Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 3, 2015
Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic m... more Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase 1 protocol. This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n=12), sarcoma (n=17), or other refractory solid tumors (n= 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5mg/kg and 10mg/kg dose levels. Pharmacokinetics revealed a half-life of 8-15 days. At day 21, ...
Ocular chronic graft-versus-host disease is one of the most bothersome common complications after... more Ocular chronic graft-versus-host disease is one of the most bothersome common complications after allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring, however, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (NCT00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test ...
Objective-To describe the ophthalmic and systemic autoimmune findings after successful adoptive c... more Objective-To describe the ophthalmic and systemic autoimmune findings after successful adoptive cell transfer of ex vivo expanded, autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) for metastatic melanoma.
Three patients with aplastic anemia were evaluated by the ophthalmology service within 2 months o... more Three patients with aplastic anemia were evaluated by the ophthalmology service within 2 months of the aplastic anemia diagnosis for bilateral visual loss. The mean age of diagnosis of aplastic anemia was 14.3 years (range: 5 to 19 years) and the mean follow-up was 25 months (range: 15 to 44 months). All 6 eyes demonstrated choroidal ischemia and vitreous hemorrhage. Pars plana vitrectomy was performed in four eyes of two patients for non-clearing vitreous hemorrhage; one patient was observed. Successful anatomic outcomes were achieved in 3 of 4 eyes that underwent vitrectomy. Initial visual acuity ranged from 20/80 to bare light perception and final visual acuity ranged from 20/20 to no light perception. All patients received immunosuppressive therapy including cyclosporine and anti-thymocyte globulin, and two underwent hematopoietic stem cell transplantation. All patients received perioperative platelet and blood transfusions. Pars plana vitrectomy resulted in functional and anatomic success in the majority of eyes in this series. Coordination of medical and surgical care with the hematology service is advisable to stabilize hematologic parameters prior to undertaking a vitreoretinal procedure.
This study was conducted to test whether cortical activation varies across successive epoques dur... more This study was conducted to test whether cortical activation varies across successive epoques during functional magnetic resonance imaging (fMRI) studies. Ten normal adult volunteers were studied with a 1.5-T MR scanner. Pseudocoronal study planes were chosen perpendicular to the tentorium cerebelli, at two thirds the distance from the posterior edge of the splenium of the corpus callosum to the transverse sinuses. Functional images were acquired with a T2*-weighted spoiled gradient echo sequence. The visual cortex was stimulated by goggles flashing at 8 Hz. Each study consisted of 82 sequential scans, lasting 15 seconds each for a total of 20.5 minutes. Two scans without stimulation were alternated with two scans of visual stimulation. Scans 3 through 83 were divided into five sequences of 16 scans. For each sequence, the number of pixels within a predefined rectangular region of interest that showed increased activity during stimulation were counted. Least squares regression models of straight lines were fit to the data. The initial level of visual cortex activation in the region of interest, as measured by the y-intercept, varied substantially from subject to subject (range: 4-68, p < 0.001). There was sufficient evidence of systematic change with time to reject the hypothesis of constant activation with the same stimulus over time (p=0.02). The observed visual cortex activation with single-plane fMRI varied both with time over successive epoques and among subjects. Possible factors responsible for the variation may include head movement, eyelid position, attention, and physiologic fatigue. These factors must be accounted for in experimental design and in data analysis and interpretation.
For most of the past 25 years, the federal government and many states have adopted a tough, punit... more For most of the past 25 years, the federal government and many states have adopted a tough, punitive approach to drug offenses. In recent years, changes in public perception and state budget shortfalls have spurred a policy reform movement across the political spectrum that advocates diverting low-level, nonviolent drug offenders into treatment rather than incarcerating them. In nine of the
To examine the role of public health agencies (PHAs) in providing access to drug treatment servic... more To examine the role of public health agencies (PHAs) in providing access to drug treatment services for adolescents by describing the proportion of youth who obtain access to these services through PHA involvement in school health clinics, juvenile drug courts, and other community agencies. Analysis of cross-sectional telephone interview data collected from 1999-2003 from a national sample of 1793 PHA key informants from communities surrounding schools in the nationally representative Monitoring the Future (MTF) study of 8th, 10th and 12th grade students. Fifty-eight percent of youth in the MTF sample were served by PHAs that participated in some way in school health clinics, with 30% served by PHAs that provided resources for drug treatment in schools. Twenty-nine percent of youth were served by PHAs involved in juvenile drug court (JDC) programs, 23% by PHAs acting as JDC referral agencies, and 13% by PHAs providing direct JDC drug assessment, treatment and monitoring services. In addition, 44% of youth were served by PHAs providing drug treatment resources in community settings. Treatment access for youth through PHAs varied by region, race/ethnicity, urbanicity, community income level, and youth population density. The largest variation occurred in access via JDC programs. PHAs may help bridge gaps between drug treatment need and service provision for adolescents who need access to drug treatment services. Strengthening the linkages between PHAs and schools, juvenile drug courts, and other community settings may serve to increase youth access to drug treatment.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2010
Background-This study aimed to assess the relationship between IFN related adverse effects and HC... more Background-This study aimed to assess the relationship between IFN related adverse effects and HCV virologic response in HIV/HCV co-infected individuals treated with pegylated interferon and ribavirin.
