Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.

Radiotherapy as sole adjuvant treatment for older patients with low-risk breast cancer.

Partly as a result of screening, increasing numbers of older patients are presenting with 'low risk' breast cancer: tumours from which the likelihood of breast cancer death is minute; even so, these patients have a measurable risk of local recurrence if conservative surgery is not followed by some form of adjuvant treatment. However, it must be acknowledged that any such treatment has no detectable impact upon survival, and the value of all such interventions must be considered in the context of the individual patient's non-cancer life expectancy and the complex psychosocial factors that affect older patients. If no impact on survival can be expected and the risk of local recurrence is high enough to warrant some post-operative treatment, the most powerful agent in this respect is radiotherapy. Whilst adjuvant endocrine treatment is becoming increasingly accepted as monotherapy in low risk patients, we propose that radiotherapy should not be forgotten as an alternative which, with its attendant benefits of shorter duration and high compliance, may be more suitable for a number of patients.

Heat shock protein accumulation is upregulated in a long-lived mutant of Caenorhabditis elegans.

We present evidence for elevated levels of heat shock protein 16 (HSP16) in an intrinsically thermotolerant, long-lived strain of Caenorhabditis elegans during and after heat stress. Mutation of the age-1 gene, encoding a phosphatidylinositol 3-kinase catalytic subunit, results in both extended life span (Age) and increased intrinsic thermotolerance (Itt) in adult hermaphrodites. We subjected age-synchronous cohorts of worms to lethal and nonlethal thermal stress and observed the accumulation of a small (16-18 kd) heat-shock-specific polypeptide detected by an antibody raised against C. elegans HSP16. Strains carrying the mutation hx546 consistently accumulated HSP16 to higher levels than a wild-type strain. Significantly, overaccumulation of HSP16 in the age-1(hx546) strain following heat was observed throughout the adult life span. A chimeric transgene containing the Escherichia coli beta-galactosidase gene fused to a C. elegans HSP16-41 transcriptional promoter was introduced into wild-type and age-1(hx546) backgrounds. Heat-inducible expression of the transgene was elevated in the age-1(hx546) strain compared with the wild-type strain under a wide variety of heat shock and recovery conditions. These observations are consistent with a model in which Age mutations exhibit thermotolerance and extended life span as a result of elevated levels of molecular chaperones.

Myofibroblasts: molecular crossdressers.

Myofibroblasts are unique mesenchymal cells with properties inherent to both muscle and nonmuscle cells. They are widely distributed in embryos, are essential for the formation of functional adult tissues, and are intimately involved in tissue homeostasis and wound healing. Cytoskeletal protein expression and contractile properties distinguish them from other cell types. Myofibroblasts also express skeletal muscle structural and regulatory proteins, including sarcomeric myosin heavy chain and MyoD. Despite the presence of such myogenic regulatory proteins, these cells do not terminally differentiate into skeletal muscle. This article focuses on the interesting biology of myofibroblasts, their origin, and the molecular mechanisms that allow these cells to maintain a state intermediate between muscle and nonmuscle cells.

Suppression outside the classical cortical receptive field.

The important visual stimulus parameters for a given cell are defined by the classical receptive field (CRF). However, cells are also influenced by visual stimuli presented in areas surrounding the CRF. The experiments described here were conducted to determine the incidence and nature of CRF surround influences in the primary visual cortex. From extracellular recordings in the cat's striate cortex, we find that for over half of the cells investigated (56%, 153/271), the effect of stimulation in the surround of the CRF is to suppress the neuron's activity by at least 10% compared to the response to a grating presented within the CRF alone. For the remainder of the cells, the interactions were minimal and a few were of a facilitatory nature. In this paper, we focus on the suppressive interactions. Simple and complex cell types exhibit equal incidences of surround suppression. Suppression is observed for cells in all layers, and its degree is strongly correlated between the two eyes for binocular neurons. These results show that surround suppression is a prevalent form of inhibition and may play an important role in visual processing.

