Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes.

BACKGROUND: The European Pain in Cancer survey sought to increase understanding of cancer-related pain and treatment across Europe. PATIENTS AND METHODS: Patients with all stages of cancer participated in a two-phase telephone survey conducted in 11 European countries and Israel in 2006-2007. The survey screened for patients experiencing pain at least weekly, then randomly selected adult patients with pain of at least moderate intensity occurring several times per week for the last month completed a detailed attitudinal questionnaire. RESULTS: Of 5084 adult patients contacted, 56% suffered moderate-to-severe pain at least monthly. Of 573 patients randomly selected for the second survey phase, 77% were receiving prescription-only analgesics, with 41% taking strong opioids either alone or with other drugs for cancer-related pain. Of those prescribed analgesics, 63% experienced breakthrough pain. In all, 69% reported pain-related difficulties with everyday activities; however, 50% believed that their quality of life was not considered a priority in their overall care by their health care professional. CONCLUSIONS: Across Europe and Israel, treatment of cancer pain is suboptimal. Pain and pain relief should be considered integral to the diagnosis and treatment of cancer; management guidelines should be revised to improve pain control in patients with cancer.

Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling.

Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge.

Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.

Prevalence of untreated asthma in a population sample of 6000 older adults in Bristol, UK.

BACKGROUND: A study was undertaken to estimate the prevalence of untreated asthma in older adults. METHODS: A cross sectional population based survey of 6000 men and women aged 65 years and over was performed in 21 general practices in north Bristol, south west England. The main outcome measure was untreated asthma as defined by a two stage process comprising a respiratory questionnaire (symptoms suggestive of asthma or doctor diagnosed asthma not receiving respiratory treatment) followed by lung function tests (significant reversibility following bronchodilators or corticosteroids and/or significant within day variability in peak expiratory flow). RESULTS: 4792 of the 6000 participants (80%) completed the respiratory questionnaire and, of those not receiving respiratory treatment, 55 reported a previous doctor diagnosis of asthma and a further 696 had symptoms suggestive of asthma. Lung function testing in 280 of 501 randomly selected individuals from these groups resulted in 38 being defined as having asthma and an estimated population prevalence for untreated asthma of 2.4% (95% CI 1.6% to 3.6%) in men and 1.2% (95% CI 0.7% to 2.1%) in women. Most subjects (84%) with untreated asthma had moderate or severe disease. Untreated asthma was most common in individuals with doctor diagnosed asthma (21%) and those with breathlessness or wheeze (13-20%). CONCLUSION: Untreated asthma in the elderly is a common and important problem. Opportunistic use of appropriate lung function tests in older people with a history of doctor diagnosed asthma or wheeze or breathlessness at rest could identify untreated asthmatics who might benefit from treatment.

Illusion processing in hemispatial neglect.

Twelve patients with hemispatial neglect and two control groups were tested to examine the effects of the Müller-Lyer and Judd illusions on bisection behaviour. The studies were designed to investigate whether neglect patients were indeed unaware of the left sides of the illusory figures. In Experiment 1, participants were asked to describe the illusory figures prior to bisection, whereas in Experiment 2, they compared two illusions whose fins, in the critical condition, differed on the left and then performed the bisection. It was found that the illusions worked equally well in all three groups. Interestingly, apart from one exception, almost all neglect patients explicitly reported the left-sided fins in Experiment 1. Only five patients failed to do so but only on an average of 16% of trials. In Experiment 2, six patients made errors in the comparison task but four of these patients did not neglect any left-sided fins in Experiment 1 (with the exception of three overall trials for LC and EdR). This finding seems a good indication that the two tasks differ in their requirements. The comparison task may be perceived as harder as it requires discrimination rather than detection and thus lead to more neglect type errors than the bisection task. In one neglect patient, the illusions consistently failed to work. This patient presented with an occipito-temporal and basal ganglia lesion and the mechanisms responsible for the processing of simple visual features might have possibly been impaired in her case.

Is grasping impaired in hemispatial neglect?

Patients with right unilateral cerebral stroke, four of which showed acute hemispatial neglect, and healthy aged-matched controls were tested for their ability to grasp objects located in either right or left space at near or far distances. Reaches were performed either in free vision or without visual feedback from the hand or target object. It was found that the patient group showed normal grasp kinematics with respect to maximum grip aperture, grip orientation, and the time taken to reach the maximum grip aperture. Analysis of hand path curvature showed that control subjects produced straighter right hand reaches when vision was available compared to when it was not. The right hemisphere lesioned patients, however, showed similar levels of curvature in each of these conditions. No behavioural differences, though, could be found between right hemisphere lesioned patients with or without hemispatial neglect on either grasp parameters, path deviation or temporal kinematics.

