Intramembranous bone regeneration differs among common inbred mouse strains following marrow ablation

Various intact and post‐injury bone phenotypes are heritable traits. In this study, we sought to determine if intramembranous bone regeneration following marrow ablation differed among common inbred mouse strains and to identify how early the differences appear. We found a ～four‐fold difference in the regenerated bone volume 21 days after marrow ablation in females from four inbred mouse strains: FVB/N (15.7 ± 8.1%, mean and standard deviation), C3H/He (15.5 ± 4.2%), C57BL/6 (12.2 ± 5.2%), and BALB/c (4.0 ± 4.4%); with BALB/c different from FVB/N (p = 0.007) and C3H/He (p = 0.002). A second experiment showed that FVB/N compared to BALB/c mice had more regenerated bone 7 and 14 days after ablation (p < 0.001), while at 21 days FVB/N mice had a greater fraction of mineralizing surface (p = 0.008) without a difference in mineral apposition rate. Thus, differences among strains are evident early during intramembranous bone regeneration following marrow ablation and appear to be associated with differences in osteogenic cell recruitment, but not osteoblast activity. The amount of regenerating bone was not correlated with other heritable traits such as the intact bone phenotype or soft tissue wound healing, suggesting that there may be independent genetic pathways for these traits. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1374–1381, 2015.     

Randomized, controlled trial of integrated heart failure management: The Auckland Heart Failure Management Study.

AIMS: To determine the effect of an integrated heart failure management programme, involving patient and family, primary and secondary care, on quality of life and death or hospital readmissions in patients with chronic heart failure. METHODS AND RESULTS: This trial was a cluster randomized, controlled trial of integrated primary/secondary care compared with usual care for patients with heart failure. The intervention involved clinical review at a hospital-based heart failure clinic early after discharge, individual and group education sessions, a personal diary to record medication and body weight, information booklets and regular clinical follow-up alternating between the general practitioner and heart failure clinic. Follow-up was for 12 months. One hundred and ninety-seven patients admitted to Auckland Hospital with an episode of heart failure were enrolled in the study. There was no significant difference between the intervention and control groups for the combined end-point of death or hospital readmission. The physical dimension of quality of life showed a greater improvement in the intervention group from baseline to 12 months compared with the control group (-11.1 vs -5.8 respectively, 2 P=0.015). The main effect of the intervention was attributable to the prevention of multiple admissions (56 intervention group vs 95 control group, 2 P=0.015) and associated reduction in bed days. CONCLUSIONS: This integrated management programme for patients with chronic heart failure improved quality of life and reduced total hospital admissions and total bed days.     

Prolactin-releasing peptide and its homolog RFRP-1 act in hypothalamus but not in anterior pituitary gland to stimulate stress hormone secretion

The RF-amide peptides (RFRPs), including prolactin (PRL)-releasing peptide-31 (PrRP-31) and RFRP-1, have been reported to stimulate stress hormone secretion by either direct pituitary or indirect hypothalamic actions. We examined the possible direct effects of these peptides on PRL and adrenocorticotropin (adrenocorticotropic hormone [ACTH]) release from dispersed anterior pituitary cells in culture and on PRL and ACTH secretion following intracerebroventricular (icv) administration in vivo. Neither peptide significantly altered PRL or ACTH release from cultured pituitary cells (male rat donors). Central administration of 1.0 and 3.0 nmol of PrRP-31, but only the higher dose of RFRP-1, significantly elevated serum corticosterone levels in conscious male rats. The effect of PrRP-31 was not blocked by pretreatment (iv) with the corticotropin-releasing hormone (CRH) antagonist, α-helical CRH 9–41; however, pretreatment of the animals (iv) with an antiserum to CRH significantly lowered the hypothalamic-pituitary-adrenal axis response to central administration of PrRP-31. On the other hand, the release of PRL was significantly elevated by 3.0 nmol of RFRP-1, but not PrRP-31, in similarly treated, conscious male rats. Pretreatment with the catecholamine synthesis inhibitor, α-methyl-para-tyrosine, prevented the stimulation of PRL secretion observed following central administration of RFRP-1. RFRP-1 similarly did not alter PRL secretion in rats pretreated with the dopamine, D₂ receptor blocker, domperidone. These results suggest that the RF-amide peptides are not true neuroendocrine regulators of stress hormone secretion in the rat but, instead, act centrally to alter the release of neuroendocrine factors that do act in the pituitary gland to control PRL and ACTH release. In the case of RFRP-1, stimulation of PRL secretion is potentially owing to an action of the peptide to inhibit dopamine release into the median eminence. The corticosterone secretion observed following central administration of PrRP-31 does not appear, based on our current results, to be solely owing to an action of the peptide on CRH-producing neurons but, instead, may be a result of the ability of PrRP-31 to increase as well the exposure of the corticotrophs in vivo to other ACTH secretagogues, such as oxytocin or vasopressin.     

