bluuebunny/crossref_metadata_2025 huggingface dataset:
An unexpected evolution of symptomatic mild middle cerebral artery (MCA) stenosis: asymptomatic occlusion
Authors: Malferrari Giovanni , Zedde Marialuisa , De Berti Gianni , Maggi Massimo , Marcello Norina
Published: December 2011

Background

The intracranial localization of large artery disease is recognized as the main cause of ischemic stroke in the world, considering all countries, although its global burden is widely underestimated. Indeed it has been reported more frequently in Asians and African-American people, but the finding of intracranial stenosis as a cause of ischemic stroke is relatively common also in Caucasians. The prognosis of patients with stroke due to intracranial steno-occlusion is strictly dependent on the time of recanalization. Moreover, the course of the vessel involvement is highly dynamic in both directions, improvement or worsening, although several data are derived from the atherosclerotic subtype, compared to other causes.

Case description

We report the clinical, neurosonological and neuroradiological findings of a young woman, who came to our Stroke Unit because of the abrupt onset of aphasia during her work. An urgent neurosonological examination showed a left M1 MCA stenosis, congruent with the presenting symptoms; magnetic resonance imaging confirmed this finding and identified an acute ischemic lesion on the left MCA territory. The past history of the patient was significant only for a hyperinsulinemic condition, treated with metformine, and a mild overweight. At this time a selective cerebral angiography was not performed because of the patient refusal and she was discharged on antiplatelet and lipid-lowering therapy, having failed to identify autoimmune or inflammatory diseases. Within 1 month, she went back to our attention because of the recurrence of aphasia, lasting about ten minutes. Neuroimaging findings were unchanged, but the patient accepted to undergo a selective cerebral angiography, which showed a mild left distal M1 MCA stenosis.

During the follow-up the patient did not experienced any recurrence, but a routine neurosonological examination found an unexpected evolution of the known MCA stenosis, i.e. left M1 MCA occlusion. Neuroradiological imaging did not identify new lesions of the brain parenchyma and a repeated selective cerebral angiography confirmed the left M1 MCA occlusion.

Conclusions

Regardless of the role of metabolic and/or inflammatory factors on the aetiology of the intracranial stenosis in this case, the course of the vessel disease was unexpected and previously unreported in the literature at our knowledge.
Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma
Authors: Telang Sucheta , Rasku Mary Ann , Clem Amy L , Carter Karen , Klarer Alden C , Badger Wesley R , Milam Rebecca A , Rai Shesh N , Pan Jianmin , Gragg Hana , Clem Brian F , McMasters Kelly M , Miller Donald M , Chesney Jason
Published: December 2011

Background

We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4+CD25HIFoxp3+regulatory T cells and expanded melanoma-specific CD8+T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.

Methods

In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[18F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.

Results

After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%;pvalue < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.

Conclusions

These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.

Trial registration

NCT00299689
Antioxidant rich flavonoids from Oreocnide integrifolia enhance glucose uptake and insulin secretion and protects pancreatic β-cells from streptozotocin insult
Authors: Ansarullah  , Bharucha Bhavna , Dwivedi Mitesh , Laddha Naresh C , Begum Rasheedunnisa , Hardikar Anandwardhan A , Ramachandran AV
Published: December 2011

Background

Insulin deficiency is the prime basis of all diabetic manifestations and agents that can bring about insulin secretion would be of pivotal significance for cure of diabetes. To test this hypothesis, we carried out bioactivity guided fractionation of Oreocnide integrifolia (Urticaceae); a folklore plant consumed for ameliorating diabetic symptoms using experimental models.

Methods

We carried out bioassay guided fractionation using RINmF and C2C12 cell line for glucose stimulated insulin secretion (GSIS) and glucose uptake potential of fractions. Further, the bioactive fraction was challenged for its GSIS in cultured mouse islets with basal (4.5 mM) and stimulated (16.7 mM) levels of glucose concentrations. The Flavonoid rich fraction (FRF) was exposed to 2 mM streptozotocin stress and the anti-ROS/RNS potential was evaluated. Additionally, the bioactive fraction was assessed for its antidiabetic and anti-apoptotic property in-vivo using multidose streptozotocin induced diabetes in BALB/c mice.

