Several recent studies have shown that hippocampal neurons fire during the delay period in between trials and that these firing patterns differ when different behaviors are required, suggesting that the neuronal responses may be involved in maintaining the memories needed for the upcoming trial. In particular, one study found that hippocampal neurons reliably fired at particular times, referred to as ‘episode fields’ (EFs), during the delay period of a spatial alternation task (Pastalkova et al, 2008, Science 321:1322-7). The firing of these neurons resulted in distinct sequential firing patterns on left and right turn trials, and these firing patterns could be used to predict the upcoming behavioral response. In the present study, we examined neuronal firing during the delay period of a hippocampal dependent plus maze task which involved learning to approach two different reward locations (east and west) and we examined the development of these firing patterns with learning. As in the previous study, hippocampal neurons exhibited discrete periods of elevated firing during the delay (EFs) and the firing patterns were distinct on the east and west trials. Moreover, these firing patterns emerged and began to differentiate the east and west conditions during the first training session and continued to develop as the rats learned the task. The finding of similar firing patterns in different tasks suggests that the EFs are a robust phenomenon, which may occur whenever subjects must maintain distinct memory representations during a delay period. Additionally, in the previous study (Pastalkova et al, 2008), the distinct firing patterns could have been due to the differing goal locations, behavioral responses (left or right turns) or trajectories. In the present study, neuronal firing varied with the goal location regardless of the trajectories or responses, suggesting that the firing patterns encode the behavioral context rather than specific behaviors.

OBJECTIVE

This retrospective study examined the association between ICD-9-CM–coded outpatient hypoglycemic events (HEs) and acute cardiovascular events (ACVEs), i.e., acute myocardial infarction, coronary artery bypass grafting, revascularization, percutaneous coronary intervention, and incident unstable angina, in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Data were derived from healthcare claims for individuals with employer-sponsored primary or Medicare supplemental insurance. A baseline period (30 September 2006 to 30 September 2007) was used to identify eligible patients and collect information on their clinical and demographic characteristics. An evaluation period (1 October 2007 to 30 September 2008) was used to identify HEs and ACVEs. Patients aged ≥18 years with type 2 diabetes were selected for analysis by a modified Healthcare Effectiveness Data and Information Set algorithm. Data were analyzed with multiple logistic regression and backward stepwise selection (maximum P = 0.01) with adjustment for important confounding variables, including age, sex, geography, insurance type, comorbidity scores, cardiovascular risk factors, diabetes complications, total baseline medical expenditures, and prior ACVEs.

RESULTS

Of the 860,845 patients in the analysis set, 27,065 (3.1%) had ICD-9-CM–coded HEs during the evaluation period. The main model retained 17 significant independent variables. Patients with HEs had 79% higher regression-adjusted odds (HE odds ratio [OR] 1.79; 95% CI 1.69–1.89) of ACVEs than patients without HEs; results in patients aged ≥65 years were similar to those for the entire population (HE OR 1.78, 95% CI 1.65–1.92).

CONCLUSIONS

ICD-9-CM–coded HEs were independently associated with an increased risk of ACVEs. Further studies of the relationship between hypoglycemia and the risk of ACVEs are warranted.

In the eukaryotic 26S proteasome, the 20S particle is regulated by six AAA ATPase subunits, and in archaea by a homologous ring complex, PAN. To clarify the role of ATP in proteolysis, we studied how nucleotides bind to PAN. Although PAN has six identical subunits it binds ATPs in pairs, and its subunits exhibit three conformational states with high, low, or no affinity for ATP. When PAN binds two ATPγS molecules, or two ATPγS plus two ADP molecules it is maximally active in binding protein substrates, associating with the 20S particle, and promoting 20S gate-opening. However, binding of four ATPγS molecules reduces these functions. The 26S proteasome shows similar nucleotide dependence. These findings imply an ordered cyclical mechanism in which two ATPase subunits bind ATP simultaneously and dock into the 20S. These results can explain how these hexameric ATPases interact with and “wobble” on top of the heptameric 20S proteasome.

