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A biosocial model of medication use among older women and men in Ismailia, Egypt.

In Western industrialized countries, women report using health services, and certain medications, more often than do men. Often, analyses are based on data that exclude objective measures of morbidity and that come from cross-sectional surveys, which precludes the use of socioeconomic covariates that are endogenous to seeking care. Here, differences in objective cognitive and physical function, as well as differences in reporting on illness, propensity to seek care, and socioeconomic resources are expected to account for differences in care-seeking behaviour among women and men. This model is applied to the question of medication use in Ismailia, Egypt, using two waves of survey data and in-home tests of physical function from 896 adults aged 50 years and older. The results show that women use "modern" medications more often than do men, and that differences between women and men in reported morbidity and disability, observed cognitive and physical function, and economic resources account for women's greater use of medication. The findings underline a need for biosocial models to understand differences in women's and men's care-seeking behaviour in later life.

Aged↗

The influence of race on health status outcomes one year after an acute coronary syndrome.

OBJECTIVES: The goal of this study was to compare health status (symptoms, function, and quality of life) outcomes of whites and blacks one year after an acute coronary syndrome (ACS). BACKGROUND: Although racial differences in the use of angiography and revascularization after ACS are known to exist, differences in health status outcomes have not been described. METHODS: We conducted a prospective registry of 1,159 consecutive ACS patients treated between February 1, 2000 and October 31, 2001. One-year health status was quantified with the Seattle Angina Questionnaire (SAQ) and Short Form-12 Physical Component Score (SF-12 PCS). Multivariable models were used to adjust for racial differences in sociodemographic, clinical, and treatment characteristics. RESULTS: Mortality rates were similar among the 196 black and 963 white patients (7.1% vs. 7.0%, p = 0.93); 81 died during follow-up, and 199 (17%) could not be interviewed. At one year, blacks had a higher prevalence of angina (43.4% vs. 27.1%), worse quality of life (SAQ score = 70.6 +/- 28.3 vs. 83.9 +/- 20.8), and poorer physical function (SF-12 PCS = 36.8 +/- 12.3 vs. 43.2 +/- 11.4; p < 0.0001 for all). Multivariable models, including hospital treatments, revealed a trend for more angina (odds ratio 1.46 [95% confidence interval 0.91 to 2.34]) and significantly worse quality of life (mean difference = -7.7 +/- 2.4, p = 0.002) and physical function (-3.6 +/- 1.3, p = 0.005). CONCLUSIONS: Blacks have more angina, worse quality of life, and worse physical function one year after an ACS than do whites. Closer surveillance of black ACS patients is needed to determine whether additional treatment can improve their outcomes.

Acute Disease↗

Relationship between health status and utility measures in older claudicants.

The purpose of this study was to examine the relationship between health status and health utility measures in 34 older claudicants and to determine which attributes of health status were significant predictors of health state valuation/preference. The MOS SF-36 was used to assess health status and the rating scale and multiattribute Health Utility Index (HUI) were used to assess utility scores. With regard to health status, the bodily pain and physical functioning subscales contributed the most to reductions in quality of life (QoL) with mean subscale scores substantially lower than reported population norms. Patients rated their health status approximately one-third below a state of perfect health on both utility measures. Moderate correlations were observed between the MOS SF-36 subscale scores and the HUI and rating scale scores. In multivariable regression models, physical functioning and mental health were the best predictors of HUI scores, whereas general health and vitality were the best predictors of rating scale scores. Approximately 50% of the variance in utility scores was explained by these attributes. This study provides further documentation that bodily pain and reductions in physical function contribute to reductions in QoL in older patients with intermittent claudication. Other attributes of health status, however, notably psychological distress, were predictive of patients' preference for health states. Recognized constructs of physical and mental health explained the substantial variation in the utility/preference assessment in this population. Furthermore, these data are consistent with those reported in the Dutch Iliac Stent Trial.

Aged↗

Medical cost for disability: a longitudinal observation of national health insurance beneficiaries in Japan.