Structural studies of the high mobility group globular domain and basic tail of HMG-D bound to disulfide cross-linked DNA.

HMG-D is an abundant high mobility group chromosomal protein present during early embryogenesis in Drosophila melanogaster. It is a non-sequence-specific member of a protein family that uses the HMG domain for binding to DNA in the minor groove. The highly charged C-terminal tail of HMG-D contains AK motifs that contribute to high-affinity non-sequence-specific DNA binding. To understand the interactions of the HMG domain and C-terminal tail of HMG-D with DNA in solution, a complex between a high-affinity truncated form of the protein and a disulfide cross-linked DNA fragment was studied using heteronuclear NMR techniques. Despite its relatively high affinity for the single "prebent" site on the DNA, K(d) = 1.4 nM, HMG-D forms a non-sequence-specific complex with the DNA as indicated by exchange broadening of the protein resonances at the DNA interface in solution. The secondary structural elements of the protein are preserved when the protein is complexed with the DNA, and the DNA-binding interface maps to the regions of the protein where the largest chemical shift differences occur. The C-terminal tail of HMG-D confers high-affinity DNA binding, has an undefined structure, and appears to make direct contacts in the major groove of DNA via residues that are potentially regulated by phosphorylation. We conclude that while the HMG domain of HMG-D recognizes DNA with a mode of binding similar to that used by the sequence-specific HMG domain transcription factors, there are noteworthy differences in the structure and interactions of the C-terminal end of the DNA-binding domain and the C-terminal tail.

Analysis of HIV type 1 protease and reverse transcriptase in antiretroviral drug-naive Ugandan adults.

We analyzed plasma HIV-1 from 27 antiretroviral drug-naive Ugandan adults. Previous subtype analysis of env and gag sequences from these samples identified subtypes A, C, D, and recombinant HIV-1. Sequences of HIV-1 protease and reverse transcriptase (RT) were obtained with a commercial HIV-1 genotyping system. Subtypes based on protease sequences differed from gag subtypes for 5 of 27 samples, demonstrating a high rate of recombination between the gag and pol regions. Protease and RT sequences were analyzed for the presence of amino acid polymorphisms at positions that are sites of previously characterized drug resistance mutations. At those sites, frequent polymorphisms were detected at positions 36 and 69 in protease and positions 179, 211, and 214 in RT. Subtype-specific amino acid motifs were identified in protease. Most of the subtype A sequences had the amino acids DKKM at positions 35, 57, 69, and 89, whereas most subtype D sequences had the amino acids ERHL at those positions. Detection of those polymorphisms may provide a useful approach for rapid identification of subtype A and D isolates in Uganda. This analysis significantly increases the number of Ugandan protease and RT sequences characterized to date and demonstrates successful use of a commercial HIV-1 genotyping system for analysis of diverse non-B HIV-1 subtypes.

The coordination of bimanual prehension movements in a centrally deafferented patient.

Many everyday tasks require that we use our hands co-operatively, for example, when unscrewing a jar. For tasks where both hands are required to perform the same action, a common motor programme can be used. However, where each hand needs to perform a different action, some degree of independent control of each hand is required. We examined the coordination of bimanual movement kinematics in a female patient recovering from a cerebrovascular accident involving anterior regions of the parietal lobe of the right hemisphere, which resulted in a dense hemianaesthesia of her left arm. Our results indicate that unimanual movements executed by our patient using her non-sensate hand are relatively unimpaired. In contrast, during bimanual movements, reaches executed by our patient using her non-sensate hand show gross directional errors and spatiotemporal irregularities, including the inappropriate coupling of movement velocities. These data are discussed with reference to the role played by limb proprioception in the planning and control of prehension movements.

Respiratory symptoms in older people and use of domestic gas appliances.

