A clinical trial of progesterone for severe traumatic brain injury.

BACKGROUND: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial. METHODS: We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. RESULTS: Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.).

Vascular risk factors and diabetic neuropathy.

BACKGROUND: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. METHODS: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (+/-SD) follow-up of 7.3+/-0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. RESULTS: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. CONCLUSIONS: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension.

Death Receptor 3 Signaling Controls the Balance between Regulatory and Effector Lymphocytes in SAMP1/YitFc Mice with Crohn's Disease-Like Ileitis.

Death receptor 3 (DR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, has been implicated in regulating T-helper type-1 (TH1), type-2 (TH2), and type-17 (TH17) responses as well as regulatory T cell (Treg) and innate lymphoid cell (ILC) functions during immune-mediated diseases. However, the role of DR3 in controlling lymphocyte functions in inflammatory bowel disease (IBD) is not fully understood. Recent studies have shown that activation of DR3 signaling modulates Treg expansion suggesting that stimulation of DR3 represents a potential therapeutic target in human inflammatory diseases, including Crohn's disease (CD). In this study, we tested a specific DR3 agonistic antibody (4C12) in SAMP1/YitFc (SAMP) mice with CD-like ileitis. Interestingly, treatment with 4C12 prior to disease manifestation markedly worsened the severity of ileitis in SAMP mice despite an increase in FoxP3+ lymphocytes in mesenteric lymph node (MLN) and small-intestinal lamina propria (LP) cells. Disease exacerbation was dominated by overproduction of both TH1 and TH2 cytokines and associated with expansion of dysfunctional CD25-FoxP3+ and ILC group 1 (ILC1) cells. These effects were accompanied by a reduction in CD25+FoxP3+ and ILC group 3 (ILC3) cells. By comparison, genetic deletion of DR3 effectively reversed the inflammatory phenotype in SAMP mice by promoting the expansion of CD25+FoxP3+ over CD25-FoxP3+ cells and the production of IL-10 protein. Collectively, our data demonstrate that DR3 signaling modulates a multicellular network, encompassing Tregs, T effectors, and ILCs, governing disease development and progression in SAMP mice with CD-like ileitis. Manipulating DR3 signaling toward the restoration of the balance between protective and inflammatory lymphocytes may represent a novel and targeted therapeutic modality for patients with CD.

Progress Toward Eliminating Hepatitis A Disease in the United States.

Hepatitis A virus (HAV) disease disproportionately affects adolescents and young adults, American Indian/Alaska Native and Hispanic racial/ethnic groups, and disadvantaged populations. During 1996-2006, the Advisory Committee on Immunization Practices (ACIP) made incremental changes in hepatitis A (HepA) vaccination recommendations to increase coverage for children and persons at high risk for HAV infection. This report examines the temporal association of ACIP-recommended HepA vaccination and disparities (on the absolute scale) in cases of HAV disease and on seroprevalence of HAV-related protection (measured as antibody to HAV [anti-HAV]). ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ≥1-dose and ≥2-dose vaccine coverage. However, the increasing proportion of cases of HAV disease among adults with identified and unidentified sources of exposure underscores the importance of considering new strategies for preventing HAV infection among U.S. adults. For continued progress to be made toward elimination of HAV disease in the United States, additional strategies are needed to prevent HAV infection among an emerging population of susceptible adults. Notably, HAV infection remains endemic in much of the world, contributing to U.S. cases through international travel and the global food economy.

Titanium miniplates or stainless steel wire for cranial fixation: a prospective randomized comparison.

OBJECT: The authors designed a study to compare low-profile titanium miniplate fixation to that in which stainless steel wire is used. METHODS: Before undergoing craniotomy, 40 patients gave informed consent and were randomized to receive either wire or miniplate fixation. After dural closure, bone flap fixation was timed. The bone flap was measured for inward or outward offset and mobility to manual pressure on its margin. Three months postoperatively the bone flap margins were graded for appearance or palpation of an offset and for the presence of burr hole depressions. Twenty-four patients were randomized to receive miniplate fixation and 16 to receive stainless steel wire fixation. The time required for wire fixation was approximately 40% longer than that for miniplates (11.8 +/- 5.1 minutes compared with 8.3 +/- 5 minutes, p = 0.02). The offset of bone flaps after wire fixation was significantly greater than that with miniplates (1.6 +/- 1 mm compared with 0.3 +/- 0.6 mm, p < 0.001), as was the mobility of the bone flap on digital pressure (1.2 +/- 0.9 mm compared with 0.2 +/- 0.5 mm, p < 0.001). At the 3-month follow-up review, two of 12 patients had suboptimal results after wire fixation, whereas none of 14 patients had suboptimal results after miniplate fixation. When dichotomized for excellent or less-than-excellent postoperative results, the data were significantly better for patients who underwent miniplate fixation (p < 0.05). CONCLUSIONS: Titanium miniplate cranial fixation provides more accurate and rigid reapproximation of the bone edges, with results that are significantly better on close inspection or palpation. The additional cost of miniplate fixation may thus be justified in many cases.

