Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

The original version of this article, published on 21 March 2019, unfortunately contains some typos in Figs. 2, 3, 4, and Supplemental Fig. 1. The corrected figures are given below.

Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

The original version of this article, published on 21 March 2019, unfortunately contained a mistake.

Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

PURPOSE: Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture. METHODS: Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463). RESULTS: After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p < 0.001) and 1.54 percentage points greater for abaloparatide compared with teriparatide (95% CI 0.64, 2.45, p < 0.001). At 18 months, 1/3 radius BMD losses (versus baseline) were similar for abaloparatide compared with placebo (-0.42; 95% CI -1.03, 0.20; p = 0.19) but losses with teriparatide exceeded those of placebo (-1.66%; 95% CI -2.27, -1.06; p < 0.001). The decline with abaloparatide was less than that seen with teriparatide (group difference 1.22%; 95% CI 0.57, 1.87; p < 0.001). The radius BMD findings, at both ultradistal and 1/3 sites, are consistent with the numerically lower incidence of wrist fractures observed in women treated with abaloparatide compared with teriparatide (HR = 0.43; 95% CI 0.18, 1.03; p = 0.052) and placebo (HR = 0.49, 95% CI 0.20, 1.19, p = 0.11). CONCLUSIONS: Compared with teriparatide, abaloparatide increased BMD at the ultradistal radius (primarily trabecular bone) and decreased BMD to a lesser extent at the 1/3 radius (primarily cortical bone), likely contributing to the numerically lower wrist fracture incidence observed with abaloparatide.

Physical activity and motivational predictors of changes in health behavior and health among DM2 and CAD patients.

This study tested a physical activity intervention and the self-determination theory (SDT) process model of health-behavior change and health among 108 adult patients with both diabetes mellitus type 2 (DM2) and coronary artery disease (CAD). Patients were randomly assigned to an organized physical activity intervention group (led by instructors) or a non-physical activity control group. At baseline and after 12 months, we measured the following: needs satisfaction, autonomous and controlled motivation for physical activity, perceived competence for physical activity and blood sugar testing, physical activity and blood sugar testing, body weight, glucose control (HbA1c), and self-perceptions of general health and vitality. The intervention produced, as hypothesized, significant changes in all study variables in favor of the experimental group (Cohen's d effect sizes: 0.23-0.72), except the non-significant result for controlled motivation and body weight. The data supported the SDT process model, in which the effect of the intervention significantly predicted indirect changes in behavior and health through motivation variables. Considering the moderate to large effects on increases in motivation, behavior, and health, promoting organized physical activity programs that are perceived as need-supportive may have important health implications for patients with DM2 and CAD.

Defects of bile acid synthesis in Zellweger's syndrome.

Abnormal mitochondrial structure and function have been documented in patients with Zellweger's syndrome (cerebrohepatorenal syndrome). In vitro studies have suggested that the formation of C24 bile acids (chenodeoxycholic acid and cholic acid) from C27 cholesterol requires mitochondrial oxidative clevage of the terminal three carbons of the side chain. Therefore, three patients with Zellweger's syndrome were examined for the presence of mitochondrial defects in bile acid synthesis. All three excreted excessive amounts of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestan-26-oicacid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, and 3 alpha, 7 alpha, 12 alpha, 24 xi-tetrahydroxy-5 beta-cholestan-26-oic acid (varanic acid), precursors of chenodeoxycholic acid and cholic acid that have undergone only partial side chain oxidation. These findings give added support to the role of mitochondrial oxidative side chain cleavage in the overall scheme of bile acid synthesis.

Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial.

BACKGROUND: Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE. METHODS: Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites. RESULTS: At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds. CONCLUSIONS: In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.

The metabolism of 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. An apparent inborn error of cholic acid synthesis.

Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of (3H)THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of (3H)cholic acid was also identified after (3H)THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3alpha, 7alpha, 12alpha, 24xi-tetrahydorxy-5beta-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid. This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal sibling nor the two parents have increased amount of THCA in their bile.

Formation of cholic acid via 3 alpha, 7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid in the dog.

