. Incident knee symptomatic ROA (sROA) was defined as the development of ROA and symptoms in at least 1 knee at followup. Weibull regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for interval-censored data. RESULTS: In multivariable models, meeting the 2008 Department of Health and Human Services (HHS) physical activity guidelines (≥150 minutes/week) was not significantly associated with ROA (HR 1.20 [95% CI 0.92-1.56]) or sROA (HR 1.24 [95% CI 0.87-1.76]). Adults in the highest level (≥300 minutes/week) of physical activity had a higher risk of knee ROA and sROA compared with inactive (0 to <10 minutes/week) participants; however, these associations were not statistically significant (HR 1.62 [95% CI 0.97-2.68] and HR 1.42 [95% CI 0.76-2.65], respectively). CONCLUSION: Meeting the HHS physical activity guidelines was not associated with incident knee ROA or sROA in a cohort of middle-aged and older adults.

Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats.

BACKGROUND: Many anaesthetics when given to young animals cause cell death and learning deficits that persist until much later in life. Recent attempts to compare the relative safety or toxicity between different agents have not adequately controlled for the relative dose of anaesthetic given, thereby making direct comparisons difficult. METHODS: Isoflurane or sevoflurane were given at 1 minimum alveolar concentration (MAC) for 4 h to postnatal day 7 (P7) rat pups. Beginning at P75 these animals underwent fear conditioning and at P83 Morris water maze testing to assess working memory, short-term memory and early long-term memory using delays of 1 min, 1 h, and 4 h. RESULTS: No difference between groups was seen in fear conditioning experiments. Morris water maze learning was equivalent between groups, and no difference was seen in working memory. Sevoflurane-treated animals had a deficit in early long-term memory, and isoflurane-treated animals had a deficit in both short-term and early long-term memory. CONCLUSIONS: Both isoflurane and sevoflurane delivered at 1 MAC for 4 h to immature rats caused a deficit in long-term memory. Isoflurane also caused a deficit in short-term memory. Isoflurane might be more detrimental than sevoflurane in very young animals.

Renal function and nonvertebral fracture risk in multiethnic women: the Women's Health Initiative (WHI).

UNLABELLED: To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women's Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups. INTRODUCTION: The purpose of this study was to determine whether renal function is associated with fracture risk within racial/ethnic groups. METHODS: A nested case-control study was conducted among 93,673 postmenopausal women; incident nonvertebral fractures were identified in 362 Black, 183 Hispanic, 110 Asian, and 45 American-Indian women. A random sample of 395 White women with incident nonvertebral fracture was chosen. One nonfracture control for each case was selected (matched on age, race/ethnicity, and blood draw date). Cystatin C levels were measured using baseline serum, and estimated glomerular filtration rate calculated (eGFR(cys-c)). RESULTS: Each 1 SD increase in cystatin C was associated with a 1.2-fold increased risk of fracture among White women (adjusted odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.04-1.46). The OR of fracture was 1.16 (95% CI, 0.85-1.58) among women with eGFR(cys-c) 60-90 mL/min/1.73 m(2) and 2.46 (95% CI, 1.16-5.21) among those with eGFR(cys-c) <60 mL/min/1.73 m(2) compared to the reference group (eGFR(cys-c) >90 mL/min/1.73 m(2)) (p trend = 0.05). The association was reduced after adjustment for cytokine TNFα soluble receptors (OR, 1.62; 95% CI, 0.59-4.46 for eGFR(cys-c) <60 mL/min/1.73 m(2)). Among Blacks, there was an association between cystatin C and fracture risk (OR per 1 SD increase, 1.15; 95% CI, 1.00-1.32); after adjustment, this association was only modestly attenuated, but no longer statistically significant. There was no evidence of significant associations among Hispanic, Asian, or American-Indian women. CONCLUSION: Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture. Effects of renal function on chronic inflammation may mediate this association. Reduced renal function may increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.

The effects of adiponectin and leptin on changes in bone mineral density.