Analysis of the Pediatric Health Information System Database as a Surveillance Tool for Travel-Associated Infectious Diseases

The Pediatric Health Information System (PHIS) database collects admission, diagnostic, and treatment data among 44 children''s hospitals across the United States (U.S.) and presents an opportunity for travel-associated infectious disease (TAID) surveillance. We calculated cumulative incidence rates among children admitted to 16 PHIS hospitals for dengue, malaria, and typhoid, and pooled TAID using discharge codes from 1999 to 2012. We compared incidence rates before, during, and after the 2007–2009 economic recession. Among 16 PHIS hospitals during the study period (1999–2012), incidence of dengue and pooled TAID (malaria, dengue, typhoid fever) increased significantly, and rates of malaria and typhoid trended upward. Admissions for dengue and pooled TAIDs increased significantly among 16 children''s hospitals across the United States from 1999 to 2012. The PHIS database may provide a useful surveillance tool for TAIDs among children in the United States.International travel to other countries has increased 5% in the United States and 48% worldwide in the last decade, and more travelers visit low- and middle-income countries (LMICs) than ever before.¹ As many as 8% of U.S. travelers seek medical care, and many more suffer from milder illness while abroad.^2–4 A significant proportion of the 62 million annual U.S. international travelers develops illness after returning to the United States with infections that may be unfamiliar to local health-care providers.^5–7 Estimating incidence rates of non-endemic diseases may help public health officials direct educational resources and raise awareness among local practitioners.Currently, surveillance systems for travel-associated infectious diseases (TAIDs) in the United States are limited. Many TAIDs are reportable to state health departments, but reporting is often unreliable.⁸ The GeoSentinel Surveillance Network (GSSN) is a system of 57 travel disease clinics worldwide, including 15 clinics in the United States. Although the GSSN obtains robust clinical and diagnostic information, it surveys only those seeking care at specialty travel clinics, and only 7% of GSSN patients are children.¹The Pediatric Health Information System (PHIS) database was established to collect administrative and financial data from pediatric hospitals across the Unites States. More recently, the database has been augmented (PHIS+) to also collect clinical, laboratory, treatment, and outcome data at multiple health-care settings (inpatient, outpatient, and emergency departments [EDs]) among 44 freestanding children''s hospitals across the United States.^9,10 It offers an opportunity for objective hospitalized TAID surveillance among the greater than 5 million children hospitalized annually at these institutions.¹¹ We evaluated the PHIS database as a potential TAID surveillance tool by determining cumulative incidence rates of three TAIDs (malaria, dengue, and typhoid fever) among PHIS hospitals over a 14-year period.A total of 16 PHIS hospitals from geographically diverse metropolitan areas (median population 426,001 people, interquartile range 247,026–757,907 people)¹² had non-missing data available during the study period (1999–2012). The metropolitan areas include San Diego, CA; Norfolk, VA; St. Petersberg, FL; Orange County, CA; Corpus Christi, TX; Miami, FL; Denver, CO; Memphis, TN; Chicago, IL; Akron, OH; Little Rock, AR; Columbus, OH; Fort Worth, TX; Omaha, NE; Milwaukee, WI; and St. Louis, MO. All inpatient discharges from these sites with a principal discharge diagnosis (International Classification of Diseases 9 [ICD-9]) code¹³ for malaria (0840, 0841, 0842, 0843, 0846, 0849), typhoid (0020), and dengue (061) were identified within the PHIS database. Readmissions for the same ICD-9 diagnosis were excluded from the analysis. Cumulative incidence rates of malaria, typhoid, and dengue as well as pooled TAID incidence rates for all three diseases were determined by dividing hospitalized cases by total hospital discharges per year. Individual disease and pooled incidence rates were compared over the study period (1999–2012). We hypothesized that TAID incidence rates may have decreased during the 2007–2009 economic recession due to decreased international travel, and thus, rates for before (1999–2006), during (2007–2009), and after the U.S. economic recession were compared.^7,14,15 Categorical variables were compared using χ² with Fisher''s exact testing when appropriate.The 16 PHIS hospitals represented 2,203,063 pediatric hospital admissions during the study period. Individual and pooled cumulative TAID incidence trended upward from 1999 to 2012, though the trend did not achieve statistical significance (r² = 0.158). When comparing cumulative incidence rates from before (1999–2006), during, and after (2010–2012) the 2007–2009 economic recession, there was a significant change in incidence rates for dengue (P = 0.016) and pooled TAID (p = 0.009), though all diseases studied showed a similar trend with decreases during the recession and highest rates after (Figure 1 ).Open in a separate windowFigure 1.Comparison of pooled and individual travel-associated infectious diseases (TAIDs) in the Pediatric Health Information System (PHIS) database, 1999–2012.

