Topiramate use does not reduce flares of inflammatory bowel disease.

BACKGROUND: Additional medications are needed for inflammatory bowel disease (IBD) as existing therapies are incompletely effective and can be costly and toxic. Preclinical studies suggest that topiramate (an anticonvulsant) may have disease-modifying properties in IBD, but its efficacy in humans is unknown. AIM: To evaluate whether topiramate use is associated with clinical benefit in IBD patients. METHODS: We conducted a retrospective cohort study using administrative claims data from the MarketScan databases. Persons with IBD were identified between 2000 and 2010. New users of topiramate were compared with users of other anticonvulsant and anti-migraine medications. The primary outcome was a new prescription for an oral steroid (≥14 days). Secondary outcomes included initiation of biologic agents, abdominal surgery, and hospitalization. Cox proportional hazard modeling was used to adjust for potential confounders. RESULTS: We identified 773 new users of topiramate and 958 users of comparator drugs. After adjusting for potential confounders, topiramate use was not associated with the primary outcome of steroid prescriptions [hazard ratio (HR) 1.14, 95 % confidence interval (CI) 0.74, 1.73]. Results did not differ significantly by IBD subtype. There was no difference between topiramate users and users of comparator drugs with respect to post-exposure initiation of biologic agents (HR 0.93, 95 % CI 0.39, 2.19), abdominal surgery (HR 1.04, 95 % CI 0.17, 6.41), or hospitalization (HR 0.86, 95 % CI 0.62, 1.19). CONCLUSION: In this large U.S. administrative claims study, topiramate use was not associated with markers of IBD flares. These results cast doubt on whether topiramate may be an effective adjunct to current IBD therapy.

A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex.

Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here, we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole-cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation.

The human brain is made up of billions of nerve cells called neurons which receive and send signals to one another. To avoid being over- or under-stimulated, neurons can adjust the strength of the inputs they receive by altering how connected they are to other nerve cells. This process, known as homeostatic plasticity, is thought to be necessary for normal brain activity as it helps keep the outgoing signals of neurons relatively constant. However, homeostatic plasticity can lead to seizures if it becomes too strong and overcompensates for weak input signals. Regulating this process is therefore central to brain health, but scientists do not understand if or how it is controlled. To address this, Valakh et al. analyzed the genes activated in neurons lacking incoming signals to find proteins that regulate homeostatic plasticity. This revealed a class of molecules called transcription factors (which switch genes on or off) that constrain the process. In brain samples from mice without these regulatory proteins, neurons received twice as much input, leading to an increase in brain activity resembling that observed during seizures. Valakh et al. confirmed this finding using live mice, which developed seizures in the absence of these transcription factors. These findings suggest that this type of regulation to keep homeostatic plasticity from becoming too strong may be important. This could be especially vital as the brain develops, when the strength of connections between neurons changes rapidly. The discovery of the transcription factors involved provides a potential target for activating or restraining homeostatic plasticity. This control could help researchers better understand how the process stabilizes brain signaling.

Postpartum glucose tolerance screening in women with gestational diabetes in the state of North Carolina.

OBJECTIVE: To determine how frequently health care providers taking care of women with gestational diabetes mellitus (GDM) are screening for postpartum glucose tolerance and what practice approaches they are using to care for women with GDM. METHODS: A mailed survey assessed health care providers' knowledge of GDM and practice patterns. Factors influencing practice protocols for measuring glucose tolerance postpartum were identified. RESULTS: Of 1,002 eligible North Carolina health professionals, 399 responded (40%); 327 of these (82%) were providing prenatal and postpartum care and returned the completed surveys. Almost all providers (98%) screen for GDM, and the majority (97%) use the 50-gram one-hour glucose challenge test. Only 27% of respondents always screen for diabetes mellitus (DM) postpartum. The most common method for screening was the 75-gram two-hour glucose tolerance test (54%). The factors most commonly associated with failure to screen were patients lost to follow-up, patient inconvenience, and inconsistent screening guidelines. A majority (59%) stated that increased reimbursement would have little to no impact on their consistency in providing diabetic counseling. CONCLUSIONS: The rate of postpartum glucose tolerance testing is low in this study of providers of postpartum care. Several modifiable barriers to screening were identified. There is a need for improved screening practices and early intervention that could help prevent the complications of DM and benefit subsequent pregnancies in this high risk population.