Results

The results suggested FRF to be the most active fraction as assessed by GSIS in RINm5F cells and its ability for glucose uptake in C2C12 cells. FRF displayed significant potential in terms of increasing intracellular calcium and cAMP levels even in presence of a phosphodiesterase inhibitor, IBMX in cultured pancreatic islets. FRF depicted a dose-dependent reversal of all the cytotoxic manifestations except peroxynitrite and NO formation when subjected in-vitro along with STZ. Further scrutinization of FRF for its in-vivo antidiabetic property demonstrated improved glycemic indices and decreased pancreatic β-cell apoptosis.

Conclusions

Overall, the flavonoid mixture has shown to have significant insulin secretogogue, insulinomimetic and cytoprotective effects and can be evaluated for clinical trials as a therapeutant in the management of diabetic manifestations.
Changing individual-level risk factors for malaria with declining transmission in southern Zambia: a cross-sectional study
Authors: Sutcliffe Catherine G , Kobayashi Tamaki , Hamapumbu Harry , Shields Timothy , Kamanga Aniset , Mharakurwa Sungano , Thuma Philip E , Glass Gregory , Moss William J
Published: December 2011

Background

Malaria elimination will require that both symptomatic- and asymptomatic-infected persons be identified and treated. However, well-characterized, individual-level risk factors for malaria may not be valid in regions with declining malaria transmission. Changes in individual-level correlates of malaria infection were evaluated over three years in a region of declining malaria transmission in southern Zambia.

Methods

Malaria surveys were conducted in two study areas within the catchment area of Macha Hospital, Zambia in 2007 and 2008/2009. A random sample of households was identified from a digitized satellite image of the study areas. Cross-sectional surveys were conducted approximately five times throughout the year in each of the two study areas. During study visits, adults and caretakers of children were administered questionnaires and a blood sample was obtained for a rapid diagnostic test (RDT) for malaria.

Results

In the 2007 study area, 330 individuals were surveyed. 40.9% of participants lived in a household with at least one insecticide-treated bed net (ITN); however, only 45.2% reported sleeping under the ITN. 23.9% of participants were RDT positive. Correlates of RDT positivity included younger age, the presence of symptoms, testing during the rainy season, using an open water source, and not sleeping under an ITN. In the 2008 study area, 435 individuals were surveyed. 77.0% of participants lived in a household with at least one ITN; however, only 56.4% reported sleeping under the ITN. 8.1% of participants were RDT positive. RDT positivity was negatively correlated with the presence of symptoms within the last two weeks but positively correlated with documented fever. In 2009, 716 individuals were surveyed in the same area as 2008. 63.7% of participants lived in a household with at least one ITN; however, only 57.7% reported sleeping under the ITN. 1.5% of participants were RDT positive. Only self-reported fever was significantly correlated with RDT positivity.

Conclusions

With declining malaria prevalence, few individual-level characteristics were correlated with RDT positivity. This lack of correlation with individual characteristics hampers identification of individuals infected with malaria. Strategies based on ecological or environmental risk factors may be needed to target control efforts and achieve further reductions and elimination.
Detailed genetic analysis of hemagglutinin-neuraminidase glycoprotein gene in human parainfluenza virus type 1 isolates from patients with acute respiratory infection between 2002 and 2009 in Yamagata prefecture, Japan
Authors: Mizuta Katsumi , Saitoh Mika , Kobayashi Miho , Tsukagoshi Hiroyuki , Aoki Yoko , Ikeda Tatsuya , Abiko Chieko , Katsushima Noriko , Itagaki Tsutomu , Noda Masahiro , Kozawa Kunihisa , Ahiko Tadayuki , Kimura Hirokazu
Published: December 2011

