Publications by authors named "Kathleen Bethin"

18 Publications

  • Page 1 of 1

Association of same-day discharge with hospital readmission after pediatric thyroidectomy.

Pediatr Surg Int 2021 May 20. Epub 2021 May 20.

Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 1001 Main Street, Buffalo, NY, 14203, USA.

Background: Studies have demonstrated that same-day discharge (SDD) following thyroid resection is safe and feasible in adults but there are no similar studies in the pediatric age group. The purpose of this study is to evaluate the influence of SDD on 30-day readmission rates following thyroid surgery in pediatric patients.

Methods: This retrospective cohort study used the American College of Surgeons National Surgical Quality Improvement Program-Pediatric database to evaluate 30-day readmission rates among patients < 19 years of age who underwent thyroid resection between 2012 and 2017. Patients excluded were those discharged more than 2 days after surgery. The main exposure variable was SDD and the primary outcome was 30-day readmission. Secondary outcomes included wound complications, unplanned reoperation and death. Patient characteristics were compared using chi-squared testing and odds ratios for readmission were calculated using multivariate logistic regression.

Results: Of the 1125 patients (79% female, median age 15 years), 122 (11%) were discharged on the day of surgery. Total or near-total thyroidectomy represented the majority of operations (714, 63.5%) and patients undergoing these operations were less likely to be discharged on the same day as surgery compared to those undergoing thyroid lobectomy (4.3 vs. 22.1%, P < 0.001). Twenty-nine patients were readmitted within 30 days (3 in the same day group, 26 in the later group). There was no difference in the odds of readmission between the two groups (adjusted odds ratio in SDD compared to later discharge 1.04 [95% CI 0.29-3.75, P = 0.96; readmission rate, 2.46 vs. 2.59%). Wound complications were reported in two patients, both in the later discharge group.

Conclusion: Same-day discharge in pediatric patients undergoing thyroidectomy is not associated with an increase in 30-day readmissions or wound complications when compared to patients discharged 1 or 2 days after surgery. In selected patients, SDD may be an appropriate alternative to traditional overnight stay.
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May 2021

Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels.

Ann Intern Med 2017 07 13;167(2):95-102. Epub 2017 Jun 13.

From International Diabetes Center Park Nicollet, Minneapolis, Minnesota; Jaeb Center for Health Research, Tampa, Florida; University Hospitals of Cleveland, Cleveland, Ohio; Henry Ford Health System, Detroit, Michigan; Children's Hospital of Philadelphia and Perelman School of Medicine and Rodebaugh Diabetes Center, University of Pennsylvania, Philadelphia, Pennsylvania; Northwestern University, Chicago, Illinois; SUNY Upstate Medical University, Syracuse, New York; Children's Hospital of Los Angeles, Los Angeles, California; Indiana University School of Medicine, Indianapolis, Indiana; SUNY Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York; and Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, Washington.

Background: Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin.

Objective: To determine whether a racial difference exists in the relationship of mean glucose and HbA1c.

Design: Prospective, 12-week observational study.

Setting: 10 diabetes centers in the United States.

Participants: 104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%.

Measurements: Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values.

Results: The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons).

Limitation: There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals.

Conclusion: On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes.

Primary Funding Source: Helmsley Charitable Trust.
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July 2017

Barriers to participation in industry-sponsored clinical trials in pediatric type 2 diabetes.

Pediatr Diabetes 2017 Nov 3;18(7):574-578. Epub 2016 Nov 3.

Department of Pediatrics, University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, Ohio.

Background: The rapid emergence of type 2 diabetes (T2D) in the pediatric population has left pediatric endocrinologists with limited artillery in terms of management. While multiple medications are available for adults, Food and Drug Administration (FDA)-approved medications in children are limited to only metformin and insulin. Additional treatment options require randomized controlled trials, yet heretofore several barriers at the participant and institutional level have impeded these studies from proceeding in children and adolescents. Identification of the most challenging obstacles that pediatric endocrinologists experience in participating in industry-sponsored T2D trials may facilitate development of feasible platforms for future studies.