OBJECTIVES: To measure the impact of disability on the use of medical care and its costs. DESIGN: A 1-year prospective cohort study of National Health Insurance beneficiaries in a rural Japanese community. Their physical function was examined by the Medical Outcomes Study questionnaire at the end of 1994; medical care and its costs were then monitored for 1 year. SETTING AND PARTICIPANTS: Participants were the 49,364 subjects, aged 40 to 79 years, who were beneficiaries of National Health Insurance and lived in the catchment area of Ohsaki Public Health Center, Miyagi, Japan. The subjects were mainly farmers, self-employed persons, housewives, or pensioners. MEASUREMENTS: Medical care utilization (number of outpatient visits and days of inpatient care) and the costs for each subject were obtained from National Health Insurance Claim History files. These measurements were collected from January to December 1995, and the relationship between physical functioning levels and medical costs was analyzed. RESULTS: The medical costs per capita increased with poorer physical function. Medical costs among those with limitations in performing self-care increased by 4 times in men and 3 times in women compared with those with no functional limitation. In this cohort, the 4.3% of the subjects who were dependent in self-care used 15% of the total inpatient days and 10% of the total medical costs. CONCLUSION: Treatment of patients with disability requires a huge amount of medical resources. There is an urgent need for cost-effective intervention programs for disability prevention, which could be offset against the cost for treating the disabled.

Activities of Daily Living↗

Characteristics of patients admitted to hospital with chronic obstructive pulmonary disease.

AIMS: To examine the characteristics of patients admitted to Auckland Hospital with chronic obstructive pulmonary disease (COPD) and to assess their management prior to hospitalisation. METHODS: Prospective survey of 99 patients admitted with COPD over an 8 week period. Of these, 80 patients were interviewed about their social circumstances, physical functioning, smoking habits and medical treatment. They also had their inhaler technique checked and FEV1 measured. RESULTS: Subjects had a mean age of 70.6 years with a mean FEV1 of 29% of predicted. 45% lived alone and a third still smoked. The mean value for their usual physical functioning was 15.4 (possible 10-30) on the SF-36 health status questionnaire. 84% of all subjects used a beta-agonist, 50% an anticholinergic bronchodilator, 69% inhaled steroids, 18% oral steroids, and 19% theophylline. 40% used nebulised medication and only 6% had domiciliary oxygen. 40% reported having an influenza vaccination in the preceding year and 27% had participated in some form of pulmonary rehabilitation. The mean length of stay was 7.5 days. CONCLUSIONS: Patients hospitalized for COPD report marked impairment in physical functioning, despite which many live alone. They frequently use inhaled and oral steroids, and nebulised medication, but only a minority had received an influenza vaccination or attended pulmonary rehabilitation.

Activities of Daily Living↗

Interventions to enhance physical and psychological functioning among younger women who are ending nonhormonal adjuvant treatment for early-stage breast cancer.

PURPOSE: To conduct a clinical trial to determine if an educational intervention and a nutritional intervention could enhance physical and psychological functioning among younger women completing treatment for early-stage breast cancer. PATIENTS AND METHODS: Younger women (50 years of age or younger, N = 252), within 2 months of having completed active nonhormonal adjuvant therapy, diagnosed with stage 0, I, or II breast cancer with 10 or fewer positive lymph nodes were randomly assigned to a three-arm clinical trial. Women in the control arm of the trial received standard medical care. Women in the two active arms received either an educational intervention, designed to provide information about their illness and enhance adjustment, or a nutritional intervention, designed to promote a more healthy diet. Primary end points included mental functioning, physical functioning, and depressive symptoms. Women were assessed before random assignment, 4 months later (immediately post-intervention), and 13 months later (9 months post-intervention). RESULTS: Participants assigned to the two active treatment arms had significantly less depressive symptomatology and better physical functioning by 13-month follow-up (differences between the two active arms were nonsignificant). These effects were primarily accounted for by changes in intrusive thoughts, concerns regarding cancer recurrence and mortality, self-concept perceptions, and self-efficacy expectations. CONCLUSION Tailored psychosocial interventions can be effectively designed to enhance adjustment among younger women who are completing nonhormonal adjuvant therapy.

Adaptation, Psychological↗

Mobility-related function in older adults: assessment with a 6-minute walk test.