UNLABELLED: We tested the hypothesis that low leptin and high adiponectin levels are associated with higher rates of bone mineral density (BMD) loss among 3,075 men and women, aged 70-79, from the Health Aging and Body Composition Study. Results suggest that adiponectin, but not leptin, is a risk factor for bone loss in women. INTRODUCTION: Adiponectin and leptin are hormones secreted by adipose cells that may impact BMD. Few studies have evaluated the longitudinal association of leptin and adiponectin levels with rates of BMD change. METHODS: Hip and whole-body areal BMD (aBMD) were measured five times using dual-energy X-ray absorptiometry over 10 years (average follow-up time, 7.95 ± 1.92 years). Trabecular lumbar spine volumetric BMD (vBMD) was measured using quantitative computed topography at baseline and year 6 in the Pittsburgh cohort only. Random slope and intercept models were used to account for within person correlation as a result of repeated measures of hip and whole-body aBMD. Linear regression was used to model changes in spine trabecular vBMD. RESULTS: Among women, the annualized rate of hip aBMD loss in the highest tertile of adiponectin was -0.67% (95% CI -0.77, -0.58) compared to [-0.43% (95% CI -0.51, -0.35)] in the lowest tertile (p trend = 0.019) after adjusting for age, race, BMI, diabetes, baseline hip aBMD, and weight change. In men, hip aBMD loss was greatest in the high adiponectin group (tertile 3), however this association was not significant (p trend = 0.148). After adjusting for weight change in women, the association between higher leptin and lower hip aBMD loss was attenuated and no longer significant (p trend = 0.134). Leptin and adiponectin levels were not associated with whole-body aBMD or trabecular lumbar spine vBMD loss. CONCLUSIONS: Adiponectin was associated with increased hip aBMD loss in women only, supporting evidence that adiponectin may have an important role in bone health.

The association of serum 25-hydroxyvitamin D with indicators of bone quality in men of Caucasian and African ancestry.

UNLABELLED: We examined the association of serum 25-hydroxyvitamin D [25(OH)D] with indices of bone quality in older men. Positive associations for 25(OH)D and bone mineral density, content, cortical thickness, and axial and polar strength strain indices were observed among Caucasians; however, among men of African descent findings were either null or negative. INTRODUCTION: There are limited data on serum 25(OH)D and bone measures in men of African ancestry. To better understand racial differences in vitamin D status and bone health, a cross-sectional study among 446 Caucasian men in the US and 496 men of African ancestry in Tobago (age ≥ 65 years) was conducted. METHODS: Serum 25(OH)D (liquid chromatography and tandem mass spectrometry) was measured, and peripheral quantitative computed tomography scans were administered. Bone measures estimated included trabecular and cortical volumetric bone mineral density (vBMD), bone mineral content (BMC), bone geometry (cross-sectional area and cortical thickness), and polar and axial strength strain indices (SSIp and SSIx). RESULTS: Men of African ancestry had higher 25(OH)D than Caucasians (34.7 vs. 27.6 ng/ml, p < 0.01). Among Caucasians, 25(OH)D was positively (p trend < 0.05) associated with cortical vBMD, total BMC, cortical thickness, SSIp, and SSIx at the distal radius after adjustment for potential confounders. Similar patterns were observed at the distal tibia. In contrast, in men of African ancestry, there was an inverse association (p trend < 0.05) between 25(OH)D and the cross-sectional area, and SSIx. Race modified (p for interaction < 0.05) the association between 25(OH)D and total BMC, cross-sectional area, SSIp, SSIx, and trabecular vBMD of the radius. In men of African ancestry, there was evidence of a threshold effect (at approximately 18 ng/ml) for 25(OH)D on tibial total BMC and cortical thickness. CONCLUSIONS: More studies are needed to better comprehend these race differences for 25(OH)D and bone density, geometry, and indices of bone strength.

The use of ureteral stents and suprapubic catheter in vesicoureteric reflux surgery.

The use of ureteric stents in reimplantation surgery is important. The younger the patient, the more important the stenting of ureters post reimplantation becomes, because even minimal oedema following surgery will produce ureteric obstruction unless stents are in place. JJ stents are now the preferred method of choice in ureteric reimplantation surgery, but in the past the patient required another admission to hospital and general anaesthetic to have the stents removed endoscopically. We describe a technique whereby the stents are attached to the suprapubic catheter and are therefore removed prior to the patient's discharge from hospital, thus obviating the need for a second admission and second anaesthetic for the stent removal. We have studied 23 patients with this technique and find that it is a reliable and safe method to use.

Activity of human trypanosome lytic factor in mice.