Summary

The Ubiquitin-Proteasome System catalyzes the degradation of intracellular proteins. Although ubiquitination of proteins determines their stabilities, there is growing evidence that proteasome function is also regulated. We report the functional characterization of a conserved proteasomal regulatory complex. We identified DmPI31 as a binding partner of the F-box protein Nutcracker, a component of an SCF ubiquitin ligase (E3) required for caspase activation during sperm differentiation in Drosophila. DmPI31 binds Nutcracker via a conserved mechanism that is also used by mammalian FBXO7 and PI31. Nutcracker promotes DmPI31 stability, which is necessary for caspase activation, proteasome function and sperm differentiation. DmPI31 can activate 26S proteasomes in vitro, and increasing DmPI31 levels suppresses defects caused by diminished proteasome activity in vivo. Furthermore, loss of DmPI31 function causes lethality, cell-cycle abnormalities and defects in protein degradation, demonstrating that DmPI31 is physiologically required for normal proteasome activity.

Nanometer-sized polyhedral wire-frame objects hold a wide range of potential applications both as structural scaffolds as well as a basis for synthetic nanocontainers. The utilization of DNA as basic building blocks for such structures allows the exploitation of bottom-up self-assembly in order to achieve molecular programmability through the pairing of complementary bases. In this work, we report on a hollow but rigid tetrahedron framework of 75 nm strut length constructed with the DNA origami method. Flexible hinges at each of their four joints provide a means for structural variability of the object. Through the opening of gaps along the struts, four variants can be created as confirmed by both gel electrophoresis and direct imaging techniques. The intrinsic site addressability provided by this technique allows the unique targeted attachment of dye and/or linker molecules at any point on the structure's surface, which we prove through the superresolution fluorescence microscopy technique DNA PAINT.

Background

Limited data are available on the predictors of insulin delivery device choice. This study assessed the patient- and health-care-system-related factors that predict the initiation of one rapid-acting insulin analog (RAIA) delivery system over another.

Methods

A retrospective analysis using a claims database (January 1, 2007, through March 31, 2009) was conducted. Patients were required to be diagnosed with type 2 diabetes mellitus, and have ≥12 months of continuous eligibility prior to their first prescription of a RAIA on or after January 1, 2008. The three cohorts in the study were vial/syringe (n = 6820), prefilled pen (n = 5840), and reusable pen (n = 2052). Multiple factors were examined using stepwise logistic regression.

Results

Factors that increased the likelihood of initiating RAIA using prefilled pen versus vial/syringe included endocrinologist visit [odds ratio (OR) = 3.13, 95% confidence interval (CI) = 2.56, 3.82], prior basal insulin use with pen (OR = 4.85, 95% CI = 4.21, 5.59), and use of ≥1 oral antihyperglycemic agents (OR = 1.32, 95% CI = 1.20, 1.45). Factors that decreased the likelihood included inpatient admission (OR = 0.76, 95% CI = 0.70, 0.83), nursing home visit (OR = 0.22, 95% CI = 0.18, 0.27), and obesity (OR = 0.67, 95% CI = 0.53, 0.83). There were fewer differences between prefilled and reusable pen initiators. Factors that increased the likelihood of initiating with prefilled versus reusable pen included endocrinologist visit (OR = 1.87, CI = 1.50, 2.34) and inpatient admission (OR = 1.46, 95% CI = 1.30, 1.64).

Conclusion

Significant differences in predictors were observed between prefilled pen and vial/syringe initiators. The differences were fewer between prefilled and reusable pen initiators. These differences should be taken into consideration when evaluating outcomes associated with specific insulin delivery systems.

OBJECTIVE

Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11β-HSD1 inhibitors improve insulin sensitivity.

RESEARCH DESIGN AND METHODS

Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11β-HSD1 inhibition upon insulin signaling and action.

RESULTS

Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer307 insulin receptor substrate (IRS)-1. 11β-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11β-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer307 IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11β-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer307 IRS1 decreased and pThr308 Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.

CONCLUSIONS

Prereceptor facilitation of glucocorticoid action via 11β-HSD1 increases pSer307 IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11β-HSD1 inhibition decreases pSer307 IRS1, increases pThr308 Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.

The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial is a randomized, controlled, single-masked trial designed to determine whether cognitive training interventions (memory, reasoning, and speed of information processing), which have previously been found to be successful at improving mental abilities under laboratory or small-scale field conditions, can affect cognitively based measures of daily functioning. Enrollment began during 1998; 2-year follow-up will be completed by January 2002. Primary outcomes focus on measures of cognitively demanding everyday functioning, including financial management, food preparation, medication use, and driving. Secondary outcomes include health-related quality of life, mobility, and health-service utilization. Trial participants (n = 2832) are aged 65 and over, and at entry into the trial, did not have significant cognitive, physical, or functional decline. Because of its size and the carefully developed rigor, ACTIVE may serve as a guide for future behavioral medicine trials of this nature.

