Components of self-awareness affecting caregiver burden: a long-term follow-up study.

OBJECTIVE: Studies utilizing the discrepancy model of the Mayo-Portland Adaptability Inventory-4 (MPAI-4) have commonly used the cognitive and physical domains to estimate self-awareness. This study included other aspects of self-awareness such as awareness of one's social and emotional status and daily functioning to explore their effects on caregiver burden for ABI survivors. METHODS: We studied 64 patient-caregiver pairs up to 29 years post-discharge from a holistic, milieu-oriented outpatient neurorehabilitation program. Discrepancy scores between ABI survivors' and caregivers' reports on the MPAI-4 subscales (i.e. Abilities, Adjustment, and Participation) and Total Score were used to determine self-awareness. Caregiver burden was measured using the Zarit Burden Interview (ZBI). RESULTS: Exploratory linear regression analyses revealed that caregiver burden derived from the ZBI was predicted by the discrepancy scores generated from the Abilities (p < 0.0001), Adjustment (p < 0.01), Participation subscales (p = 0.01), and Total Score (p < 0.001), respectively. Among the exploratory models generated, the Total Score model had the highest predictive value (R2 = .33) for caregiver burden. CONCLUSIONS: Measures of self-awareness should be comprehensive by considering diverse components of self-awareness. Increasing ABI survivors' self-awareness in different domains has the potential to effectively alleviate caregiver burden.

Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies.

RNA-dependent RNA polymerases (RdRPs) represent a distinctive yet versatile class of nucleic acid polymerases encoded by RNA viruses for the replication and transcription of their genome. The structure of the RdRP is comparable to that of a cupped right hand consisting of fingers, palm, and thumb subdomains. Despite the presence of a common structural core, the RdRPs differ significantly in the mechanistic details of RNA binding and polymerization. The present review aims at exploring these incongruities in light of recent structural studies of RdRP complexes with diverse cofactors, RNA moieties, analogs, and inhibitors.

The presentation, etiologies, pathophysiology, and treatment of pulmonary renal syndrome: A review of the literature.

Pulmonary renal syndrome (PRS) is a constellation of different disorders that cause both rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. While antineutrophil cytoplasmic antibody associated vasculitis and anti-glomerular basement membrane disease are the predominant causes of PRS, numerous other mechanisms have been shown to cause this syndrome, including thrombotic microangiopathies, drug exposures, and infections, among others. This syndrome has high morbidity and mortality, and early diagnosis and treatment is imperative to improve outcomes. Treatment generally involves glucocorticoids and immunosuppressive agents, but treatment targeted to the underlying disorder can improve outcomes and mitigate side effects. Familiarity with the wide range of possible causes of PRS can aid the clinician in workup, diagnosis and early initiation of treatment. This review provides a summary of the clinical presentation, etiologies, pathophysiology, and treatment of PRS.

Clofarabine with topotecan, vinorelbine, and thiotepa reinduction regimen for children and young adults with relapsed AML.

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline-based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate, defined as complete remission or complete remission with partial recovery of platelet count, was 71.4% (95% confidence interval [CI], 41.9-91.6) for those patients in first relapse (n = 14) and 47.4% (95% CI, 24.4-71.1) for patients in second or greater relapse or with refractory disease. Responses were seen across multiple high-risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year overall survival for patients in first relapse was 46.2% (95% CI, 19.1-73.3) and 50.0% (95% CI, 26.9-73.1) for patients who responded to TVTC. For pediatric and young adult patients with relapsed/refractory AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.

Long-term neurorehabilitation outcomes of pediatric vs. adult onset acquired brain injury.

