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1.  Sex chromosome-to-autosome transposition events counter Y-chromosome gene loss in mammals 
Genome Biology  2015;16(1):104.
Although the mammalian X and Y chromosomes evolved from a single pair of autosomes, they are highly differentiated: the Y chromosome is dramatically smaller than the X and has lost most of its genes. The surviving genes are a specialized set with extraordinary evolutionary longevity. Most mammalian lineages have experienced delayed, or relatively recent, loss of at least one conserved Y-linked gene. An extreme example of this phenomenon is in the Japanese spiny rat, where the Y chromosome has disappeared altogether. In this species, many Y-linked genes were rescued by transposition to new genomic locations, but until our work presented here, this has been considered an isolated case.
We describe eight cases of genes that have relocated to autosomes in mammalian lineages where the corresponding Y-linked gene has been lost. These gene transpositions originated from either the X or Y chromosomes, and are observed in diverse mammalian lineages: occurring at least once in marsupials, apes, and cattle, and at least twice in rodents and marmoset. For two genes - EIF1AX/Y and RPS4X/Y - transposition to autosomes occurred independently in three distinct lineages.
Rescue of Y-linked gene loss through transposition to autosomes has previously been reported for a single isolated rodent species. However, our findings indicate that this compensatory mechanism is widespread among mammalian species. Thus, Y-linked gene loss emerges as an additional driver of gene transposition from the sex chromosomes, a phenomenon thought to be driven primarily by meiotic sex chromosome inactivation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0667-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4446799  PMID: 26017895
2.  Development of Apical Blebbing in the Boar Epididymis 
PLoS ONE  2015;10(5):e0126848.
Microvesicles are of increasing interest in biology as part of normal function of numerous systems; from the immune system (T cell activation) to implantation of the embryo (invasion of the trophoblasts) and sperm maturation (protein transfer in the epididymis). Yet, the mechanisms involved in the appearance of apical blebbing from healthy cells as part of their normal function remain understudied. Microvesicles are produced via one of two pathways: exocytosis or apical blebbing also termed ectocytosis. This work quantifies the histological appearance of apical blebbing in the porcine epididymis during development and examines the role of endogenous estrogens in regulating this blebbing. Apical blebbing appears at puberty and increases in a linear manner into sexual maturity suggesting that this blebbing is a mature phenotype. Endogenous estrogen levels were reduced with an aromatase inhibitor but such a reduction did not affect apical blebbing in treated animals compared with their vehicle-treated littermates. Epididymal production of apical blebs is a secretion mechanism of functionally mature principal cells regulated by factors other than estradiol.
PMCID: PMC4440725  PMID: 25996942
3.  Enhanced Mental Health Interventions in the Emergency Department: Suicide and Suicide Attempt Prevention in the ED 
Suicide is the third leading cause of death in adolescents, and often youths with suicidal behavior or ideation present to the emergency department (ED) for care. Many suicidal youths do not receive mental health care after discharge from the ED, and interventions are needed to enhance linkage to outpatient intervention. This paper describes the Family Intervention for Suicide Prevention (FISP). Designed for use in emergency settings, the FISP is a family-based cognitive-behavior therapy session designed to increase motivation for follow-up treatment, support, coping, and safety, augmented by care linkage telephone contacts after discharge. In a randomized trial of the intervention, the FISP was shown to significantly increase the likelihood of youths receiving outpatient treatment, including psychotherapy and combined medication and psychotherapy. The FISP is a brief, focused, efficacious treatment that can be delivered in the ED to improve the probability of follow-up treatment for suicidal youths.
PMCID: PMC4402934  PMID: 25904825
suicide prevention; cognitive behavior intervention; adolescents; family
4.  Loss from Treatment for Drug Resistant Tuberculosis: Risk Factors and Patient Outcomes in a Community-Based Program in Khayelitsha, South Africa 
PLoS ONE  2015;10(3):e0118919.
A community based drug resistant tuberculosis (DR-TB) program has been incrementally implemented in Khayelitsha, a high HIV and TB burden community in South Africa. We investigated loss from treatment (LFT), and post treatment outcomes of DR-TB patients in this setting.
LFT, defined as interruption of treatment for ≥2 consecutive months was assessed among patients initiating DR-TB treatment for the first time between January 2009 and July 2011. Patients were traced through routine data sources to identify those who subsequently restarted treatment and those who died. Additional information on patient status and survival after LTF was obtained from community DR-TB counselors and from the national death registry. Post treatment outcomes were observed until July 2013.