Context

Cognitive function in older adults is related to independent living and need for care. However, few studies have addressed whether improving cognitive functions might have short- or long-term effects on activities related to living independently.

Objective

To evaluate whether 3 cognitive training interventions improve mental abilities and daily functioning in older, independent-living adults.

Design

Randomized, controlled, single-blind trial with recruitment conducted from March 1998 to October 1999 and 2-year follow-up through December 2001.

Setting and Participants

Volunteer sample of 2832 persons aged 65 to 94 years recruited from senior housing, community centers, and hospital/clinics in 6 metropolitan areas in the United States.

Interventions

Participants were randomly assigned to 1 of 4 groups: 10-session group training for memory (verbal episodic memory; n=711), or reasoning (ability to solve problems that follow a serial pattern; n=705), or speed of processing (visual search and identification; n=712); or a no-contact control group (n=704). For the 3 treatment groups, 4-session booster training was offered to a 60% random sample 11 months later.

Main Outcome Measures

Cognitive function and cognitively demanding everyday functioning.

Results

Thirty participants were incorrectly randomized and were excluded from the analysis. Each intervention improved the targeted cognitive ability compared with baseline, durable to 2 years (P<.001 for all). Eighty-seven percent of speed-, 74% of reasoning-, and 26% of memory-trained participants demonstrated reliable cognitive improvement immediately after the intervention period. Booster training enhanced training gains in speed (P<.001) and reasoning (P<.001) interventions (speed booster, 92%; no booster, 68%; reasoning booster, 72%; no booster, 49%), which were maintained at 2-year follow-up (P<.001 for both). No training effects on everyday functioning were detected at 2 years.

Conclusions

Results support the effectiveness and durability of the cognitive training interventions in improving targeted cognitive abilities. Training effects were of a magnitude equivalent to the amount of decline expected in elderly persons without dementia over 7- to 14-year intervals. Because of minimal functional decline across all groups, longer follow-up is likely required to observe training effects on everyday function.

This paper is based on a presentation made during the Indiana Alzheimer Disease Center’s Symposium on Mild Cognitive Impairment on April 19, 2008. The results of the ACTIVE study (Advanced Cognitive Training for Independent and Vital Elderly) were presented at the symposium including review of previously published study findings. The ACTIVE study is a multicenter, randomized, controlled clinical trial that has been examining the long-term effectiveness of cognitive training on enhancing mental abilities (memory, reasoning, and attention) and preserving activities of daily living (managing finances, taking medication, using the telephone, and driving) in older adults. Six centers across the eastern United States enrolled nearly 3000 people initially. Participants underwent detailed assessments of mental and functional ability on multiple occasions over several years of follow-up. ACTIVE has shown positive effects of cognitive training at 5 years post-intervention for basic mental abilities, health-related quality of life, and improved ability to perform instrumental activities of daily living (IADL). A subgroup analysis through 2 years of follow-up suggested that subjects with mild cognitive impairment (MCI) did not benefit from memory training; however, they did benefit, to the same degree as cognitively normal participants, from training in reasoning and speed of processing. This finding suggests that MCI may interfere with a person’s ability to benefit from some forms of cognitive enhancement. Limitations of ACTIVE and directions for future research are reviewed.

Cognitive training improves mental abilities in older adults, but the trainability of persons with memory impairment is unclear. We conducted a subgroup analysis of subjects in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial to examine this issue. ACTIVE enrolled 2802 non-demented, community-dwelling adults aged 65 years and older and randomly assigned them to one of four groups: Memory training, reasoning training, speed-of-processing training, or no-contact control. For this study, participants were defined as memory-impaired if baseline Rey Auditory Verbal Learning Test (AVLT) sum recall score was 1.5 SD or more below predicted AVLT sum recall score from a regression-derived formula using age, education, ethnicity, and vocabulary from all subjects at baseline. Assessments were taken at baseline (BL), post-test, first annual (A1), and second annual (A2) follow-up. One hundred and ninety-three subjects were defined as memory-impaired and 2580 were memory-normal. Training gain as a function memory status (impaired vs. normal) was compared in a mixed effects model. Results indicated that memory-impaired participants failed to benefit from Memory training but did show normal training gains after reasoning and speed training. Memory function appears to mediate response to structured cognitive interventions in older adults.

