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1.
Nutrition ; 121: 112358, 2024 May.
Article in English | MEDLINE | ID: mdl-38401197

ABSTRACT

INTRODUCTION: Nutritional intake and dysregulation of fatty acid metabolism play a role in the progression of various tumors, but the consumption of fatty acids is difficult to assess accurately with dietary questionnaires. Biomarkers can objectively assess intake, storage and bioavailability. OBJECTIVE: We studied the association between the polyunsaturated fatty acid (PUFA) composition of abdominal subcutaneous adipose tissue (good indicator of dietary intake over 2-3 years) and all-cause mortality. METHODS: In the multicenter AGARIC study, samples from 203 patients with colorectal cancer (CRC) undergoing curative surgery, were harvested from subcutaneous adipose tissue, which were then analyzed for PUFA composition. RESULTS: After a median follow-up of 45 months, 76 patients died. These patients were more often men (72.4% versus 57.5%, P = 0.04), diabetic (32.9% versus 13.4%, P = 0.001), old (median: 74.5 versus 66.6 years, P < 0.001) and with high alcohol consumption (47.4% versus 30.7%, P = 0.005). An increased risk of death was observed with higher levels of 20:2 ω-6 (hazard ratiotertile3 vstertile1 (HRT3vsT1) 2.12; 95% confidence interval (CI) 1.01-4.42; p-trend = 0.04), 22:4 ω-6 (HRT3vsT1 = 3.52; 95% CI = 1.51-8.17; p-trend = 0.005), and 22:5 ω-6 (HRT3vsT1 = 3.50; 95% CI = 1.56-7.87; p-trend = 0.002). Conversely, the risk of death seemed lower when higher concentrations of 18:3 ω-6 (HRT3vsT1 = 0.52; 95% CI = 0.27-0.99; p-trend = 0.04) and the essential fatty acid, α-linolenic acid 18:3 ω-3 (HRT3vsT1 = 0.47; 95% CI = 0.24-0.93; p-trend = 0.03) were observed. CONCLUSION: The risk of death was increased in CRC patients with higher concentrations of certain ω-6 PUFAs and lower concentrations of α-linolenic acid in their subcutaneous adipose tissue. These results reflect dietary habits and altered fatty acid metabolism. Our exploratory results warrant confirmation in larger studies with further exploration of the mechanisms involved.


Subject(s)
Colorectal Neoplasms , Fatty Acids, Omega-3 , Male , Humans , alpha-Linolenic Acid , Fatty Acids, Unsaturated , Fatty Acids , Adipose Tissue , Colorectal Neoplasms/surgery
2.
Epilepsy Behav ; 146: 109365, 2023 09.
Article in English | MEDLINE | ID: mdl-37523797

ABSTRACT

OBJECTIVE: In patients with treatment-refractory temporal lobe epilepsy (TLE), a single stereotactic laser interstitial thermotherapy (LITT) procedure is sometimes insufficient to ablate epileptogenic tissue, particularly the medial structures often implicated in TLE. In patients with seizure recurrence after initial ablation, the extent to which a second ablation may achieve improved seizure outcomes is uncertain. The objective of this study was to investigate the feasibility and potential efficacy of repeat LITT amygdalohippocampotomy as a worthwhile strategy for intractable temporal lobe epilepsy by quantifying changes to targeted mesial temporal lobe structures and seizure outcomes. METHODS: Patients who underwent two LITT procedures for drug-resistant mesial TLE at our institution were included in the study. Lesion volumes for both procedures were calculated by comparing post-ablation intraoperative sequences to preoperative anatomy. Clinical outcomes after the initial procedure and repeat procedure were classified according to Engel scores. RESULTS: Five consecutive patients were included in this retrospective case series: 3 with right- and 2 with left-sided TLE. The median interval between LITT procedures was 294 days (range: 227-1918). After the first LITT, 3 patients experienced class III outcomes, 1 experienced a class IV, and 1 experienced a class IB outcome. All patients achieved increased seizure freedom after a second procedure, with class I outcomes (3 IA, 2 IB). CONCLUSIONS: Repeat LITT may be sufficient to achieve satisfactory seizure outcomes in some individuals who might otherwise be considered for more aggressive resection or palliative neuromodulation. A larger study to establish the potential value of repeat LITT amygdalohippocampotomy vs. other re-operation strategies for persistent, intractable temporal lobe epilepsy is worth pursuing.