Background

Human parainfluenza virus type 1 (HPIV1) causes various acute respiratory infections (ARI). Hemagglutinin-neuraminidase (HN) glycoprotein of HPIV1 is a major antigen. However, the molecular epidemiology and genetic characteristics of such ARI are not exactly known. Recent studies suggested that a phylogenetic analysis tool, namely the maximum likelihood (ML) method, may be applied to estimate the evolutionary time scale of various viruses. Thus, we conducted detailed genetic analyses including homology analysis, phylogenetic analysis (using both the neighbor joining (NJ) and ML methods), and analysis of the pairwise distances ofHNgene in HPIV1 isolated from patients with ARI in Yamagata prefecture, Japan.

Results

A few substitutions of nucleotides in the second binding site ofHNgene were observed among the present isolates. The strains were classified into two major clusters in the phylogenetic tree by the NJ method. Another phylogenetic tree constructed by the ML method showed that the strains diversified in the late 1980s. No positively selected sites were found in the present strains. Moreover, the pairwise distance among the present isolates was relatively short.

Conclusions

The evolution ofHNgene in the present HPIV1 isolates was relatively slow. The ML method may be a useful phylogenetic method to estimate the evolutionary time scale of HPIV and other viruses.
The BTB/POZ zinc finger protein Broad-Z3 promotes dendritic outgrowth during metamorphic remodeling of the peripheral stretch receptor dbd
Authors: Scott Janet A , Williams Darren W , Truman James W
Published: December 2011

Background

Various members of the family of BTB/POZ zinc-finger transcription factors influence patterns of dendritic branching. One such member, Broad, is notable because its BrZ3 isoform is widely expressed in Drosophila in immature neurons around the time of arbor outgrowth. We used the metamorphic remodeling of an identified sensory neuron, the dorsal bipolar dendrite sensory neuron (dbd), to examine the effects of BrZ3 expression on the extent and pattern of dendrite growth during metamorphosis.

Results

Using live imaging of dbd in Drosophila pupae, we followed its normal development during metamorphosis and the effect of ectopic expression of BrZ3 on this development. After migration of its cell body, dbd extends a growth-cone that grows between two muscle bands followed by branching and turning back on itself to form a compact dendritic bundle. The ectopic expression of the BrZ3 isoform, using the GAL4/UAS system, caused dbd's dendritic tree to transform from its normal, compact, fasciculated form into a comb-like arbor that spread over on the body wall. Time-lapse analysis revealed that the expression of BrZ3 caused the premature extension of the primary dendrite onto immature myoblasts, ectopic growth past the muscle target region, and subsequent elaboration onto the epidermis. To control the timing of expression of BrZ3, we used a temperature-sensitive GAL80 mutant. When BrZ3 expression was delayed until after the extension of the primary dendrite, then a normal arbor was formed. By contrast, when BrZ3 expression was confined to only the early outgrowth phase, then ectopic arbors were subsequently formed and maintained on the epidermis despite the subsequent absence of BrZ3.

Conclusions

The adult arbor of dbd is a highly branched arbor whose branches self-fasciculate to form a compact dendritic bundle. The ectopic expression of BrZ3 in this cell causes a premature extension of its growth-cone, resulting in dendrites that extend beyond their normal muscle substrate and onto the epidermis, where they form a comb-shaped, ectopic arbor. Our quantitative data suggest that new ectopic arbor represents an 'unpacking' of the normally fasciculated arbor onto the epidermis. These data suggest that the nature of their local environment can change dendrite behavior from self-adhesion to self-avoidance.
Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene: a case series
Authors: Ueno Hiroki , Kobatake Keitaro , Matsumoto Masayasu , Morino Hiroyuki , Maruyama Hirofumi , Kawakami Hideshi
Published: December 2011

Introduction

Previous studies have shown widespread multisystem degeneration in patients with sporadic amyotrophic lateral sclerosis who develop a total locked-in state and survive under mechanical ventilation for a prolonged period of time. However, the disease progressions reported in these studies were several years after disease onset. There have been no reports of long-term follow-up with brain imaging of patients with familial amyotrophic lateral sclerosis at an advanced stage of the disease. We report the cases of siblings with amyotrophic lateral sclerosis with homozygous deletions of the exon 5 mutation of the gene encoding optineurin, in whom brain computed tomography scans were followed up for more than 20 years.