The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agent... more The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agents used to treat a broad spectrum of lymphoid malignancies. Their toxicity profiles include dose-limiting myelosuppression, immunosuppression, opportunistic infection and severe neurotoxicity. This review summarizes the neurotoxicity of high- and standard-dose fludarabine, focusing on the clinical and pathological manifestations in the eye. The mechanisms of ocular toxicity are probably multifactorial. With increasing clinical use, an awareness of the neurological and ocular vulnerability, particularly to fludarabine, is important owing to the potential for life- and sight-threatening consequences.
The authors regret that a typographical error in the above-referenced article incorrectly lists t... more The authors regret that a typographical error in the above-referenced article incorrectly lists the units for C-reactive protein (CRP) as "mg/L" rather than "mg/dL" in the Abstract, the Results section under the subheading "Biomarkers in IRIS patients at baseline (pre-ART)," and in , and 2d. CRP units are correctly given as "mg/dL" in the Methods section.
Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A co... more Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A cohort of 45 HIV-1-infected, antiretroviral treatment (ART)-naïve patients with baseline CD4 T cell counts ≤100 cells/μL who were started on ART, suppressed HIV-RNA to <50 copies/mL, and seen every 1-3 months for 1 year were retrospectively evaluated for suspected or confirmed IRIS. D-dimer, C-reactive protein (CRP), and selected autoantibodies were analyzed at baseline, 1 and 3 months post-ART in cryopreserved plasma. Median differences between cases and controls were compared with Mann-Whitney and Fischer's exact tests. Sixteen patients (35.6%) developed IRIS (median of 35 days post-ART initiation): unmasking=8, paradoxical=7, autoimmune=1. Pre-ART D-dimer and CRP were higher in IRIS cases versus controls (D-dimer: 0.89mg/L versus 0.66mg/L, p=0.037; CRP: 0.74mg/L versus 0.39mg/L, p=0.022), while D-dimer was higher in unmasking cases at IRIS onset (2.04mg/L versus 0.36mg/L, p=0.05). These biomarkers may be useful in identifying patients at risk for IRIS.
Several studies report a relationship between body mass index (BMI) and disinhibited eating (a fa... more Several studies report a relationship between body mass index (BMI) and disinhibited eating (a failure to restrict intake and to overeat). However, the aetiology of disinhibited eating has received scant attention. In this study, we consider a role for 'attachment orientation', a trait that reflects the quality of bonding in early life and remains stable throughout adulthood. Participants (N ¼ 200, females ¼ 135, BMI range from 17.4 to 41.1 kg m À2 ) completed measures of disinhibition and attachment orientation. 'Attachment anxiety' was a good predictor of disinhibited eating (Po0.001). Furthermore, mediation analysis confirmed that it is through this relationship that attachment anxiety also predicts BMI (P ¼ 0.02). These findings are consistent with other studies, showing an association between attachment orientation and other disinhibited behaviours, including alcohol and substance abuse. Our interpretation is that disinhibited eaters engage in external affect regulation. In doing so, they seek to mitigate the anxiety associated with poor interpersonal attachments.
Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is es... more Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.
regression and targets normal tissues expressing cognate antigen Gene therapy with human and mous... more regression and targets normal tissues expressing cognate antigen Gene therapy with human and mouse T-cell receptors mediates cancer http://bloodjournal.hematologylibrary.org/cgi/content/full/114/3/535 Updated information and services can be found at: (426 articles) Gene Therapy (2679 articles) Clinical Trials and Observations (3931 articles) Immunobiology collections: Blood Articles on similar topics may be found in the following http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests
Objective-Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neo... more Objective-Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 3, 2015
Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic m... more Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase 1 protocol. This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n=12), sarcoma (n=17), or other refractory solid tumors (n= 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5mg/kg and 10mg/kg dose levels. Pharmacokinetics revealed a half-life of 8-15 days. At day 21, ...