Materials And Methods: We conducted an anonymous online survey consisting of 31 questions that assessed potential barriers to industry-sponsored clinical trials in pediatric patients with T2D. The survey was sent to members of the Pediatric Endocrine Society (PES), and members conducted the survey between October and November of 2014. As part of the survey, respondents rated the significance of several possible barriers to participation in industry-sponsored T2D studies.

Results: We received a total of 207 responses from members of PES. Baseline demographics showed that 50% of represented institutions care for 50 or fewer T2D patients age 18 years and younger; 70% of institutions diagnose 20 or fewer new T2D cases per year; and 3 racial groups predominated: African American, Hispanic, and Caucasian. A total of 70% of responders have a research infrastructure to participate in clinical trials, but only half have dedicated research nurses. Protocol restrictions on participant recruitment due to current glycemic control or medication use as well as frequent visit schedules were reported to be major obstacles. In addition, the financial support provided to centers to carry out the studies is insufficient.

Conclusions: Efforts must be made to ease the burden of research participation on both pediatric T2D patients as well as pediatric endocrinologists.
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November 2017

Glucagon Nasal Powder: A Promising Alternative to Intramuscular Glucagon in Youth With Type 1 Diabetes.

Diabetes Care 2016 Apr 16;39(4):555-62. Epub 2016 Feb 16.

Jaeb Center for Health Research, Tampa, FL.

Objective: Treatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years.

Research Design And Methods: A total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL).

Results: All 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts.

Conclusions: Results of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range.
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April 2016

Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study.

Diabetes Care 2016 Feb 17;39(2):264-70. Epub 2015 Dec 17.

Jaeb Center for Health Research, Tampa, FL.

Objective: Treatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia.

Research Design And Methods: At eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon.

Results: Mean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively.

Conclusions: Intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.
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February 2016

Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial.

JAMA 2015 Dec;314(21):2241-50

University of Colorado, Anschutz Medical Campus, Aurora.

Importance: Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results.

Objective: To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes.

Design, Setting, And Participants: Multicenter (26 pediatric endocrinology clinics), double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1 to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1 diabetes duration 7.0 (3.3) years, mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and mean HbA1c 8.8% (0.7%).

Interventions: Randomization to receive metformin (n = 71) (≤2000 mg/d) or placebo (n = 69).

Main Outcomes And Measures: Primary outcome was change in HbA1c from baseline to 26 weeks adjusted for baseline HbA1c. Secondary outcomes included change in blinded continuous glucose monitor indices, total daily insulin, BMI, waist circumference, body composition, blood pressure, and lipids.

Results: Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA1c was 8.8% in each group. At 13-week follow-up, reduction in HbA1c was greater with metformin (-0.2%) than placebo (0.1%; mean difference, -0.3% [95% CI, -0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, -0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24% (17) of participants in the metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36% [95% CI, 19% to 51%]; P < .001).

Conclusions And Relevance: Among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months. Of multiple secondary end points, findings favored metformin only for insulin dose and measures of adiposity; conversely, use of metformin resulted in an increased risk for gastrointestinal adverse events. These results do not support prescribing metformin to overweight adolescents with type 1 diabetes to improve glycemic control.

Trial Registration: Identifier: NCT01881828.
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December 2015

Prevalence of cardiovascular risk factors in youth with type 1 diabetes and elevated body mass index.

Acta Diabetol 2016 Apr 16;53(2):271-7. Epub 2015 Jun 16.

Indiana University School of Medicine, 702 Barnhill Dr, Indianapolis, IN, 46202, USA.

Aim: The prevalence of cardiovascular risk factors in children with type 1 diabetes and elevated BMI in the USA is poorly defined. We aimed to test the hypothesis that children with type 1 diabetes who are overweight or obese have increased frequencies of hypertension, dyslipidemia, and micro-/macroalbuminuria compared to their healthy weight peers.

Methods: We studied 11,348 children 2 to <18 years of age enrolled in T1D Exchange between September 2010 and August 2012 with type 1 diabetes for ≥1 year and BMI ≥ 5th age-/sex-adjusted percentile (mean age 12 years, 49 % female, 78 % non-Hispanic White). Overweight and obesity were defined based on Centers for Disease Control and Prevention criteria. Diagnoses of hypertension, dyslipidemia, and micro-/macroalbuminuria were obtained from medical records. Logistic and linear regression models were used to assess factors associated with weight status.