Effects of immobilization on plantar-flexion torque, fatigue resistance, and functional ability following an ankle fracture.

BACKGROUND AND PURPOSE: The goal of this investigation was to study the recovery of ankle plantar-flexor peak torque, fatigue resistance, and functional ability (stair climbing, walking) following cast immobilization in patients with ankle fractures. SUBJECTS: The participants were 10 patients who underwent open reduction-internal fixation and 8 weeks of cast immobilization following a fracture of the ankle mortise and 10 age- and sex-matched, noninjured comparison subjects. METHODS: Plantar-flexor torque and fatigue resistance were measured at 1, 5, and 10 weeks of rehabilitation using an isokinetic dynamometer. Ankle plantar-flexor peak torque and fatigue resistance were correlated to timed ambulation, timed stair climbing, and unilateral heel-rises. RESULTS: Following immobilization, plantar-flexor peak torque was decreased at all angular speeds and positions. The decrease in peak torque was associated with an increase in fatigue resistance. With rehabilitation, ankle plantar-flexor torque and fatigue resistance normalized. Regression analysis revealed a strong relationship between plantar-flexor peak torque and functional measures. By 10 weeks post-immobilization, peak torque, fatigue resistance, and all measures of functional performance had returned to control levels. CONCLUSION AND DISCUSSION: The decrease in muscle performance, functional ability, and fatigue resistance induced by 8 weeks of cast immobilization can be reversed with 10 weeks of supervised physical therapy. In addition, this study demonstrated that ankle-plantar flexor torque is a good predictor of stair-climbing and walking performance in patients with ankle fractures.

Asymmetric suppression outside the classical receptive field of the visual cortex.

Areas beyond the classical receptive field (CRF) can modulate responses of the majority of cells in the primary visual cortex of the cat (). Although general characteristics of this phenomenon have been reported previously, little is known about the detailed spatial organization of the surrounds. Previous work suggests that the surrounds may be uniform regions that encircle the CRF or may be limited to the "ends" of the CRF. We have examined the spatial organization of surrounds of single-cell receptive fields in the primary visual cortex of anesthetized, paralyzed cats. The CRF was stimulated with an optimal drifting grating, whereas the surround was probed with a second small grating patch placed at discrete locations around the CRF. For most cells that exhibit suppression, the surrounds are spatially asymmetric, such that the suppression originates from a localized region. We find a variety of suppressive zone locations, but there is a slight bias for suppression to occur at the end zones of the CRF. The spatial pattern of suppression is independent of the parameters of the suppressive stimulus used, although the effect is clearest with iso-oriented surround stimuli. A subset of cells exhibit axially symmetric or uniform surround fields. These results demonstrate that the surrounds are more specific than previously realized, and this specialization has implications for the processing of visual information in the primary visual cortex. One possibility is that these localized surrounds may provide a substrate for figure-ground segmentation of visual scenes.

P13-kinase inhibition induces dauer formation, thermotolerance and longevity in C. elegans.

The effects of 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), an inhibitor of mammalian phosphatidylinositol 3-OH kinase, was tested on an insulin signaling-like pathway in the nematode Caenorhabditis elegans. Populations of C. elegans were treated with LY294002 at different stages of the life cycle, and its effects on development, thermotolerance and longevity were assessed. At concentrations of 160 microM and above, LY294002 significantly induced both dauer formation and thermotolerance. Treatment of adult worms also resulted in a small, but significant, increase in life span. The results presented are consistent with the view that a neuroendocrine signaling pathway functions in adult worms to determine stress resistance and longevity.

A relationship between thermotolerance and longevity in Caenorhabditis elegans.

Studies of aging in the nematode Caenorhabditis elegans have revealed a relationship between stress resistance and the rate of aging: Mutations which extend mean and maximum life-span also confer resistance to thermal stress. We review the molecular genetics of aging in C. elegans and introduce methods for obtaining novel mutants which display altered aging rates. We present the use of the "surrogate" phenotype of thermotolerance to develop a selection for novel mutations which slow aging.

