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Introduction: Using risk stratification to determine eligibility for cancer screening is likely to improve the efficiency of screening programmes by targeting resources towards those most likely to benefit. We aimed to explore the implications of this approach from a societal perspective by understanding public views on the most acceptable stratification strategies. Methods: We conducted three online community juries with 9 or 10 participants in each. Participants were purposefully sampled by age (40–79 years), sex, ethnicity, social grade and English region. On the first day, participants were informed of the potential benefits and harms of cancer screening and the implications of different ways of introducing stratification using scenarios based on phenotypic and genetic risk scores. On the second day, participants deliberated to reach a verdict on the research question, ‘Which approach(es) to inviting people to screening are acceptable, and under what circumstances?’ Deliberations and feedback were recorded and analysed using thematic analysis. Results: Across the juries, the principle of risk stratification was generally considered to be an acceptable approach for determining eligibility for screening. Disregarding increasing capacity, the participants considered it to enable efficient resource allocation to high‐risk individuals and could see how it might help to save lives. However, there were concerns regarding fair implementation, particularly how the risk assessment would be performed at scale and how people at low risk would be managed. Some favoured using the most accurate risk prediction model whereas others thought that certain risk factors should be prioritized (particularly factors considered as non‐modifiable and relatively stable, such as genetics and family history). Transparently justifying the programme and public education about cancer risk emerged as important contributors to acceptability. Conclusion: Using risk stratification to determine eligibility for cancer screening was acceptable to informed members of the public, particularly if it included risk factors they considered fair and when communicated transparently. Patient or Public Contribution: Two patient and public involvement representatives were involved throughout this study. They were not involved in synthesizing the results but contributed to producing study materials, co‐facilitated the community juries and commented on the interpretation of the findings and final report.

Cancer screening programmes aim to save lives and reduce cancer burden through prevention or early detection of specific cancers. Risk stratification, where one or more elements of a screening programme are systematically tailored based on multiple individual-level risk factors, could improve the balance of screening benefits and harms and programme efficiency. In this article, we explore the resulting ethical issues and how they impact risk-stratified screening policymaking using Beauchamp and Childress's principles of medical ethics. First, in line with universal screening programme principles, we acknowledge that risk-stratified screening should be introduced only when the expected total benefits outweigh the harms, and where it has a favourable overall impact compared to alternative options. We then discuss how these are difficult to both value and quantify, and that risk models typically perform differently in sub-populations. Second, we consider whether screening is an individual right and whether it is fair to offer more or less intensive screening to some and not others based on personal characteristics. Third, we discuss the need to maintain respect for autonomy, including ensuring informed consent and considering the screening implications for those who cannot or choose not to participate in the risk assessment. In summary, from an ethical perspective, focusing on population-level effectiveness alone is insufficient when planning risk-stratified screening programmes and the range of ethical principles must be considered.

Lockdown measures in response to the COVID-19 pandemic involve placing huge burdens on some members of society for the sake of benefiting other members of society. How should we decide when these policies are permissible? Many writers propose we should address this question using cost-benefit analysis (CBA), a broadly consequentialist approach. We argue for an alternative non-consequentialist approach, grounded in contractualist moral theorising. The first section sets up key issues in the ethics of lockdown, and sketches the apparent appeal of addressing these problems in a CBA frame. The second section argues that CBA fundamentally distorts the normative landscape in two ways: first, in principle, it allows very many morally trivial preferences—say, for a coffee—might outweigh morally weighty life-and-death concerns; second, it is insensitive to the core moral distinction between victims and vectors of disease. The third section sketches our non-consequentialist alternative, grounded in Thomas Scanlon’s contractualist moral theory. On this account, the ethics of self-defence implies a strong default presumption in favour of a highly restrictive, universal lockdown policy: we then ask whether there are alternatives to such a policy which are justifiable to all affected parties, paying particular attention to the complaints of those most burdened by policy. In the fourth section, we defend our contractualist approach against the charge that it is impractical or counterintuitive, noting that actual CBAs face similar, or worse, challenges.