Among 452 patients initiating treatment for the first time within the given period, 30% (136) were LFT, with 67% retention at 18 months. Treatment was restarted in 27 (20%) patients, with additional resistance recorded in 2/25 (8%), excluding two with presumed DR-TB. Overall, 34 (25%) patients died, including 11 who restarted treatment. Males and those in the age category 15-25 years had a greater hazard of LFT; HR 1.93 (95% CI 1.35-2.75), and 2.43 (95% CI 1.52-3.88) respectively. Older age (>35 years) was associated with a greater hazard of death; HR 3.74 (1.13- 12.37) post treatment. Overall two-year survival was 62%. It was lower (45%) in older patients, and was 92% among those who received >12 months treatment.
LFT was high, occurred throughout the treatment period and was particularly high among males and those aged 15-25 years. Overall long term survival was poor. High rates of LFT should however not preclude scale up of community based care given its impact in increasing access to treatment. Further research is needed to support retention of DR-TB patients on treatment, even within community based treatment programs.
PMCID: PMC4364980  PMID: 25785451
5.  Impact of Decentralized Care and the Xpert MTB/RIF Test on Rifampicin-Resistant Tuberculosis Treatment Initiation in Khayelitsha, South Africa 
Open Forum Infectious Diseases  2015;2(1):ofv014.
Decentralization of treatment for rifampicin-resistant tuberculosis was associated with high treatment initiation and resulted in reduced time to treatment initiation. Xpert for TB diagnosis resulted in a significant further reduction in time to treatment.
Background. Globally, case detection and treatment access are poor for rifampicin-resistant tuberculosis (RR-TB). The Xpert MTB/RIF test has the potential to increase detection and reduce time to treatment (TTT). However, these benefits are dependent on health system capacity to provide treatment.
Methods. We retrospectively assessed the impact of Xpert on treatment initiation and TTT in the context of decentralized RR-TB care in Khayelitsha, Cape Town, using routine programmatic data. Community-based treatment was introduced progressively from 2008. Before 2007, diagnosis relied on phenotypic resistance (culture). During 2007–2008, the line probe assay (LPA) was introduced, followed by Xpert in 2012.
Results. Before decentralization (2003–2006), median TTT was 71 days (interquartile range [IQR], 49–134; n = 158). The LPA introduction during 2007–2008 was associated with reduced median TTT from 76 to 50 days (P < .0001, n = 257). Between January 2009 and June 2013, 938 RR-TB cases were diagnosed (74% human immunodeficiency virus [HIV]-infected). Decentralization during 2008–2011 was associated with declining TTT (P < .0001, test for trend), a decline to 28 days in 2011 (IQR, 16–40; n = 173). Xpert was associated with a further reduction to 8 days in 2013 (IQR, 5–25; n = 89; P < .0001). Treatment initiation remained unchanged with Xpert and was lower among HIV-infected (2010–2013); 87.9% (445 of 506) compared with 96.9% (188 of 194) for HIV-uninfected (P < .0001) patients.
Conclusions. Improved case detection and rapid treatment initiation are required to interrupt transmission and reduce mortality. In this setting, decentralization was associated with high treatment initiation and reduced TTT. Xpert implementation significantly enhanced the reduction in TTT and has the potential to reduce transmission.