Background: Functional outcomes of intensive neurorehabilitation for pediatric onset acquired brain injury (ABI) are understudied. The extent and pervasiveness of impairments are often uncovered years after an ABI and can worsen over time, leading to a cascade of academic, functional, and psychosocial difficulties. Objective: To examine the long-term outcomes of survivors with pediatric onset vs. adult onset ABI who completed holistic milieu-oriented neurorehabilitation up to 30 years ago. Methods: One hundred twenty-three survivors of ABI including a pediatric onset group (n = 22) and an adult onset group (n = 101) with heterogeneous neurological etiologies who attended holistic, milieu-oriented neurorehabilitation. Productivity, driving, and functional outcomes were evaluated using the Mayo-Portland Adaptability Inventory-4 (MPAI-4) and a psychosocial outcome questionnaire. Treatment for the pediatric onset group started much later than onset. Results: A one-way analysis of covariance revealed no significant differences between the two groups on the MPAI-4. At the follow-up survey, there was no significant difference between age at onset of injury and productivity status. The average follow-up time was ~8 years (SD = 6.28) from time of discharge to the time of the survey. Although there was no significant difference between the two groups for driving at the time of admission, the adult onset group was significantly more likely to return to driving after treatment. Conclusions: This study demonstrates the positive and enduring benefits of holistic, milieu-oriented neurorehabilitation for survivors of pediatric onset ABI regardless of the time between initial injury and engagement in rehabilitative therapies.

Impact of Bridging Chemotherapy on Clinical Outcomes of CD19-Specific CAR T Cell Therapy in Children/Young Adults with Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia.

Chimeric antigen receptor (CAR) T cells achieve response and durable remission in patients with relapsed/refractory (R/R) B cell malignancies. Following collection of patient T cells, chemotherapy ("bridging chemotherapy") is utilized during the manufacture of CAR T cells. However, the optimal bridging chemotherapy has yet to be defined. Our objective in this study was to report clinical outcomes following bridging chemotherapy in a cohort of pediatric/young adult patients with R/R B cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cell therapy. This retrospective study included patients enrolled on clinical trial NCT01860937 or referred to Memorial Sloan Kettering Cancer Center for commercial CAR T cell therapy (tisagenlecleucel). Bridging chemotherapy (given after T cell collection and before CAR T cell infusion) was defined as high intensity if myelosuppression was expected for >7 days. Outcome comparison analyses were performed in high-intensity versus low-intensity bridging chemotherapy, 1 cycle versus ≥2 cycles of bridging chemotherapy, disease burden at the start of bridging chemotherapy, disease burden at the start of bridging chemotherapy with chemotherapy intensity, tumor debulking by bridging chemotherapy, and disease burden pre-lymphodepleting chemotherapy (LDC) for CAR T cell treatment. The outcomes of this analysis showed that the incidence of grade ≥3 infection was significantly higher (94% versus 56%; P = .019) and overall survival (OS) was significantly lower (hazard ratio, 3.73; 95% confidence interval, 1.39 to 9.97; P = .006) in patients who received ≥2 cycles versus 1 cycle of bridging chemotherapy. No difference in incidence was found for cytokine release syndrome (P > .99) or neurotoxicity/immune effector cell-associated neurotoxicity syndrome (P = .70). Disease burden at the start of bridging chemotherapy, disease burden prior to LDC, and tumor debulking by bridging chemotherapy also did not significantly affect outcomes after CAR T cell therapy in this cohort. In this study, patients receiving ≥2 cycles of bridging chemotherapy had higher rates of infection and lower OS but no difference in CAR-specific toxicity. Clinicians should carefully consider the use of additional cycles of chemotherapy during the bridging period as it delays treatment with CAR T cells and increases the risk of infectious complications. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Macrophage and adipocyte interaction as a source of inflammation in kidney disease.