Subject(s)
Drug Resistant Epilepsy , Epilepsy, Temporal Lobe , Laser Therapy , Humans , Epilepsy, Temporal Lobe/surgery , Epilepsy, Temporal Lobe/pathology , Retrospective Studies , Treatment Outcome , Laser Therapy/methods , Seizures/surgery , Drug Resistant Epilepsy/surgery , Lasers , Magnetic Resonance Imaging
3.
Expert Rev Neurother ; 23(2): 123-140, 2023 02.
Article in English | MEDLINE | ID: mdl-36731858

ABSTRACT

INTRODUCTION: Epilepsy is a common, often debilitating disease of hyperexcitable neural networks. While medically intractable cases may benefit from surgery, there may be no single, well-localized focus for resection or ablation. In such cases, approaching the disease from a network-based perspective may be beneficial. AREAS COVERED: Herein, the authors provide a narrative review of normal thalamic anatomy and physiology and propose general strategies for preventing and/or aborting seizures by modulating this structure. Additionally, they make specific recommendations for targeting the thalamus within different contexts, motivated by a more detailed discussion of its distinct nuclei and their respective connectivity. By describing important principles governing thalamic function and its involvement in seizure networks, the authors aim to provide a primer for those now entering this fast-growing field of thalamic neuromodulation for epilepsy. EXPERT OPINION: The thalamus is critically involved with the function of many cortical and subcortical areas, suggesting it may serve as a compelling node for preventing or aborting seizures, and so it has increasingly been targeted for the surgical treatment of epilepsy. As various thalamic neuromodulation strategies for seizure control are developed, there is a need to ground such interventions in a mechanistic, circuit-based framework.


Subject(s)
Deep Brain Stimulation , Drug Resistant Epilepsy , Epilepsy , Humans , Thalamus , Epilepsy/therapy , Seizures , Drug Resistant Epilepsy/therapy
4.
Ann Surg Oncol ; 29(12): 7568-7576, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35882692

ABSTRACT

BACKGROUND: Survival of patients affected by colorectal cancer peritoneal metastases (CRC-PM) can be improved with combined complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Two chemotherapeutic agents are mainly used: mitomycin C (MMC) and oxaliplatin. A recent prospective randomized clinical trial showed that oxaliplatin-based HIPEC does not improve survival compared with CCRS alone. The purpose of our study was to compare the survival effectiveness of MMC versus oxaliplatin-based HIPEC using a homogeneous surgical technique and drug protocol. METHODS: This retrospective monocentric study included all patients prospectively registered for having undergone CCRS and HIPEC using MMC or oxaliplatin for CRC-PM in Strasbourg University Hospital, France, from December 2004 until December 2019. MMC-based HIPEC and oxaliplatin-based HIPEC groups were compared with an inverse probability of treatment weighting. RESULTS: A total of 137 patients were included. Groups were comparable for all baseline characteristics except for peritoneal carcinomatosis index. In the weighted multivariate analysis, disease-free survival (DFS) and peritoneal disease-free survival (PDFS) were significantly higher in the MMC-based HIPEC group compared with the oxaliplatin-based HIPEC group with a hazard ratio of 0.74 (CI 95% 0.56-0.98), p = 0.035 and 0.59 (CI 95% 0.40-0.98), p = 0.0084, respectively. There was no difference in overall survival or postoperative morbidity between groups. CONCLUSIONS: These results favor a superiority of MMC for DFS and PDFS in comparison with oxaliplatin in HIPEC after CCRS in treatment with curative intent for CRC-PM.


