Genetic Variants in Toll-Like Receptor 2 (TLR2), TLR4, TLR9, and FCγ Receptor II Are Associated with Antibody Response to Quadrivalent Meningococcal Conjugate Vaccine in HIV-Infected Youth

This study examined the association of host genetic variants with the antibody response to the quadrivalent meningococcal conjugate vaccine (MCV4) in HIV-infected youth. Genetic variants associated with severity of meningococcal disease, including the IgG Fc receptor (FCγRII)-A484T, interleukin-10 (IL-10)-A1082G, -C819T, and -C627A, IL-4-C589T, mannose binding lectin-2 (MBL2)-A/O, -H/L, -P/Q, and -X/Y, toll-like receptor 2 (TLR2)-G2408A, TLR4-A12874G and -C13174T, and TLR9-T1237C and -T1486C were determined by real-time PCR (RT-PCR) for 271 HIV-infected subjects (median, 17 years). Response was defined as a ≥4-fold increase from entry in bactericidal antibody titers to each serogroup. Generalized estimating equation (GEE) models were used to evaluate the association of allelic variants with the immunologic response to all serogroups within each subject with and without adjusting for CD4 percentage and HIV viral load. At week 4, but not after, subjects with TLR2-2408-G/A versus -G/G genotypes and the TLR4-12874-A/A genotype were more likely to achieve a ≥4-fold increase overall in the four serogroups (unadjusted P of 0.006 and adjusted P of 0.008 and unadjusted P of 0.008 and adjusted P of 0.019, respectively). At week 28, the TLR9-1237 T allele was associated with enhanced antibody response (T allele versus C/C, unadjusted P of 0.014 and adjusted P of 0.009), which was maintained at week 72 (unadjusted and adjusted P of 0.008). At week 72, the FcγRII-131Arg allotype was associated with a ≥4-fold increase in antibody titer versus those with His/His (unadjusted P of 0.009; adjusted P of <0.001). These findings suggest that for HIV-infected youth, the initial antibody response to MCV4 is associated with variants in TLR2 and TLR4 while the long-term response is associated with genetic polymorphisms in TLR9 and FcγRIIa.     

Perampanel,a selective,noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor antagonist,as adjunctive therapy for refractory partial‐onset seizures: Interim results from phase III,extension study 307

Purpose: To evaluate safety, tolerability, and seizure outcome data during long‐term treatment with once‐daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial‐onset seizures. Methods: Study 307 was an extension study for patients completing the double‐blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open‐label treatment phase (including a 16‐week blinded conversion period and a planned 256‐week maintenance period) and a 4‐week follow‐up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1–128.1) weeks. Treatment‐emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent‐to‐treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13‐week interval of perampanel treatment were ?39.2% for weeks 14–26 (n = 1,114), ?46.5% for weeks 40–52 (n = 731), and ?58.1% for weeks 92–104 (n = 59). Overall responder rates in patients included in each 13‐week interval of perampanel treatment were 41.4% for weeks 14–26 (n = 1,114), 46.9% for weeks 40–52 (n = 731), and 62.7% for weeks 92–104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (?42.4%, n = 369) was similar to that in patients previously randomized to perampanel (?41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial‐onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.     

Manganese-Enhanced Magnetic Resonance Imaging Detects Declining Pancreatic β-Cell Mass in a Cyclophosphamide-Accelerated Mouse Model of Type 1 Diabetes