PMCID: PMC4438894  PMID: 26034764
delay; MDR-TB; RR-TB; treatment; Xpert
6.  The Common Marmoset Genome Provides Insight into Primate Biology and Evolution 
Worley, Kim C. | Warren, Wesley C. | Rogers, Jeffrey | Locke, Devin | Muzny, Donna M. | Mardis, Elaine R. | Weinstock, George M. | Tardif, Suzette D. | Aagaard, Kjersti M. | Archidiacono, Nicoletta | Rayan, Nirmala Arul | Batzer, Mark A. | Beal, Kathryn | Brejova, Brona | Capozzi, Oronzo | Capuano, Saverio B. | Casola, Claudio | Chandrabose, Mimi M. | Cree, Andrew | Dao, Marvin Diep | de Jong, Pieter J. | del Rosario, Ricardo Cruz-Herrera | Delehaunty, Kim D. | Dinh, Huyen H. | Eichler, Evan | Fitzgerald, Stephen | Flicek, Paul | Fontenot, Catherine C. | Fowler, R. Gerald | Fronick, Catrina | Fulton, Lucinda A. | Fulton, Robert S. | Gabisi, Ramatu Ayiesha | Gerlach, Daniel | Graves, Tina A. | Gunaratne, Preethi H. | Hahn, Matthew W. | Haig, David | Han, Yi | Harris, R. Alan | Herrero, Javier M. | Hillier, LaDeana W. | Hubley, Robert | Hughes, Jennifer F. | Hume, Jennifer | Jhangiani, Shalini N. | Jorde, Lynn B. | Joshi, Vandita | Karakor, Emre | Konkel, Miriam K. | Kosiol, Carolin | Kovar, Christie L. | Kriventseva, Evgenia V. | Lee, Sandra L. | Lewis, Lora R. | Liu, Yih-shin | Lopez, John | Lopez-Otin, Carlos | Lorente-Galdos, Belen | Mansfield, Keith G. | Marques-Bonet, Tomas | Minx, Patrick | Misceo, Doriana | Moncrieff, J. Scott | Morgan, Margaret B. | Muthuswamy, Raveendran | Nazareth, Lynne V. | Newsham, Irene | Nguyen, Ngoc Bich | Okwuonu, Geoffrey O. | Prabhakar, Shyam | Perales, Lora | Pu, Ling-Ling | Puente, Xose S. | Quesada, Victor | Ranck, Megan C. | Raney, Brian J. | Deiros, David Rio | Rocchi, Mariano | Rodriguez, David | Ross, Corinna | Ruffier, Magali | Ruiz, San Juana | Sajjadian, S. | Santibanez, Jireh | Schrider, Daniel R. | Searle, Steve | Skaletsky, Helen | Soibam, Benjamin | Smit, Arian F. A. | Tennakoon, Jayantha B. | Tomaska, Lubomir | Ullmer, Brygg | Vejnar, Charles E. | Ventura, Mario | Vilella, Albert J. | Vinar, Tomas | Vogel, Jan-Hinnerk | Walker, Jerilyn A. | Wang, Qing | Warner, Crystal M. | Wildman, Derek E. | Witherspoon, David J. | Wright, Rita A. | Wu, Yuanqing | Xiao, Weimin | Xing, Jinchuan | Zdobnov, Evgeny M. | Zhu, Baoli | Gibbs, Richard A. | Wilson, Richard K.
Nature genetics  2014;46(8):850-857.
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
PMCID: PMC4138798  PMID: 25038751
7.  Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators 
Nature  2014;508(7497):494-499.
The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three percent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was non-random, and in two cases, convergent across placental and marsupial mammals. We conclude that the Y chromosome's gene content became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and plays unappreciated roles in Turner syndrome and in phenotypic differences between the sexes in health and disease.
PMCID: PMC4139287  PMID: 24759411
8.  Development and Validation of a Falls Grading Scale 
Journal of geriatric physical therapy (2001)  2013;36(2):10.1519/JPT.0b013e31825f6777.
Background and Purpose
The recording of fall events is usually subjective and imprecise, which limits clinical practice and falls-related research. We sought to develop and validate a scale to grade near-fall and fall events based on their severity represented by the use of healthcare resources, with the goal of standardizing fall reporting in the clinical and research settings.
Qualitative instrument development was based on a literature review and semi-structured interviews to assess face and content validity. We queried older individuals and healthcare professionals with expertise in the care of patients at risk of falling about clinically important differences to detect and how to optimize the scale's ease of use. To assess the scale's inter-rater reliability, we created 30 video-vignettes of falls and compared how healthcare professionals and volunteers rated each of the falls according to our grading scale.
We developed the illustrated 4-point Hopkins Falls Grading Scale (HFGS). The grades distinguish a near-fall (Grade 1) from a fall for which an individual did not receive medical attention (Grade 2), a fall associated with medical attention but not hospital admission (Grade 3), and a fall associated with hospital admission (Grade 4). Overall, the HFGS exhibited good face and content validity, and had an intraclass correlation coefficient of 0.998.
The 4-point HFGS demonstrates good face and content validity and high inter-rater reliability. We predict this tool will facilitate the standardization of falls reporting in both the clinical and research settings.