Table 1

Hospital admission incidence rates of travel-associated infectious diseases (TAIDs) in children before, during, and after the 2007–2009 economic recession.

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb-null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.During vertebrate evolution, the female reproductive pattern underwent a remarkable transition from spawning of large number of eggs in primitive species under favorable conditions to more tightly controlled ovarian cycles in higher vertebrates, such that only a limited number (rodents) or a single (human and nonhuman primates) egg is released per cycle (1, 2). Coincident with this event, the single pituitary gonadotropic hormone that exists in primitive vertebrates has given rise to two gonadotropins, FSH and luteinizing hormone (LH), which coordinate gametogenesis and steroidogenesis (3–7). FSH and LH are heterodimeric glycoproteins that contain a common α-subunit and a hormone-specific β-subunit (3). Although synthesized in the same cell, the gonadotrope, FSH is mostly constitutively released in many species, whereas LH is stored in dense core granules (DCGs) and secreted in pulses via the regulated pathway in response to gonadotropin-releasing hormone (GnRH) (8, 9). Although this pattern is evolutionarily conserved, how distinct modes of gonadotropin secretion affect ovarian development and target cell responses remain unclear. Although models in which variations in secretion of gonadotropins have been achieved in vivo (10) and in vitro, including basolateral and apically polarized secretion (11), the in vivo consequences of altered mode of gonadotropin trafficking and release (constitutive vs. regulated) from pituitary are untested. We sought to identify why the two gonadotropins, LH and FSH, expressed in the same pituitary cell have evolved to exit via different routes to regulate ovarian physiology.     

A preliminary investigation of the long-term outcome of the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders

Objective

The aim of this study is to conduct a preliminary examination of long-term outcomes on a broad range of affective disorder symptoms treated with a newly developed intervention: The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP).

Method

Maintenance of treatment gains at long-term follow-up (LTFU) were explored in patients (N = 15, mean age = 32.27; 60% female) who completed a clinical trial of the UP.

Results

Treatment gains observed at 6-month follow-up (6MFU) on measures of clinical severity, general symptoms of depression and anxiety, and a measure of symptom interference in daily functioning were largely maintained 12 months later (at an average of 18 months posttreatment), and any significant changes from 6MFU to LTFU reflected small increases in symptoms that remained, on average, in the subclinical range.

Conclusions

These findings provide the first initial support for the durability of broad treatment gains following transdiagnostic treatment.