The changing nature of risk and risk management: the challenge of borders, uncertainty and resilience

No abstract available

Neural processing of criticism and positive comments from relatives in individuals with schizotypal personality traits

Objectives. High negative expressed emotion by family members towards schizophrenia patients increases the risk of subsequent relapse. The study aimed to determine whether individuals with high schizotypy (HS) and low schizotypy (LS) would differ in activation of brain areas involved in cognitive control when listening to relative criticism

Molecular monitoring of Plasmodium falciparum resistance to artemisinin in Tanzania

Artemisinin-based combination therapies (ACTs) are recommended for use against uncomplicated malaria in areas of multi-drug resistant malaria, such as sub-Saharan Africa. However, their long-term usefulness in these high transmission areas remains unclear. It has been suggested that documentation of the S769N PfATPase6 mutations may indicate an emergence of artemisinin resistance of Plasmodium falciparum in the field. The present study assessed PfATPase6 mutations (S769N and A623E) in 615 asymptomatic P. falciparum infections in Tanzania but no mutant genotype was detected. This observation suggests that resistance to artemisinin has not yet been selected in Tanzania, supporting the Ministry of Health's decision to adopt artemether+lumefantrine as first-line malaria treatment. The findings recommend further studies to assess PfATPase6 mutations in sentinel sites and verify their usefulness in monitoring emergency of ACT resistance

Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors.

BACKGROUND: Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach. METHODS: Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings. RESULTS: HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors. CONCLUSION: These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV negative disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT and mTOR inhibitors in HNSCC

Family resources study: part 1: family resources, family function and caregiver strain in childhood cancer

<p>Abstract</p> <p>Background</p> <p>Severe illness can disrupt family life, cause family dysfunction, strain resources, and cause caregiver burden. The family's ability to cope with crises depends on their resources. This study sought to assess families of children with cancer in terms of family function-dysfunction, family caregiver strain and the adequacy of family resources using a new family resources assessment instrument.</p> <p>Methods</p> <p>This is a cross-sectional study involving 90 Filipino family caregivers of children undergoing cancer treatment. This used a self-administered questionnaire composed of a new 12-item family resources questionnaire (SCREEM-RES) based on the SCREEM method of analysis, Family APGAR to assess family function-dysfunction; and Modified Caregiver Strain Index to assess strain in caring for the patient.</p> <p>Results</p> <p>More than half of families were either moderately or severely dysfunctional. Close to half of caregivers were either predisposed to strain or experienced severe strain, majority disclosed that their families have inadequate economic resources; many also report inaccessibility to medical help in the community and insufficient educational resources to understand and care for their patients. Resources most often reported as adequate were: family's faith and religion; help from within the family and from health providers. SCREEM-RES showed to be reliable with Cronbach's alpha of 0.80. There is good inter-item correlation between items in each domain: 0.24-0.70. Internal consistency reliability for each domain was also good: 0.40-0.92. Using 2-point scoring system, Cronbach's alpha were slightly lower: full scale (0.70) and for each domain 0.26-.82. Results showed evidence of association between family resources and family function based on the family APGAR but none between family resources and caregiver strain and between family function and caregiver strain.</p> <p>Conclusion</p> <p>Many Filipino families of children with cancer have inadequate resources, especially economic; and are moderately or severely dysfunctional. Many caregivers are predisposed to caregiver strain or are already experiencing severe strain. To provide appropriate care for these families, physicians should regularly assess family function, resources and strain experienced by caregivers. The SCREEM-RES questionnaire used in this study is a helpful and reliable instrument to assess adequacy of family resources.</p

Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens

Neural Correlate of Filtering of Irrelevant Information from Visual Working Memory