Results: Of the 11,348 participants, 22 % were overweight and 14 % obese. Hypertension and dyslipidemia were diagnosed in 1.0 % and 3.8 % of participants, respectively; micro-/macroalbuminuria was diagnosed in 3.8 % of participants with available data (n = 7,401). The odds of either hypertension or dyslipidemia were higher in obese than healthy weight participants [OR 3.5, 99 % confidence interval (CI) 2.0-6.1 and 2.2, 99 % CI 1.6-3.1, respectively]. Obese participants tended to be diagnosed with micro-/macroalbuminuria less often than healthy weight participants (OR 0.6, 99 % CI 0.4-1.0).

Conclusions: Obese children with type 1 diabetes have a higher prevalence of hypertension and dyslipidemia than healthy weight children with type 1 diabetes. The possible association of obesity with lower micro-/macroalbuminuria rates warrants further investigation.
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April 2016

Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes.

Diabetes Care 2015 Mar 17;38(3):476-81. Epub 2014 Dec 17.

Benaroya Research Institute, Seattle, WA.

Objective: It is generally accepted that complete β-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown.

Research Design And Methods: The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control.

Results: The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with ≤18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing.

Conclusions: The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide.
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March 2015

Weight trajectory of youth with new-onset type 1 diabetes comparing standard and enhanced dietary education.

Endocrine 2015 May 31;49(1):155-62. Epub 2014 Oct 31.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo & Women and Children's Hospital of Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA,

Youth with type 1 diabetes (T1DM) gain weight after insulin therapy initiation. We aimed to study the effects of Enhanced Dietary Counseling (EDC) compared to Standard of Care Dietary Counseling (SDC) on BMI trajectory in youth with new-onset T1DM. Youth with new-onset T1DM (n = 47; 8.9 + 4.2 years) were randomized 6 weeks post-diagnosis to either SDC per American Diabetes Association guidelines (n = 25) or EDC (n = 22: SDC plus monthly nutritional education and 3-day food records (FRs) at 6 and 24 weeks). Weights and heights were measured at diagnosis, 6 weeks, 3, 6, and 12 months post-diagnosis; pre-diagnosis BMI was obtained from pediatricians' records. BMI Z score was used to track BMI change. Knowledge of recommended daily energy intake (DEI) and daily carbohydrate intake was assessed at follow-up visits. Changes in BMI Z scores were similar in SDC versus EDC subjects from pre-diagnosis to 12 months post-diagnosis. BMI Z score at 12 months exceeded pre-diagnosis level in 58.5 % subjects (54.5 % EDC vs. 63.1 % SDC, p = 0.75). From 6 weeks to 6 months, percentage of subjects correctly recalling recommended DEI increased in EDC along with percentage of subjects meeting recommended daily fruit servings intake from 25 % (6 weeks) to 64 % (6 months), p = 0.047). EDC did not prevent BMI Z score increases in youth with new-onset T1DM, and BMI Z score exceeded pre-diagnosis levels in >50 % 12 months post-diagnosis. A family-based approach and/or additional intervention may be needed to prevent excessive weight gain.
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May 2015

Role of the GH/IGF-I axis in the growth retardation of weaver mice.

Endocrine 2007 Oct 27;32(2):227-34. Epub 2007 Nov 27.

Department of Pediatrics, Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

IGF-I is a well-established anabolic growth factor essential for growth and development. Although the role of the GH/IGF-I axis is established for normal postnatal growth, its functional state in neurodegenerative diseases is not fully characterized. The weaver mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides an opportunity to investigate the function of IGF-I in postnatal growth following neurodegeneration. Previously, we reported that weaver mice are growth retarded and their body weights correlate with a decrease in circulating IGF-I levels. Because weaver mice have the same food intake/body weight ratios as their wild type littermates, our observation suggests that an impairment of the GH/IGF-I axis, rather than poor nutrition, likely contributes to their growth retardation. This study further investigated the etiology of reduced circulating IGF-I levels. We found that GH levels in weaver mice were reduced following acute insulin injection, but the hepatic GH receptor transduction pathway signaled normally as evidenced by increased STAT5b phosphorylation and IGF-I mRNA levels in response to acute GH administration. In addition, 2-week GH treatment induced a significant increase in body weight and circulating IGF-I levels in homozygous weaver mice but not in wild type littermates. In summary, a deficiency in the GH/IGF-I axis may be partially responsible for postnatal growth retardation in weaver mutant mice. This deficiency may occur at the level of the pituitary and/or hypothalamus and can be improved with GH administration.
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October 2007

GNAS mutation detection is related to disease severity in girls with McCune-Albright syndrome and precocious puberty.