Case presentation

The patients were a Japanese brother and sister. The elder sister was 33 years of age at the onset of disease, which began with muscle weakness of her left lower limb. Two years later she required mechanical ventilation. She became bedridden at the age of 34, and died at the age of 57. A computed tomography scan of her brain at the age of 36 revealed no abnormality. Atrophy of her brain gradually progressed. Ten years after the onset of mechanical ventilation, atrophy of her whole brain, including the cerebral cortex, brain stem and cerebellum, markedly progressed. Her younger brother was 36 years of age at the onset of disease, which presented as muscle weakness of his left upper limb. One year later, he showed dysphagia and dysarthria, and tracheostomy ventilation was performed. He became bedridden at the age of 37 and died at the age of 55. There were no abnormal intracranial findings on brain computed tomography scans obtained at the age of 37 years. At the age of 48 years, computed tomography scans showed marked brain atrophy with ventricular dilatation. Subsequently, atrophy of the whole brain rapidly progressed as in his elder sister.

Conclusion

We conclude that a homozygous deletion-type mutation in the optineurin gene may be associated with widespread multisystem degeneration in amyotrophic lateral sclerosis.
Delineation of the clinical phenotype associated with non-mosaic type-2 NF1 deletions: two case reports
Authors: Vogt Julia , Nguyen Rosa , Kluwe Lan , Schuhmann Martin , Roehl Angelika C , Mußotter Tanja , Cooper David N , Mautner Victor-Felix , Kehrer-Sawatzki Hildegard
Published: December 2011

Introduction

Large deletions of the NF1 gene and its flanking regions are frequently associated with a severe clinical manifestation. Different types of gross NF1 deletion have been identified that are distinguishable both by their size and the number of genes included within the deleted regions. Type-1 NF1 deletions encompass 1.4 Mb and include 14 genes, whereas the much less common type-2 NF1 deletions span 1.2 Mb and contain 13 genes. Genotype-phenotype correlations in patients with large NF1 deletions are likely to be influenced by the nature and number of the genes deleted in addition to the NF1 gene. Whereas the clinical phenotype associated with type-1 NF1 deletions has been well documented, the detailed clinical characterization of patients with non-mosaic type-2 NF1 deletions has not so far been reported.

Case presentation

In the present report we characterized two Caucasian European patients with non-mosaic (germline) type-2 NF1 deletions. Our first patient was a 13-year-old girl with dysmorphic facial features, mild developmental delay, large hands and feet, hyperflexibility of the joints, macrocephaly and T2 hyperintensities in the brain. A whole-body magnetic resonance imaging scan indicated two internal plexiform neurofibromas. Our second patient was an 18-year-old man who exhibited dysmorphic facial features, developmental delay, learning disability, large hands and feet, hyperflexibility of the joints, macrocephaly and a very high subcutaneous and internal tumor load as measured volumetrically on whole-body magnetic resonance imaging scans. At the age of 18 years, he developed a malignant peripheral nerve sheath tumor and died from secondary complications. Both our patients exhibited cardiovascular malformations.

Conclusions

Our two patients with non-mosaic type-2 NF1 deletions exhibited clinical features that have been reported in individuals with germline type-1 NF1 deletions. Therefore, a severe disease manifestation is not confined to only patients with type-1 NF1 deletions but may also occur in individuals with type-2 NF1 deletions. Our findings support the concept of an NF1 microdeletion syndrome with severe clinical manifestation that is caused by type-1 as well as type-2 NF1 deletions.
Mychonastes aferHSO-3-1 as a potential new source of biodiesel
Authors: Yuan Cheng , Liu Junhan , Fan Yong , Ren Xiaohui , Hu Guangrong , Li Fuli
Published: December 2011

Background

Biodiesel is considered to be a promising future substitute for fossil fuels, and microalgae are one source of biodiesel. The ratios of lipid, carbohydrates and proteins are different in different microalgal species, and finding a good strain for oil production remains a difficult prospect. Strains producing valuable co-products would improve the viability of biofuel production.