BACKGROUND: Studies in children and young women have indicated an increased risk of respiratory illness in association with the use of domestic gas appliances, possibly caused by oxides of nitrogen generated when gas is burned. It is not known whether risks are similarly increased in older subjects. METHODS: A questionnaire about respiratory symptoms in the past year and potential risk factors for respiratory disease was mailed to 6000 men and women aged 65 years and older who were selected at random from the lists of general practices in North Bristol, UK. Associations between symptoms and the use of gas appliances were examined by logistic regression with adjustment for age, sex, social class, and smoking habits. RESULTS: Questionnaires were completed by 4792 (80%) of those mailed. The most common symptoms were exercise induced breathlessness, wheeze, or chest tightness (51%); wheeze (27%); morning phlegm (20%); and daytime breathlessness at rest (19%). In an analysis that included all subjects only weak associations were found with use of gas appliances, odds ratios all being 1.2 or less. The risks associated with use of a gas hob tended to be higher in women, with odds ratios of 1.36 (95% CI 1.01 to 1.83) for wheeze and 1.33 (95% CI 0.56 to 3.17) for morning chest tightness, but were lower than had been reported previously in younger women. CONCLUSION: The absence of stronger associations cannot readily be explained by bias or confounding. Gas cookers and fires are unlikely to be an important cause of respiratory illness in the elderly. If they do cause such illness, the largest risks are likely to be in women who use gas hobs.

Co-crystallization and preliminary crystallographic analysis of the high mobility group domain of HMG-D bound to DNA.

Structural studies are essential to understand mechanisms of non-sequence-specific DNA binding used by chromosomal proteins. A non-histone high-mobility group (HMG) chromosomal protein from Drosophila melanogaster, HMG-D, binds duplex DNA in a non-sequence-specific fashion. The DNA-binding domain of HMG-D has been co-crystallized with a duplex DNA fragment in the primitive orthorhombic space group P2(1)2(1)2(1), with unit-cell dimensions a = 43.74, b = 53.80, c = 86.84 A. Data have been collected to 2.20 A at 99 K, with diffraction observed to at least 2.0 A. Heavy-atom derivative crystals have been obtained by co-crystallization with oligonucleotides halogenated at major-groove positions near the end of the DNA.

An outbreak of viral gastroenteritis associated with consumption of sandwiches: implications for the control of transmission by food handlers.

Although food handlers are often implicated as the source of infection in outbreaks of food-borne viral gastroenteritis, little is known about the timing of infectivity in relation to illness. We investigated a gastroenteritis outbreak among employees of a manufacturing company and found an association (RR = 14.1, 95% CI = 2.0-97.3) between disease and eating sandwiches prepared by 6 food handlers, 1 of whom reported gastroenteritis which had subsided 4 days earlier. Norwalk-like viruses were detected by electron microscopy or reverse transcriptase-polymerase chain reaction (RT-PCR) in stool specimens from several company employees, the sick food handler whose specimen was obtained 10 days after resolution of illness, and an asymptomatic food handler. All RT-PCR product sequences were identical, suggesting a common source of infection. These data support observations from recent volunteer studies that current recommendations to exclude food handlers from work for 48-72 h after recovery from illness may not always prevent transmission of Norwalk-like viruses because virus can be shed up to 10 days after illness or while exhibiting no symptoms.

Asthma in older people.

From the clinical perspective, asthma in the older patient may be difficult to diagnose because of the non-specificity of presentation and the wide range of differential diagnoses. Prior to confirmation of asthma in the older patient, both respiratory and cardiac investigation may be necessary. Polypharmacy is inherent in treating older people and accurate drug histories are essential in order to identify patients with drug-induced bronchospasm and avoid interactions with asthma medication. Patient and carer education is vital, and a structured approach to follow-up which includes measurement of lung function and assessment of inhaler technique should be carried out in every asthmatic regardless of age. Finally, there is a great need for health services and those in the commercial sector that are involved in asthma care to ensure that future research and development rises to the challenge of an ageing population.

Oxidation of a critical methionine modulates DNA binding of the Drosophila melanogaster high mobility group protein, HMG-D.

HMG-D is a major high mobility group chromosomal protein present during early embryogenesis in Drosophila melanogaster. During overexpression and purification of HMG-D from E. coli, a key DNA binding residue, methionine 13, undergoes oxidation to methionine sulfoxide. Oxidation of this critical residue decreases the affinity of HMG-D for DNA by three-fold, altering the structure of the HMG-D-DNA complex without affecting the structure of the free protein. This work shows that minor modification of DNA intercalating residues may be used to fine tune the DNA binding affinity of HMG domain proteins.