Ocular chronic graft-versus-host disease is one of the most bothersome common complications after... more Ocular chronic graft-versus-host disease is one of the most bothersome common complications after allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring, however, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (NCT00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test ...
Objective-To describe the ophthalmic and systemic autoimmune findings after successful adoptive c... more Objective-To describe the ophthalmic and systemic autoimmune findings after successful adoptive cell transfer of ex vivo expanded, autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) for metastatic melanoma.
Three patients with aplastic anemia were evaluated by the ophthalmology service within 2 months o... more Three patients with aplastic anemia were evaluated by the ophthalmology service within 2 months of the aplastic anemia diagnosis for bilateral visual loss. The mean age of diagnosis of aplastic anemia was 14.3 years (range: 5 to 19 years) and the mean follow-up was 25 months (range: 15 to 44 months). All 6 eyes demonstrated choroidal ischemia and vitreous hemorrhage. Pars plana vitrectomy was performed in four eyes of two patients for non-clearing vitreous hemorrhage; one patient was observed. Successful anatomic outcomes were achieved in 3 of 4 eyes that underwent vitrectomy. Initial visual acuity ranged from 20/80 to bare light perception and final visual acuity ranged from 20/20 to no light perception. All patients received immunosuppressive therapy including cyclosporine and anti-thymocyte globulin, and two underwent hematopoietic stem cell transplantation. All patients received perioperative platelet and blood transfusions. Pars plana vitrectomy resulted in functional and anatomic success in the majority of eyes in this series. Coordination of medical and surgical care with the hematology service is advisable to stabilize hematologic parameters prior to undertaking a vitreoretinal procedure.
This study was conducted to test whether cortical activation varies across successive epoques dur... more This study was conducted to test whether cortical activation varies across successive epoques during functional magnetic resonance imaging (fMRI) studies. Ten normal adult volunteers were studied with a 1.5-T MR scanner. Pseudocoronal study planes were chosen perpendicular to the tentorium cerebelli, at two thirds the distance from the posterior edge of the splenium of the corpus callosum to the transverse sinuses. Functional images were acquired with a T2*-weighted spoiled gradient echo sequence. The visual cortex was stimulated by goggles flashing at 8 Hz. Each study consisted of 82 sequential scans, lasting 15 seconds each for a total of 20.5 minutes. Two scans without stimulation were alternated with two scans of visual stimulation. Scans 3 through 83 were divided into five sequences of 16 scans. For each sequence, the number of pixels within a predefined rectangular region of interest that showed increased activity during stimulation were counted. Least squares regression models of straight lines were fit to the data. The initial level of visual cortex activation in the region of interest, as measured by the y-intercept, varied substantially from subject to subject (range: 4-68, p &lt; 0.001). There was sufficient evidence of systematic change with time to reject the hypothesis of constant activation with the same stimulus over time (p=0.02). The observed visual cortex activation with single-plane fMRI varied both with time over successive epoques and among subjects. Possible factors responsible for the variation may include head movement, eyelid position, attention, and physiologic fatigue. These factors must be accounted for in experimental design and in data analysis and interpretation.
For most of the past 25 years, the federal government and many states have adopted a tough, punit... more For most of the past 25 years, the federal government and many states have adopted a tough, punitive approach to drug offenses. In recent years, changes in public perception and state budget shortfalls have spurred a policy reform movement across the political spectrum that advocates diverting low-level, nonviolent drug offenders into treatment rather than incarcerating them. In nine of the
To examine the role of public health agencies (PHAs) in providing access to drug treatment servic... more To examine the role of public health agencies (PHAs) in providing access to drug treatment services for adolescents by describing the proportion of youth who obtain access to these services through PHA involvement in school health clinics, juvenile drug courts, and other community agencies. Analysis of cross-sectional telephone interview data collected from 1999-2003 from a national sample of 1793 PHA key informants from communities surrounding schools in the nationally representative Monitoring the Future (MTF) study of 8th, 10th and 12th grade students. Fifty-eight percent of youth in the MTF sample were served by PHAs that participated in some way in school health clinics, with 30% served by PHAs that provided resources for drug treatment in schools. Twenty-nine percent of youth were served by PHAs involved in juvenile drug court (JDC) programs, 23% by PHAs acting as JDC referral agencies, and 13% by PHAs providing direct JDC drug assessment, treatment and monitoring services. In addition, 44% of youth were served by PHAs providing drug treatment resources in community settings. Treatment access for youth through PHAs varied by region, race/ethnicity, urbanicity, community income level, and youth population density. The largest variation occurred in access via JDC programs. PHAs may help bridge gaps between drug treatment need and service provision for adolescents who need access to drug treatment services. Strengthening the linkages between PHAs and schools, juvenile drug courts, and other community settings may serve to increase youth access to drug treatment.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2010
Background-This study aimed to assess the relationship between IFN related adverse effects and HC... more Background-This study aimed to assess the relationship between IFN related adverse effects and HCV virologic response in HIV/HCV co-infected individuals treated with pegylated interferon and ribavirin.