Background

Health care expenditures for older adults are disproportionately high and increasing at both the individual and population levels. We evaluated the effects of the three cognitive training interventions (memory, reasoning, or speed of processing) in the ACTIVE study on changes in predicted medical care expenditures.

Methods

ACTIVE was a multisite randomized controlled trial of older adults (≥ 65). Five-year follow-up data were available for 1,804 of the 2,802 participants. Propensity score weighting was used to adjust for potential attrition bias. Changes in predicted annualmedical expenditures were calculated at the first and fifth annual follow-up assessments using a new method for translating functional status scores. Multiple linear regression methods were used in this cost-offset analysis.

Results

At one and five years post-training, annual predicted expenditures declinedby $223 (p = .024) and $128 (p = .309), respectively, in the speed of processing treatment group, but there were no statistically significant changes in the memory or reasoning treatment groups compared to the no-contact control group at either period. Statistical adjustment for age, race, education, MMSE scores, ADL and IADL performance scores, EPT scores, chronic condition counts, and the SF-36 PCS and MCS scores at baseline did not alter the one-year ($244; p = .012) or five-year ($143; p = .250) expenditure declines in the speed of processing treatment group.

Conclusion

The speed of processing intervention significantly reduced subsequent annual predicted medical care expenditures at the one-year post-baseline comparison, but annual savings were no longer statistically significant at the five-year post-baseline comparison.

Summary

The 20S proteasome functions in protein degradation in eukaryotes together with the 19S ATPases or in archaea with the homologous PAN ATPase complex. PAN and the 19S ATPases contain a conserved C-terminal hydrophobic-tyrosine-X motif (HbYX). We show that these residues are essential for PAN to associate with the 20S and open its gated-channel for substrate entry. Upon ATP binding, these C-terminal residues bind to pockets between the 20S’s α-subunits. Furthermore, seven-residue peptides from PAN’s C-terminus that contain the HbYX motif also bind to these sites and induce gate-opening in both archaeal and mammalian 20S proteasomes. Gate-opening could be induced by short C-terminal peptides from the 19S ATPase subunits, Rpt2 and Rpt5, but not by ones from PA28/26, which lack the HbYX motif and cause gate-opening by distinct mechanism. The C-terminal YX residues in the 19S ATPases were also shown to be critical for gating and stability of mammalian and yeast 26S proteasomes. Thus, the C-termini of the proteasomal ATPases function like a “key-in-a-lock” to induce gate-opening and allow substrate entry.

Co-infection with HIV and P. falciparum worsens the prognosis of both infections; however, the mechanisms driving this adverse interaction are not fully delineated. To evaluate this, we studied HIV-1 and P. falciparum interactions in vitro using peripheral blood mononuclear cells (PBMCs) from human malaria naïve volunteers experimentally infected with P. falciparum in a malaria challenge trial.PBMCs collected before the malaria challenge and at several time points post-infection were infected with HIV-1 and co-cultured with either P. falciparum infected (iRBCs) or uninfected (uRBCs) red blood cells. HIV p24Ag and TNF-α, IFN-γ, IL-4, IL-6, IL-10, IL-17, and MIP-1α were quantified in the co-culture supernatants. In general, iRBCs stimulated more HIV p24Ag production by PBMCs than did uRBCs. HIV p24Ag production by PBMCs in the presence of iRBCs (but not uRBCs) further increased during convalescence (days 35, 56, and 90 post-challenge). In parallel, iRBCs induced higher secretion of pro-inflammatory cytokines (TNF-α, IFN-γ, and MIP-1α) than uRBCs, and production increased further during convalescence. Because the increase in p24Ag production occurred after parasitemia and generalized immune activation had resolved, our results suggest that enhanced HIV production is related to the development of anti-malaria immunity and may be mediated by pro-inflammatory cytokines.

Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of d-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to d-mannitol (Mr 182), polyethylene glycol (Mr 4000), and 10,000-Mr methylated dextran but not to 2,000,000-Mr methylated dextran. This implies a “ceiling” on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.