Epidemiology of depressive symptoms in the National Longitudinal Study of Adolescent Health.

OBJECTIVE: To describe the range of depressive symptoms reported by adolescents in a nationally representative U.S. sample and to examine factors associated with persistent depressive symptoms. METHOD: Secondary analysis was done on National Longitudinal Study of Adolescent Health (AddHealth) data from 13,568 adolescents who completed the initial survey in 1995 and follow-up 1 year later. Main outcomes of Center for Epidemiologic Studies-Depression Scale (CES-D) scores were analyzed by chi2 comparisons and sample-weighted logistic regression. RESULTS: Over 9% of adolescents reported moderate/severe depressive symptoms at baseline (CES-D > or = 24). Females, older adolescents, and ethnic minority youths were more likely to report depressive symptoms at baseline. Only 3% of adolescents with low initial CES-D scores (CES-D < 16) developed moderate/severe depressive symptoms at follow-up. Factors associated with persistent depressive symptoms at 1-year follow-up included: female gender, fair/poor general health, school suspension, weaker family relationships, and health care utilization. Other factors, including race and socioeconomics, did not predict persistent depressive symptoms. CONCLUSIONS: Depressive symptoms are common in adolescents and have a course that is difficult to predict. Most adolescents with minimal symptoms of depression maintain their status and appear to be at low risk for depression; however, adolescents with moderate/severe depressive symptoms warrant long-term follow-up and reevaluation.

Complications, revision fusions, readmissions, and utilization over a 1-year period after bone morphogenetic protein use during primary cervical spine fusions.

BACKGROUND CONTEXT: Nationwide estimates examining bone morphogenetic protein (BMP) use with cervical spine fusions have been limited to perioperative outcomes. PURPOSE: To determine the 1-year risk of complications, cervical revision fusions, hospital readmissions, and health care services utilization. STUDY DESIGN: A retrospective cohort study from 2002 to 2009 using a nationwide claims database. PATIENT SAMPLE: There were 61,937 primary cervical spine fusions of which 1,677 received BMP. OUTCOME MEASURES: Complications, revision fusions, 30-day hospital readmission, and health care utilization. METHODS: Data for these analyses come from the Thomson Reuters MarketScan Commercial Claims and Encounters Database 2010. Patients were aged 18 to 64 years, receiving and not receiving BMP with a primary (C2-C7) cervical spine fusion. All outcomes were defined by International Classification of Diseases, 9th edition Clinical Modification and Current Procedural and Terminology, 4th edition codes. Complications were analyzed as any complication and stratified by nervous system, wound, and dysphagia or hoarseness. Cervical revision fusions were determined in the 1-year follow-up. Hospital readmission discharge records defined 30-day hospital readmission and reason for the readmission. The utilization of at least one health care service of cervical spine imaging, epidural usage or rehabilitation service was examined. Poisson regression models were used to estimate the relative risk and 95% confidence interval (CI). Linear regression was used to determine the time to hospital readmission. Results were stratified by anterior or posterior and circumferential approaches. RESULTS: Patients receiving BMP were 29% more likely to have a complication (adjusted relative risk [aRR]=1.29 [95% CI, 1.14-1.46]) and a nervous system complication (aRR=1.42 [95% CI, 1.10-1.83]). Cervical revision fusions were more likely among patients receiving BMP (aRR=1.69 [95% CI, 1.35-2.13]). The risk of 30-day readmission was greater with BMP use (aRR=1.37 [95% CI, 1.07-1.73]) and readmission occurred 27.4% sooner on an average. Patients receiving BMP were more likely to receive computed tomography scans (aRR=1.34 [95% CI, 1.06-1.70]) and epidurals with anterior surgical approaches (aRR=1.29 [95% CI, 1.00-1.65]). CONCLUSIONS: These findings question both the safety and effectiveness of off-label BMP use in primary cervical spine fusions.

Subclinical hypothyroidism and risk for incident ischemic stroke among postmenopausal women.

