The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.

BACKGROUND & AIMS: Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice. METHODS: Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay. RESULTS: Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior. CONCLUSIONS: The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.

Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

BACKGROUND & AIMS: Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. METHODS: AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. RESULTS: T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. CONCLUSIONS: Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve.

Menstrual bleeding patterns in adolescents using etonogestrel (ENG) implant.

BACKGROUND: Etonogestrel (ENG) implant is an effective method of contraception. The implant is designed to provide contraceptive efficacy for 3 years with a relatively quick return of fertility upon its removal. Menstrual irregularities are not uncommon on long-acting progestins and can often be the factor for discontinuation or removal. A retrospective chart analysis was done on 58 patients who chose to be on the ENG implant. Age ranged from 12 to 24 years. The cycle ranged from 1 to 17 months. The mean length of use of the implant was 10.9 months. Over the 20-month period, 13 ENG implants were removed because of menstrual bleeding problems. METHOD: We conducted a chart review of the adolescent patients who received the ENG implant in our adolescent clinic. An analysis was done based on symptoms experienced by patients who were on the ENG implant and their management, which in some cases resulted in its removal. SETTING: The data is presented on adolescent and young adult patients who receive their reproductive care in the Adolescent Medicine Clinic at the University of Kentucky, Lexington, KY, USA. CONCLUSIONS: ENG implant when used correctly and as indicated is extremely effective in providing contraception for up to 3 years. However, menstrual irregularities can be very troublesome and often a reason for its removal. In our experience, 22.4% (13 out of the 58 subjects) had menstrual problems post-insertion that led to its removal. It is crucial for a clinician to inform and be informed about such side effects.

Teaching Pediatric Straddle Injury Repair with Use of a 3D Printed Model.

STUDY OBJECTIVE: To determine the utility of a 3D vulvar model for teaching pediatric straddle injury repair. DESIGN: Prospective study. SETTING: Two academic hospitals. PARTICIPANTS: Twenty obstetrics and gynecology residents INTERVENTIONS AND MAIN OUTCOME MEASURES: Knowledge score on the basis of a 7-question pre/post test. Likert scale questions evaluated the 3D model as a teaching tool. RESULTS: Twenty residents participated; 2 (10%) had ever repaired a straddle injury. Knowledge scores increased after model use and didactic session from 3.05 of possible 7 to 6.35; P = .001. Only 2/20 (10%) residents "agreed" or "strongly agreed" with the statement, "I am comfortable repairing a straddle injury" before the intervention, compared with 19/20 (95%) afterward (P < .001). Of 20 residents, 19 (95%) believed that it simulated surgical experience "very well" or "well." CONCLUSION: The use of a 3D pediatric vulvar model can simulate surgical experience and can be an effective teaching tool when combined with a didactic session on pediatric straddle injury.

Consumer-clinician co-taught training about borderline personality disorder.

OBJECTIVE: The aim of this paper is to provide further outcome data on a novel consumer-clinician co-taught borderline personality disorder training program. METHOD: Participants (n=216) who attended consumer-clinician co-taught borderline personality disorder training had their ratings of the training compared to ratings of participants who attended the previous clinician-only borderline personality disorder training. RESULTS: Mean training ratings of the consumer-clinician co-taught borderline personality disorder trainings were 37 percentile points higher (77th vs 40th percentile) than the ratings of the previous clinician-only borderline personality disorder training, which already had evidence of effectiveness. CONCLUSION: Data confirm preliminary findings that adding a consumer-presenter to training adds considerable value.

Premature birth and later insulin resistance.