PMCID: PMC3867809  PMID: 22810170
Falls definition; falls classification; falls reporting
9.  Sequencing of rhesus macaque Y chromosome clarifies origins and evolution of the DAZ (Deleted in AZoospermia) genes 
Studies of Y chromosome evolution often emphasize gene loss, but this loss has been counterbalanced by addition of new genes. The DAZ genes, which are critical to human spermatogenesis, were acquired by the Y chromosome in the ancestor of Old World monkeys and apes. We and our colleagues recently sequenced the rhesus macaque Y chromosome, and comparison of this sequence to human and chimpanzee enables us to reconstruct much of the evolutionary history of DAZ. We report that DAZ arrived on the Y chromosome about 36 million years ago via the transposition of at least 1.1 megabases of autosomal DNA. This transposition also brought five additional genes to the Y chromosome, but all five genes were subsequently lost through mutation or deletion. As the only surviving gene, DAZ experienced extensive restructuring, including intragenic amplification and gene duplication, and has been the target of positive selection in the chimpanzee lineage.
PMCID: PMC3581811  PMID: 23055411
Y chromosome; DAZ; rhesus macaque; chimpanzee; ampliconic
10.  Effective Components of TORDIA Cognitive–Behavioral Therapy for Adolescent Depression: Preliminary Findings 
In this report, we conducted a secondary analysis of the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study to explore the impact of specific cognitive–behavioral therapy (CBT) treatment components on outcome. In TORDIA, 334 youths (ages 12 to 18 years) with major depressive disorder who had failed to respond to an adequate course of selective serotonin reuptake inhibitor (SSRI) medication were randomized to a medication switch (either to an alternative SSRI or venlafaxine) with or without 12 weeks of adjunctive CBT. Participants who had more than 9 CBT sessions were 2.5 times more likely to have adequate treatment response than those who had 9 or fewer sessions. CBT participants who received problem-solving and social skills treatment components, controlling for number of sessions and other confounding variables, were 2.3 and 2.6 times, respectively, more likely to have a positive response. These preliminary findings underscore the importance of receiving an adequate number of sessions to attain an adequate clinical response. Finally, social skills and problem solving may be active elements in CBT for adolescent depression and should be considered in treatment by those working with seriously depressed youths.
PMCID: PMC3705725  PMID: 19968380
cognitive–behavioral therapy; adolescent depression; treatment components
11.  Decline in semicircular canal and otolith function with age 
To characterize the physiologic nature of the vestibular dysfunction that occurs with the normative aging process.
Study design
Cross-sectional study.
Tertiary care academic medical center.
Fifty individuals age 70 and above.
Head thrust dynamic visual acuity testing (htDVA) and cervical and ocular vestibular-evoked myogenic potential (VEMP) testing.
Main Outcome Measures
Semicircular canal function measured by htDVA in each of the three semicircular canal planes, and saccular and utricular function measured by cVEMP and oVEMP testing, respectively.
We observed significant declines in semicircular canal function in each of the canal planes as well as otolith function associated with aging. We found that individuals with impaired horizontal and superior semicircular canal function were likely to also have concomitant deficits in utricular but not saccular function. Overall, we noted that the prevalence of semicircular canal dysfunction was highest followed by saccular then utricular impairment, although we did observe individuals with isolated otolith deficits.
These data suggest an overall decline in semicircular canal as well as otolith function associated with aging, although the magnitude of impairment was greater for the semicircular canals than the otoliths in this elderly population. A better understanding of the specific vestibular deficits that occur with aging can inform the development of rational screening, vestibular rehabilitation and fall risk reduction strategies in older individuals.
PMCID: PMC3376350  PMID: 22699991
12.  Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content 
Nature  2010;463(7280):536-539.
The human Y chromosome began to evolve from an autosome hundreds of millions of years ago, acquiring a sex-determining function and undergoing a series of inversions that suppressed crossing over with the X chromosome1,2. Little is known about the Y chromosome’s recent evolution because only the human Y chromosome has been fully sequenced. Prevailing theories hold that Y chromosomes evolve by gene loss, the pace of which slows over time, eventually leading to a paucity of genes, and stasis3,4. These theories have been buttressed by partial sequence data from newly emergent plant and animal Y chromosomes5-8, but they have not been tested in older, highly evolved Y chromosomes like that of humans. We therefore finished sequencing the male-specific region of the Y chromosome (MSY) in our closest living relative, the chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. We then compared the MSYs of the two species and found that they differ radically in sequence structure and gene content, implying rapid evolution during the past 6 million years. The chimpanzee MSY harbors twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. We suggest that the extraordinary divergence of the chimpanzee and human MSYs was driven by four synergistic factors: the MSY’s prominent role in sperm production, genetic hitchhiking effects in the absence of meiotic crossing over, frequent ectopic recombination within the MSY, and species differences in mating behavior. While genetic decay may be the principal dynamic in the evolution of newly emergent Y chromosomes, wholesale renovation is the paramount theme in the ongoing evolution of chimpanzee, human, and perhaps other older MSYs.