In a dynamic environment stimulus task relevancy could be altered through time and it is not always possible to dissociate relevant and irrelevant objects from the very first moment they come to our sight. In such conditions, subjects need to retain maximum possible information in their WM until it is clear which items should be eliminated from WM to free attention and memory resources. Here, we examined the neural basis of irrelevant information filtering from WM by recording human ERP during a visual change detection task in which the stimulus irrelevancy was revealed in a later stage of the task forcing the subjects to keep all of the information in WM until test object set was presented. Assessing subjects' behaviour we found that subjects' RT was highly correlated with the number of irrelevant objects and not the relevant one, pointing to the notion that filtering, and not selection, process was used to handle the distracting effect of irrelevant objects. In addition we found that frontal N150 and parietal N200 peak latencies increased systematically as the amount of irrelevancy load increased. Interestingly, the peak latency of parietal N200, and not frontal N150, better correlated with subjects' RT. The difference between frontal N150 and parietal N200 peak latencies varied with the amount of irrelevancy load suggesting that functional connectivity between modules underlying fronto-parietal potentials vary concomitant with the irrelevancy load. These findings suggest the existence of two neural modules, responsible for irrelevant objects elimination, whose activity latency and functional connectivity depend on the number of irrelevant object

Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

Inappropriate use of the title 'chiropractor' and term 'chiropractic manipulation' in the peer-reviewed biomedical literature

BACKGROUND: The misuse of the title 'chiropractor' and term 'chiropractic manipulation', in relation to injury associated with cervical spine manipulation, have previously been reported in the peer-reviewed literature. The objectives of this study were to - 1) Prospectively monitor the peer-reviewed literature for papers reporting an association between chiropractic, or chiropractic manipulation, and injury; 2) Contact lead authors of papers that report such an association in order to determine the basis upon which the title 'chiropractor' and/or term 'chiropractic manipulation' was used; 3) Document the outcome of submission of letters to the editors of journals wherein the title 'chiropractor', and/or term 'chiropractic manipulation', had been misused and resulted in the over-reporting of chiropractic induced injury. METHODS: One electronic database (PubMed) was monitored prospectively, via monthly PubMed searches, during a 12 month period (June 2003 to May 2004). Once relevant papers were located, they were reviewed. If the qualifications and/or profession of the care provider/s were not apparent, an attempt was made to confirm them via direct e-mail communication with the principal researcher of each respective paper. A letter was then sent to the editor of each involved journal. RESULTS: A total of twenty four different cases, spread across six separate publications, were located via the monthly PubMed searches. All twenty four cases took place in one of two European countries. The six publications consisted of four case reports, each containing one patient, one case series, involving twenty relevant cases, and a secondary report that pertained to one of the four case reports. In each of the six publications the authors suggest the care provider was a chiropractor and that each patient received chiropractic manipulation of the cervical spine prior to developing symptoms suggestive of traumatic injury. In two of the four case reports contact with the principal researcher revealed that the care provider was not a chiropractor, as defined by the World Federation of Chiropractic. The authors of the other two case reports did not respond to my communications. In the case series, which involved twenty relevant cases, the principal researcher conceded that the term chiropractor had been inappropriately used and that his case series did not relate to chiropractors who had undergone appropriate formal training. The author of the secondary report, a British Medical Journal editor, conceded that he had misused the title chiropractor. Letters to editors were accepted and published by all four journals to which they were sent. To date one of the four journals has published a correction. CONCLUSION: The results of this year-long prospective review suggests that the words 'chiropractor' and 'chiropractic manipulation' are often used inappropriately by European biomedical researchers when reporting apparent associations between cervical spine manipulation and symptoms suggestive of traumatic injury. Furthermore, in those cases reported here, the spurious use of terminology seems to have passed through the peer-review process without correction. Additionally, these findings provide further preliminary evidence, beyond that already provided by Terrett, that the inappropriate use of the title 'chiropractor' and term 'chiropractic manipulation' may be a significant source of over-reporting of the link between the care provided by chiropractors and injury. Finally, editors of peer-reviewed journals were amenable to publishing 'letters to editors', and to a lesser extent 'corrections', when authors had inappropriately used the title 'chiropractor' and/or term 'chiropractic manipulation'