Subject(s)
Colorectal Neoplasms , Hyperthermia, Induced , Peritoneal Neoplasms , Colorectal Neoplasms/pathology , Combined Modality Therapy , Cytoreduction Surgical Procedures/methods , Humans , Hyperthermia, Induced/methods , Mitomycin , Oxaliplatin , Peritoneal Neoplasms/secondary , Retrospective Studies , Survival Rate
5.
J Orthop Surg Res ; 16(1): 536, 2021 Aug 27.
Article in English | MEDLINE | ID: mdl-34452626

ABSTRACT

BACKGROUND: The prevalence of anaemia in patients planned for total hip and knee arthroplasty is about 20%. Optimising pre-operative haemoglobin levels by iron supplementation has been shown to decrease transfusion rates, complications and associated morbidity. The need for universal screening with iron studies of all elective arthroplasty patients is not clearly defined at present. METHODS: Retrospective review of 2 sequential cohorts of patients undergoing primary hip or knee arthroplasty by a single surgeon at a single centre between January 2013 and December 2017. The first group of patients underwent pre-operative iron studies only if found to be anaemic, with a haemoglobin below 12g/dl. From January 2015, all patients irrespective of the presence of anaemia were screened with a complete iron profile before surgery. Patients with a confirmed iron deficiency were administered with intravenous iron prior to surgery. The 2 cohorts were compared with regard to blood transfusion rate post-operatively and cost efficiency for universal screening with iron studies. RESULTS: There was a net decrease in the allogenic blood transfusion rate from 4.76 to 2.92% when universal iron studies were introduced but the difference was not statistically significant. Obtaining universal pre-operative iron studies is cost neutral with the price of allogenic blood transfusion in a similar cohort. We also diagnosed 5 patients with occult malignancies. CONCLUSIONS: Universal screening with pre-operative iron studies and iron infusion in elective arthroplasty patients may reduce allogenic blood requirements and is cost neutral. An additional benefit is the potential to diagnose asymptomatic malignancies. Further studies are required to show the true benefit of universal pre-operative iron screening.


Subject(s)
Anemia , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Iron Deficiencies , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Cost-Benefit Analysis , Hemoglobins/analysis , Humans , Iron/chemistry , Retrospective Studies
6.
Drug Deliv ; 28(1): 240-251, 2021 Dec.
Article in English | MEDLINE | ID: mdl-33501859

ABSTRACT

Colorectal cancer is one of the most common cancers in the United States and treatment options are limited for patients who develop liver metastases. Several chemotherapeutic regimens have been used for transvascular liver-directed therapy in the treatment of colorectal liver metastases without clear evidence of superiority of one therapy over another. We describe the development of a novel nanoemulsion through combining irinotecan (IRI), a first line systemic agent used for the treatment of colon cancer, with lipiodol, an oily contrast medium derived from poppy seed oil, and evaluated its pharmacokinetic and biodistribution profile as a function of portal venous chemoembolization (PVCE) versus transarterial chemoembolization (TACE) delivery. The Tessari technique was used to create a stable emulsion (20 mg IRI mixed with 2 mL lipiodol) with resultant particle size ranging from 28.9 nm to 56.4 nm. Pharmacokinetic profile established through venous sampling in Buffalo rats demonstrate that the area under the curve (AUC0-∞) of IRI was significantly less after PVCE with IRI-lipiodol as compared to IRI alone (131 vs. 316 µg*min/mL, p-value = .023), suggesting significantly higher amounts of IRI retention in the liver with the IRI-lipiodol nanoemulsion via first-pass extraction. Subseqent biodistribution studies in tumor-bearing WAG/Rjj rats revealed more IRI present in the tumor following TACE versus PVCE (29.19 ± 12.33 µg/g versus 3.42 ± 1.62; p-value = .0033) or IV (29.19 ± 12.33 µg/g versus 1.05 ± 0.47; p-value = .0035). The IRI-lipiodol nanoemulsion demonstrated an acceptable hepatotoxicity profile in all routes of administration. In conclusion, the IRI-lipiodol nanoemulsion via TACE showed promise and warrants further investigation as an option for the treatment of metastatic colorectal cancer.