Results

In this study, we performed sequence analysis of the 18S rRNA gene and internal transcribed spacer (ITS) of an algal strain designated HSO-3-1, and found that it was closely related to the Mychonastes afer strain CCAP 260/6. Morphology and cellular structure observation also supported the identification of strain HSO-3-1 as M. afer. We also investigated the effects of nitrogen on the growth and lipid accumulation of the naturally occurring M. afer HSO-3-1, and its potential for biodiesel production. In total, 17 fatty acid methyl esters (FAMEs) were identified in M. afer HSO-3-1, using gas chromatography/mass spectrometry. The total lipid content of M. afer HSO-3-1 was 53.9% of the dry cell weight, and we also detected nervonic acid (C24:1), which has biomedical applications, making up 3.8% of total fatty acids. The highest biomass and lipid yields achieved were 3.29 g/l and 1.62 g/l, respectively, under optimized conditions.

Conclusion

The presence of octadecenoic and hexadecanoic acids as major components, with the presence of a high-value component, nervonic acid, renders M. afer HSO-3-1 biomass an economic feedstock for biodiesel production.
Risky driving behaviors for road traffic accident among drivers in Mekele city, Northern Ethiopia
Authors: Hassen Abrahim , Godesso Ameyu , Abebe Lakew , Girma Eshetu
Published: December 2011

Background

Due to its perception as a disease of development, road traffic accident and related injuries tend to be under recognized as a major health problem in developing countries. However, majority of the world's fatalities on the roads occur in low income and middle income countries. Since the main cause of road traffic accident is attributed to human risky behaviors, it is important to identify significant factors for risky behaviors of drivers.

Methods

A quantitative cross-sectional study with a sample size of 350 drivers was conducted in April 2011. The study was conducted among Taxi, Bajaj (three tire vehicles) and private owned car drivers. After proportion to size allocation for Taxi (75), Baja (103) and private owned car (172) drivers, we used systematic random sampling method to identify illegible study subjects. Data was collected with face to face interview using a pretested questioner. Univariate, bivariate and multivariate analysis was done using SPSS version 16.

Results

The mean age of the respondents was 28.7 (SD 9.9). Majority were 339 (96.9%) males. Significant number of the study subjects 233 (66.6%) had risky driving behaviors. More than a quarter 100 (28.6%) had less knowledge about basic traffic signs. Majority of drivers 181 (51.7%) had negative attitude towards risky driving behaviors. Significant percent of them 148 (42.3%) had a habit of using mobile phone while driving vehicle and 28 (9.7%) had experience of driving after drinking alcohol. All the Bajaj, 97(62.6%) house car and 58(37.4%) taxi unfasten their seat belt while driving. Majority 303 (86.6%) followed the recommended speed limit of driving. About 66 (18.9%) of them had experience of punishment or warning by traffic polices in the previous 1 year and 77 (22%) ever had car accident while driving.

Conclusions

Drivers of secondary education and with high average monthly income were more likely to have risky driving behavior. Having supportive attitude towards risky driving behaviors and not getting advice about risky driving from significant others increases the likelihood of developing risky driving behavior. Interventions targeted at developing negative attitude towards risky driving behaviors on drivers and significant others should be implemented to bring positive behavior change. The interventions need to be segmented with educational status and income.
Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples
Authors: Scoles Haley A , Urraca Nora , Chadwick Samuel W , Reiter Lawrence T , LaSalle Janine M
Published: December 2011

Background

Duplication of chromosome 15q11-q13 (dup15q) accounts for approximately 3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (imprinting center of the Prader-Willi locus, PWS-IC). Maternal dup15q occurs as both interstitial duplications and isodicentric chromosome 15. Overexpression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two postmortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of the GABAA receptor genes, UBE3A and SNRPN in a manner not predicted by copy number or parental imprint.