BACKGROUND: Subclinical hypothyroidism (SCH) is postulated to increase stroke risk via atherogenic changes associated with abnormal thyroid function. However, the direct relationship of SCH with subsequent stroke is poorly studied. METHODS: In this nested case-cohort study, we prospectively evaluated the association between any SCH and severity of SCH in relation to incident ischemic stroke risk among postmenopausal women in the Women's Health Initiative Observational Study. Trained Women's Health Initiative staff, masked to thyroid status, adjudicated stroke cases. We assessed thyroid function using baseline blood specimens. Women with normal free thyroxine levels and thyrotropin (TSH) levels ≥4.69 mU/L were considered to have SCH. Primary analysis included 639 ischemic stroke cases and 2927 randomly selected subcohort members with an average of seven years of follow-up. RESULTS: The multivariable adjusted hazard ratios (HR) from weighted Cox models were 1.06 (95% confidence interval [CI]: 0.77, 1.46) and 0.99 (95% CI: 0.67, 1.47) for women with any SCH and with mild SCH (TSH 4.69 to 6.99 mU/L), when compared with women with normal thyroid function. The HR for moderate/severe SCH (TSH ≥7.00 mU/L) was modestly elevated (HR: 1.22; 95% CI: 0.73, 2.05). CONCLUSIONS: We found no evidence to suggest an association between SCH and ischemic stroke among healthy postmenopausal women.

Subclinical hypothyroidism and risk for incident myocardial infarction among postmenopausal women.

CONTEXT: Subclinical hypothyroidism (SCH) has been associated with an increased risk for cardiovascular disease. However, few studies have specifically examined the association between SCH and myocardial infarction (MI), and the relationship is poorly understood. OBJECTIVES: The purpose of this study was to evaluate incident MI risk in relation to SCH and severities of SCH among postmenopausal women. METHODS: We used a population-based nested case-cohort design within the Women's Health Initiative observational study to examine the association between SCH and incident first-time MI risk among postmenopausal women in the United States. SCH was assessed using blood specimens collected at baseline. Participants presenting with normal free T4 levels and with thyrotropin levels of greater than 4.68-6.99 mU/L or 7.00 mU/L or greater were defined as having mild SCH or moderate/severe SCH, respectively. MI cases were centrally adjudicated by trained Women's Health Initiative staff. The primary analysis included 736 incident MI cases and 2927 randomly selected subcohort members. Multivariable adjusted Cox-proportional hazard models were used to assess MI risk in relation to SCH. RESULTS: Compared with euthyroid participants, the multivariable adjusted hazard ratio (HR) for participants with any SCH was 1.05 [95% confidence interval (CI) 0.77-1.44]. HRs for participants with mild SCH, moderate/severe SCH, and moderate/severe SCH and the presence of antithyroid peroxidase antibodies (TPOAb) were 0.99 (95% CI 0.67-1.46), 1.19 (95% CI 0.72-1.96), and 0.90 (95% CI 0.47-1.74), respectively. CONCLUSION: We did not find evidence to suggest that SCH is associated with increased MI risk among a population of predominantly older postmenopausal women with no prior history of MI.

Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study.

BACKGROUND: Statin medications have antiinflammatory effects. We sought to determine whether statin use in persons with inflammatory bowel disease (IBD) was associated with reduced rates of steroid use or other markers of disease activity. METHODS: We performed a retrospective cohort study using administrative data. Statin users with IBD were compared to statin-unexposed IBD subjects. The primary outcome was an oral steroid prescription; secondary outcomes included anti-tumor necrosis factor (TNF) initiation, hospitalization, or abdominal surgery. Cox proportional hazard models were used to estimate hazard ratios (HRs) adjusted for potential confounders. RESULTS: The study cohort included 1986 statin-exposed and 9871 unexposed subjects. Statin use was associated with an 18% reduction in the rate of steroid initiation (HR 0.82, 95% confidence interval [CI] 0.71, 0.94). A statistically significant result was seen with atorvastatin only (HR 0.76, 95% CI 0.60, 0.96). Statins were associated with a reduced rate of steroids in ulcerative colitis (HR 0.75, 95% CI 0.62, 0.91), but not in Crohn's disease (HR 0.91, 95% CI 0.74, 1.12). Statin use was associated with reduced hazard of anti-TNF use (HR 0.72, 95% CI 0.46, 1.11), abdominal surgery (HR 0.80, 95% CI 0.63, 1.02), and hospitalization (HR 0.88, 95% CI 0.74, 1.05), but these results did not reach statistical significance. CONCLUSIONS: In this large retrospective cohort study, statin use among persons with IBD was associated with reduced use of oral steroids, particularly for ulcerative colitis. Prospective clinical trials are needed to confirm whether adjuvant treatment of IBD with statin drugs may spare immunosuppressant therapy or ameliorate flares.