OBJECTIVE: To determine the usefulness of the 6-minute walk test as an integrated measure of mobility in older adults. DESIGN: Observational study. SETTING: Community centers and retirement homes in the Los Angeles area. PATIENTS: Eighty-six older adults without significant disease. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Assessments included the 6-minute walk, chair stands, standing balance, gait speed, body mass index, and self-reported physical functioning and general health perceptions. RESULTS: One-week test-retest reliability of the 6-minute walk was .95. As hypothesized, the 6-minute walk distance was significantly greater for active than for inactive older adults (p < .0001), moderately correlated with chair stands (r = .67), standing balance (r = .52), and gait speed (r = -.73). It had a low correlation with body mass index (r = -.07). The correlation of the 6-minute walk with self-reported physical functioning was .55, and its correlation with general health perceptions was .39. Self-report and performance measures explained 69% of the variance in 6-minute walk scores. CONCLUSIONS: The 6-minute walk test is reliable and is valid in relation to the performance and self-reported indicators of physical functioning tested in this study. It could serve as a useful integrated measure of mobility.

Activities of Daily Living↗

A physical and functional constituent of telomerase anchor site.

Telomerase is a ribonucleoprotein reverse transcriptase responsible for the maintenance of one strand of the telomere terminal repeats. It consists minimally of a catalytic protein component (TERT) and an RNA subunit that provides the template. Compared with prototypical reverse transcriptases, telomerase is unique in possessing a DNA binding domain (anchor site) that is distinct from the catalytic site. Yeast TERT mutants bearing deletion or point mutations in an N-terminal domain (known as N-GQ) were found to be selectively impaired in extending primers that form short hybrids with telomerase RNA. The mutants also suffered a significant loss of repeat addition processivity but displayed an enhancement in nucleotide addition processivity. Furthermore, the mutants manifested altered primer utilization properties for oligonucleotides containing non-telomeric residues in the 5'-region. Cross-linking studies indicate that the N-GQ domain physically contacts the 5'-region of the DNA substrate in the context of a telomerase-telomere complex. Together, these results implicate the N-GQ domain of TERT as a physical and functional constituent of the telomerase anchor site. Coupled with previous genetic analysis, our data confirm that anchor site interaction is indeed important for telomerase function in vivo.

Amino Acid Motifs↗

Exercise reduces fatigue in chronic fatigued Hodgkins disease survivors--results from a pilot study.

The aims of this pilot study were to compare aerobic capacity in non-fatigued and fatigued Hodgkin's disease survivors (HDS) and to assess the feasibility of an exercise-programme and its effects upon fatigue, physical functioning and aerobic capacity in chronic fatigued HDS. 53 HDS (85%) of originally 62 survivors treated at the Trondheim University Hospital in the period 1987-1997 completed a questionnaire including the Fatigue Questionnaire (FQ). 18 subjects were identified with chronic fatigue. 15 non-fatigued HDS matched for gender and age were drawn as controls. Both groups were invited to medical examination and exercise tests. All 15 fifteen non-fatigued HDS showed up to the medical examination. 12 of the 18 patients with chronic fatigue completed the tests and nine agreed to enter a home-based exercise intervention. Outcome measures were aerobic capacity, fatigue and physical functioning. No significant difference in aerobic capacity was found between the chronic fatigued HDS and the controls. Fatigue, physical functioning and maximal aerobic capacity were significantly improved after the intervention. Aerobic exercise had a positive effect upon chronic fatigue in HDS. However, the study is a pilot study and needs confirmation in a larger group of subjects. The intervention was well accepted, and the majority of the patients adhered to the programme.

Adult↗

Physical and functional independency of p70 and p58 natural killer (NK) cell receptors for HLA class I: their role in the definition of different groups of alloreactive NK cell clones.

Natural killer (NK) cells express clonally distributed receptors for different groups of HLA class I alleles. The Z27 monoclonal antibody described in this study recognizes a p70 receptor specific for HLA-B alleles belonging to the Bw4 supertypic specificity. Single amino acid substitutions in the peptide-binding groove of HLA-B2705 molecules influenced the recognition by some, but not all, p7O/Z27+ clones. This suggests the existence of a limited polymorphism within the p7O family of receptors. The pattern of reactivity of monoclonal antibody Z27 revealed that Bw4-specific receptors may be expressed alone or in combination with different (GL183 and/or EB6) p58 molecules. Analysis of NK clones coexpressing p58 and p7O receptors allowed us to demonstrate that the two molecules represent physically and functionally independent receptors. The expression of p7O molecules either alone or in combination with EB6 molecules provided the molecular basis for understanding the cytolytic pattern of two previously defined groups of "alloreactive" NK cell clones ("group 3" and "group 5").