Methods

Postmortem human brain tissue (Brodmann area 19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control tissue samples. Quantitative PCR was used to confirm duplication status. Quantitative RT-PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high-resolution melting-curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.

Results

Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that dup15q was maternal in origin. UBE3A transcript and protein levels were significantly higher than control and autism in dup15q, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3 levels but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.

Conclusions

Although these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain.
Quantification of atopy, lung function and airway hypersensitivity in adults
Authors: Marinho Susana , Simpson Angela , Marsden Paul , Smith Jacky A , Custovic Adnan
Published: December 2011

Background

Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR).

Objective

To determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK.

Methods

FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5‐breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population‐based birth cohort enriched with 183 patients with physician‐diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes.

Results

Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose‐response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10‐8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10‐8, cat p = 3.93 × 10‐10, dog p = 3.03 × 10‐15, grass p = 2.95 × 10‐9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT‐3 mm>negative control).

Conclusions

In the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR.
Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis
Authors: Guyot Patricia , Taylor Peter , Christensen Robin , Pericleous Louisa , Poncet Coralie , Lebmeier Maximilian , Drost Pieter , Bergman Gert
Published: December 2011

Introduction

The goal of this study was to compare the efficacy in terms of Health Assessment Questionnaire change from baseline (HAQ CFB), 50% improvement in American College of Rheumatology criterion (ACR-50) and Disease Activity Score in 28 joints (DAS28) defined remission (< 2.6) between abatacept and other biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX-IR).

Methods

A systematic literature review identified controlled trials investigating the efficacy of abatacept (three studies), etanercept (two studies), infliximab (two), adalimumab (two), certolizumab pegol (two) ritixumab (three), and tocilizumab (two) in MTX-IR patients with RA. The clinical trials included in this analysis were similar with respect to trial design, baseline patient characteristics and background therapy (MTX). The key clinical endpoints of interest were HAQ CFB, ACR-50 and DAS28 < 2.6 measured at 24 and 52 weeks. The results were analysed using network meta-analysis methods that enabled calculation of an estimate for expected relative effect of comparative treatments. Analysis results were expressed as the difference in HAQ CFB score and odds ratio (OR) of achieving an ACR-50 and DAS28 response and associated 95% credible intervals (CrI).

Results

The analysis of HAQ CFB at 24 weeks and 52 weeks showed that abatacept in combination with MTX is expected to be more efficacious than MTX monotherapy and is expected to show a comparable efficacy relative to other biologic DMARDs in combination with MTX. Further, abatacept showed comparable ACR-50 and DAS28 < 2.6 response rates with other biologic DMARDs at 24 and 52 weeks, except for ACR-50 compared to certolizumab pegol at 52 weeks and for DAS28 < 2.6 compared to tocilizumab at 24 weeks. Sensitivity analyses confirmed the robustness of the findings.

Conclusions

Abatacept in combination with MTX is expected to result in a comparable change from baseline in HAQ score and comparable ACR-50 and DAS28 < 2.6 response rates in MTX-IR patients compared to other approved biologic agents.
Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients
Authors: Iirola Timo , Aantaa Riku , Laitio Ruut , Kentala Erkki , Lahtinen Maria , Wighton Andrew , Garratt Chris , Ahtola-Sätilä Tuula , Olkkola Klaus T
Published: December 2011

Introduction

Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.

Methods

Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.

Results

The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.

Conclusions

The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.

Trial Registration

ClinicalTrials.gov: NCT00747721
Long-term psychological effects of a no-sedation protocol in critically ill patients
Authors: Strøm Thomas , Stylsvig Mette , Toft Palle
Published: December 2011

Introduction

A protocol of no sedation has been shown to reduce the time patients receive mechanical ventilation and to reduce intensive care and total hospital length of stay. The long-term psychological effects of this strategy have not yet been described. The purpose of the study was to test whether a strategy of no sedation alters long-term psychological outcome compared with a standard strategy with sedation.

