Patients treated with chemoradiation for head and neck cancer often report difficulty with swallowing and are frequently diagnosed with dysphagia. The extent to which patient awareness of dysphagia ...corresponds to observed physiologic changes in swallowing is unclear. The purpose of this study was to determine how both patient awareness of swallowing function and swallowing physiology individually change following chemoradiation and then to clarify the relationship between them. Twenty-one patients with head and neck cancer treated with chemoradiation were assessed before and after treatment and matched with twenty-one control subjects. The modified barium swallow test was utilized to examine swallowing physiology. Each subject was also given a series of items regarding awareness of specific dysphagia symptoms. Results showed decreased swallow efficiencies, higher percentages of residue, and more occurrences of penetration and aspiration following chemoradiation. Patients also had significantly higher ratings for 4 of the 12 items (“dry mouth,” “food sticking in my mouth,” “need water to help food go down,” and “change in sense of taste”). Only one strong and significant correlation was found between ratings for “I have difficulty swallowing” and swallow efficiency values. Based on these findings, it appears that patients sense a general difficulty with swallowing but have less awareness of specific symptoms of dysphagia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Introduction This study aims to report the outcome and toxicity of combined hyperthermia (HT) and radiation therapy (RT) in treatment of locally advanced or loco-regionally recurrent breast ...cancer. Patients and Methods Patients treated with HT and RT from January 1991 to December 2007 were reviewed. RT doses for previously irradiated patients were > 40 Gy and for RT naïve patients > 60 Gy, at 1.8–2 Gy/day. HT was planned for 2 sessions/week, immediately after RT, for a minimum of 20 min and for > 4 sessions. Superficial or interstitial applicators were used with temperature measured by superficial or interstitial thermistors based on target thickness. HT treatment was assessed by thermal equivalent dose (TED), > 42.5 °C and > 43 °C. Endpoints included treatment response, lack of local progression (local control), and survival. Results 127 patients received HT and RT to 167 sites. These included the intact breast (24.4%), chest wall/skin (67.7%), and breast/chest wall and nodes (7.9%). At a median follow-up of 13 months (mean 30 ± 38), improved overall survival was significantly associated with increasing RT dose (p < 0.0001), median TED 42.5 °C ≥ 200 min (p = 0.003), and local control (p = 0.0002). Local control at last follow-up was seen in 55.1% of patients. Complete response was significantly associated with median TED 42.5 °C ≥ 200 min (p = 0.002) and median TED 43 °C ≥ 100 min (p = 0.03). Conclusion HT and RT are effective for locally advanced or recurrent breast cancer in patients that have been historically difficult to treat by RT alone. Over 50% of patients achieved control of locoregional disease. Overall survival was improved with local control.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Monoclonal antibodies to different domains of the porcine intestinal 1,25-dihydroxyvitamin D3 1,25-(OH)2D3 receptor have been produced. A nuclear extract enriched in the 1,25-(OH)2D3 receptor was ...prepared from small intestinal mucosa of young pigs. The receptor was purified an additional 6600-fold by chromatography on DNA-cellulose, ammonium sulfate precipitation, gel filtration high-performance liquid chromatography, and DEAE-Sepharose chromatography, with an overall yield of 23% and an average purity of 24%. A BALB/c mouse immunized with this material developed serum polyclonal antibodies to the 1,25-(OH)2D3 receptor, as demonstrated by a change in sedimentation of the porcine receptor on sucrose gradients. Spleen cells from this animal were fused with mouse myeloma cells (P3-NSI/1-Ag4-1, SP2/0-Ag14), and 24 hybridomas secreting antibodies to the 1,25-(OH)2D3 receptor were identified by both a radiometric immunosorbent assay and an immunoprecipitation assay. Twenty-one hybridoma lines were cloned by limiting dilution and further characterized as subclass IgG1 antibodies with the exception of one which is an IgA. All but two of the antibodies cross-react with the 1,25-(OH)2D3 receptor from both mammalian (human, monkey, and rat) and avian (chicken) intestine; two antibodies recognize only porcine intestinal receptor. All antibodies are unreactive to the vitamin D serum transport protein. Eight of the antibodies bind denatured receptor on an immunoblot. A solid-phase competition assay was used to identify four groups of antibodies that bind to distinct epitopes on the 1,25-(OH)2D3 receptor. One antibody from each of the four groups was used to examine the effect of antibody binding on the DNA-binding activity of the receptor-hormone complex. One antibody completely inhibited the binding of the 1,25-(OH)2D3 receptor complex to DNA-cellulose, suggesting that the epitope for this antibody may be located in the polynucleotide binding domain of the protein. Antibodies from two additional groups only slightly perturbed DNA binding, while one had no effect, suggesting that these antibodies bind to receptor epitopes distant from the region of the polypeptide directly involved in polynucleotide binding. These antibodies that are directed to several different binding sites on the 1,25-(OH)2D3 receptor provide important new tools to probe the biochemistry and topology of the 1,25-(OH)2D3 receptor and to investigate its role in mediating target tissue response to hormone.
Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a ...recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A fusion protein comprising factor IX and the dimeric Fc domain of IgG1 has a half-life that is five times as long as that of native factor IX, allowing prophylactic injections to be spaced as far as ...2 weeks apart while maintaining levels of factor IX that are sufficient to prevent bleeding.
In patients with severe hemophilia B, recurrent bleeding leads to painful hemarthroses, disabling hemophilic arthropathy, and other sequelae.
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Prophylactic replacement of coagulation factor IX is associated with improved clinical outcomes
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The frequency of injections is a considerable burden, cited by patients as a key deterrent to undertaking prophylactic treatment.
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Various strategies to reduce this burden and improve the treatment of hemophilia B are under investigation, . . .
This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative ...hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.
Key Points
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Early identification of autism spectrum disorder (ASD) is essential to ensure that children can access specialized evidence-based interventions that can help to optimize long-term outcomes. Early ...identification also helps shorten the stressful "diagnostic odyssey" that many families experience before diagnosis. There have been important advances in research into the early development of ASDs, incorporating prospective designs and new technologies aimed at more precisely delineating the early emergence of ASD. Thus, an updated review of the state of the science of early identification of ASD was needed to inform best practice. These issues were the focus of a multidisciplinary panel of clinical practitioners and researchers who completed a literature review and reached consensus on current evidence addressing the question "What are the earliest signs and symptoms of ASD in children aged ≤24 months that can be used for early identification?" Summary statements address current knowledge on early signs of ASD, potential contributions and limitations of prospective research with high-risk infants, and priorities for promoting the incorporation of this knowledge into clinical practice and future research.
This article reviews current evidence for autism spectrum disorder (ASD) screening based on peer-reviewed articles published to December 2013. Screening provides a standardized process to ensure that ...children are systematically monitored for early signs of ASD to promote earlier diagnosis. The current review indicates that screening in children aged 18 to 24 months can assist in early detection, consistent with current American Academy of Pediatrics' recommendations. We identify ASD-specific and broadband screening tools that have been evaluated in large community samples which show particular promise in terms of accurate classification and clinical utility. We also suggest strategies to help overcome challenges to implementing ASD screening in community practice, as well as priorities for future research.
In the last two decades, the widespread application of genetic and genomic approaches has revealed a bacterial world astonishing in its ubiquity and diversity. This review examines how a growing ...knowledge of the vast range of animal–bacterial interactions, whether in shared ecosystems or intimate symbioses, is fundamentally altering our understanding of animal biology. Specifically, we highlight recent technological and intellectual advances that have changed our thinking about five questions: how have bacteria facilitated the origin and evolution of animals; how do animals and bacteria affect each other’s genomes; how does normal animal development depend on bacterial partners; how is homeostasis maintained between animals and their symbionts; and how can ecological approaches deepen our understanding of the multiple levels of animal–bacterial interaction. As answers to these fundamental questions emerge, all biologists will be challenged to broaden their appreciation of these interactions and to include investigations of the relationships between and among bacteria and their animal partners as we seek a better understanding of the natural world.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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