Public health policy often involves a trade-off between promoting population health and protecting the interests of identifiable individuals. This paper analyses this trade-off as it arises in the context of decisions about the vaccination of children against Covid-19, where vaccination may be in the interests of society as a whole, as a means to stopping transmission, but not in the interests of individual children. The paper argues that the UK's Joint Committee on Vaccination and Immunisation resolved this tension by appeal to a version of a non-maleficence principle. It argues that, while this principle can be a useful guide to some public health policy decision-making, it is inappropriate in the case of vaccination.

IntroductionAfrica has one of the world's highest populations of young people. In addition, Africa has one of the highest proportions of young people facing the worst health challenges. Although previous scholars have reported that young people were using mobile phones to fill in the gaps in accessing reproductive health services, among other health services, there was little comprehensive research on the perception of young people in Tamale, Ghana, on the use of mobile phones to access reproductive health services. This study analyzed the perceptions on mobile phone use to access reproductive health services among young people in Tamale, Ghana.MethodsThe research used a quantitative method design from a target population of 72,706 young people from selected peri-urban, low-income, middle income and high-income residential areas in Tamale Metropolis, Ghana. The sample size used was 397 young people. Participants were selected using a stratified multistage sampling strategy. Descriptive statistics were used to analyse the data.ResultsA total of 86% of the respondents agree that the use of mobile phones helps to overcome cultural challenges that young people in Tamale encounter in accessing reproductive health care. Also, 84.6% of the respondents agree that the use of mobile phones helps them to overcome inadequate access to reproductive health information and services. The use of mobile phones helps to overcome the negative attitude of health providers toward young people in need of reproductive health services was agreed by most of the respondents [strongly agree (35.4%) and agree (49.4%)].ConclusionThis study informed highly positive perceptions and attitudes toward the use of mobile phones to access Reproductive Health Services in Tamale, Ghana. There is, therefore the need for the health sector to reform its mode of prescriptions of medication, consultation, and service delivery to leverage on the advantages that mHealth presents.

Cyclobutane pyrimidine dimers (CPDs) are the major products of DNA produced by direct absorption of UV light, and result in C to T mutations linked to human skin cancers. Most recently a new pathway to CPDs in melanocytes has been discovered that has been proposed to arise from a chemisensitized pathway involving a triplet sensitizer that increases mutagenesis by increasing the percentage of C-containing CPDs. To investigate how triplet sensitization may differ from direct UV irradiation, CPD formation was quantified in a 129-mer DNA designed to contain all 64 possible NYYN sequences. CPD formation with UVB light varied about 2-fold between dipyrimidines and 12-fold with flanking sequence and was most frequent at YYYR and least frequent for GYYN sites in accord with a charge transfer quenching mechanism. In contrast, photosensitized CPD formation greatly favored TT over C-containing sites, more so for norfloxacin (NFX) than acetone, in accord with their differing triplet energies. While the sequence dependence for photosensitized TT CPD formation was similar to UVB light, there were significant differences, especially between NFX and acetone that could be largely explained by the ability of NFX to intercalate into DNA., Graphical Abstract Graphical AbstractBy using a sequence designed to contain all possible NYYN sites, the effect of the dipyrimidine and its flanking sequence, as well as wavelength, and sensitizer on the relative frequency of cyclobutane pyrimidine dimer formation was revealed.