The proposed cholic precursor, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-[3H]cholestan-26-oic acid, and [14C]cholesterol were infused intravenously at a constant rate into two dogs for 25 days. If the specific activities of trihydroxy[3H]cholestanoic acid and [3H]cholic acid will be equal after an isotopic steady-state is achieved. The specific activities of [14C]deoxycholic acid (formed from [14C]cholic acid) isolated in the stool of these two dogs were equal the last four days of the infusion indicating that labeled deoxycholic acid (and presumably labeled cholic acid) was in an isotopic steady-state. However, the specific activities of trihydroxy[3H]cholestanoic acid were 3.3 and 5.7 times greater than the specific activities of [3H]cholic acid, respectively. These data suggest that either an alternate route of cholic acid synthesis exists exclusive of trihydroxycholestanoic acid or that an isotopic steady state of trihydroxycholestanoic acid cannot be reached during an infusion of labeled trihydroxycholestanoic acid.

Evidence for carrier proteins in bile acid synthesis. The effect of squalene and sterol carrier protein and albumin on the activity of 12alpha-hydroxylase.

The possibility that carrier proteins are involved in bile acid synthesis was investigated using rat liver homogenates. The 105 000 X g supernatant fraction was found to contain heat stable proteins that bound the bile acid precursor, 7alpha-hydroxy-4-cholesten-3-one, and increased the amount of 7alpha, 12alpha-dihydroxy-4-cholesten-3-one formed by the microsomal enzyme, 12alpha-hydroxylase. Subsequent studies were carried out to determine if squalene and sterol carrier protein or albumin, two lipid binding proteins present in the 105 00 X g supernatant fraction of rat liver homogenates, may be responsible for the effects seen with this fraction. Squalene and sterol carrier protein bound several water insoluble bile acid precursors, including 7alpha-hydroxy-4-cholesten-3-one, and increased the apparent activity of 12alpha-hydroxylase. Squalene and sterol carrier protein, however, did not bind either cholic acid or chenodeoxycholic acid. Rat serum albumin also bound 7alpha-hydroxy-4-cholesten-3-one and increased the apparent activity of 12alpha-hydroxylase. Kinetic analysis indicated that the apparent stimulation of 12alpha-hydroxylase by squalene and sterol carrier protein and albumin was due to increased solubilization of the substrate, 7alpha-hydroxy-4-cholesten-3-one. Thus, these studies indicate that bile acid precursor carrier proteins are present in the 105 000 Xg supernatant fraction of rat liver homogenates and suggest that squalene and sterol carrier protein or albumin may participate as carrier proteins in bile acid synthesis.

Formation of bile acids in man. Metabolism of 7alpha-hydroxy-4-cholesten-3-one in normal subjects with an intact enterohepatic circulation.

The formation of bile acids in man is thought to involve a series of reactions in which the initial steps are the same for both cholic acid and chenodeoxycholic acid. The point of bifurcation of the pathway is postulated to occur after the formation of 7alpha-hydroxy-4-cholesten-3-one. To test the hypothesis that the entire synthesis of both bile acids proceeds through this intermediate we studied the metabolism of labeled 7alpha-hydroxy-4-cholesten-3-one in eight normal subjects with an intact enterohepatic circulation. If all the production of cholic acid and chenodeoxycholic acid takes place via 7alpha-hydroxy-4-cholesten-3-one, the areas under the specific decay curves of cholic acid and chenodeoxycholic acid should be identical following a single injection of this labeled intermediate. However, in 6 of the 8 subjects studied the area under the cholic acid specific activity decay curve was significantly less than the area under the chenodeoxycholic acid specific activity decay curve. These results that the production of cholic acid in man may not always involve the intermediate 7alpha-hydroxy-4-cholesten-3-one.

Supporting autonomy to motivate patients with diabetes for glucose control.

OBJECTIVE: We applied the self-determination theory of human motivation to examine whether patient perceptions of autonomy supportiveness (i.e., patient centeredness) from their diabetes care providers related to improved glucose control over a 12-month period. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of patients with diabetes from a diabetes treatment center at a university-affiliated community hospital. Participants were 128 patients between 18 and 80 years of age who took medication for diabetes, had no other major medical illnesses, and were responsible for monitoring their glucose and taking their medications. The main outcome measure was a change in HbA1c values over the 12 months of the study RESULTS: Patient perception of autonomy support from a health care provider related to a change in HbA1c values at 12 months (P < 0.05). Further analyses showed that perceived autonomy support from the staff related to significant increases in patient autonomous motivation at 12 months (P < 0.05); that increases in autonomous motivation related to significant increases in perceived competence (P < 0.05); and that increases in a patient's perceived competence related to significant reductions in their HbA1c values over 12 months (P < 0.001). CONCLUSIONS: The findings support the prediction of the self-determination theory that patients with diabetes whose health care providers are autonomy supportive will become more motivated to regulate their glucose levels, feel more able to regulate their glucose, and show improvements in their HbA1c values.