Binocular cross-orientation suppression in the cat's striate cortex.

When a cortical cell is activated by an optimal sinusoidal grating, its response can be attenuated by a superimposed second grating oriented orthogonally to the optimal stimulus. This effect is known as cross-orientation suppression (COS). In previous work, monocular characteristics have been explored and interocular tests have been conducted in an attempt to locate the origin of the suppression. In this study, we have recorded extracellularly from cortical cells to investigate the binocular characteristics of COS. Our hypothesis is that binocular disparity influences the strength of the effect. Our results do not support this supposition. We find that binocular COS is as strong as monocular COS, but disparity changes are of no consequence. We also conducted interocular tests in which the optimal grating and the orthogonal mask were seen by separate eyes. Although most interocular effects were weak, they were present in almost every cell and spanned a wide range of suppression strengths. We also tested the effect of asynchronous presentation of optimal and orthogonal gratings. These temporal offsets did not affect the strength of COS. We conclude that the suppressive mechanism underlying COS is primarily monocular and acts prior to the convergence of the two monocular streams.

Membrane mirror and bias electronics.

We have designed and built an electrostatically deformable membrane mirror with simple bias and driver electronics to evaluate its suitability for a curvature-sensing adaptive optics system. It has a 100-mm-diameter aluminized nitrocellulose membrane, with 31 actuators arranged concentrically. The unit operates at atmospheric pressure with a high bias voltage applied to the membrane. The high-voltage electronics are contained within the mirror housing for safety reasons. An entrance window reduces the effects of air-coupled vibration. Details of the device and design rationale are presented. With a proper bias, the unit can provide low-order (including tip-tilt) wave-front correction.

A meta-analysis of randomized, double-blind, placebo-controlled studies of the effect of buflomedil on intermittent claudication.

A meta-analysis was performed on the results of clinical trials of buflomedil in intermittent claudication. The analysis used results from 744 patients enrolled in ten studies, conducted at 42 centers in seven countries. All studies were randomized, double-blind, placebo-controlled trials which measured improvement in "pain-free" walking distance by treadmill ergometry as the primary measure of efficacy. The meta-analysis results were based on "effect size", a standardized difference in mean response between buflomedil and placebo. Results demonstrated a statistically superior response to buflomedil compared with placebo, indicating that the average buflomedil treated patient was likely to have a greater improvement in walking distance than at least 60% of the placebo treated patients. Results were corroborated using various weighting schemes proportional to study quality ratings and sample sizes.

Identification and characterization of an anti-isoaspartic acid monoclonal antibody.

The deamidation and rearrangement of protein-bound asparagine residues occurs when peptides and proteins are exposed to acidic or alkaline aqueous media. Asn99 of bovine growth hormone (bGH) is readily modified via these mechanisms. We have generated a monoclonal antibody (MAb) that interacts with a bGH fragment that contains an isoaspartyl residue. To obtain this antibody, CAF1/J mice were immunized with [isoaspartyl99]-bGH(96-112) conjugated to BSA. Using a competitive ELISA assay, the interaction of this MAb to [isoaspartyl99]-bGH(96-112) has been observed to have an apparent Km of 150 nM. The corresponding native peptide and other bGH fragments do not bind to this antibody with high affinity. For example, the binding affinities of [Asp99]-bGH(96-112) and [Glu99]-bGH(96-112) to this antibody are 54- and 78-fold lower than the corresponding isoaspartyl peptide. The antibody also binds to bGH that is enriched in isoaspartic acid at position 99, but not to the unmodified protein. The binding epitope of the peptide has been further characterized by comparing the binding of bGH(96-112) analogues to the MAb. Alanine substitution at residues 99, 100, 101, and 103 reduce binding affinity to the antibody by more than 10(3)-fold. Replacement of valine with alanine at position 102 has much less impact on antibody affinity. Further experiments suggest that the relative insensitivity to this substitution is due to the structural similarity of these sidechains. Other isoaspartic acid-containing peptides not derived from the bGH sequence do not bind to the antibody. We conclude that the epitope binding site of this MAb is highly specific for 99-103 of [isoaspartyl99]-bGH (96-112).(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphorus deficiency in a dairy herd.