Background: Tricuspid annuloplasty is the most common surgical approach to correct tricuspid regurgitation (TR). In some patients, however, anterior leaflet patch augmentation may be necessary to optimize tricuspid competence. We reviewed our center cohort over the midterm and long term. Methods: From January 2013 to August 2018, 424 tricuspid valve procedures were performed, of which 420 were repairs and 4 were replacements. Indications were either isolated severe TR or moderate or greater TR, concomitant with other surgery. In the repair cohort, we identified those that had a patch augmentation, and the database was interrogated for preoperative characteristics. The resulting patients had outpatient assessment (clinical and echocardiography) at 6 weeks and at a later interval. Additionally, a comparison was made between those who had good and poor results (moderate or greater TR or cardiac death). Results: In the repair cohort, 19 patients underwent complex tricuspid valve repair with CorMatrix anterior leaflet augmentation. Preoperative characteristics were as follows: age, 65.5 ± 13.5 years; New York Heart Association (NYHA) class, 3.5 ± 0.5; left ventricular ejection fraction, 48.3% ± 5.9%; tricuspid annular plane systolic excursion, 17.1 ± 3.7 mm; right ventricle (good, mild, moderate, poor), 10, 5, 4, 0; annulus size, 40.9 ± 6.9 mm; mean tethering distance, 1.00 ± 0.3 cm; and mean tethering area, 1.53 ± 1.16 cm2. Mean follow-up was 2.1 ± 1.9 years, and survival at 2 years was 73.8%. There were 2 in-hospital deaths. Mean NYHA class was 1.0 ± 0.5 (6 weeks) and 1.5 ± 0.6 (later follow-up); mean residual TR grade was 0.5 ± 0.6 (6 weeks) and 1.3 ± 1.4 (follow-up). Ten of 13 survivors had a good result at last follow-up (TR 0 to 1). We compared the preoperative and operative data of this group versus those with poor results (TR >1 or cardiac mortality). Significant univariate predictors of poor results were larger preoperative tethering area (1.18 ± 0.43 versus 2.4 ± 1.5 cm2; P = .02), longer tethering distance (0.87 ± 0.21 versus 1.2 ± 0.19 cm; P = .007), or the presence of mild or greater TR at 6 weeks (0.2 ± 0.4 vs 1.25 ± 0.5; P = .03). Conclusions: CorMatrix anterior leaflet augmentation produces successful, stable repair in the majority of this complex population. The presence of even mild TR at 6 weeks’ follow-up predicts a poor result. When the tethering area or the tethering distance is significantly high, replacement is probably a better option.

Summary Background The WHO VISION 2020 global initiative against blindness, launched in 2000, prioritised childhood visual disability by aiming to end avoidable childhood blindness by 2020. However, progress has been hampered by the global paucity of epidemiological data concerning childhood visual disability. The British Childhood Visual Impairment and Blindness Study 2 (BCVIS2) was done to address this evidence gap. Methods BCVIS2 was a prospective UK-wide, cross-sectional, observational study to establish an inception cohort of children newly diagnosed with visual impairment. Ophthalmologists and paediatricians reported cases from 89 hospitals and community centres across the UK. We included children aged 18 years or younger who were newly diagnosed with any condition causing impaired visual acuity to a level of 0·5 logMAR or worse (worse than 6/18 Snellen) in each eye, or equivalent vision as assessed by standard qualitative measures, between Oct 1, 2015, and Nov 1, 2016. Eligible children were notified simultaneously but independently by their managing ophthalmologists and paediatricians via the two national active surveillance schemes, the British Ophthalmological Surveillance Unit and the British Paediatric Surveillance Unit. Standardised detailed demographic, socioeconomic, and clinical data about detection, management, and treatment were collected at diagnosis and 1 year later. We calculated incidence estimates and relative rates by key sociodemographic factors. We did descriptive analyses of underlying ophthalmic disorders and non-ophthalmic comorbidities. Findings 61 (7%) of 845 eligible children initially notified were ineligible at follow-up because of improved vision after treatment. Thus, the study sample comprised 784 children with permanent newly-diagnosed all-cause visual impairment, severe visual impairment, or blindness. 559 (72%) of 778 children had clinically significant non-ophthalmic impairments or conditions. 28 (4%) of 784 children died within a year after diagnosis of visual disability (all had underlying systemic disorders). Incidence of visual disability in the first year of life was 5·19 per 10 000 children (95% CI 4·71–5·72), almost ten times higher than among 1-to-4-year-olds and between 20 times and 100 times higher than in the older age groups. The overall cumulative incidence (or lifetime risk) of visual impairment, severe visual impairment, or blindness was 10·03 per 10 000 children (9·35–10·76). Incidence rates were higher for those from any ethnic minority group, the lowest quintile of socioeconomic status, and those born preterm or with low birthweight. 345 (44%) of 784 children had a single affected anatomical site. Disorders of the brain and visual pathways affected 378 (48%) of 784 children. Interpretation BCVIS2 provides a contemporary snapshot of the heterogeneity, multi-morbidity, and vulnerability associated with childhood visual disability in a high-income country. These findings could facilitate developing and delivering health care and planning of interventional research. Our findings highlight the importance of including childhood visual disability as a sentinel event and metric in global child health initiatives. Funding Fight for Sight, National Institute for Health Research, and Ulverscroft Foundation.