In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized. We studied the contribution of adipose tissue to uremic inflammation in-vitro, in-vivo and in human samples. Exposure to uremic serum resulted in activation of inflammatory pathways including NFκB and HIF1, upregulation of inflammatory cytokines/chemokines and catabolism with lipolysis, and lactate production. Also, co-culture of adipocytes with macrophages primed by uremic serum resulted in higher inflammatory cytokine expression than adipocytes exposed only to uremic serum. Adipose tissue of end stage renal disease subjects revealed increased macrophage infiltration compared to controls after BMI stratification. Similarly, mice with kidney disease recapitulated the inflammatory state observed in uremic patients and additionally demonstrated increased peripheral monocytes and inflammatory polarization of adipose tissue macrophages (ATMS). In contrast, adipose tissue in uremic IL-6 knock out mice showed reduced ATMS density compared to uremic wild-type controls. Differences in ATMS density highlight the necessary role of IL-6 in macrophage infiltration in uremia. Uremia promotes changes in adipocytes and macrophages enhancing production of inflammatory cytokines. We demonstrate an interaction between uremic activated macrophages and adipose tissue that augments inflammation in uremia.

Does self-awareness influence caregiver burden?

BACKGROUND: Caregiver burden is experienced by a significant number of caregivers of survivors of acquired brain injury (ABI). It is known that self-awareness can impact functioning following ABI. However, the impact of self-awareness on caregiver burden has not been established. OBJECTIVE: To investigate the relationship between self-awareness and caregiver burden following ABI. METHODS: We studied 57 patient-caregiver pairs up to 28 years post-discharge from a post-acute comprehensive holistic milieu-oriented neurorehabilitation program. The Mayo-Portland Adaptability Inventory-4 (MPAI-4) was completed by survivors of ABI and their caregivers. Discrepancies in reports between survivors of ABI and their caregivers were used to determine self-awareness. Additionally, caregivers completed the Zarit Burden Interview (ZBI). RESULTS: Survivors of ABI with impaired self-awareness reported significantly higher levels of functioning than survivors of ABI with unimpaired self-awareness (p < 0.001). Unimpaired self-awareness (p < 0.001) and lower survivor self-reported MPAI-4 Total Score (p < 0.001) significantly predicted caregiver burden. CONCLUSIONS: Survivors of ABI's level of functioning and their level of self-awareness significantly impacted caregiver burden. Survivors of ABI with impaired self-awareness not only lack insight into their functional abilities but also tend to overestimate their capabilities; this likely contributes to the need for greater levels of supervision and worsened caregiver burden.

Individualized dialysate sodium prescriptions using sodium gradients for high-risk hemodialysis patients lowered interdialytic weight gain and achieved target weights.

INTRODUCTION: Large interdialytic weight gain (IDWG) is associated with increased morbidity and mortality in chronic hemodialysis patients. Over 50% of patients at our inner city tertiary academic center dialysis unit had IDWG and target weights (TW) above goal. We conducted an open-label nonrandomized study to explore the effects of an individualized dialysate sodium (DNa) prescription using Na gradients in patients at high risk for large IDWG. Thirty-three patients receiving chronic hemodialysis received individualized DNa prescriptions with a DNa bath of 0 to -2 meq/L below their serum Na level in the intervention group, while patients in the control group were prescribed the standard dialysate Na at 138 mmol/L. Serum Na level, predialysis SBP, symptomatic hypotensive episodes, and %hemodialysis treatments with large IDWG (%TxAIDWG) and above TW(%TxATW) were recorded before and three months after the intervention. We used student t tests to compare continuous variables and Chi-square tests to compare binary variables between the groups at baseline and after the intervention. Age- and sex-adjusted linear regression models were also constructed to assess the differences in each continuous outcome between the groups. Multivariable logistic regression models were conducted by modeling IDWG decrease and above estimated-dry-weight (EDW) decrease as binary dependent variables with adjustment for age, sex, and EDW change. FINDINGS: Patients with individualized DNa concentrations had 3.6 times greater odds of having lower IDWG than those with standard dialysate Na concentration. This significant association remained after adjustment for age, sex, and changes in EDW (OR: 3.63; 95% CI, 1.03-12.9). There was no difference in predialysis BP or symptomatic hypotensive episodes between the two groups. DISCUSSION: Individualized DNa prescriptions appeared to be well tolerated and may be effective for optimal fluid management in high-risk hemodialysis patients.