PMCID: PMC3653425  PMID: 20072128
13.  Maternal Transmission of a Humanised Igf2r Allele Results in an Igf2 Dependent Hypomorphic and Non-Viable Growth Phenotype 
PLoS ONE  2013;8(2):e57270.
The cation independent mannose 6-phosphate/insulin-like growth factor 2 receptor (IGF2R) functions in the transportation and regulation of insulin-like growth factor 2 (IGF2) and mannose 6-phosphate modified proteins. The relative and specific titration of IGF2 by high affinity binding of IGF2R represents a mechanism that supports the parental conflict theory of genomic imprinting. Imprinting of Igf2 (paternal allele expressed) and Igf2r (maternal allele expressed) arose to regulate the relative supply of both proteins. Experiments in the mouse have established that loss of the maternal allele of Igf2r results in disproportionate growth and peri-natal lethality. In order to systematically investigate the consequences of loss of function and of hypomorphic alleles of Igf2r on growth functions, we introduced a conditional human IGF2R exon 3–48 cDNA into the intron 2 region of murine Igf2r. Here we show that the knock-in construct resulted in over-growth when the humanised Igf2r allele was maternally transmitted, a phenotype that was rescued by either paternal transmission of the humanised allele, expression of a wild-type paternal allele or loss of function of Igf2. We also show that expression of IGF2R protein was reduced to less than 50% overall in tissues previously known to be Igf2 growth dependent. This occurred despite the detection of mouse derived peptides, suggesting that trans-splicing of the knock-in human cDNA with the endogenous maternal mouse Igf2r allele. The phenotype following maternal transmission of the humanised allele resulted in overgrowth of the embryo, heart and placenta with partial peri-natal lethality, suggesting that further generation of hypomorphic Igf2r alleles are likely to be at the borderline of maintaining Igf2 dependent viability.
PMCID: PMC3585325  PMID: 23468951
14.  Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes 
Nature  2012;483(7387):82-86.
The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200–300 million years1–3. Due to genetic decay, the human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes’ genes4,5. This evolutionary decay was driven by a series of five “stratification” events. Each event suppressed X-Y crossing over within a chromosome segment or “stratum”, incorporated that segment into the MSY, and subjected its genes to the erosive forces that attend the absence of crossing over2,6. The last of these events occurred 30 million years ago (mya), or 5 million years before the human and Old World monkey (OWM) lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome7–10, remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the OWM lineage. To explore this question, we sequenced the MSY of the rhesus macaque, an OWM, and compared it to the human MSY. We discovered that, during the last 25 million years, MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. Within the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 mya. Likewise, the rhesus MSY has not lost any older genes (from strata 1–4) during the past 25 million years, despite major structural differences from the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection.
PMCID: PMC3292678  PMID: 22367542
15.  IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults 
Age and Ageing  2011;40(4):475-481.
Background: neopterin is a monocyte/macrophage-derived immune activation marker and its levels increase with age. Frailty is an important clinical syndrome of old age. Previous studies have shown significant association between elevated interleukin-6 (IL-6) levels and frailty. The objective of this study was to evaluate IL-6-independent association of serum neopterin levels with prevalent frailty.
Methods: this is a cross-sectional study in community-dwelling older adults recruited from residential and retirement communities in Baltimore, MD, USA. Frailty was determined using validated screening criteria. Serum neopterin and IL-6 levels were measured using standard enzyme-linked immunosorbent assay. Pearson correlation and multivariate linear regression analysis was performed to assess the relationship between log(neopterin) and log(IL-6). Odds ratios (ORs) for frailty were calculated using log(neopterin) and log(IL-6) as continuous measures and across tertiles of neopterin and IL-6 levels, adjusting for age, race, sex, education and body mass index.