Amino Acid Sequence↗

The protein tyrosine kinase Hck is located on lysosomal vesicles that are physically and functionally distinct from CD63-positive lysosomes in human macrophages.

In macrophages, lysosomes are suspected to have a heterogenous population of vesicles. This study was thus undertaken to identify and to characterize lysosomal compartments in human macrophages. Hck is a Src-family tyrosine kinase associated with secretory lysosomes in neutrophils and with cytoplasmic vesicles in macrophages that fuse with phagosomes. We identified these Hck-positive vesicles and compared them to CD63-positive, M6PR-negative vesicles known as classical lysosomes. Hck vesicles exhibited lysosomal features. Indeed, Hck-positive vesicles could be loaded with rhodamine-dextran, which has been shown to accumulate in lysosomal compartments. Hck was delivered to zymosan-containing phagosomes at a late stage of the maturation process, which occurs after the fusion with CD63-positive lysosomes. Finally, when mycobacteria were used to prevent phagolysosome biogenesis, Hck was not recruited to phagosomes. Moreover, Hck lysosomes were physically and functionally distinct from CD63-lysosomes. For instance, sucrose induced swelling of CD63-lysosomes without affecting Hck-positive ones. Only CD63-lysosomes fused with phagosomes in a microtubule-dependent manner. Entry of particles through the mannose receptor and Fcgamma receptors drove the phagosome towards a fusion with CD63-lysosomes, whereas only Fcgamma receptors induced the mobilisation of Hck-lysosomes. This study provides further evidence for the existence of sub-populations of lysosomes in macrophages: one stained by CD63 and another one characterized by the presence of Hck. Therefore, Hck represents a new tool to study the fusion dynamics of lysosomal compartments and their subversion by several intracellular pathogens.

Antigens, CD↗

A randomized controlled trial to evaluate the effectiveness of an exercise program in women with rheumatoid arthritis taking low dose prednisone.

OBJECTIVE: To evaluate the effects of a 12 month, weight bearing, aerobic exercise program on disease activity, physical function, and bone mineral density (BMD) in women with rheumatoid arthritis (RA) taking low dose prednisone. METHODS: A group of women with RA (n = 23) not receiving steroid therapy and in American College of Rheumatology functional class I or II was compared to 30 steroid treated patients with similar demographics. The latter group was randomized to usual care (n = 16) or an aerobic, weight bearing exercise program (n = 14) 3 times a week for 12 months. All subjects were recruited from an outpatient rheumatology clinic or physical therapy department and met the study inclusion criteria. Outcome measures included disease activity (erythrocyte sedimentation rate, active joint count), physical function (Health Assessment Questionnaire disability index, activity level) and BMD of the spine and femoral neck (by dual energy projection radiology). RESULTS: Subjects in the exercise group had a small but nonsignificant decrease in disease activity and statistically significant improvements in function (p = 0.05) and activity levels (p = 0.05). BMD remained unchanged in the exercise group, decreased significantly (p = 0.004) in the nonsteroid comparison group (hip), and changed nonsignificantly in the control group. However, between-group changes in spinal BMD of the steroid treated groups was not significant (p = 0.09). CONCLUSION: Women with RA taking low dose steroid therapy can safely participate in a dynamic, weight bearing exercise program with positive effects on their physical function, activity and fitness levels, and BMD with no exacerbation of disease activity.

Arthritis, Rheumatoid↗

Validation of a Dutch translation of the fibromyalgia impact questionnaire.

OBJECTIVES: To validate a Dutch translation of the fibromyalgia impact questionnaire (FIQ). MATERIALS AND METHODS: Data were taken from two randomized clinical trials on Spa treatment and venlafaxine in fibromyalgia (FM). Participants completed the Dutch FIQ and a set of validated questionnaires for general health (RAND-36), depression (Beck depression inventory, BDI), pain (McGill pain questionnaire, MPQ) and fatigue (checklist individual strength, CIS). Internal consistency within the FIQ item 'physical functioning' was studied using Cronbach's alpha. Test-retest reliability was studied with intra-class-correlation (ICC) in a subsample of 76 control subjects over a 3 month period without specific intervention. Construct validity was evaluated by correlating the FIQ to other questionnaires. Sensitivity to change was studied using standardized response means (SRM). RESULTS: The study sample consisted of 213 women and 11 men (mean age 47 yrs, mean disease duration 11 yrs). Cronbach's alpha for the item 'physical functioning' was 0.91, indicating high internal consistency. Test-retest reliability was acceptable, with ICC ranging from 0.45 for 'morning tiredness' to 0.71 for 'physical function'. FIQ correlated significantly with the RAND-36, with Spearman's rho ranging from -0.60 to -0.70 for items measuring the same concept. Similar patterns of correlation were seen with MPQ, BDI and CIS. Sensitivity to change was sufficient, with SRM after Spa treatment ranging from 0.3 for 'work days missed' to 0.9 for 'days felt good'. Similar SRM were found in the venlafaxine trial for patients reporting general improvement. CONCLUSION: The Dutch FIQ is a valid instrument for measuring health status in FM, showing sufficient reliability, construct validity and responsiveness.