BACKGROUND: Term infants who are small for gestational age appear prone to the development of insulin resistance during childhood. We hypothesized that insulin resistance, a marker of type 2 diabetes mellitus, would be prevalent among children who had been born prematurely, irrespective of whether they were appropriate for gestational age or small for gestational age. METHODS: Seventy-two healthy prepubertal children 4 to 10 years of age were studied: 50 who had been born prematurely (32 weeks' gestation or less), including 38 with a birth weight that was appropriate for gestational age (above the 10th percentile) and 12 with a birth weight that was low (i.e., who were small) for gestational age, and 22 control subjects (at least 37 weeks' gestation, with a birth weight above the 10th percentile). Insulin sensitivity was measured with the use of paired insulin and glucose data obtained by frequent measurements during intravenous glucose-tolerance tests. RESULTS: Children who had been born prematurely, whether their weight was appropriate or low for gestational age, had an isolated reduction in insulin sensitivity as compared with controls (appropriate-for-gestational-age group, 14.2x10(-4) per minute per milliunit per liter [95 percent confidence interval, 11.5 to 16.2]; small-for-gestational-age group, 12.9x10(-4) per minute per milliunit per liter [95 percent confidence interval, 9.7 to 17.4]; and control group, 21.6x10(-4) per minute per milliunit per liter [95 percent confidence interval, 17.1 to 27.4]; P=0.002). There were no significant differences in insulin sensitivity between the two premature groups (P=0.80). As compared with controls, both groups of premature children had a compensatory increase in acute insulin release (appropriate-for-gestational-age group, 2002 pmol per liter [95 percent confidence interval, 1434 to 2432] [corrected]; small-for-gestational-age group, 2253 pmol per liter [95 percent confidence interval, 1622 to 3128]; and control group, 1148 pmol per liter [95 percent confidence interval, 875 to 1500]; P<0.001). CONCLUSIONS: Like children who were born at term but who were small for gestational age, children who were born prematurely have an isolated reduction in insulin sensitivity, which may be a risk factor for type 2 diabetes mellitus.

Increasing numbers of admissions to the adult burns service at the Royal Adelaide Hospital 2001-2004.

BACKGROUND: The purpose of the study was to illustrate the increasing trend in the number of adult burns patients admitted to the Royal Adelaide Hospital and attempt to explain it and to describe the burn patients admitted to the Royal Adelaide Hospital in terms of age, sex, origin, cause and burn size, particularly since the increasing trend began, in an effort to identify a particular group or burn cause, which may make up a large proportion of the increasing numbers. METHODS: A retrospective review of 1548 acute burn-injured patients using information from the burns unit database between 1996 and 2004 was carried out. RESULTS: Of 1841 total admissions, 1548 were admitted for acute burn injury. There has been an increase in the number of admissions since 2001 amounting to approximately 20% per annum. The cumulative rise in total admissions 2000-2004 is 107% where the increase in acute burn admission in the same period is 82%. There appears to be no difference whether the patient is from a rural or a metropolitan area. Burns of <10% total body surface area constitute most of the increase and are mainly flame and scald injuries. Chemical and contact burns are proportionately increasing. CONCLUSION: The increase in acute admissions is mainly due to the increasing presentation of smaller burns to the unit. The statewide rural burn education programme and media exposure following the 2002 Bali bombings may have contributed to the increase in acute admissions.

Consumer-clinician co-taught borderline personality disorder training: a pilot evaluation.

This paper describes a consumer-clinician co-taught borderline personality disorder training programme for clinicians, of whom the largest group were nurses, working in mental health and substance use fields. A pilot evaluation of 73 participants attending the training rated the training as superior to evaluations of an earlier clinician-only-taught training. This study of a novel co-taught training programme found that the consumer input added substantial value. Findings indicate that consumer input into education programmes can make a significant positive contribution to the delivery of mental health services training with likely impacts on mental health service delivery. The potential importance of the findings warrants a comprehensive multicentre study. Confirming the findings would have implications for future borderline personality disorder training programmes.

Family group decision making and disproportionality in foster care: a case study.

Research on the disproportionate number of children of color in the child welfare system suggests that we should focus on key decision points such as investigations, substantiations, and placements to understand how experiences of children vary by race and ethnicity. This article describes one community's efforts to use Family Group Decision Making in placement decisions to reduce disproportionality in foster care by diverting children from regular foster care services and keeping them within their extended families.

The Biological Basis of Chronic Traumatic Encephalopathy following Blast Injury: A Literature Review.

The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.

The endocrine consequences for very low birth weight premature infants.