Community reintegration following holistic milieu-oriented neurorehabilitation up to 30 years post-discharge.

BACKGROUND: The primary goal of neurorehabilitation for individuals with acquired brain injury (ABI) is successful community reintegration, which commonly focuses on home independence, productivity, and social engagement. Previous research has demonstrated that holistic treatment approaches have better long-term outcomes than other treatment approaches. Holistic approaches go beyond the fundamental components of neurorehabilitation and address metacognition and self-awareness, as well as interpersonal and functional skills. OBJECTIVES: The present study aimed to examine community reintegration of individuals with ABI who completed holistic milieu-oriented neurorehabilitation at the Center for Transitional Neuro-Rehabilitation (CTN), Barrow Neurological Institute (BNI) at up to 30-years post-discharge. We evaluated (a) functional independence, (b) productivity and driving status, and (c) psychosocial profiles of the brain injury survivors. METHOD: Participants included 107 individuals with ABI with heterogeneous etiologies who attended holistic milieu-oriented neurorehabilitation between 1986 and 2016. These participants completed the Mayo-Portland Adaptability Inventory-4 (MPAI-4) and a long-term outcome questionnaire (LOQ) specifically developed for this study. RESULTS: The results demonstrate that 89% of participants were productive at up to 30 years post-discharge (73% engaged in competitive work and/or school) after excluding the retired participants. Almost all of the participants who were engaged in work and/or school reported using compensatory strategies on a long-term basis. Furthermore, only 14% out of 102 study participants were driving at the time of program admission; whereas 58% out of 96 were driving at the time of discharge; and impressively, 70% out of 107 participants were driving at the time of follow-up. Regression analyses revealed that older age at the time of injury, shorter duration between injury and treatment, and better functionality indicated by lower MPAI-4 Ability Index scores significantly predicted a return to driving status at the time of study participation. Psychosocial data from the LOQ revealed positive findings with respect to patients' marital status, living situation, income, and quality of social life. CONCLUSION: The findings from this study suggest that functional gains made during holistic neurorehabilitation have enduring effects and that patients can benefit highly from holistic milieu therapy beyond the early post-acute phases of their recovery. Additionally, they provide evidence that there is potential to return to driving, years after treatment completion.Our holistic milieu treatment approach addressing metacognition, self-awareness, social and coping skills training, and actively transitioning to community settings, is thought to have contributed to the exceptional and long-lasting outcomes in this study.

Kidney transplantation for the primary care provider.

Advancement in kidney transplantation has led to prolonged survival in our population with kidney disease. Newer agents of immunosuppression have made this possible with less rejections and lesser opportunistic infections and transplant related deaths. Preventative care like timely vaccines, cancer screenings, aggressive blood pressure, blood sugar, lipid control, timely referral to consultants is required in these patient population to provide quality care and to prolong their survival. Primary care physicians are the best advocate for our transplant populations. To care for these complex transplant patients, it is vital for primary care physicians to be familiar with the overall approach on our patients.

Maintenance chemotherapy to reduce the risk of a metachronous Wilms tumor in children with bilateral nephroblastomatosis.

From 2009 to 2018, 10 consecutive patients with Wilms tumors and bilateral nephroblastomatosis, who had completed standard therapy, were provided a maintenance chemotherapy regimen consisting of vincristine and dactinomycin every 3 months for 12 months in order to prevent an early metachronous Wilms tumor. One patient (10%) with Beckwith-Wiedemann syndrome developed a new tumor, without anaplasia. There were no significant toxicities reported during maintenance. All patients are currently alive with no evidence of disease. Further investigations are recommended to determine the utility of this approach.

A case of KMT2A-SEPT9 fusion-associated acute megakaryoblastic leukemia.