Immunodeficiency, xanthomas and obstructive liver disease.

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.

T-cell lymphoproliferative disorder of vitreous associated with mycosis fungoides.

59-year-old man with a history of mycosis fungoides developed loss of visual acuity and visual field in the left eye. Epiretinal lesions were present in the right eye and multifocal choroidal lesions, optic disc edema, and vitritis were present in the left eye. A diagnostic vitrectomy was performed and cytologic examination of the vitreous confirmed the diagnosis of T-cell lymphoproliferative disorder. Systemic and intrathecal chemotherapy resulted in marked improvement in ocular signs and symptoms. At last follow-up, the patient was found to have improved visual acuity in the left eye; however, significant worsening of his systemic condition developed and he died shortly thereafter.

Presenting the facts about smoking to adolescents: effects of an autonomy-supportive style.

OBJECTIVES: To test the self-determination model of health-related behavior by examining whether the degree to which adolescents experience an appeal to not smoke as autonomy supportive would affect their autonomous motivation for not smoking and, in turn, their behavior of either refraining from smoking or smoking less, and to validate the measures of perceived autonomy support and autonomous motivation for not smoking. DESIGN: Two studies of physicians presenting information about not smoking using 2 message styles, 1 of which was designed to be more autonomy supportive. The preliminary study involved nonrandomized assignment to message style and only immediate assessment of perceptions, motivation, and behavior, while the primary study involved randomized assignment and 4-month longitudinal assessments. SETTING AND PARTICIPANTS: Nearly 400 ninth- through 12th-grade students at 2 suburban high schools in upstate New York. MAIN OUTCOME MEASURES: Adolescents' perceptions of the presentations' autonomy supportiveness of the presenters, as well as adolescents' autonomous motivation for not smoking and their self-reports of smoking. The primary study also assessed change in students' autonomous motivation and change in their self-reported smoking during 4 months. RESULTS: In both studies, the measures were reliable and valid. Students perceived significantly (P = .04 and P<.001, respectively) greater autonomy support in the "It's Your Choice" presentation, after controlling for whether the students were smokers. Perceived autonomy supportiveness of the presentation was positively correlated with autonomous reasons for not smoking in the preliminary study and with increases in autonomous motivation for not smoking in the primary study. Change in autonomous reasons for not smoking significantly (P<.001) predicted reduction in smoking during 4 months. CONCLUSION: When adolescents perceived messages about not smoking as autonomy supportive, they had more autonomous motivation for not smoking, and that, in turn, predicted a decrease in their self-reports of smoking.

Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides.

Novel targeted proapoptotic anticancer drug delivery systems were developed and evaluated. Poly(ethyleneglycol) (PEG) conjugates were used as carriers. Camptothecin (CPT) was used as an anticancer agent-apoptosis inductor. Two types of molecular targets were investigated: (1) an extracellular membrane receptor specific to ovarian cancer and (2) intracellular controlling mechanisms of apoptosis. Synthetic peptides similar to luteinizing hormone-releasing hormone (LHRH) and BCL-2 homology 3 (BH3) peptide were used as a targeting moiety and a suppressor of cellular antiapoptotic defense, respectively. Three different conjugates (CPT-PEG, CPT-PEG-BH3 and CPT-PEG-LHRH) were synthesized and examined in A2780 human ovarian cancer cells. Cytotoxicity, expression of genes encoding BCL-2, BCL-XL, SMAC, APAF-1 proteins and caspases 3 and 9, the activity of caspases 3 and 9 and apoptosis induction were studied. Taken together the results indicate much higher cytotoxicity and apoptosis-inducing activity of PEG-CPT conjugates when compared to free CPT. Moreover, the effects of targeted CPT-PEG-BH3 and CPT-PEG-LHRH conjugates were more pronounced than the non-targeted PEG-CPT conjugate. The results confirmed the feasibility of this new two-tier molecular targeting strategy for enhancing the efficacy of cancer chemotherapy.