Hip status in cerebral palsy after one year of continuous intrathecal baclofen infusion.

The purpose of this study was to assess whether reduction of muscle tone by continuous intrathecal baclofen infusion affects the progression of hip subluxation in persons with cerebral palsy. This prospective, open-label, case series was conducted at multiple specialty referral centers. There were 33 subjects, ages 4 to 31 years. All had a pretreatment lower extremity Ashworth score of >/=3; all subjects had a significant reduction in tone after a bolus injection of intrathecal baclofen and received an implanted pump for continuous delivery of intrathecal baclofen. Subjects had hip x-rays before and 1 year after pump implantation. The primary outcome measure was change in absolute hip migration percentage. One third of the hips had an increase of absolute migration percentage of 5% or more; 12% of the hips had a decrease of migration percentage of 5% or more. Change of migration percentage class was used as a second outcome criterion. 90.9% of hips manifested no deterioration or had improvement of their migration percentage class during the year of intrathecal baclofen therapy. The observed changes were not associated with the subject's age or the severity of cerebral palsy.

Delayed repair of myelomeningoceles.

OBJECTIVE: Myelomeningocele is a defect that typically is repaired surgically within the first few days of life in developed countries to minimize the risk of meningitis. If left unrepaired, these children may survive to have their meningocele sac epithelialize. The surgical reduction and closure of an epithelialized myelomeningocele represents a unique challenge for the neurosurgeon because it requires a modification of the typical closure technique. METHODS: Our 10 years' experience in 97 patients with the delayed (>6 months) repair of myelomeningoceles formed the basis of this report. RESULTS: We present repair techniques in a child with a myelomeningocele that was not repaired at birth and presented a surgical challenge. CONCLUSION: Delayed closure of myelomeningoceles is facilitated by lessons learned from our surgical experience during a medical missions to Guatemala.

A model for neurosurgical humanitarian aid based on 12 years of medical trips to South and Central America.

The pediatric neurosurgical mission trips led by physicians at Virginia Commonwealth University (VCU) Health Systems began in 1996 with the formation of Medical Outreach to Children, founded by 1 of the authors (J.D.W.) after a visit to Guatemala. Since then, 19 surgical trips to 4 different countries in Central and South America have been coordinated from 1996 to 2008. This humanitarian work serves a number of purposes. First and foremost, it provides children with access to surgical care that they would otherwise not receive, thereby significantly improving their quality of life. Second, the visiting surgical team participates in the education of local physicians, parents, and caregivers to help improve the healthcare provided to the children. Last, the team works to promote sustainable global health solutions in the countries it travels to by generating a forum for clinical and public health research discourse. Thus far, a total of 414 children have undergone 463 operations, including 154 initial shunt surgeries, 110 myelomeningocele repairs, 39 lipoma resections, 33 tethered cord releases, 18 shunt revisions, 16 encephalocele repairs, 9 lipomyelomeningocele repairs, and 7 diastematomyelia repairs. The complication rate has been 5-8%, and the team has obtained reliable follow-up in approximately 77% of patients. A correlation was found between an increase in the number of trained neurosurgeons in the host countries and a decrease in the average age of patients treated by the visiting surgical team over time. It is also hypothesized that a decrease in the percentage of myelomeningocele repairs performed by the surgical team (as a fraction of total cases between 1996 and 2006) correlates to an increase in the number of local neurosurgeons able to treat common neural tube defects in patients of younger ages. Such analysis can be used by visiting surgical teams to assess the changing healthcare needs in a particular host country.

GMFM 1 year after continuous intrathecal baclofen infusion.

The purpose of this study was to assess whether there is an improvement in motor function in persons with cerebral palsy (CP) who have had a reduction of muscle tone by continuous intrathecal baclofen infusion. This was a prospective, open label, non-blinded case series without a control group, conducted at multiple centres. There were 31 subjects, aged 4-29 years. All had a pre-treatment mean lower extremity Ashworth scores of >or= 3 and a significant reduction in tone after a bolus injection of intrathecal baclofen (ITB) and received an implanted pump for continuous delivery of ITB. Motor function was assessed by the Gross Motor Function Measure (GMFM) prior to and 1 year following pump implantation. Significant improvement (p < 0.05) in mean GMFM scores was seen in subjects < 8 years (mean change 4.1) and in those from 8-18 years (mean change 3.7) and in subjects with CP Classes 2 and 5 (mean changes 6.2 and 2.9). There was a statistically significant decrease (p < 0.05) in Ashworth scores in CP classes 2-5. Subjects or their caregivers that completed a survey about perceived changes stated that motor control, positioning and endurance improved.