Activities of Daily Living↗

Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial.

OBJECTIVE: The Arthritis, Diet, and Activity Promotion Trial (ADAPT) was a randomized, single-blind clinical trial lasting 18 months that was designed to determine whether long-term exercise and dietary weight loss are more effective, either separately or in combination, than usual care in improving physical function, pain, and mobility in older overweight and obese adults with knee osteoarthritis (OA). METHODS: Three hundred sixteen community-dwelling overweight and obese adults ages 60 years and older, with a body mass index of > or =28 kg/m(2), knee pain, radiographic evidence of knee OA, and self-reported physical disability, were randomized into healthy lifestyle (control), diet only, exercise only, and diet plus exercise groups. The primary outcome was self-reported physical function as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included weight loss, 6-minute walk distance, stair-climb time, WOMAC pain and stiffness scores, and joint space width. RESULTS: Of the 316 randomized participants, 252 (80%) completed the study. Adherence was as follows: for healthy lifestyle, 73%; for diet only, 72%; for exercise only, 60%; and for diet plus exercise, 64%. In the diet plus exercise group, significant improvements in self-reported physical function (P < 0.05), 6-minute walk distance (P < 0.05), stair-climb time (P < 0.05), and knee pain (P < 0.05) relative to the healthy lifestyle group were observed. In the exercise group, a significant improvement in the 6-minute walk distance (P < 0.05) was observed. The diet-only group was not significantly different from the healthy lifestyle group for any of the functional or mobility measures. The weight-loss groups lost significantly (P < 0.05) more body weight (for diet, 4.9%; for diet plus exercise, 5.7%) than did the healthy lifestyle group (1.2%). Finally, changes in joint space width were not different between the groups. CONCLUSION: The combination of modest weight loss plus moderate exercise provides better overall improvements in self-reported measures of function and pain and in performance measures of mobility in older overweight and obese adults with knee OA compared with either intervention alone.

Aged↗

Relationships between long-term stroke disability, handicap and health-related quality of life.

OBJECTIVES: To estimate levels of disability, handicap and health-related quality of life (HRQOL) up to 3 years after stroke and examine the relationships between these domains. DESIGN: A longitudinal, observational study SETTING: Population-based register of first-ever strokes METHODS: Subjects, registered between 1 January 1995 and 31 December 1997, were assessed at 1 year (n = 490) and 3 years (n = 342) post-stroke for disability [Barthel index (BI)], handicap [Frenchay activity index (FAI)] and HRQOL (SF-36). BI was categorised as severe, moderate, mild and independent (0-9, 10-14, 15-19 and 20); FAI was categorised as inactive, moderately active and very active (0-15, 16-30 and 31-45). SF-36 domains include: Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE) and Mental Health (MH). Physical (PHSS) and Mental Health (MHSS) Summary Scores were computed. RESULTS: at 1 and 3 years, 26.1 and 26.3%, respectively, were disabled (BI < 15); 55 and 51%, respectively, were handicapped (FAI = 0-15); and survivors had low mean PHSS (37.1 and 37.9), but satisfactory mean MHSS (46.6 and 47.7). There was a graded positive relationship between all SF-36 domains and the categories of BI and FAI. Spearman rank correlations were significant between BI and all SF-36 domains at both time points: strong (r > 0.70) with PF, moderate (r = 0.31-0.70) with RP, SF and PHSS, but weak (r < 0.30) with other domains. Correlations between FAI and SF-36 domains were strong with PF, weak with BP, RE and MHSS, and moderate with other domains. CONCLUSIONS: Disability and handicap remain highly prevalent up to 3 years after stroke. Patients' perception of physical health is persistently low, but mental health perception is satisfactory up to 3 years. Due to variable correlations between different HRQOL domains with disability and handicap, it is suggested that disability, handicap and HRQOL should all be assessed to acquire a broader measure of stroke outcome.