Pediatr Endocrinol Rev 2007 Aug;4 Suppl 4:395-400

Department of Pediatrics, Division of Endocrinology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh PA 15213-2524, USA.

Background: McCune-Albright syndrome (MAS) is characterized by a triad of gonadotropin-independent precocious puberty, café au lait skin pigmentation and fibrous dysplasia of bone. MAS is due to activating mutations of GNAS, the gene encoding Gsalpha. Interest exists in the use of GNAS mutation analysis to make a definitive diagnosis when the phenotype is not diagnostic, i.e. in partial forms of MAS. The utility of using peripheral blood for mutation analysis in this setting has not been thoroughly evaluated.

Objective: We performed a systematic analysis of genomic DNA for the detection of GNAS activating mutations in girls with MAS who presented with precocious puberty to evaluate whether identification of an activating mutation in peripheral blood is related to the presence of other features of MAS.

Study Design: Genomic DNA was isolated from blood from 13 girls with gonadotropin-independent precocious puberty. A polymerase chain reaction (PCR)-based technique was performed for GNAS mutation identification.

Results: GNAS activating mutations were identified in 4 patients, all of whom had classic MAS based on clinical evidence.

Conclusions: Detection of activating mutations in leukocyte genomic DNA extracted from peripheral blood samples from girls with gonadotropin-independent precocious puberty was associated with the presence of other phenotypic manifestations of MAS. Until improvements in the diagnostic utility of GNAS activating mutation analysis from leukocyte genomic DNA occur, such testing in patients with atypical forms of MAS should continue to be reserved for research settings.
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August 2007

Identification of 9 uterine genes that are regulated during mouse pregnancy and exhibit abnormal levels in the cyclooxygenase-1 knockout mouse.

Reprod Biol Endocrinol 2007 Jul 6;5:28. Epub 2007 Jul 6.

Department of Pediatrics and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN 46202, USA.

Background: Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition.

Methods: Gestational d18.0 uteri (n = 4) were collected from pregnant wild-type and cyclooxygenase-1 knockout mice. Part of the uterus was used for frozen sections and RNA was isolated from the remainder. Microarray analysis was performed at the Indiana University School of Medicine Genomic Core and analyzed using the Microarray Data Portal. Northern analysis was performed to confirm microarray data and the genes localized in the gravid uterus by in situ hybridization.

Results: We identified 277 genes that are abnormally expressed in the gravid d18.0 cyclooxygenase-1 knockout mouse. Nine of these genes are also regulated in the normal murine uterus during the last half of gestation. Many of these genes are involved in the immune response, consistent with an important role of the immune system in parturition. Expression of 4 of these genes; arginase I, IgJ, Tnfrsf9 and troponin; was confirmed by Northern analysis to be mis-regulated during pregnancy in the knockout mouse. In situ hybridization of these genes demonstrated a similar location in the gravid wild-type and Cox-1 knockout mouse uteri.

Conclusion: To our knowledge, this is the first work to demonstrate the uterine location of these 4 genes in the mouse during late pregnancy. There are several putative transcription factor binding sites that are shared by many of the 9 genes identified here including; estrogen and progesterone response elements and Ets binding sites. In summary, this work identifies 9 uterine murine genes that may play a role in parturition. The function of these genes is consistent with an important role of the immune system in parturition.
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July 2007

Identification of transcription factors at the site of implantation in the later stages of murine pregnancy.

Reproduction 2006 Mar;131(3):561-71

Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, 702 Barnhill Dr., RI 5960, Indianapolis, Indiana 46202, USA.