Despite extraordinary advances that have been made in cancer therapy, the number of cancer cases continue to surge, making it the leading cause of death across the world. As a result, early detection is one of the key aspects in the battle against the disease. Screening and early diagnosis play a pivotal role for effective treatment and to lower the cancer mortality rate. Cancer nanotechnology is a new branch in biology that provides a link between nanotechnology and clinical cancer research. Moreover, it also aims to integrate the advancements made in the manufacture of nanoscale devices with cellular and molecular components associated with cancer diagnosis and therapy. Understanding these new technologies is crucial to integrating these practices into clinical settings. This novel approach has facilitated the conjugation of nanoscale devices with agents such as tumor-specific li-gands, antibodies, and imaging probes. This review summarizes the advancements made in nanotechnology based approaches in diagnosing cancer. Coupling of nanoparticles with targeting molecules enables an efficient interaction between biological systems with extraordinary accuracy. The progress associated with nanoscale devices such as metal based nanomaterials, exosomes, magnetic nanoparticles, in addition to quantum dots and lab on chip devices with regard to diagnostic applications has been discussed. We summarize how nanoparticles take advantage of the tumor microenvironment for targeting cancer cells. Further, the review outlines the drawbacks, challenges, and future prospects associated with these techniques as effective strategies to replace current clinical trends.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents.

To the Editor: Acute kidney injury (AKI) is a lesser-known complication of hip fracture that may come about owing to decreased kidney perfusion and heightened inflammation from trauma, pain, bleeding, and fasting. Approximately 15%-20% of patients undergoing surgery for a hip fracture develop AKI, with 0.5%-1.8% receiving dialysis. [...]

AIM To evaluate the current opinion of magnetic resonance imaging (MRI) reports amongst specialist clinicians involved in colorectal cancer multidisciplinary teams (CRC MDTs). MATERIALS AND METHODS Active participants at 16 UK CRC MDTs across a population of 5.7 million were invited to complete a questionnaire, this included 22 closed and three open questions. Closed questions used ordinal (Likert) scales to judge the subjective inclusion of tumour descriptors and impressions on the clarity and consistency of the MRI report. Open (free-text) questions allowed overall feedback and suggestions. RESULTS A total of 69 participants completed the survey (21 radiologists and 48 other CRC MDT clinicians). Both groups highlighted that reports commonly omit the status of the circumferential resection margin (CRM; 83% versus 81% inclusion, other clinicians and radiologists, respectively, p>0.05), presence or absence of extra-mural venous invasion (EMVI; 67% versus 57% inclusion, p>0.05), and lymph node status (90% inclusion in both groups). Intra-radiologist agreement across MRI examinations is reported as 75% by other clinicians. Free-text comments included suggestions for template-style reports. CONCLUSION Both groups recognise a proportion of MRI reports are suboptimal with key tumour descriptors omitted. There are also concerns around the presentation style of MRI reports and inter- and intra-radiologist report variability. The widespread implementation of standardised report templates may improve completeness and clarity of MRI reports for rectal cancer and thus clinical management and outcomes in rectal cancer.