Subject(s)
Colorectal Neoplasms/pathology , Ethiodized Oil/pharmacokinetics , Hepatic Artery , Irinotecan/pharmacokinetics , Liver Neoplasms/secondary , Liver/metabolism , Portal Vein , Topoisomerase I Inhibitors/pharmacokinetics , Animals , Cell Line, Tumor , Chemoembolization, Therapeutic/methods , Drug Carriers , Emulsions/pharmacokinetics , In Vitro Techniques , Irinotecan/administration & dosage , Liver Neoplasms/therapy , Nanostructures , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , Rats , Topoisomerase I Inhibitors/administration & dosage
7.
Oper Neurosurg (Hagerstown) ; 20(2): 226-231, 2021 01 13.
Article in English | MEDLINE | ID: mdl-33269389

ABSTRACT

BACKGROUND: Numerous C1-C2 fixation techniques exist for the treatment of atlantoaxial instability. Limitations of screw-rod and sublaminar wiring techniques include C2 nerve root sacrifice and dural injury, respectively. We present a novel technique that utilizes a femoral head allograft cut with a keyhole that rests posteriorly on the arches of C1 and C2 and straddles the C2 spinous process, secured by sutures. OBJECTIVE: To offer increased fusion across C1-C2 without the passage of sublaminar wiring or interarticular arthrodesis. METHODS: A total of 6 patients with atlantoaxial instability underwent C1-C2 fixation using our method from 2015 to 2016. After placement of a C1-C2 screw/rod construct, a cadaveric frozen femoral head allograft was cut into a half-dome with a keyhole and placed over the already decorticated dorsal C1 arch and C2 spinous process. Notches were created in the graft and sutures were placed in the notches and around the rods to secure it firmly in place. RESULTS: The femoral head's shape allowed for creation of a graft that provides excellent surface area for fusion across C1-C2. There were no intraoperative complications, including dural tears. Postoperatively, no patients had sensorimotor deficits, pain, or occipital neuralgia. 5 patients demonstrated clinical resolution of symptoms by 3 mo and radiographic (computed tomography) evidence of fusion at 1 yr. One patient had good follow-up at 1 mo but died due to complications of Alzheimer disease. CONCLUSION: The posterior arch femoral head allograft strut technique with securing sutures is a viable option for supplementing screw-rod fixation in the treatment of complex atlantoaxial instability.


Subject(s)
Atlanto-Axial Joint , Spinal Fusion , Allografts , Atlanto-Axial Joint/diagnostic imaging , Atlanto-Axial Joint/surgery , Bone Screws , Cervical Vertebrae , Dietary Supplements , Femur Head , Humans
8.
J Biol Chem ; 295(39): 13516-13531, 2020 09 25.
Article in English | MEDLINE | ID: mdl-32723867

ABSTRACT

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) NMR spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mm), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. Whereas orthogonal binder discovery methods could yield high-affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.


Subject(s)
Benzimidazoles/pharmacology , Prion Diseases/drug therapy , Prion Proteins/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Benzimidazoles/chemistry , Drug Discovery , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Prion Diseases/metabolism , Prion Proteins/metabolism , Small Molecule Libraries/chemistry
9.
Nature ; 553(7687): 217-221, 2018 01 11.
Article in English | MEDLINE | ID: mdl-29258297

ABSTRACT

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.


Subject(s)
CRISPR-Associated Proteins/administration & dosage , Gene Editing/methods , Genes, Dominant/genetics , Genetic Therapy/methods , Hearing Loss/genetics , Acoustic Stimulation , Alleles , Animals , Animals, Newborn , Auditory Threshold , Base Sequence , CRISPR-Associated Proteins/metabolism , CRISPR-Associated Proteins/therapeutic use , CRISPR-Cas Systems , Cell Survival , Cochlea/cytology , Cochlea/metabolism , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem , Female , Fibroblasts , Hair Cells, Auditory/cytology , Hearing Loss/physiopathology , Hearing Loss/prevention & control , Humans , Liposomes , Male , Membrane Proteins/genetics , Mice , Reflex, Startle
10.
Nanomedicine (Lond) ; 11(10): 1193-205, 2016 05.
Article in English | MEDLINE | ID: mdl-27102240