Despite medical advances, preterm delivery continues to complicate 12% of all births in the United States and is a major cause of neonatal deaths. One of the reasons that preterm labor continues to be a significant problem is that very little is understood about the factors involved in normal labor. Many investigators have studied parturition in the mouse and defined essential pathways for normal labor. Prostaglandins play an essential role in mouse labor and are important in human labor as well. We examined the 23 transcription factors from pregnant mouse uterus that change expression after the induction of cyclooxygenase-1, the enzyme that catalyzes the first committed step in prostaglandin synthesis. Using in situ hybridization, we have identified three of these transcription factors, Hoxa10, Hoxa11 and GILZ as being expressed in the decidua and regulated at the end of pregnancy. Both Hoxa10 and Hoxa11 are known to be critical for implantation, but very little is known about their roles in late gestation. GILZ has not previously been identified in the gravid uterus. In summary, we have identified three transcription factors that are regulated in the decidua at the end of pregnancy, suggesting a role in detachment of the fetus and placenta.
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March 2006

The rare occurrence of absent adrenals in a term infant: a case report and review of the literature.

Am J Perinatol 2006 Feb;23(2):111-4

Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri, USA.

A female infant (gestational age, 37 weeks) presented with respiratory distress and pulmonary hypertension. Incidental to her clinical course, she was discovered by abdominal ultrasound to have absent adrenal glands bilaterally. This is the first case report of congenitally absent adrenal glands noted at birth. The exons of the patient's SF-1 gene were sequenced, and despite identifying a single nucleotide polymorphism that preserves proline at position 125 of SF-1, none of the previously identified mutations were detected in our samples. The known role of SF-1 and its mutations in adrenal gland development are discussed.
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February 2006

Microarray analysis of uterine gene expression in mouse and human pregnancy.

Mol Endocrinol 2003 Aug 29;17(8):1454-69. Epub 2003 May 29.

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Improved care of infants born prematurely has increased their survival. However, the incidence of preterm labor has not changed. To understand the processes involved in preterm labor, we used oligonucleotide microarrays to study gene expression in murine and human uterus during pregnancy. The induction of enzymes for prostaglandin synthesis was used as a marker for important changes during pregnancy because prostaglandins strongly contribute to both human and murine labor. We identified 504 genes that changed at least 2-fold between d 13.5 and 19.0 in the gravid mouse uterus. In the pregnant human myometrium, we found 478 genes that changed at least 2-fold in either term or preterm labor compared with preterm nonlabor specimens and 77 genes that significantly varied in both preterm and term labor. Patterns of gene regulation within functional groups comparing human preterm and term labor were similar, although the magnitude of change often varied. Surprisingly, few genes that changed significantly throughout pregnancy were the same in the mouse and human. These data suggest that functional progesterone withdrawal in human myometrium may not be the primary mechanism for labor induction, may implicate similar mechanisms for idiopathic preterm and term labor in humans, and may identify novel targets for further study.
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August 2003

Dissecting adrenal and behavioral responses to stress by targeted gene inactivation in mice.

Stress 2003 Jun;6(2):121-5

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.

To define the molecular pathways modulating adrenal and behavioral responses to stress, we have generated mice with inactivation of hypothalamic neuropeptides and signaling pathways. Studies in mice deficient in corticotropin-releasing hormone (CRH) have revealed the essential role for CRH in adrenal glucocorticoid production in response to many physiological and psychological stressors. Immune system activation in CRH-deficient mice provides a unique exception to the necessity for CRH in stimulating adrenal glucocorticoid production. By analyzing mice deficient in interleukin-6 (IL-6) and CRH, we find that restoration of glucocorticoid output with inflammation is largely mediated by dysregulated IL-6 production. Current studies focus on identifying cellular and gene targets by which glucocorticoids regulate immune system function. In contrast to impaired adrenocortical responses to stress, CRH-deficient mice exhibit normal behavioral responses to stress. To determine signaling pathways that may contribute to the behavioral responses to stress, we have generated and analyzed mice deficient in adenylyl cyclase type 8 (AC8). AC8 deficient mice have intact adrenocortical responses to stress, but an inability to undergo stress-induced alterations in behavior.
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June 2003