Results: one hundred and thirty-three individuals with a mean age of 84 years (range 72–97) completed the study. Neopterin levels were significantly higher in frail older adults than those in non-frail controls [median: 8.94 versus 8.35 nM, respectively, P < 0.001 t-test on log(neopterin)]. Log(neopterin) was significantly associated with prevalent frailty, adjusting for log(IL-6). Participants in the top tertile of neopterin had OR of 3.80 [95% confidence interval (CI) = 1.36–10.6, P < 0.01] for frailty. As expected, participants in the top tertile of IL-6 had OR of 3.29 (95% CI = 1.21–7.86, P < 0.05) for frailty. Log(neopterin) correlated with log(IL-6) (correlation coefficient = 0.19, P < 0.05). Moreover, OR for participants in the top neopterin tertile remained significant after adjusting for IL-6 (OR = 3.97, 95% CI = 1.15–13.72, P < 0.05).
Conclusion: elevated neopterin levels had IL-6-independent association with prevalent frailty, suggesting potential monocyte/macrophage-mediated immune activation in the frail elderly.
PMCID: PMC3114624  PMID: 21586579
frailty; neopterin; monocyte/macrophage-mediated immune activation; IL-6; elderly
16.  Reduction in Ki-67 in Benign Breast Tissue of High Risk Women with the Lignan Secoisolariciresinol Diglycoside (SDG) 
Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a greater than 3-fold increase in 5 year risk, and baseline Ki-67 ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG 50 mg daily was given for 12 months, followed by repeat RPFNA. The primary endpoint was change in Ki-67. Secondary endpoints included change in cytomorphology, mammographic breast density, serum bioavailable estradiol, and testosterone IGF-I and IGFBP-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ~ 9-fold, and total lignans 16 fold. Thirty-six (80%) of the 45 evaluable subjects demonstrated a decrease in Ki-67, from a median of 4% (range 2–16.8 %) to 2% (range 0–15.2%) (p<0.001 by Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (p=0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG vs. placebo in premenopausal women.
PMCID: PMC2955777  PMID: 20724470
17.  Utility of Early Insulin Response and Proinsulin to Assess Insulin Resistance 
The Journal of pediatrics  2009;155(6):893-899.
To determine whether obesity and premature adrenarche are additive events increasing the risk of insulin resistance and β-cell failure, using early insulin response (EIR) or the insulinogenic index and proinsulin as markers.
Study design
Prospective case-control study at a tertiary care academic medical center; 81 prepubertal, predominantly Hispanic children (34 M/47 F): Lean Control [(4M, 6F) age(y), 6.5±1.2; BMI-z, 0.08±0.6], Obese Control [(20M, 10F) age(y), 7.2±1.5; BMI-z, 2.5±0.5], lean premature adrenarche [(3M, 11F) age(y), 7.1±1.2; BMI-z, 0.09±0.6], and obese premature adrenarche [(7M, 20F) age(y), 7.3±1.0; BMI-z, 2.2±0.4]. Fasting glucose (G0), insulin (I0), PI0, androgen levels, IGF-1, IGFBP-1, and lipids were obtained. OGTT was performed. EIR was calculated as (I30 – I0)/(G30 – G0). Between group differences were assessed with two-way analysis of variance with interactions and associations explored with correlation/regression.
EIR was greater in all obese patients with and without premature adrenarche. Combined analysis of the independent variables, obesity and premature adrenarche, showed that obese premature adrenarche had the greatest EIR. Obese subjects with premature adrenarche had greater fasting PI levels than their lean counterparts. Fasting PI/I ratio showed no statistical significance between groups.
We have used EIR and PI as markers to assess risk of insulin resistance and impaired insulin secretion, and have shown that obese children with premature adrenarche may be at greater risk for the development of pre-diabetes and T2DM than their lean counterparts.
PMCID: PMC2823814  PMID: 19643436
Pre-diabetes; Insulinogenic index; Overweight children
19.  Cognitive Behavior Therapy for Suicide Prevention (CBT-SP): Treatment Model, Feasibility and Acceptability 
To describe the elements of a manualized cognitive behavior psychotherapy for suicide prevention (CBT-SP) and to report its feasibility in preventing the recurrence of suicidal behavior in adolescents who have recently attempted suicide.
CBT-SP was developed using a risk reduction, relapse prevention approach and theoretically grounded in principles of cognitive behavior therapy, dialectical behavioral therapy and targeted therapies for suicidal, depressed youth. CBT-SP consists of acute and continuation phases, each lasting about 12 sessions, and includes a chain analysis of the suicidal event, safety plan development, skill building, psychoeducation, family intervention, and relapse prevention.