Methods

During intensive care stay, 140 patients requiring mechanical ventilation were randomized to either no sedation or sedation with daily interruption of sedation. This study was done as a single-blinded cohort study. After discharge, patients were interviewed by a neuropsychologist assessing quality of life, depression, anxiety, and posttraumatic stress disorder.

Results

Two years after randomization, 38 patients were eligible for interview, and 26 patients were interviewed (13 from each group). No difference was found with respect to quality of life (Medical Outcome Study, 36-item short-form health survey). Both mental and physical components were nonsignificant. The Beck depression index was low in both groups (one patient in intervention group versus three patients in the control group were depressed, p = 0.32). Evaluated with the Impact of Events Scale, both groups had low stress scores (one in the intervention group versus two in the control group had scores greater than 32; p = 0.50). State anxiety scores were also low (28 in the control group versus 30 in the intervention group, p = 0.58).

Conclusions

Our data suggest that a protocol of no sedation applied to critically ill patients undergoing mechanical ventilation does not increase the risk of long-term psychological sequelae after intensive care compared with standard treatment with sedation.
Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors
Authors: Bendell Johanna C. , Rodon Jordi , Burris Howard A. , de Jonge Maja , Verweij Jaap , Birle Diana , Demanse David , De Buck Stefan S. , Ru Qinhua C. , Peters Malte , Goldbrunner Michael , Baselga José
Published: December 2011

Purpose

This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), safety, preliminary activity, pharmacokinetics (PK), and pharmacodynamics of BKM120, a potent and highly specific oral pan-Class I PI3K inhibitor.

Patients and Methods

Thirty-five patients with advanced solid tumors received daily BKM120 12.5 to 150 mg. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Assessments included archival tumor molecular status, response by Response Evaluation Criteria in Solid Tumors (RECIST), positron emission tomography tracer uptake ([18F]fluorodeoxyglucose positron emission tomography [FDG-PET]), fasting plasma C-peptide, and phosphorylated ribosomal protein S6 (pS6) in skin biopsies.

Results

Overall, treatment was well tolerated. Dose-limiting toxicities were grade 2 mood alteration (80 mg), grade 3 epigastralgia, grade 3 rash, grade 2 and grade 3 mood alteration (100 mg), and two grade 4 hyperglycemia (150 mg). The MTD was 100 mg/d. Frequent treatment-related adverse events included rash, hyperglycemia, diarrhea, anorexia, and mood alteration (37% each); nausea (31%); fatigue (26%); pruritus (23%); and mucositis (23%). BKM120 demonstrated rapid absorption, half-life of ∼40 hours, ∼three-fold steady-state accumulation, dose-proportional exposure, and moderate interpatient variability. One patient demonstrated a confirmed partial response (triple-negative breast cancer); seven patients (20%) were on study for ≥ 8 months. BKM120 demonstrated dose-dependent pharmacodynamic effects on [18F]FDG-PET, fasting C-peptide, fasting blood glucose, and pS6. No significant trends were seen to correlate tumor molecular alterations with clinical activity.

Conclusion

This study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in patients with advanced cancers. BKM120, at the MTD of 100 mg/d, is safe and well tolerated, with a favorable PK profile, clear evidence of target inhibition, and preliminary antitumor activity.
Insulin- and Obesity-Related Variables in Early-Stage Breast Cancer: Correlations and Time Course of Prognostic Associations
Authors: Goodwin Pamela J. , Ennis Marguerite , Pritchard Kathleen I. , Trudeau Maureen E. , Koo Jarley , Taylor Sara K. , Hood Nicky
Published: December 2011

Purpose

To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time.

Patients and Methods

Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model.

Results

There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses.