The inability of the cattle pathogen Trypanosoma brucei brucei to infect humans is due to an innate factor in human serum termed Trypanosome Lytic Factor (TLF). Human haptoglobin-related protein is the proposed toxin in TLF and can exist either as a component of a minor subclass of high-density lipoprotein (TLF-1) or as a lipid free, high molecular weight protein complex (TLF-2). The trypanolytic activity of both TLF-1 and TLF-2 has been studied in vitro but their relative contributions to protection against T. b. brucei infection in vivo has not been established. In the present studies we show that treatment of T. b. brucei infected mice with TLF-1 resulted in a dose dependent decrease in parasite numbers but did not affect parasite numbers in mice infected with Trypanosoma brucei rhodesiense, the causative agent of the human sleeping sickness. Similarly, pretreatment of mice with TLF-1 resulted in protection against a challenge by T. b. brucei but had no effect on T. b. rhodesiense challenge. Induction of the acute phase protein haptoglobin, a natural antagonist of TLF-1, diminished but did not abolish the protection against trypanosome challenge. In addition, haptoglobin knockout mice showed higher levels of TLF-1 mediated protection against a T. b. brucei challenge. These results suggest that while TLF-1 is active in vivo, even in the presence of elevated levels of haptoglobin, its activity is modulated in a dose dependent fashion by haptoglobin in the circulation.

Haptoglobin, inflammation, and tumorigenesis in the MIN mouse.

We have determined that the MIN mouse, which is predisposed to adenomas of the small and large intestine, exhibits chronic inflammation characterized by the induction of haptoglobin (HP), as well as other acute phase proteins. Inflammation is initiated at about 40-70 days of age, and is maintained throughout the life of the animal. Delayed onset of inflammation brought on by dietary means is associated with a reduction in tumor number and longer life-span. Knockout mice that lack haptoglobin exhibit an increase in tumor number, indicating that the acute phase reactant suppresses tumorigenesis, perhaps through inhibition of the inflammatory response. The MIN mouse is, therefore, a useful model for studying the roles of HP and inflammation in tumorigenesis in vivo.

Task demands and limb apraxia in stroke.

The present study was designed to examine the frequency and severity of apraxia in patients with left- or right-hemisphere stroke in both pantomime and imitation conditions and to compare the frequency of apraxia in each stroke group across the three patterns of apraxia described in Roy's model (Roy, 1996). Ninety-nine stroke patients and 15 age-matched healthy adults performed eight transitive gestures to pantomime and to imitation. Gestural performance was quantified as accuracy on five performance dimensions; a composite score, an arithmetic combination of the five performance dimensions, was used as an index of the overall accuracy. Analyses revealed a comparable proportion of patients in each stroke group were classified as apraxic in the imitation condition, but a higher proportion of left stroke patients were apraxic in the pantomime condition. The severity of apraxia in each stroke group and the performance dimensions affected were, however, comparable. Analyses of the patterns of apraxia (pantomime alone, imitation alone or apraxia in both conditions) revealed a higher frequency of apraxia in both stroke groups for the pattern reflecting apraxia in both conditions, indicating that a disruption at the movement execution stage of gesture performance was most common.

Visual aiming movements in Alzheimer's disease.

This study examined whether AD affects the control of pointing movements. Sixteen older adults with probable AD and 10 age-matched healthy adults pointed at targets varying in size (3 and 7 mm in diameter) and located at three positions (at the midline and 33 degrees to the left and right). Results revealed the patients exhibited longer movement time, lower peak velocity and more time in deceleration, although they exhibited effects of target size and location comparable to the healthy controls. AD, then, would appear to slow down movement without affecting the motor system's ability to respond to task demands.

Mechanisms of acquired resistance to thymidylate synthase inhibitors: the role of enzyme stability.

Inhibitors of the enzyme thymidylate synthase (TS), such as the fluoropyrimidines 5-fluorouracil and 5'-fluoro-2'-deoxyuridine (FdUrd) or the antifolates AG337, ZD1694, and BW1843U89, are widely used in the chemotherapy of cancer, particularly cancer of the colon and rectum. Numerous studies have shown that TS gene amplification, leading to mRNA and enzyme overproduction, is a major mechanism of resistance to these inhibitors. In the present work, we have isolated and characterized FdUrd-resistant derivatives of several human colon tumor cell lines. Although gene amplification was commonly observed, the increases in mRNA and enzyme were strikingly discordant. In one drug-resistant line, a deficiency of enzyme relative to mRNA was shown to be caused by expression of a metabolically unstable TS molecule. The reduced half-life of TS in this line was caused by a Pro-to-Leu substitution at residue 303 of the TS polypeptide. The mutant enzyme conferred resistance to FdUrd as well as antifolates in transfected cells. In another FdUrd-resistant line, which had an excess of enzyme relative to mRNA, the TS molecule was more stable than in the parent line. However, no amino acid substitutions were detected in the TS polypeptide from this line, which suggests that the stabilization must be caused by changes in one or more cellular factors that regulate TS degradation. The results indicate that changes in the stability of the TS polypeptide accompany, and even contribute to, acquired resistance to TS inhibitors in colon tumor cells.