Autonomous regulation and long-term medication adherence in adult outpatients.

Self-determination theory was applied to explore the motivational basis of adherence to long-term medication prescriptions. Adult outpatients with various diagnoses who had been on a medication for at least 1 month and expected to continue (a) completed questionnaires that assessed their autonomous regulation, other motivation variables, and perceptions of their physicians' support of their autonomy by hearing their concerns and offering choice; (b) provided subjective ratings of their adherence and a 2-day retrospective pill count during an interview with a clinical psychologist; and (c) provided a 14-day prospective pill count during a subsequent, brief telephone survey. LISREL analyses supported the self-determination model for adherence by confirming that patients' autonomous motivation for adherence did mediate the relation between patients' perceptions of their physicians' autonomy support and their own medication adherence.

Eye height scaling of absolute size in immersive and nonimmersive displays.

Eye-height (EH) scaling of absolute height was investigated in three experiments. In Experiment 1, standing observers viewed cubes in an immersive virtual environment. Observers' center of projection was placed at actual EH and at 0.7 times actual EH. Observers' size judgments revealed that the EH manipulation was 76.8% effective. In Experiment 2, seated observers viewed the same cubes on an interactive desktop display; however, no effect of EH was found in response to the simulated EH manipulation. Experiment 3 tested standing observers in the immersive environment with the field of view reduced to match that of the desktop. Comparable to Experiment 1, the effect of EH was 77%. These results suggest that EH scaling is not generally used when people view an interactive desktop display because the altitude of the center of projection is indeterminate. EH scaling is spontaneously evoked, however, in immersive environments.

The importance of self-determination theory for medical education.

While some theories of human motivation focus exclusively on levels of motivation, self-determination theory argues that different types of motivators, even when the resulting motivation is high, will lead to very different outcomes. This theory differentiates between two primary kinds of motivation, controlled and autonomous. Controlled motivation depends either on explicit or implicit rewards or punishment or on people's internalized beliefs about what is expected of them. Learning in controlled situations, in which students act under pressure and anxiety, is likely to be rote, short-lived, and poorly integrated into students' long-term values and skills. In contrast, autonomous motivation, as its name implies, is personally endorsed and reflects what people find interesting and important. While controlled motivation involves compliance with pressures, autonomous motivation involves behaving with a sense of volition, agency, and choice. Autonomously motivated learning leads to better educational outcomes. There is evidence that medical students who learn in autonomy-supportive environments act in more autonomy-supportive ways in their interactions with patients. Because the reliable implementation of practice guidelines and physicians' use of an autonomy-supportive style have been associated with more positive health outcomes (particularly in the behavior-related areas of smoking cessation, weight loss, etc.), more autonomy-supportive medical education may result in more effective health care delivery.

Effect of taurocholate on the conversion of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid into cholic acid.

To determine if the conversion of the intermediate, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid is influenced by taurocholate, two rats were infused intravenously with [3H] THCA until they reached a steady state. Taurocholate was then added and infused at a rate of 1 mumole/min/rat for 48 hours. The percentage of [3H] THCA recovered in the bile did not increase indicating that taurocholate does not suppress the conversion of THCA into cholic acid.

Internalization of biopsychosocial values by medical students: a test of self-determination theory.

Two studies tested self-determination theory with 2nd-year medical students in an interviewing course. Study 1 revealed that (a) individuals with a more autonomous orientation on the General Causality Orientation Scale had higher psychosocial beliefs at the beginning of the course and reported more autonomous reasons for participating in the course, and (b) students who perceived their instructors as more autonomy-supportive became more autonomous in their learning during the 6-month course. Study 2, a 30-month longitudinal study, revealed that students who perceived their instructors as more autonomy-supportive became more autonomous in their learning, which in turn accounted for a significant increase in both perceived competence and psychosocial beliefs over the 20-week period of the course, more autonomy support when interviewing a simulated patient 6 months later, and stronger psychosocial beliefs 2 years later.