The aims of this study were: (1) to determine whether premature and small-for-gestational-age (SGA) children have alterations to the insulin-like growth factor (IGF)-IGF binding protein axis and (2) to evaluate growth in premature children. Three groups of children were evaluated: (i) premature children of 36 weeks gestation, which included AGA and SGA subgroups; and (iii) children born at term and AGA with normal childhood heights and weights. Fasting plasma IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), and IGF-II (all expressed as microgm/L) were drawn on available subjects. To examine the influence of SGA on the IGF-IGFBP axis, term SGA subjects were compared with term AGA subjects. To examine the influence of prematurity on the IGF-IGFBP axis, preterm SGA subjects were compared with term SGA subjects and preterm AGA subjects were compared with the normal-stature AGA controls. This ensured that groups of very similar stature and nutritional statuses were compared. Auxological data were available for 24 premature children, and biochemical data were available for 77 children, including the premature children. Across the height standard deviation score (SDS) range, premature children did not reach mid-parental height (MPH) SDS and were approximately 0.6 standard deviations (SDs) below the MPH SD (P < 0.0001). Plasma IGF-I and IGFBP-3 levels were higher in term SGA subjects compared with term AGA subjects (P < 0.001, respectively). Conversely, IGF-I and IGFBP-3 values were lower in the premature SGA subgroup compared with the premature AGA subgroup (P < 0.001 for both), and both were also lower in the premature AGA subgroup compared with the normal-statured AGA subgroup (P < 0.001 for both). IGF-II values were higher in the preterm group than in the term group (P < 0.001). In conclusion, very low birth weight (VLBW) children, regardless of whether they were AGA or SGA, have low plasma IGF-I and IGFBP-3 levels in mid-childhood, suggesting partial growth hormone (GH) resistance. Conversely, term SGA children have elevated plasma IGF-I and IGFBP-3 levels. When combined, premature birth plays a more dominant role than SGA on the IGF-IGF binding protein axis.

Amiodarone-induced neonatal hypothyroidism: a unique form of transient early-onset hypothyroidism.

Amiodarone is an iodine-rich drug used to treat cardiac dysrhythmias. The structure of amiodarone resembles that of thyroxine, and treatment with amiodarone may alter thyroid function. The effects of antenatal amiodarone use on fetal/neonatal thyroid function have only been addressed in a limited number of patient reports. We describe two cases of transient neonatal hypothyroidism due to in utero amiodarone exposure, followed by a brief review of the available literature.

Generation and characterization of an attenuated mutant in a response regulator gene of Francisella tularensis live vaccine strain (LVS).

Francisella tularensis is a zoonotic bacterium that must exist in diverse environments ranging from arthropod vectors to mammalian hosts. To better understand how virulence genes are regulated in these different environments, a transcriptional response regulator gene (genome locus FTL0552) was deleted in F. tularensis live vaccine strain (LVS). The FTL0552 deletion mutant exhibited slightly reduced rates of extracellular growth but was unable to replicate or survive in mouse macrophages and was avirulent in the mouse model using either BALB/c or C57BL/6 mice. Mice infected with the FTL0552 mutant produced reduced levels of inflammatory cytokines, exhibited reduced histopathology, and cleared the bacteria quicker than mice infected with LVS. Mice that survived infection with the FTL0552 mutant were afforded partial protection when challenged with a lethal dose of the virulent SchuS4 strain (4 of 10 survivors, day 21 postinfection) when compared to naive mice (0 of 10 survivors by day 7 postinfection). Microarray experiments indicate that 148 genes are regulated by FTL0552. Most of the genes are downregulated, indicating that FTL0552 controls transcription of genes in a positive manner. Genes regulated by FTL0552 include genes located within the Francisella pathogenicity island that are essential for intracellular survival and virulence of F. tularensis. Further, a mutant in FTL0552 or the comparable locus in SchuS4 (FTT1557c) may be an alternative candidate vaccine for tularemia.

Medication decision-making by adults with borderline personality disorder.

