The knowledge, attitudes and beliefs of patients and their healthcare professionals around oral dosage form modification: a systematic review of the qualitative literature

Objectives: The objective of this systematic review was to synthesize the available qualitative evidence on the knowledge, attitudes and beliefs of adult patients, healthcare professionals and carers about oral dosage form modification. Design: A systematic review and synthesis of qualitative studies was undertaken, utilising the thematic synthesis approach. Data sources: The following databases were searched from inception to September 2015: PubMed, Medline (EBSCO), EMBASE, CINAHL, PsycINFO, Web of Science, ProQuest Databases, Scopus, Turning Research Into Practice (TRIP), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR). Citation tracking and searching the references lists of included studies was also undertaken. Grey literature was searched using the OpenGrey database, internet searching and personal knowledge. An updated search was undertaken in June 2016. Review methods: Studies meeting the following criteria were eligible for inclusion; (i) used qualitative data collection and analysis methods; (ii) full-text was available in English; (iii) included adult patients who require oral dosage forms to be modified to meet their needs or; (iv) carers or healthcare professionals of patients who require oral dosage forms to be modified. Two reviewers independently appraised the quality of the included studies using the Critical Appraisal Skills Programme Checklist. A thematic synthesis was conducted and analytical themes were generated. Results: Of 5455 records screened, seven studies were eligible for inclusion; three involved healthcare professionals and the remaining four studies involved patients. Four analytical themes emerged from the thematic synthesis: (i) patient-centred individuality and variability; (ii) communication; (iii) knowledge and uncertainty and; (iv) complexity. The variability of individual patient’s requirements, poor communication practices and lack of knowledge about oral dosage form modification, when combined with the complex and multi-faceted healthcare environment complicate decision making regarding oral dosage form modification and administration. Conclusions: This systematic review has highlighted the key factors influencing the knowledge, attitudes and beliefs of patients and healthcare professionals about oral dosage form modifications. The findings suggest that in order to optimise oral medicine modification practices the needs of individual patients should be routinely and systematically assessed and decision-making should be supported by evidence based recommendations with multidisciplinary input. Further research is needed to optimise oral dosage form modification practices and the factors identified in this review should be considered in the development of future interventions.

MECHANISMS AND EFFECTS OF MITOCHONDRIAL DNA INSTABILITY AND COPY NUMBER MANIPULATION

Defects in mitochondrial DNA (mtDNA) maintenance cause a range of human diseases, including autosomal dominant progressive external ophthalmoplegia (adPEO). This study aimed to clarify the molecular background of adPEO. We discovered that deoxynucleoside triphosphate (dNTP) metabolism plays a crucial in mtDNA maintenance and were thus prompted to search for therapeutic strategies based on the modulation of cellular dNTP pools or mtDNA copy number. Human mtDNA is a 16.6 kb circular molecule present in hundreds to thousands of copies per cell. mtDNA is compacted into nucleoprotein clusters called nucleoids. mtDNA maintenance diseases result from defects in nuclear encoded proteins that maintain the mtDNA. These syndromes typically afflict highly differentiated, post-mitotic tissues such as muscle and nerve, but virtually any organ can be affected. adPEO is a disease where mtDNA molecules with large-scale deletions accumulate in patients tissues, particularly in skeletal muscle. Mutations in five nuclear genes, encoding the proteins ANT1, Twinkle, POLG, POLG2 and OPA1, have previously been shown to cause adPEO. Here, we studied a large North American pedigree with adPEO, and identified a novel heterozygous mutation in the gene RRM2B, which encodes the p53R2 subunit of the enzyme ribonucleotide reductase (RNR). RNR is the rate-limiting enzyme in dNTP biosynthesis, and is required both for nuclear and mitochondrial DNA replication. The mutation results in the expression of a truncated form of p53R2, which is likely to compete with the wild-type allele. A change in enzyme function leads to defective mtDNA replication due to altered dNTP pools. Therefore, RRM2B is a novel adPEO disease gene. The importance of adequate dNTP pools and RNR function for mtDNA maintenance has been established in many organisms. In yeast, induction of RNR has previously been shown to increase mtDNA copy number, and to rescue the phenotype caused by mutations in the yeast mtDNA polymerase. To further study the role of RNR in mammalian mtDNA maintenance, we used mice that broadly overexpress the RNR subunits Rrm1, Rrm2 or p53R2. Active RNR is a heterotetramer consisting of two large subunits (Rrm1) and two small subunits (either Rrm2 or p53R2). We also created bitransgenic mice that overexpress Rrm1 together with either Rrm2 or p53R2. In contrast to the previous findings in yeast, bitransgenic RNR overexpression led to mtDNA depletion in mouse skeletal muscle, without mtDNA deletions or point mutations. The mtDNA depletion was associated with imbalanced dNTP pools. Furthermore, the mRNA expression levels of Rrm1 and p53R2 were found to correlate with mtDNA copy number in two independent mouse models, suggesting nuclear-mitochondrial cross talk with regard to mtDNA copy number. We conclude that tight regulation of RNR is needed to prevent harmful alterations in the dNTP pool balance, which can lead to disordered mtDNA maintenance. Increasing the copy number of wild-type mtDNA has been suggested as a strategy for treating PEO and other mitochondrial diseases. Only two proteins are known to cause a robust increase in mtDNA copy number when overexpressed in mice; the mitochondrial transcription factor A (TFAM), and the mitochondrial replicative helicase Twinkle. We studied the mechanisms by which Twinkle and TFAM elevate mtDNA levels, and showed that Twinkle specifically implements mtDNA synthesis. Furthermore, both Twinkle and TFAM were found to increase mtDNA content per nucleoid. Increased mtDNA content in mouse tissues correlated with an age-related accumulation of mtDNA deletions, depletion of mitochondrial transcripts, and progressive respiratory dysfunction. Simultaneous overexpression of Twinkle and TFAM led to a further increase in the mtDNA content of nucleoids, and aggravated the respiratory deficiency. These results suggested that high mtDNA levels have detrimental long-term effects in mice. These data have to be considered when developing and evaluating treatment strategies for elevating mtDNA copy number.