CBT-SP was administered to 110 depressed, recent suicide attempters aged 13–19 years (mean 15.8±1.6) across five academic sites. Twelve or more sessions were completed by 72.4% of the sample.
A specific intervention for adolescents at high risk for repeated suicide attempts has been developed and manualized, and further testing of its efficacy appears feasible.
PMCID: PMC2888910  PMID: 19730273
Suicide; psychotherapy; depression; adolescents
20.  The Treatment of Adolescent Suicide Attempters (TASA) Study: Predictors of Suicidal Events in an Open Treatment Trial 
To identify the predictors of suicidal events and attempts in depressed adolescent suicide attempters treated in an open treatment trial.
Adolescents who had made a recent suicide attempt and had unipolar depression (n=124) were either randomized (n=22) or given a choice (n=102) among three conditions. Two participants withdrew prior to treatment assignment. The remaining 124 youth received either: a specialized psychotherapy for suicide attempting adolescents (n=17), a medication algorithm (n=14), or the combination (n=93). The participants were followed up 6 months after intake with respect to rate, timing, and predictors of a suicidal event (attempt or acute suicidal ideation necessitating emergency referral).
The morbid risks of suicidal events and attempts upon 6-month follow-up were 0.19 and 0.12, respectively, with a median time to event of 44 days. Higher self-rated depression, suicidal ideation, family income, greater number of previous suicide attempts, lower maximum lethality of previous attempt, history of sexual abuse, and lower family cohesion predicted the occurrence, and earlier time to event, with similar findings for the outcome of attempts. A slower decline in suicidal ideation was associated with the occurrence of a suicidal event.
In this open trial, the 6-month morbid risks for suicidal events and for re-attempts were lower than in other comparable samples, suggesting that this intervention should be studied further. Important treatment targets include suicidal ideation, family cohesion, and sequelae of previous abuse. Because 40% of events occurred with 4 weeks of intake, an emphasis on safety planning and increased therapeutic contact early in treatment may be warranted.
PMCID: PMC2891930  PMID: 19730274
suicide attempt; adolescents; depression; pharmacotherapy; psychotherapy
21.  Developing Cognitive Behavioral Therapy to Prevent Depressive Relapse in Youth 
Cognitive and behavioral practice  2008;15(4):387-399.
Relapse rates for children and adolescents with major depressive disorder (MDD) range from 30% to 40% within 1 to 2 years after acute treatment. Although relapse rates are high, there have been relatively few studies on the prevention of relapse in youth. While acute phase pharmacotherapy has been shown to reduce symptoms rapidly in depressed youth, children and adolescents frequently report ongoing residual symptoms and often relapse following acute treatment. Recent adult trials have begun examining augmentation with psychosocial treatment after successful medication treatment to enhance medication response and prevent future relapse. This strategy has not yet been examined in youth with depression. Here we present initial efforts to develop a sequential, combination treatment strategy to promoting rapid remission and to prevent relapse in depressed youth. We describe efforts to adapt CBT to prevent relapse (RP-CBT) in youth who respond to pharmacotherapy. The goals of RP-CBT include: preventing relapse, increasing wellness, and developing skills to promote and sustain a healthy emotional lifestyle. We describe the rationale for, components of, and methods used to develop RP-CBT. The results from a small open series sample demonstrate feasibility and indicate that youth appear to tolerate RP-CBT well. A future test of the treatment in a randomized controlled trial is described.
PMCID: PMC2882305  PMID: 20535241
22.  Remission and Recovery in the Treatment for Adolescents with Depression Study (TADS): Acute and Long-term Outcomes 
We examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS).
TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder (MDD) to 12 weeks of treatment to fluoxetine (FLX), cognitive behavioral therapy (CBT), their combination (COMB), or pill placebo (PBO). The PBO group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at week 12 (acute phase remitters) and week 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission.
At Week 36, the estimated remission rates for intention-to-treat cases were: COMB: 60%, FLX: 55%; CBT: 64%; overall: 60%. Paired comparisons reveal that at week 24 all active treatments converge on remission outcomes. The recovery rate at Week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36.
The majority of depressed adolescents in all three treatment modalities achieved remission at the end of nine months of treatment.