Acute megakaryoblastic leukemia (AMKL) constitutes ∼5%-15% of cases of non-Down syndrome AML in children, and in the majority of cases, chimeric oncogenes resulting from recurrent gene rearrangements are identified. Based on these rearrangements, several molecular subsets have been characterized providing important prognostic information. One such subset includes a group of patients with translocations involving the KMT2A gene, which has been associated with various fusion partners in patients with AMKL. Here we report the molecular findings of a 2-yr-old girl with AMKL and t(11;17)(q23;25) found to have a KMT2A-SEPT9 fusion identified through targeted RNA sequencing. A KMT2A-SEPT9 fusion in this subset of patients has not previously been reported.

Peptidomimetic blockade of MYB in acute myeloid leukemia.

Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.

Therapeutic Re-Activation of Protein Phosphatase 2A in Acute Myeloid Leukemia.

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.

The relationship of neuropsychological variables to driving status following holistic neurorehabilitation.

OBJECTIVE: The main objectives of the present study were to evaluate the cognitive and driving outcomes of a holistic neurorehabilitation program and to examine the relationship between the neuropsychological variables of attention, speed of information processing, and visuospatial functioning and driving outcomes. METHODS: One hundred and twenty-eight individuals with heterogeneous neurological etiologies who participated in a holistic neurorehabilitation program. Holistic neurorehabilitation consisted of therapies focusing on physical, cognitive, language, emotional, and interpersonal functioning, including training in compensatory strategies. Neuropsychological testing was administered at admission and prior to starting driving or program discharge. Subtests of processing speed, working memory, and perceptual reasoning from the Wechsler Adult Intelligence Scale-III and Trail Making Test were included. RESULTS: At the time of discharge, 54% of the individuals returned to driving. Statistical analyses revealed that at the time of discharge: the sample as a group made significant improvements on cognitive measures included in the study; the driving and non-driving groups differed significantly on aspects of processing speed, attention, abstract reasoning, working memory, and visuospatial functions. Further, at the time of admission, the driving group performed significantly better than the non-driving group on several neuropsychological measures. CONCLUSION: Cognitive functions of attention, working memory, visual-motor coordination, motor and mental speed, and visual scanning significantly contribute to predicting driving status of individuals after neurorehabilitation. Holistic neurorehabilitation facilitates recovery and helps individuals to gain functional independence after brain injury.

Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia in children.

OBJECTIVES: To determine the safety, tolerability, or efficacy of 2 licensed thrombopoietic agents in children with persistent and chronic immune thrombocytopenia (ITP). STUDY DESIGN: Retrospective analysis approved by the institutional review board of children with ITP not on-study who received thrombopoietin (TPO) therapy; 21 received romiplostim (11 at Children's Hospital of Orange County, 10 at Weill Cornell Medical Center) and 12 received eltrombopag (all at Weill Cornell Medical Center). Primary response measures were platelet counts ≥ 50 × 10(9)/L or ≥ 20 × 10(9)/L above baseline for 2 consecutive weeks and 50% of platelet counts ≥ 50 × 10(9)/L. Duration of treatment and adverse events, including bone marrow myelofibrosis (MF) consensus grades, were tabulated. RESULTS: Twenty-seven of 33 (82%) patients responded to TPO agents, 18 of 21 to romiplostim, and 9 of 12 to eltrombopag, after an average of 3.6 previous ITP therapies. These 27 patients had platelet counts ≥ 50 × 10(9)/L and ≥ 20 × 10(9)/L above baseline for 2 consecutive weeks; 26 had 50% of platelet counts ≥ 50 × 10(9)/L. Duration of romiplostim use ranged from 6 to 44 months (11/18 ongoing) and of eltrombopag 23 to 53 months (7/12 ongoing). One patient on eltrombopag experienced a provoked deep-vein thrombosis at site of ankle fracture. No other serious drug-related adverse events occurred. Among 24 bone marrows, 10 after greater than 2 years of therapy, 23 were normal (MF grades 0-1); 1 was MF-2. CONCLUSION: Retrospective analysis of off-study use of TPO agents in children with mainly chronic ITP showed increases in platelet counts in more than 4 of 5 children. The long-term use of TPO agents, up to 53 months, without tachyphylaxis supports their efficacy. These agents appear safe, effective, and tolerable in children with chronic ITP.

Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α.

Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1(-/-) mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1(-/-) mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.

Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism.

Anorexia nervosa (AN) is associated with low bone density in adolescents and adults. Hypercortisolemia has been reported in adults with this disorder and has been hypothesized to be a factor in bone loss. However, the secretory dynamics of cortisol in adolescents with AN and the contribution of alterations in cortisol secretion to bone metabolism in AN have not been examined. We examined the dynamics of cortisol secretion by Cluster and deconvolutional analysis in 23 girls with AN and 21 healthy adolescents of comparable age and maturity. Cortisol sampling was performed every 30 min for 12 h overnight. Twenty-four-hour urinary free cortisol (UFC) and creatinine (cr) were obtained for all subjects. The surface area (SA) of the subjects was calculated. Markers of bone turnover (type 1 procollagen, osteocalcin, and N-telopeptide) were examined. Subjects with AN were prospectively followed over 1 yr, and those who recovered weight (defined as a 10% increase in body mass index) were again studied. On Cluster analysis, girls with AN had significantly higher mean cortisol (8.6 +/- 2.0 vs. 5.9 +/- 1.1 microg/dl; P < 0.0001), nadir cortisol (5.5 +/- 2.3 vs. 3.4 +/- 1.2 microg/dl; P = 0.0008), valley mean cortisol (7.0 +/- 2.7 vs. 4.7 +/- 1.5 microg/dl; P = 0.001), peak amplitude (12.6 +/- 4.4 vs. 7.8 +/- 3.0 microg/dl; P = 0.0004), peak area (652 +/- 501 vs. 340 +/- 238 microg/dl; P = 0.02), and total area under the curve (6112 +/- 1467 vs. 4117 +/- 802 microg/dl; P < 0.0001) than healthy adolescents. On deconvolutional analysis, the frequency of nocturnal secretory bursts (7.0 +/- 1.2 vs. 5.8 +/- 1.3 /12 h; P = 0.001), total nocturnal pulsatile cortisol secretion (69.3 +/- 14.7 vs. 53.9 +/- 11.1 microg/dl; P = 0.0003), and total cortisol secretion (89.6 +/- 18.8 vs. 71.2 +/- 17.6 microg/dl; P = 0.002) were significantly higher in girls with AN than in healthy controls. Cortisol half-life trended higher in girls with AN. However, basal cortisol secretion and approximate entropy did not differ between the groups. UFC/cr and UFC/cr.SA were significantly higher in girls with AN than in controls [0.050 +/- 0.028 vs. 0.036 +/- 0.017 (P = 0.04) and 0.035 +/- 0.020 vs. 0.023 +/- 0.012 (P = 0.03)]. Six of 23 girls with AN had UFC/cr.SA values that were more than 2 sd above those in healthy controls. An inverse correlation was noted between measures of cortisol concentration as well as pulsatile secretion and measures of nutritional status (body mass index, fat mass, leptin, insulin, and IGF-I). An oral glucose load suppressed cortisol levels in healthy adolescents, but not in AN patients. Weight recovery was associated with a significant decrease in the number of secretory bursts. In girls with AN, strong inverse correlations were noted between levels of cortisol (mean, nadir, and total area under the curve) and levels of markers of bone formation (C-terminal propeptide of type 1 procollagen and osteocalcin). Conversely, in healthy controls, cortisol values did not predict levels of markers of bone turnover. Adolescent girls with AN have significantly higher serum cortisol concentrations and UFC/cr.SA values than healthy adolescents. This increased cortisol concentration is a function of increased frequency of secretory bursts, resulting in increased pulsatile secretion. Hypercortisolemia appears to be a direct consequence of undernutrition and is associated with a decrease in markers of bone formation. Therefore, high cortisol values in AN may contribute to the low bone density observed in adolescents with this disorder by decreasing bone formation.