Articulated thoughts of maritally violent and nonviolent men during anger arousal.

The cognitive correlates of anger arousal were investigated in community-based samples of maritally violent (MV), maritally distressed-nonviolent (DNV), and maritally satisfied-nonviolent (SNV) husbands. Participants performed the Articulated Thoughts in Simulated Situations (ATSS) paradigm while listening to anger-arousing audiotapes. Trained raters coded for irrational beliefs, cognitive biases, hostile attributional biases, and anger control statements. Results indicated that MV men articulated significantly more irrational thoughts and cognitive biases than DNV and SNV men. MV men articulated more hostile attributional biases than DNV and SNV men across all ATSS scenarios. SNV men, however, articulated more anger control statements during ATSS anger arousal than MV or DNV participants. Discriminant function analyses indicated that specific thoughts discriminated between the groups and differentiated mildly from severely violent participants. ATSS cognitive distortions (a) were not correlated with questionnaire measures of cognitive distortion, and (b) were superior to questionnaire measures in discriminating between the groups. The findings are interpreted in light of recent advances in understanding the relationship between information processing, anger, and marital aggression.

Evolution of transcriptional regulatory elements within the promoter of a mammalian gene.

Transcription of the murine D7Rp2e gene is highly variable among species of the genus Mus, indicating that extensive modifications in the gene's regulatory elements have occurred during evolution. Since promoter regions are well known to harbor cis-acting information that controls gene transcription, we compared the sequence and function of the D7Rp2e promoter in several Mus species, with the goal of understanding the molecular mechanisms underlying the interspecies variations in expression. Three overlapping binding sites for nuclear factors (sites A, B, and C in proximal to distal order) were identified about 300 bp upstream of the transcriptional start site. The sequences of these sites differ between the species Mus domesticus and M. pahari, which exhibit distinct D7Rp2e expression phenotypes. Site A binds a factor called RPBF-I; sites B and C bind a distinct factor that is termed RPBF-II and is likely a member of the NF-I family of transcription factors. DNase I footprinting experiments with the M. domesticus promoter show that binding of RPBF-II at site B is very strong, while binding of RPBF-I and RPBF-II at sites A and C, respectively, is weak; in contrast, with the M. pahari promoter, factor binding at sites A and C is strong, while that at site B is weak. These differences in patterns of binding-site occupancy derive from changes in the affinities of individual sites for their cognate nuclear factors. Transient transfection experiments indicate that the M. pahari binding pattern is capable of repressing transcription of a linked reporter. Such repression may contribute to the differences in D7Rp2e expression between the two species. We suggest that the species-specific footprinting patterns represent the existence of a dynamic equilibrium between two states of nuclear factor binding, the nature of which can be modified during evolution to result in new patterns of gene transcription.

Expression of the alpha 1-proteinase inhibitor gene family during evolution of the genus Mus.

alpha 1-Proteinase inhibitors (alpha 1-PIs) are members of the serpin superfamily of proteinase inhibitors, and are important in the maintenance of homeostasis in a wide variety of animal taxa. Previous studies have shown that in mice (genus Mus), evolution of alpha 1-PIs is characterized by gene amplification, region-specific concerted evolution, and rapid accumulation of amino acid substitutions. The latter occurs primarily in the reactive center, which is the region of the alpha 1-PI molecule that determines the inhibitor's specificity for target proteinases. The P1 residue within the reactive center, which is methionine in so-called orthodox alpha 1-PIs and an amino acid other than methionine in unorthodox alpha 1-PIs, is a primary determinant of inhibitor specificity. In the present study, we find that the expression of mRNAs encoding unorthodox alpha 1-PIs is polymorphic within Mus species, i.e., among individuals or inbred strains. This is in striking contrast to mRNAs that encode orthodox alpha 1-PIs, whose concentrations are relatively invariant. The intraspecies variations in mRNA expression represent polymorphisms in the structure of the alpha 1-PI gene family. The results, taken together with previously described aspects of alpha 1-PI evolution, indicate that the dissimilar levels of polymorphism exhibited by orthodox and unorthodox alpha 1-PIs, which likely have distinct physiological functions, may reflect different levels of selective constraint. The significance of this finding to the evolution of gene families is discussed.