PMCID: PMC2843506  PMID: 19127172
adolescent depression; remission; residual symptoms; recovery
23.  Cognitive-Behavioral Therapy to Prevent Relapse in Pediatric Responders to Pharmacotherapy for Major Depressive Disorder 
We present results of a feasibility test of a sequential treatment strategy using continuation phase cognitive-behavioral therapy (CBT) to prevent relapse in youths with major depressive disorder (MDD) who have responded to acute phase pharmacotherapy.
Forty-six youths (ages 11–18 years) who had responded to 12 weeks of treatment with fluoxetine were randomized to receive either 6 months of continued antidepressant medication management (MM) or antidepressant MM plus relapse prevention CBT (MM+CBT). Primary outcome was time to relapse, defined as a Childhood Depression Rating Scale-Revised score of 40 or higher and 2 weeks of symptom worsening or clinical deterioration warranting alteration of treatment to prevent full relapse.
Cox proportional hazards regression, adjusting for depression severity at randomization and for the hazard of relapsing by age across the trial, revealed that participants in the MM treatment group had a significantly greater risk for relapse than those in the MM+CBT treatment group (hazard ratio = 8.80; 95% confidence interval 1.01–76.89; χ2 = 3.86, p = .049) during 6 months of continuation treatment. In addition, patient satisfaction was significantly higher in the MM+CBT group. No differences were found between the two treatment groups on attrition rate, serious adverse events, and overall global functioning.
These preliminary results suggest that continuation phase CBT reduces the risk for relapse by eightfold compared with pharmacotherapy responders who received antidepressant medication alone during the 6-month continuation phase.
PMCID: PMC2826176  PMID: 18978634
depression; CBT; relapse prevention; sequential treatment
24.  Maternal Depressive Symptoms in Pediatric Major Depressive Disorder: Relationship to Acute Treatment Outcome 
In the present study, we assess maternal depressive symptoms at the beginning and end of treatment to investigate the possible reciprocal relationship of maternal illness with the child’s depressive illness and treatment.
We present data on 146 children and their mothers who were participating in a pediatric acute treatment study of fluoxetine. Patients were assessed with the Children’s Depression Rating Scale-Revised at baseline and at each treatment visit. Mothers completed the Quick Inventory of Depressive Symptomatology-Self Report at baseline and end of acute treatment.
Thirty percent of mothers had moderate to severe levels of depressive symptoms at the child’s baseline assessment. Overall, mothers reported improvement in maternal depressive symptoms at the end of their child’s acute treatment, although maternal depression was not specifically targeted for intervention. Furthermore, mother’s depressive symptoms appear to be associated with the child’s depression severity both at the beginning and end of treatment. Mothers with higher levels of depressive symptoms had children with higher levels of depression severity at baseline and over the course of treatment. However, maternal depressive symptoms at baseline had no association with the rate of improvement of child depression severity.
This study indicates a positive relationship between the depression severity of mothers and their children. These findings highlight potential areas of intervention in the acute treatment of childhood depression.
PMCID: PMC2826141  PMID: 18434919
maternal depressive symptoms; pediatric depression; acute treatment of pediatric depression
25.  Assessment of Safety and Long-Term Outcomes of Initial Treatment With Placebo in TADS 
The authors examined whether initial assignment to receive placebo for 12 weeks followed by open active treatment as clinically indicated was associated with different levels of benefit and risk of harm across 36 weeks as compared with initial assignment to receive active treatments.
Adolescents with major depressive disorder (N=439) were randomly assigned to receive an initial 12 weeks of treatment with fluoxetine, cognitive-behavioral therapy (CBT), combination treatment with fluoxetine and CBT, or clinical management with placebo; those assigned to placebo received open active treatment as clinically indicated after 12 weeks of placebo. Assessments were conducted every 6 weeks for 36 weeks. The primary outcome measures were response and remission based on scores on the Children’s Depression Rating Scale–Revised and the Clinical Global Impression improvement subscale.
At week 36, the response rate was 82% in the placebo/open group and 83% in the active treatment groups. The remission rate was 48% in the placebo/open group and 59% in the active treatment groups, a difference that approached statistical significance. Patients who responded to placebo generally retained their response. Those who did not respond to placebo subsequently responded to active treatment at the same rate as those initially assigned to active treatments. There were no differences between groups in rates of suicidal events, study retention, or symptom worsening.
Remission rates at 9 months were lower in patients treated initially with placebo, but 3 months of placebo treatment was not associated with any harm or diminished response to subsequent treatment.
PMCID: PMC2823118  PMID: 19147693

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