Phase I/IIa study of cisplatin and gemcitabine as induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine and paclitaxel for locally advanced non-small-cell lung cancer.

PURPOSE: This is a phase I/IIa study to assess tolerance of gemcitabine and paclitaxel with radiotherapy in locally advanced non-small-cell lung cancer after induction chemotherapy. PATIENTS AND METHODS: Fifty-seven patients with stage III non-small-cell lung cancer were treated with cisplatin 80 mg/m2 on days 1 and 22 and gemcitabine 1,250 mg/m2 on days 1, 8, 22, and 28. Chemoradiotherapy began on day 43 as follows: cohort 1 (n = 9), gemcitabine 300 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 2 (n = 9), gemcitabine 150 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 3 (n = 10) and the 25 phase IIa patients, gemcitabine 300 mg/m2 and paclitaxel 135 mg/m2 every 21 days. Patients were treated with three-dimensional thoracic radiotherapy concurrently to 60 Gy. RESULTS: Weekly chemotherapy resulted in grade 4 esophageal and grade 3 or higher pulmonary toxicities. Reduction in dose density (cohort 3) led to a tolerable toxicity profile and was chosen as the phase IIa regimen. The response rate to induction was 49%, with stable disease in 40% of the patients. The response rate after consolidation therapy was 75% (94% for weekly chemotherapy v 82% for every 3 weeks). Median survival was 23 months, and 3-year survival was 45% for eligible patients. Local relapse occurred in 20% of the patients. Performance status of more than 1 predicted for poor outcome, but baseline pulmonary function did not. Dosimetric parameters including V15, V20, V30 (percent lung volume receiving > or = 15, > or = 20, and > or = 30 Gy, respectively), and mean lung dose correlated with pulmonary toxicity. CONCLUSION: Additional investigation with the 3-week schedule is warranted in patients with a good performance status based on the safety profile and preliminary efficacy data observed in this study.     

Rehabilitation of ataxic gait following cerebellar lesions: Applying theory to practice

Damage to the cerebellum can result in ataxic gait, which affects the ability to walk safely and independently. Physiotherapy is the main treatment for ataxic gait, but there is limited high-quality evidence for interventions used. This review explores the neural mechanisms of the symptoms of ataxic gait, by discussing the cerebellum’s role in coordination, motor learning, anticipatory postural control, balance reactions and adapting gait to meet environmental demands. It discusses mechanisms that occur at cellular level throughout the whole cerebellum and then focuses on difficulties that arise from damage to specific lobes of the cerebellum. Physiotherapy-based interventions, such as balance training, developing postural control, specific gait training, and use of compensatory orthotics and aids, are discussed in relation to the theoretical understanding of cerebellar functioning. Consideration is given to difficulties of using trial-and-error–based learning, which will impact on teaching techniques and strategies used during gait rehabilitation. This theoretical understanding will aid physiotherapists to target their assessment, treatment, management, and goal setting with individuals who have difficulties with ataxic gait following a cerebellar lesion.     

Key challenges for nanotechnology: Standardization of ecotoxicity testing

Nanotechnology is expected to contribute to the protection of the environment, but many uncertainties exist regarding the environmental and human implications of manufactured nanomaterials (MNMs). Contradictory results have been reported for their ecotoxicity to aquatic organisms, which constitute one of the most important pathways for their entrance and transfer throughout the food web. The present review is focused on the international strategies that are laying the foundations of the ecotoxicological assessment of MNMs. Specific advice is provided on the preparation of MNM dispersions in the culture media of the organisms, which is considered a key factor to overcome the limitations in the standardization of the test methodologies.     

Analysis of core circadian feedback loop in suprachiasmatic nucleus of mCry1-luc transgenic reporter mouse

The suprachiasmatic nucleus (SCN) coordinates circadian rhythms that adapt the individual to solar time. SCN pacemaking revolves around feedback loops in which expression of Period (Per) and Cryptochrome (Cry) genes is periodically suppressed by their protein products. Specifically, PER/CRY complexes act at E-box sequences in Per and Cry to inhibit their transactivation by CLOCK/BMAL1 heterodimers. To function effectively, these closed intracellular loops need to be synchronized between SCN cells and to the light/dark cycle. For Per expression, this is mediated by neuropeptidergic and glutamatergic extracellular cues acting via cAMP/calcium-responsive elements (CREs) in Per genes. Cry genes, however, carry no CREs, and how CRY-dependent SCN pacemaking is synchronized remains unclear. Furthermore, whereas reporter lines are available to explore Per circadian expression in real time, no Cry equivalent exists. We therefore created a mouse, B6.Cg-Tg(Cry1-luc)01Ld, carrying a transgene (mCry1-luc) consisting of mCry1 elements containing an E-box and E′-box driving firefly luciferase. mCry1-luc organotypic SCN slices exhibited stable circadian bioluminescence rhythms with appropriate phase, period, profile, and spatial organization. In SCN lacking vasoactive intestinal peptide or its receptor, mCry1 expression was damped and desynchronized between cells. Despite the absence of CREs, mCry1-luc expression was nevertheless (indirectly) sensitive to manipulation of cAMP-dependent signaling. In mPer1/2-null SCN, mCry1-luc bioluminescence was arrhythmic and no longer suppressed by elevation of cAMP. Finally, an SCN graft procedure showed that PER-independent as well as PER-dependent mechanisms could sustain circadian expression of mCry1. The mCry1-luc mouse therefore reports circadian mCry1 expression and its interactions with vasoactive intestinal peptide, cAMP, and PER at the heart of the SCN pacemaker.     

Differences in the causes of death of HIV-positive patients in a cohort study by data sources and coding algorithms

OBJECTIVES:: To compare causes of death (CoDs) from two independent sources: National Basic Death File (NBDF) and deaths reported to the Spanish HIV Research cohort [Cohort de adultos con infección por VIH de la Red de Investigación en SIDA CoRIS)] and compare the two coding algorithms: International Classification of Diseases, 10th revision (ICD-10) and revised version of Coding Causes of Death in HIV (revised CoDe). METHODS:: Between 2004 and 2008, CoDs were obtained from the cohort records (free text, multiple causes) and also from NBDF (ICD-10). CoDs from CoRIS were coded according to ICD-10 and revised CoDe by a panel. Deaths were compared by 13 disease groups: HIV/AIDS, liver diseases, malignancies, infections, cardiovascular, blood disorders, pulmonary, central nervous system, drug use, external, suicide, other causes and ill defined. RESULTS:: There were 160 deaths. Concordance for the 13 groups was observed in 111 (69%) cases for the two sources and in 115 (72%) cases for the two coding algorithms. According to revised CoDe, the commonest CoDs were HIV/AIDS (53%), non-AIDS malignancies (11%) and liver related (9%), these percentages were similar, 57, 10 and 8%, respectively, for NBDF (coded as ICD-10). When using ICD-10 to code deaths in CoRIS, wherein HIV infection was known in everyone, the proportion of non-AIDS malignancies was 13%, liver-related accounted for 3%, while HIV/AIDS reached 70% due to liver-related, infections and ill-defined causes being coded as HIV/AIDS. CONCLUSION:: There is substantial variation in CoDs in HIV-infected persons according to sources and algorithms. ICD-10 in patients known to be HIV-positive overestimates HIV/AIDS-related deaths at the expense of underestimating liver-related diseases, infections and ill defined causes. CoDe seems as the best option for cohort studies.