ABSTRACT

AIM: We assessed the effects of flexing and massage on human skin penetration and toxicity of topically applied coated and uncoated zinc oxide nanoparticles (˜75 nm) in vivo. MATERIALS & METHODS: Noninvasive multiphoton tomography with fluorescence lifetime imaging was used to evaluate the penetration of nanoparticles through the skin barrier and cellular apoptosis in the viable epidermis. RESULTS: All nanoparticles applied to skin with flexing and massage were retained in the stratum corneum or skin furrows. No significant penetration into the viable epidermis was seen and no cellular toxicity was detected. CONCLUSION: Exposure of normal in vivo human skin to these nanoparticles under common in-use conditions of flexing or massage is not associated with significant adverse events.


Subject(s)
Skin Absorption , Skin/drug effects , Sunscreening Agents/pharmacokinetics , Sunscreening Agents/toxicity , Zinc Oxide/pharmacokinetics , Zinc Oxide/toxicity , Adult , Apoptosis/drug effects , Humans , Massage , Skin/cytology , Skin/metabolism , Skin/ultrastructure , Young Adult
11.
Proc Natl Acad Sci U S A ; 113(11): 2868-73, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26929348

ABSTRACT

A central challenge to the development of protein-based therapeutics is the inefficiency of delivery of protein cargo across the mammalian cell membrane, including escape from endosomes. Here we report that combining bioreducible lipid nanoparticles with negatively supercharged Cre recombinase or anionic Cas9:single-guide (sg)RNA complexes drives the electrostatic assembly of nanoparticles that mediate potent protein delivery and genome editing. These bioreducible lipids efficiently deliver protein cargo into cells, facilitate the escape of protein from endosomes in response to the reductive intracellular environment, and direct protein to its intracellular target sites. The delivery of supercharged Cre protein and Cas9:sgRNA complexed with bioreducible lipids into cultured human cells enables gene recombination and genome editing with efficiencies greater than 70%. In addition, we demonstrate that these lipids are effective for functional protein delivery into mouse brain for gene recombination in vivo. Therefore, the integration of this bioreducible lipid platform with protein engineering has the potential to advance the therapeutic relevance of protein-based genome editing.


Subject(s)
Gene Knockout Techniques , Genes, Synthetic , Genetic Engineering/methods , Lipids/chemistry , Nanoparticles , Animals , Bacterial Proteins/administration & dosage , Bacterial Proteins/genetics , CRISPR-Associated Protein 9 , CRISPR-Cas Systems , Ceramides/chemistry , Cholesterol/chemistry , Drug Carriers , Endocytosis , Endonucleases/administration & dosage , Endonucleases/genetics , Endosomes/metabolism , Genes, Reporter , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , HeLa Cells , Humans , Hypothalamus/metabolism , Integrases/administration & dosage , Integrases/genetics , Lipids/administration & dosage , Lipids/chemical synthesis , Luminescent Proteins/biosynthesis , Luminescent Proteins/genetics , Mice , Molecular Structure , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Nanoparticles/metabolism , Nanoparticles/toxicity , Phosphatidylethanolamines/chemistry , RNA/genetics , Recombinant Proteins/biosynthesis , Recombination, Genetic , Static Electricity , Structure-Activity Relationship , Thalamus/metabolism
12.
J Clin Oncol ; 31(28): 3517-24, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23980084

ABSTRACT

PURPOSE: Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS: Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS: The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION: Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.


Subject(s)
Alanine/analogs & derivatives , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Triazines/therapeutic use , Adult , Aged , Aged, 80 and over , Alanine/therapeutic use , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Double-Blind Method , Female , Follow-Up Studies , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Niacinamide/therapeutic use , Prognosis , Sorafenib , Survival Rate , Young Adult
13.
J Clin Oncol ; 31(28): 3509-16, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23980090

ABSTRACT

PURPOSE: Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS: In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS: Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION: In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.