Molecular Medicine and Molecular Pathology for Hematologists:II. Lets go Techno; Principles of the Molecular Technologies and their Applications in Haematology

Molecular techniques have a key role to play in laboratory and clinical haematology. Restriction enzymes allow nucleic acids to be reduced in size for subsequent analysis. In addition they allow selection of specific DNA or RNA sequences for cloning into bacterial plasmids. These plasmids are naturally occuring DNA molecules which reside in bacterial cells. They can be manipulated to act as vehicles or carriers for biologically and medically important genes, allowing the production of large amounts of cloned material for research purposes or to aid in the production of medically important recombinant molecules such as insulin. As acquired or inherited genetic changes are implicated in a wide range of haematological diseases, it is necessary to have highly specific and sensitive assays to detect these mutations. Most of these techniques rely on nucleic acid hybridisation, benefitting from the ability of DNA or RNA to bind tighly to complimentary bases in the nucleic acid structure. Production of artificial DNA molecules called probes permits nucleic acid hybridiation assays to be performed, using the techniques of southern blotting or dot blot analysis. In addition the base composition of any gene or region of DNA can be determined using DNA sequencing technology. The advent of the polymerase chain reaction (PCR) has revolutionised all aspects of medicine, but has particular relevance in haematology where easy access to biopsy material provides a wealth of material for analysis. PCR permits quick and reliable manipulation of sample material and its ability to be automated makes it an ideal tool for use in the haematology laboratory.

Manipulation of Rest Period Length Induces Different Causes of Fatigue in Vertical Jumping

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Manipulation effects of prior exercise intensity feedback by the Borg scale during open-loop cycling

Objective To verify the effects of exercise intensity deception by the Borg scale on the ratings of perceived exertion (RPE), heart rate (HR) and performance responses during a constant power output open-loop exercise. Methods Eight healthy men underwent a maximal incremental test on a cycle ergometer to identify the peak power output (PPO) and heart rate deflection point (HRDP). Subsequently, they performed a constant power output trial to exhaustion set at the HRDP intensity, in deception (DEC) and informed (INF) conditions: DEC-subjects were told that they would be cycling at an intensity corresponding to two categories below the RPE quantified at the HRDP; INF-subjects were told that they would cycle at the exact intensity corresponding to the RPE quantified at the HRDP. Results The PPO and power output at the HRDP obtained in maximal incremental tests were 247.5 +/- 32.1 W and 208.1 +/- 27.1 W, respectively. No significant difference in the time to exhaustion was found between DEC (525 +/- 244 s) or INF (499 +/- 224 s) trials. The slope and the first and second measurements of the RPE and HR parameters showed no significant difference between trials. Conclusions Psychophysiological variables such as RPE and HR as well as performance were not affected when exercise intensity was deceptively manipulated via RPE scores. This may suggest that unaltered RPE during exercise is a regulator of performance in this open-loop exercise.

Assessment of using digital manipulation tools for diagnosing mandibular radiolucent lesions

Objective: The purpose of this study was to analyse the use of digital tools for image enhancement of mandibular radiolucent lesions and the effects of this manipulation on the percentage of correct radiographic diagnoses. Methods: 24 panoramic radiographs exhibiting radiolucent lesions were selected, digitized and evaluated by non-experts (undergraduate and newly graduated practitioners) and by professional experts in oral diagnosis. The percentages of correct and incorrect diagnoses, according to the use of brightness/contrast, sharpness, inversion, highlight and zoom tools, were compared. All dental professionals made their evaluations without (T-1) and with (T-2) a list of radiographic diagnostic parameters. Results: Digital tools were used with low frequency mainly in T-2. The most preferred tool was sharpness (45.2%). In the expert group, the percentage of correct diagnoses did not change when any of the digital tools were used. For the non-expert group, there was an increase in the frequency of correct diagnoses when brightness/contrast was used in T-2 (p = 0.008) and when brightness/contrast and sharpness were not used in T-1 (p = 0.027). The use or non-use of brightness/contrast, zoom and sharpness showed moderate agreement in the group of experts [kappa agreement coefficient (kappa) = 0.514, 0.425 and 0.335, respectively]. For the non-expert group there was slight agreement for all the tools used (kappa <= 0.237). Conclusions: Consulting the list of radiographic parameters before image manipulation reduced the frequency of tool use in both groups of examiners. Consulting the radiographic parameters with the use of some digital tools was important for improving correct diagnosis only in the group of non-expert examiners. Dentomaxillofacial Radiology (2012) 41, 203-210. doi: 10.1259/dmfr/78567773

Neural networks engaged in tactile object manipulation: patterns of expression among healthy individuals

Somatosensory object discrimination has been shown to involve widespread cortical and subcortical structures in both cerebral hemispheres. In this study we aimed to identify the networks involved in tactile object manipulation by principal component analysis (PCA) of individual subjects. We expected to find more than one network.