New techniques in radiation therapy for head and neck cancer: IMRT, CyberKnife, protons, and carbon ions. Improved effectiveness and safety? Impact on survival?

The objective of this study was to assess the comparative effectiveness of intensity-modulated radiation therapy (IMRT), conformal and two-dimensional radiation therapy, proton beam, and carbon ion therapy in terms of tumor control and survival on the one hand and adverse events and quality of life on the other in irradiated head and neck cancer patients. A search of the literature was performed. At a given time, innovative techniques in radiation therapy may appear superior to routine irradiation techniques and clinical trials may therefore be considered unethical. IMRT, because of its superiority in terms of dose distributions and potential to preserve the salivary glands, has gradually replaced two-dimensional and conformal irradiation in routine use. The PARSPORT phase III trial is one among the rare trials to randomize two-dimensional and conformal irradiation against IMRT. It showed a 50% reduction in late xerostomia. Similarly, the relevance of clinical trials to prove the superiority of protons compared with photons is highly controversial. Although the expected benefit of particle beam therapy on dose distributions, local control, and quality of life seems sufficient for routine use without phase III trials, it should be noted that new toxicity profiles might be seen as was the case for IMRT (posterior alopecia, anterior mucositis, uncertainties of integral dose, and secondary cancers). Prospective clinical and medico-economic assessment, possibly in phase II trials, is therefore critically needed along with stringent quality assurance programs. Technological advances in radiation therapy clearly provide a benefit for patients despite the lack of level I evidence.     

Novel antibiotics targeting respiratory ATP synthesis in Gram-positive pathogenic bacteria

Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens.     

Personality pathology comorbidity in adult females with eating disorders

Personality pathology is examined in 100 female in-patients diagnosed with eating disorders. The Eating Disorder Inventory-II and the NEO-PI-R were self-administered and personality pathology was assessed using a structured interview. Clinicians additionally evaluated patients' global functioning. The results indicated sizeable personality disorder comorbidity, and two dimensions of personality pathology, for example, an internalizing and an externalizing factor, could be identified. Patients' global functioning was primarily associated with dimensions of personality pathology, but not with eating disorder symptoms. Assessment and therapeutic interventions should focus on this co-occurring pathology in order to improve patients' functioning.     

Design and characterization of targeted ultrasound microbubbles for diagnostic use

Targeted ultrasound (US) contrast agents represent, because of their size (1 to 5 μm), a unique class of diagnostic imaging agents enabling true vascular imaging of conditions like inflammation and tumor angiogenesis. The objective of this study was to develop technology for preparing targeted microbubbles with binding and acoustic properties compatible with diagnostic use. Phosphatidylcholine (PC) was shown to represent the most favorable wall material. Various thiolated peptide binders were effectively conjugated to PC-based microbubbles containing maleimide functionalized lipids (95:5) without the need for biotin-streptavidin or antibody technology. By optimizing the technology, specific targeting of the inflammatory target E-selectin and the angiogenic target VEGFR2 in the presence of 100% serum was achieved. Increased phospholipid chain length from 18 carbons to 22 carbons improved the stability of the microbubbles during US exposure, without compromising binding or acoustic properties. (E-mail: roald.skurtveit@ge.com)     

Ultrasound-guided sclerosis of neovessels in painful chronic patellar tendinopathy: a randomized controlled trial

BACKGROUND: Color Doppler ultrasound examination frequently reveals neovascularization in chronic painful Achilles and patellar tendinopathy. Sclerosing the area with vascular ingrowth using polidocanol has shown promising clinical results in patients with Achilles tendinopathy. PURPOSE: To investigate sclerosing treatment using polidocanol on a group of elite athletes with patellar tendinopathy. STUDY DESIGN: Randomized controlled trial/cross-over study; Level of evidence, 1. METHODS: The authors recruited 33 patients (42 tendons), mainly from the Norwegian elite divisions in basketball, team handball, and volleyball. Seventeen patients (23 knees) were randomized to the treatment group (polidocanol injections in the area of neovascularization) and 16 patients (20 knees) to the control group (similar injections with lidocaine/epinephrine). After 4 months of treatment, the control group was crossed over to active treatment. Pain and function were recorded using the Victorian Institute of Sport Assessment score before the start of treatment and 4, 8, and 12 months after the first injection. Victorian Institute of Sport Assessment scores between groups were compared using multivariate analysis of variance for repeated measures. RESULTS: The treatment group reported a significant improvement in Victorian Institute of Sport Assessment score from 51 to 62 after 4 months; there was no change for the control group (group by time interaction, P = .052). After 8 months, when the control group had also received active treatment with polidocanol, they had a greater improvement in Victorian Institute of Sport Assessment score (58-79) than did the treatment group (54-70; group by time interaction, P = .022; time effect, P < .0001). There was no further time or group effect in Victorian Institute of Sport Assessment score to the 12-month follow-up (treatment, 72; control, 85). CONCLUSION: Sclerosing injections with polidocanol resulted in a significant improvement in knee function and reduced pain in patients with patellar tendinopathy.     

Understanding and preventing noncontact anterior cruciate ligament injuries: a review of the Hunt Valley II meeting, January 2005

The incidence of noncontact anterior cruciate ligament injuries in young to middle-aged athletes remains high. Despite early diagnosis and appropriate operative and nonoperative treatments, posttraumatic degenerative arthritis may develop. In a meeting in Atlanta, Georgia (January 2005), sponsored by the American Orthopaedic Society for Sports Medicine, a group of physicians, physical therapists, athletic trainers, biomechanists, epidemiologists, and other scientists interested in this area of research met to review current knowledge on risk factors associated with noncontact anterior cruciate ligament injuries, anterior cruciate ligament injury biomechanics, and existing anterior cruciate ligament prevention programs. This article reports on the presentations, discussions, and recommendations of this group.     

Biological mechanisms of chronic fatigue

Chronic fatigue is a common, poorly understood and disabling phenomenon in many diseases. We aim to provide an overview of fatigue in chronic autoimmune and inflammatory disease. Fatigue measurement, prevalence and confounding factors such as depression, sleep disorders and pain are reviewed in the first half of the article. In the second half of the article, we describe explanatory models of fatigue and fatigue signalling, with an emphasis on cytokines and sickness behaviour, oxidative stress, mitochondrial dysfunction and the impact of certain genes on fatigue.