BACKGROUND: Animal, epidemiological and clinical studies have demonstrated the anti-tumor activity of pharmacological proteasome inhibitors and the cancer-preventive effects of green tea consumption. Previously, one of our laboratories reported that natural ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG] and (-)-gallocatechin-3-gallate [(-)-GCG], are potent and specific proteasome inhibitors. Another of our groups, for the first time, was able to enantioselectively synthesize (-)-EGCG as well as other analogs of this natural GTP. Our interest in designing and developing novel synthetic GTPs as proteasome inhibitors and potential cancer-preventive agents prompted our current study. MATERIALS AND METHODS: GTP analogs, (+)-EGCG, (+)-GCG, and a fully benzyl-protected (+)-EGCG [Bn-(+)-EGCG], were prepared by enantioselective synthesis. Inhibition of the proteasome or calpain (as a control) activities under cell-free conditions were measured by fluorogenic substrate assay. Inhibition of intact tumor cell proteasome activity was measured by accumulation of some proteasome target proteins (p27, I kappa B-alpha and Bax) using Western blot analysis. Inhibition of tumor cell proliferation and induction of apoptosis by synthetic GTPs were determined by G(1) arrest and caspase activation, respectively. Finally, inhibition of the transforming activity of human prostate cancer cells by synthetic GTPs was measured by a colony formation assay. RESULTS: (+)-EGCG and (+)-GCG potently and specifically inhibit the chymotrypsin-like activity of purified 20S proteasome and the 26S proteasome in tumor cell lysates, while Bn-(+)-EGCG does not. Treatment of leukemic Jurkat T or prostate cancer LNCaP cells with either (+)-EGCG or (+)-GCG accumulated p27 and IkappaB-alpha proteins, associated with an increased G(1) population. (+)-EGCG treatment also accumulated the pro-apoptotic Bax protein and induced apoptosis in LNCaP cells expressing high basal levels of Bax, but not prostate cancer DU-145 cells with low Bax expression. Finally, synthetic GTPs significantly inhibited colony formation by LNCaP cancer cells. CONCLUSIONS: Enantiomeric analogs of natural GTPs, (+)-EGCG and (+)-GCG, are able to potently and specifically inhibit the proteasome both, in vitro and in vivo, while protection of the hydroxyl groups on (+)-EGCG renders the compound completely inactive.

According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.

OBJECTIVE

To determine the incidence of major hemorrhage among outpatients started on warfarin therapy after the recommendation in 1986 for reduced-intensity anticoagulation therapy was made, and to identify baseline patient characteristics that predict those patients who will have a major hemorrhage.

DESIGN

Retrospective cohort study.

SETTING

A university-affiliated Veterans Affairs Medical Center.

PATIENTS

Five hundred seventy-nine patients who were discharged from the hospital after being started on warfarin therapy.

MEASUREMENTS AND MAIN RESULTS

The primary outcome variable was major hemorrhage. In our cohort of 579 patients, there were 40 first-time major hemorrhages with only one fatal bleed. The cumulative incidence was 7% at 1 year. The average monthly incidence of major hemorrhage was 0.82% during the first 3 months of treatment and decreased to 0.36% thereafter. Three independent predictors of major hemorrhage were identified: a history of alcohol abuse, chronic renal insufficiency, and a previous gastrointestinal bleed. Age, comorbidities, medications known to influence prothrombin levels, and baseline laboratory values were not associated with major hemorrhage.

CONCLUSIONS

The incidence of major hemorrhage in this population of outpatients treated with warfarin was lower than previous estimates of major hemorrhage measured before the recommendation for reduced-intensity anticoagulation therapy was made, but still higher than estimates reported from clinical trials. Alcohol abuse, chronic renal insufficiency, and a previous gastrointestinal bleed were associated with increased risk of major hemorrhage.

This investigation was undertaken to evaluate possible genetic determinants of bone mass with the premise that inheritance of bone mass could be of etiologic importance in osteoporosis.

Bone mass and width measurements were made with the photon absorption technique on the right radius of 71 juvenile and 80 adult twin paris. The variance of intrapair differences of bone mass in monozygotic (MZ) juvenile twins was 0.0013 g2/cm2 compared to 0.0052 g2/cm2 in the dizygotic (DZ) twins. For the adult twins the variance of intrapair differences in bone mass was 0.0069 for MZ and 0.0137 for DZ twins. Similar results were obtained for bone width. The significantly larger variation in intrapair differences in DZ twins indicates that these traits have significant genetic determinants. These intrapair differences were found to increase with age, suggesting that genetic-environmental interaction also contributes to the observed variation in bone mass.

These data provide evidence that bone mass does have significant genetic factors, which alone or in conjunction with environmental factors may predispose persons to the development of osteoporosis.