Subject(s)
Alanine/analogs & derivatives , Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm/drug effects , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Salvage Therapy , Triazines/therapeutic use , Adult , Aged , Aged, 80 and over , Alanine/therapeutic use , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Double-Blind Method , Female , Follow-Up Studies , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Niacinamide/adverse effects , Prognosis , Sorafenib , Survival Rate , Young Adult
14.
Acta Ophthalmol ; 91(1): 6-11, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22268800

ABSTRACT

PURPOSE: To provide a systematic review of the published studies pertaining to the lifestyle modification, dietary, nutritional and vitamins supplements for preventing occurrence or halting deterioration of age-related macular degeneration (AMD). METHODS: The literature searches from 1990 to December 2010 with following keywords, 'age related macular degeneration', 'nutrition', 'antioxidant', 'diet' and 'vitamins supplements' using search engines Pubmed, Google Scholar, Medline and the Cochrane Library. Meta-analyses, population-based cohort studies and case-controlled trials were reviewed, whereas small cases series, case reports, commentaries, abstracts in proceedings or personal observations were excluded. RESULTS: Smoking and obesity are identified risk factors for AMD. High dietary intakes of omega-3 fatty acids, and macular xanthophylls lutein and zeaxanthin have been associated with a lower risk of prevalence and incidence in AMD. Vitamin B and extracts from wolfberry, Gingko biloba and berry anthocyanins were also subjects of intense research interests, but there has been no concluding scientific evidence yet. The Age-Related Eye Disease study (AREDS) is the only large-scale randomized controlled clinical trial to show beneficial effect of AREDS formulation of vitamins C, E, beta-carotene and zinc with copper in reducing the risk progression to advanced AMD in patients with intermediate AMD or with advanced AMD in one eye. CONCLUSION: Quit smoking is an important advice to patients to prevent or slow the progress of AMD. There is no recommendation for routine nutritional or vitamins supplementation for primary prevention. However, patients with documented intermediate risk of AMD or advanced AMD in one eye are recommended to take AREDS-type vitamin supplements.


Subject(s)
Diet , Dietary Supplements , Macular Degeneration/drug therapy , Macular Degeneration/prevention & control , Nutritional Physiological Phenomena , Risk Reduction Behavior , Vitamins/administration & dosage , Behavior Therapy , Humans , Life Style , Meta-Analysis as Topic , Primary Prevention
15.
Pharm Res ; 28(11): 2931-44, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21833791

ABSTRACT

PURPOSE: To measure penetration and metabolic effects of ion-stabilized, polar, 15 nm gold nanoparticles in aqueous solution (AuNP-Aq) and sterically stabilized, non-polar, 6 nm gold nanoparticles in toluene (AuNP-TOL) on excised human skin. METHODS: Gold nanoparticles were characterized with dynamic light scattering and transmission electron microscopy (TEM). Skin penetration studies were done on frozen or fresh excised skin using static Franz diffusion cells. Viable treated skin was assessed by dermoscopy, reflectance confocal microscopy (RCM), multiphoton tomography (MPT) with fluorescence lifetime imaging microscopy (FLIM), and TEM. RESULTS: Dermoscopy and RCM showed large aggregates in the furrows of AuNP-Aq-treated skin. Treatment of thawed and viable skin only showed enhanced permeability to nanoparticles in the AuNP-TOL group with MPT and FLIM imaging to stratum spinosum of epidermis. TEM analysis revealed gold nanoparticles within AuNP-treated stratum corneum. FLIM analysis of NAD(P)H showed a significant decrease in total NAD(P)H in all toluene-treated groups. CONCLUSIONS: Gold nanoparticles, 15 nm, in aqueous solution aggregated on the skin surface. Toluene treatment eliminated skin metabolism; skin treated with toluene/gold nanoparticles (6 nm) for 24 h, but not at 4 h, showed increased nanoparticle permeability. These results are of value to nanotoxicology.