Currently, there is no ideal noninvasive method to quantify the progressive loss of pancreatic β-cell mass (BCM) that occurs in type 1 diabetes. Magnetic resonance imaging has detected gross differences in BCM between healthy and diabetic mice using the contrast agent manganese, which labels functional β-cells and increases the water proton relaxation rate (R1), but its ability to measure gradations in BCM during disease progression is unknown. Our objective was to test the hypothesis that measurements of the manganese-enhanced pancreatic R1 could detect decreasing BCM in a mouse model of type 1 diabetes. We used cyclophosphamide-accelerated BDC2.5 T-cell receptor transgenic nonobese diabetic mice, which experience development of type 1 diabetes during a 7-day time period after cyclophosphamide injection, whereas transgene-negative mice do not. We measured the manganese-enhanced pancreatic R1 before cyclophosphamide injection (day 0) and on days 3, 4, 5, and 7 afterward. Pancreatic R1 remained constant in transgene-negative mice and decreased stepwise day-to-day in transgene-positive mice, mirroring their loss of BCM, confirmed by pancreatic insulin measurements and histology. Changes in R1 in transgene-positive mice occurred before elevations in blood glucose, a clinical indicator of diabetes, suggesting potential for early noninvasive detection of changes in functional BCM.Type 1 diabetes is a metabolic disorder characterized by an inability to maintain normoglycemia. It occurs due to the autoimmune destruction of the insulin-producing pancreatic β-cells, which are diffusely dispersed throughout the pancreas in the islets of Langerhans and represent approximately 1–2% of the pancreatic mass (1). The etiology of this destructive autoimmune process remains largely unknown, although key cellular events include early functional disruption and progressive inflammatory β-cell destruction (2–4). Currently, there is no ideal method for noninvasively measuring changes in functional β-cell mass (BCM), which would be valuable for assessing diabetes progression, following therapeutic response, or for evaluating the viability of transplanted pancreatic islets (5). Provocative testing with β-cell secretogogues, the gold standard for detection of β-cell loss, is insensitive to early stages of the disease, and although biopsy techniques might be useful in monitoring the status of clustered transplanted islets in defined sites, this approach is impractical for dispersed islet transfers or in the diagnosis and staging of type 1 diabetes.Recently, noninvasive imaging techniques such as single photon emission computed tomography (SPECT) (6), positron emission tomography (7,8), bioluminescence imaging (9), and magnetic resonance imaging (MRI) (10–13) have shown promise in detecting BCM. These techniques, however, have limitations. Positron emission tomography and single photon emission computed tomography use ionizing radiation, have relatively low spatial resolution, and currently use non-ideal β-cell–specific radiotracers; bioluminescence imaging has limited spatial resolution and is not translatable to humans; and no technique has proven the ability to detect small gradations in BCM. Manganese (Mn²⁺)-enhanced MRI (MEMRI) may prove an attractive method for assessing functional BCM, because the mechanism by which Mn²⁺ ions label β-cells is inherently linked to β-cell function and may be translatable to human imaging. Manganese ions enter β-cells through voltage-gated calcium channels (10) and increase the nuclear magnetic resonance water proton longitudinal relaxation rate constant (R1) proportionally with Mn²⁺ concentration. Recent data supporting this mechanism showed that glucose stimulation before MEMRI increased pancreatic R1, and that this effect is essentially abolished with calcium channel blockade (12). Thus, the glucose-stimulated Mn²⁺-enhanced pancreatic R1 has been interpreted as a measurement of functional BCM (12). MEMRI studies previously have detected gross decreases in BCM in mice in a streptozotocin-induced model of type 1 diabetes (11–13), a model characterized by a precipitous loss of BCM after streptozotocin injection. The sensitivity of MEMRI, or any other imaging modality, to detect gradual changes in functional BCM that occur during the progression of diabetes has not yet been demonstrated, although the ability to measure gradations in BCM is necessary for clinical translation of any technique that assesses functional BCM.To test the hypothesis that MEMRI can detect gradations in BCM, we performed MRI on cyclophosphamide-accelerated BDC2.5 T-cell receptor transgenic mice on a nonobese diabetic background (NOD-BDC2.5) (14–16). After injection of cyclophosphamide, NOD-BDC2.5 mice expressing a transgenic T-cell receptor (Tg⁺ mice) exhibit progressive autoimmune β-cell destruction, with virtually 100% of mice becoming overtly diabetic within 7 days of cyclophosphamide injection (14). Mice lacking the transgenic T-cell receptor (Tg⁻ mice) do not have development of diabetes within this time frame after cyclophosphamide injection. Because of the kinetics and reproducibility of diabetes progression, this model allows the investigation of the ability to detect small decrements in functional BCM.