Phosphorus deficiency was diagnosed in a 90 cow seasonal supply dairy herd which showed low milk production, ill-thrift, infertility and osteophagia. Serum inorganic phosphorus and pasture phosphorus levels were low, pasture Ca:P ratios high and soil phosphorus levels very low; the soil phosphate retention value was 96%. The deficiency, which had probably existed for several years, was considered to be due to inadequate annual phosphate fertiliser applications on a high phosphate retaining soil. Phosphorus deficiency may have been exacerbated by the application of lime without phosphate several months before the onset of severe clinical disease. The finding of low sodium levels in pasture samples suggested that sodium deficiency may have co-existed and contributed to the clinical picture. Treatment, comprising bone flour dusting of pasture, water trough supplementation and phosphorus-containing injections, appeared to induce ovarian activity in anoestrous cows and suppress osteophagia, though controlled treatment trials were not performed. No improvement was noted in milk production or cow condition. Increased annual super-phosphate and reduced potassium applications were recommended, together with the monitoring of pasture and soil macro elements and serum phosphorus levels. A decision on whether to supplement with sodium would be based on the results of pasture monitoring, since a direct animal test is not currently available. It is suggested that phosphorus deficiency may not be uncommon in dairy herds in some North Island districts; based on the present case, the decline in New Zealand superphosphate quality in the 1970's and recently published data which has shown a high proportion of pasture phosphorus deficient sites in some North Island areas.

Determination of potential content of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) in gelatin-coated beadlets, oil-based mixtures, and multivitamin tablet and capsule formulations.

A high-performance liquid chromatographic procedure was used to determine routinely the potential vitamin D content in raw materials and multivitamin formulations. The method employs a microparticulate silica column to separate vitamin D from its degradation products as well as other fat-soluble vitamins. Sample preparation is simple, and the chromatographic time is less than 20 min when progesterone is added to the injection mixture as an internal standard. Replicate analyses of complex multivitamin formulations demonstrate precision with a relative standard deviation of less than 4%. Spiked placebos typically show 98--100% recovery and a linear chromatographic response. The use of bulk drug as a working reference standard is recommended for the determination of the potential vitamin D concentration in pharmaceutical multivitamin preparations.

The psychiatrist-woman patient relationship.

This paper contends that the psychiatrist-woman patient relationship is affected by a number of powerful, yet often subtle, pressures. There are three major interacting sets of factors: the medical and mental health systems and the process of medicalization of life that has taken place over the last century; the psychiatrist, his or her training, attitude and theoretical background; and the woman patient, her socialization and view of the world which is based on perspectives formulated from a male viewpoint. As a result of these factors, any woman referred to a psychiatrist is likely to be given a psychiatric diagnosis, her problems viewed as individual and intrapsychic, the societal obstacles she faces ignored or minimized, and treatment probably geared to helping her adapt to traditional expectations. The implications for therapy are discussed, with emphasis on the need to appreciate how women have been forced into a second-hand understanding of the world. Alternatives to traditional psychotherapy are discussed briefly, stressing the need for recognition and use of these resources.

Dopamine-beta-hydroxylase-induced changes in the electrical conductance of bimolecular lipid membranes.

Dopamine-beta-hydroxylase (DBH), an enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE) in adrenal medullary chromaffin granules, increases the electrical conductance of bimolecular lipid membranes. The conductances increase requires both DA and Ca2+ and occurs in discrete steps. The conductance, which increases as the square of the DBH concentration, is nonselective for cations over anions and requires the native conformation of DBH. NE cannot replace DA.