Subject(s)
Gold/chemistry , Metal Nanoparticles/chemistry , Skin Absorption , Skin/metabolism , Solvents/metabolism , Toluene/metabolism , Administration, Cutaneous , Drug Compounding , Drug Delivery Systems , Drug Evaluation, Preclinical , Epidermis/metabolism , Gold/analysis , Gold/metabolism , Gold/pharmacology , Humans , Metal Nanoparticles/analysis , NADP/analysis , NADP/metabolism , Particle Size , Permeability
16.
Dev Psychol ; 44(2): 523-31, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18331141

ABSTRACT

Theory of mind is claimed to develop universally among humans across cultures with vastly different folk psychologies. However, in the attempt to test and confirm a claim of universality, individual studies have been limited by small sample sizes, sample specificities, and an overwhelming focus on Anglo- European children. The current meta-analysis of children's false-belief performance provides the most comprehensive examination to date of theory-of-mind development in a population of non-Western children speaking non-Indo-European languages (i.e., Mandarin and Cantonese). The meta-analysis consisted of 196 Chinese conditions (127 from mainland China and 69 from Hong Kong), representing responses from more than 3,000 children, compared with 155 similar North American conditions (83 conditions from the United States and 72 conditions from Canada). The findings show parallel developmental trajectories of false-belief understanding for children in China and North America coupled with significant differences in the timing of development across communities-children's false-belief performance varied across different locales by as much as 2 or more years. These data support the importance of both universal trajectories and specific experiential factors in the development of theory of mind.


Subject(s)
Asian People/psychology , Cross-Cultural Comparison , Language , Personal Construct Theory , Child , Child, Preschool , China , Female , Hong Kong , Humans , Male , North America , White People/psychology
17.
Med Biol Eng Comput ; 45(12): 1223-8, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17965897

ABSTRACT

The purpose of this study was to develop a biofeedback tilt-table for automatic tilt-table training, helping patients with spinal cord injury (SCI) to recover more rapidly from orthostatic hypotension, and increasing safety to avoid syncope during training. This biofeedback tilt-table implemented automatic training maneuvers and included three closed feedback loops to monitor the acquisition of physiological signals from patients and the feedback of presyncope symptoms (PS) to regulate the angle of tilt. The results of clinical testing revealed that the mean blood pressure and oxygen saturation represented the most useful physiological signals for determining PS feedback and the quantitative criteria adopted were practicable and useful in describing the level of PS. This novel biofeedback tilt-table system offered higher patient throughput, faster training and safety in training of SCI patients to overcome their orthostatic hypotension than traditional tilt-table training, and could provide quantitative information of PS to assist medical staff in studying the mechanism of orthostatic syncope.


Subject(s)
Biomedical Engineering/methods , Hypotension, Orthostatic/rehabilitation , Physical Therapy Modalities/instrumentation , Spinal Cord Injuries/rehabilitation , Adult , Biofeedback, Psychology , Equipment Design , Female , Humans , Hypotension, Orthostatic/etiology , Male , Middle Aged , Posture , Spinal Cord Injuries/complications , Tilt-Table Test/instrumentation
20.
Acupunct Med ; 23(2): 83-5, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16025789

ABSTRACT

A 39 year old woman, scheduled for elective caesarean section in her second pregnancy, developed thrombocytopenia. Therefore, at the time of surgery, spinal anaesthesia and non-steroidal analgesic drugs were avoided and she was given a standard general anaesthetic procedure including fentanyl 100 microg and morphine 10 mg. In the early postoperative period she received tramadol 100 mg and a further 10 mg of morphine. These drugs did not control her pain, but caused side effects--in particular nausea and retching. Acupuncture to LI4 and PC6 on the right side produced dramatic pain relief within minutes.


Subject(s)
Acupuncture Analgesia/methods , Cesarean Section/adverse effects , Pain, Postoperative/prevention & control , Pregnancy Complications, Hematologic/physiopathology , Thrombocytopenia/physiopathology , Acupuncture Therapy/methods , Acute Disease , Adjuvants, Anesthesia/administration & dosage , Adult , Analgesics, Opioid/administration & dosage , Anesthetics, Local/administration & dosage , Female , Humans , Infant, Newborn , Pain, Postoperative/drug therapy , Pain, Postoperative/etiology , Postoperative Nausea and Vomiting/prevention & control , Pregnancy , Time Factors , Treatment Outcome
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