The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agent... more The purine analogs, fludarabine and cladribine represent an important class of chemotherapy agents used to treat a broad spectrum of lymphoid malignancies. Their toxicity profiles include dose-limiting myelosuppression, immunosuppression, opportunistic infection and severe neurotoxicity. This review summarizes the neurotoxicity of high- and standard-dose fludarabine, focusing on the clinical and pathological manifestations in the eye. The mechanisms of ocular toxicity are probably multifactorial. With increasing clinical use, an awareness of the neurological and ocular vulnerability, particularly to fludarabine, is important owing to the potential for life- and sight-threatening consequences.
The authors regret that a typographical error in the above-referenced article incorrectly lists t... more The authors regret that a typographical error in the above-referenced article incorrectly lists the units for C-reactive protein (CRP) as "mg/L" rather than "mg/dL" in the Abstract, the Results section under the subheading "Biomarkers in IRIS patients at baseline (pre-ART)," and in , and 2d. CRP units are correctly given as "mg/dL" in the Methods section.
Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A co... more Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A cohort of 45 HIV-1-infected, antiretroviral treatment (ART)-naïve patients with baseline CD4 T cell counts ≤100 cells/μL who were started on ART, suppressed HIV-RNA to <50 copies/mL, and seen every 1-3 months for 1 year were retrospectively evaluated for suspected or confirmed IRIS. D-dimer, C-reactive protein (CRP), and selected autoantibodies were analyzed at baseline, 1 and 3 months post-ART in cryopreserved plasma. Median differences between cases and controls were compared with Mann-Whitney and Fischer's exact tests. Sixteen patients (35.6%) developed IRIS (median of 35 days post-ART initiation): unmasking=8, paradoxical=7, autoimmune=1. Pre-ART D-dimer and CRP were higher in IRIS cases versus controls (D-dimer: 0.89mg/L versus 0.66mg/L, p=0.037; CRP: 0.74mg/L versus 0.39mg/L, p=0.022), while D-dimer was higher in unmasking cases at IRIS onset (2.04mg/L versus 0.36mg/L, p=0.05). These biomarkers may be useful in identifying patients at risk for IRIS.
Several studies report a relationship between body mass index (BMI) and disinhibited eating (a fa... more Several studies report a relationship between body mass index (BMI) and disinhibited eating (a failure to restrict intake and to overeat). However, the aetiology of disinhibited eating has received scant attention. In this study, we consider a role for 'attachment orientation', a trait that reflects the quality of bonding in early life and remains stable throughout adulthood. Participants (N ¼ 200, females ¼ 135, BMI range from 17.4 to 41.1 kg m À2 ) completed measures of disinhibition and attachment orientation. 'Attachment anxiety' was a good predictor of disinhibited eating (Po0.001). Furthermore, mediation analysis confirmed that it is through this relationship that attachment anxiety also predicts BMI (P ¼ 0.02). These findings are consistent with other studies, showing an association between attachment orientation and other disinhibited behaviours, including alcohol and substance abuse. Our interpretation is that disinhibited eaters engage in external affect regulation. In doing so, they seek to mitigate the anxiety associated with poor interpersonal attachments.
Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is es... more Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.
regression and targets normal tissues expressing cognate antigen Gene therapy with human and mous... more regression and targets normal tissues expressing cognate antigen Gene therapy with human and mouse T-cell receptors mediates cancer http://bloodjournal.hematologylibrary.org/cgi/content/full/114/3/535 Updated information and services can be found at: (426 articles) Gene Therapy (2679 articles) Clinical Trials and Observations (3931 articles) Immunobiology collections: Blood Articles on similar topics may be found in the following http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests
Objective-Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neo... more Objective-Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID.
Uploads
Papers by Rachel Bishop