OBJECTIVE: The aim of this paper is to describe an effective construct for medication decision-making by adults diagnosed with borderline personality disorder. CONCLUSION: A collaborative decision-making process with an emphasis, wherever possible, on the decision-making of the adult diagnosed with borderline personality disorder, provides a relationship structure promoting effective medication decision-making.

Professionally indicated short-term risk-taking in the treatment of borderline personality disorder.

OBJECTIVE: To define and explore the rationale for professionally indicated short-term risk-taking in treating adults with borderline personality disorder, and discuss prerequisites for the approach, clinical implementation and medicolegal contexts. CONCLUSION: When prerequisites are met and clinical and medicolegal practice is sound and thorough, taking short-term risk, as part of a comprehensive treatment, is a legitimate professional consideration in working with some adults with borderline personality disorder.

Evaluation of HOMA and QUICKI as measures of insulin sensitivity in prepubertal children.

BACKGROUND: Simple fasting sample methods to measure insulin sensitivity (SI) such as homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) have been widely promoted in adult studies but have not been formally evaluated in children. The aim of this study was to compare HOMA and QUICKI to the minimal model as measures of SI in prepubertal children. METHOD: The study population consisted of twins (n = 44), premature (n = 17), small for gestational age (SGA) (15), and normal (n = 3) prepubertal children. The insulin-sensitivity index derived by the minimal model (SIMM) was calculated by the minimal model with plasma glucose and insulin data from a 90-min frequently sampled intravenous glucose test with tolbutamide. The HOMA resistance index (RHOMA) and QUICKI were calculated from fasting plasma glucose and insulin values. RESULTS: The correlation between RHOMA and SIMM (r = -0.4, p < 0.001) was no better than that between fasting insulin and SIMM (r = -0.4, p < 0.001). QUICKI was poorly correlated with SIMM (r = 0.2, p = 0.02). The correlation between SIMM and RHOMA is largely confined to low SI values (< 10 x 10(-4)/min microU/mL.) In seven SGA subjects, the introduction of growth hormone treatment led to an expected fall in SIMM by 8.2 +/- 2.8 x 10(-4)/min microU/mL (p = 0.02) that was not detected by either RHOMA (p = 0.1) or QUICKI (p = 0.2). Similarly, SIMM values were lower in obese (n = 9) compared to non-obese subjects (p = 0.04); however, no difference was found between these two groups with either RHOMA (p = 0.21) or QUICKI (p = 0.8). CONCLUSION: As measures of SI in prepubertal children, RHOMA is no better than fasting insulin and QUICKI, a poor measure. Neither RHOMA nor QUICKI was able to detect changes in SI induced by either obesity or growth hormone therapy.

Reduced insulin sensitivity during growth hormone therapy for short children born small for gestational age.

OBJECTIVES: To examine the influence of recombinant human growth hormone (rhGH) therapy on insulin sensitivity in short children born small for gestational age (SGA). STUDY DESIGN: Twelve short (height standard deviation score, -3.2 +/- 0.1) non-GH-deficient children SGA (7 boys/5 girls) were studied at 9.3 +/- 1.0 years of age. The insulin sensitivity index was measured with Bergman's minimal model before (11 children) and during (12 children) rhGH therapy (21 +/- 6 months) administered daily at 20 IU/m(2) per week. No child had a change in pubertal status during the study. In addition, 5 children who remained prepubertal had insulin sensitivity remeasured 3 months after rhGH therapy was suspended. RESULTS: With rhGH therapy, insulin sensitivity fell 44% +/- 10% (P =.018), with a compensatory rise in the acute insulin response of 123% +/- 59% (P <.009). Reassessment of insulin sensitivity in 5 children (3 boys/2 girls) 3 months after suspension of rhGH occurred at 9.9 +/- 0.7 years. Insulin sensitivity remained unchanged after rhGH therapy was stopped: 31.6 (20.5-42.3) before treatment, 11.5 (5.7-24.4) with treatment, and 10.7 (6.2-16.9) 10(-4). min(-1) microU/mL after treatment. CONCLUSIONS: Children SGA are known to have reduced insulin sensitivity. There was a further reduction in insulin sensitivity with rhGH therapy that did not recover 3 months after rhGH therapy was stopped.