Disability Evaluation↗

Item response theory was used to shorten EORTC QLQ-C30 scales for use in palliative care.

BACKGROUND AND OBJECTIVE: The goal was to develop a shortened version of the EORTC QLQ-C30 for use in palliative care. We wanted to keep as few items as possible in each scale while still being able to compare results with studies using the original scales. We examined the possibilities of shortening the physical functioning, cognitive functioning, fatigue, and nausea and vomiting scales. STUDY DESIGN AND SETTING: The shortening was based on 2,366 (physical functioning) and 10,815 (three other scales) observations, respectively. We used item response theory to construct scoring algorithms for predicting scores on the original scales. RESULTS: Evaluations showed that a three-item physical scale, a two-item fatigue scale, and a one-item nausea or vomiting scale predicted the scores on the original scales with excellent agreement and had measurement abilities similar to the original scales with no loss or only a little loss in power to detect group differences. The results of the cognitive functioning scale indicated problems when predicting scores from a shortened version. CONCLUSION: Given the favorable results for the physical functioning, fatigue, and nausea or vomiting scales we expect that the shortened versions of these scales will be included in the abbreviated version of the EORTC QLQ-C30 for palliative care.

Cognition↗

SMAD proteins transactivate the human ApoCIII promoter by interacting physically and functionally with hepatocyte nuclear factor 4.

Cotransfection of HepG2 cells with SMADs established that SMAD3 and SMAD3-SMAD4 transactivated (15-70-fold) the -890/+24 apoCIII promoter and shorter promoter segments, whereas cotransfection with a dominant negative SMAD4 mutant repressed the apoCIII promoter activity by 50%, suggesting that SMAD proteins participate in apoCIII gene regulation. Transactivation required the presence of a hormone response element, despite the fact that SMADs could not bind directly to it. Cotransfection of SMAD3-SMAD4 along with hepatocyte nuclear factor-4 resulted in a strong synergistic transactivation of the -890/+24 apoCIII promoter, proximal promoter segments, or synthetic promoters containing either the apoCIII enhancer or the proximal apoCIII hormone response element. Inhibition of endogenous hepatocyte nuclear factor-4 synthesis by an antisense ribozyme construct reduced the constitutive activity of the apoCIII promoter in HepG2 cells to 10% and abolished the SMAD-mediated transactivation. Co-immunoprecipitation and GST pull-down assays provided evidence for physical interactions between SMAD3, SMAD4, and hepatic nuclear factor-4. Our findings indicate that transforming growth factor beta and its signal transducer SMAD proteins can modulate gene transcription by novel mechanisms that involve their physical and functional interaction with hepatocyte nuclear factor-4, suggesting that SMAD proteins may play an important role in apolipoprotein gene expression and lipoprotein metabolism.

Animals↗

A physical and functional interaction between yeast Pol4 and Dnl4-Lif1 links DNA synthesis and ligation in nonhomologous end joining.

Genetic studies have implicated the Saccharomyces cerevisiae POL4 gene product in the repair of DNA double-strand breaks by nonhomologous end joining. Here we show that Pol4 preferentially catalyzes DNA synthesis on small gaps formed by the alignment of linear duplex DNA molecules with complementary ends, a DNA substrate specificity that is compatible with its predicted role in the repair of DNA double-strand breaks. Pol4 also interacts directly with the Dnl4 subunit of the Dnl4-Lif1 complex via its N-terminal BRCT domain. This interaction stimulates the DNA synthesis activity of Pol4 and, to a lesser extent, the DNA joining activity of Dnl4-Lif1. Notably, the joining of DNA substrates that require the combined action of Pol4 and Dnl4-Lif1 is much more efficient than the joining of similar DNA substrates that require only ligation. Thus, the physical and functional interactions between Pol4 and Dnl4-Lif1 provide a molecular mechanism for both the recruitment of Pol4 to in vivo DNA double-strand breaks and the coupling of the gap filling DNA synthesis and DNA joining reactions that complete the microhomology-mediated pathway of nonhomologous end joining.

DNA↗