Conclusion

Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.
Treatment of Colorectal Peritoneal Carcinomatosis With Systemic Chemotherapy: A Pooled Analysis of North Central Cancer Treatment Group Phase III Trials N9741 and N9841
Authors: Franko Jan , Shi Qian , Goldman Charles D. , Pockaj Barbara A. , Nelson Garth D. , Goldberg Richard M. , Pitot Henry C. , Grothey Axel , Alberts Steven R. , Sargent Daniel J.
Published: December 2011

Purpose

Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC).

Methods

A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations.

Results

The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001).

Conclusion

pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.
Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986
Authors: De Santis Maria , Bellmunt Joaquim , Mead Graham , Kerst J. Martijn , Leahy Michael , Maroto Pablo , Gil Thierry , Marreaud Sandrine , Daugaard Gedske , Skoneczna Iwona , Collette Sandra , Lorent Julie , de Wit Ronald , Sylvester Richard
Published: December 2011

Purpose

This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy.

Patients and Methods

The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life.

Results

In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI.

Conclusion

There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.
Interim [18F]Fluorodeoxyglucose Positron Emission Tomography Scan in Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Based Chemotherapy Plus Rituximab
Authors: Safar Violaine , Dupuis Jehan , Itti Emmanuel , Jardin Fabrice , Fruchart Christophe , Bardet Stéphane , Véra Pierre , Copie-Bergman Christiane , Rahmouni Alain , Tilly Hervé , Meignan Michel , Haioun Corinne
Published: December 2011

Purpose

The prognostic value of [18F]fluorodeoxyglucose–positron emission tomography (PET), interpreted according to visual criteria, is a matter of debate for diffuse large B-cell lymphoma (DLBCL). Moreover, most published studies do not differentiate between patients treated with or without rituximab. We retrospectively investigated the prognostic value of PET performed in patients with DLBCL receiving chemotherapy plus rituximab. Images were interpreted both visually and by computing maximum standardized uptake value (SUVmax) between PET performed at baseline and after two cycles of chemotherapy.

Patients and Methods

One hundred twelve patients newly diagnosed with DLBCL were treated with an anthracycline-based regimen plus rituximab. A PET was performed after two cycles of treatment. PET positivity or negativity was related to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis.

Results

Visual analysis showed that 70 patients (62.5%) presented with a negative PET scan after two cycles of treatment. The 3-year PFS and OS rates were 84% and 88%, respectively, in patients with PET-negative results versus 47% and 62%, respectively, in patients with PET-positive results (P < .0001 and P < .003, respectively). A second analysis was performed on 85 patients by using interim PET in a quantitative approach on the basis of a ΔSUVmax evaluation of more than 66%. The 3-year PFS was 77% for patients with PET-negative results and 37.5% for patients with PET-positive results (P = .002).

Conclusion

An early PET scan after two cycles of treatment can effectively predict the outcome in patients with DLBCL treated with rituximab and anthracycline-based chemotherapy by using either a visual or quantitative approach.
Happiness and Time Preference: The Effect of Positive Affect in a Random-Assignment Experiment
Authors: Ifcher John , Zarghamee Homa
Published: December 2011

We conduct a random-assignment experiment to investigate whether positive affect impacts time preference, where time preference denotes a preference for present over future utility. Our result indicates that, compared to neutral affect, mild positive affect significantly reduces time preference over money. This result is robust to various specification checks, and alternative interpretations of the result are considered. Our result has implications for the effect of happiness on time preference and the role of emotions in economic decision making, in general. Finally, we reconfirm the ubiquity of time preference and start to explore its determinants. (DJEL D12, D83, I31)
The Cross Section of Foreign Currency Risk Premia and Consumption Growth Risk: Comment
Authors: Burnside Craig
Published: December 2011

Lustig and Verdelhan (2007) argue that the excess returns to borrowing US dollars and lending in foreign currency “compensate US investors for taking on more US consumption growth risk,” yet the stochastic discount factor corresponding to their benchmark model is approximately uncorrelated with the returns they study. Hence, one cannot reject the null hypothesis that their model explains none of the cross sectional variation of the expected returns. Given this finding, and other evidence, I argue that the forward premium puzzle remains a puzzle. JEL: C58, E21, F31, G11, G12