Brain tumors pose a serious burden to health care because the cancers are usually incurable, despite advancements in treatment strategies including surgery, radiotherapy, and chemotherapy. Most studies report that specific drugs are effective in vitro, but many lose their therapeutic value in clinical settings. Maintaining therapeutic drug concentrations as an agent reaches a cancer target is the efficacy prerequisite for any form of treatment. However, in the case of brain tumors, the blood-brain barrier (BBB) acts to physically and physiologically block the drug, which complicates treatment options. In addition, strategies are limited by a number of factors such as difficulties that are associated with targeting tumor cells. The therapeutic potential of targeted drug delivery as an alternative to current strategies is gaining significant ground, with many studies highlighting its efficacy and compatibility in overcoming the BBB before reaching its final target in brain. In this review, we briefly describe basic physiology associated with the BBB and how modern science is taking advantage of physiological processes to deliver anticancer agents to brain. We also summarize different modes of drug delivery and highlight how nanoparticles as drug-delivery vehicles are used for drug transport in brain tumors as well as different types of surface modification that are used to increase target potential.

Human milk is a complex liquid that contains multifaceted compounds which provide nutrition to infants and helps to develop their immune system. The presence of secretory immunoglobulins (IgA), leucocytes, lysozyme, lactoferrin, etc., in breast milk and their role in imparting passive immunity to infants as well as modulating development of an infant's immune system is well-established. Breast milk miRNAs (microRNAs) have been found to be differentially expressed in diverse tissues and biological processes during various molecular functions. Lactation is reported to assist mothers and their offspring to adapt to an ever-changing food supply. It has been observed that certain subtypes of miRNAs exist that are codified by non-human genomes but are still present in circulation. They have been termed as xeno-miRNA (XenomiRs). XenomiRs in humans have been found from various exogenous sources. Route of entry in human systems have been mainly dietary. The possibility of miRNAs taken up into mammalian circulation through diet, and thereby effecting gene expression, is a distinct possibility. This mechanism suggests an interesting possibility that dietary foods may modulate the immune strength of infants via highly specific post-transcriptional regulatory information present in mother's milk. This serves as a major breakthrough in understanding the fundamentals of nutrition and cross-organism communication. In this review, we elaborate and understand the complex crosstalk of XenomiRs present in mother's milk and their plausible role in modulating the infant immune system against infectious and inflammatory diseases.

UVB irradiation of human telomeric d(GGGTTA)3 GGG sequences in potassium ion solution crosslinks the first and third TTA segments through anti cyclobutane pyrimidine dimer (CPD) formation. The photocrosslinking reaction was first proposed to occur through a form 3 two-tetrad G-quadruplex in which the lateral four-nucleotide GTTA loop can interact with an adjacent TTA loop. Curiously, the reaction does not occur with sodium ion, which was explained by the formation of a basket structure which only has three-nucleotide TTA loops that cannot interact. Sequences known or expected to favor the two-tetrad basket did not show enhanced photocrosslinking, suggesting that some other structure was the reactive intermediate. Herein, we report that anti CPDs form in human telomeric DNA sequences with lithium ion that is known to disfavor G-quadruplex formation, as well as with potassium ion when the bases are modified to interfere with G-quartet formation. We also show that anti CPDs form in sequences containing A's in place of G's that cannot form Hoogsteen hairpins, but can form reverse Hoogsteen hairpins. These results suggest that reverse Hoogsteen hairpins may play a hitherto unrecognized role in the biology and photoreactivity of DNA in telomeres, and possibly in other purine-rich sequences found in regulatory regions.

Neuroinflammation, the condition associated with the hyperactivity of immune cells within the CNS (central nervous system), has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the blood-brain barrier for the delivery of drugs. Hence, research has focused on novel modes of transport for drugs to cross the barrier through drug delivery and nanotechnology approaches. In this Review, we highlight the therapeutic advancement made in the field of neurodegenerative disorders by focusing on the effect neuroinflammation treatment has on these conditions.

Cyclobutane pyrimidine dimers (CPDs) are DNA photoproducts linked to skin cancer, whose mutagenicity depends in part on their frequency of formation and deamination. Nucleosomes modulate CPD formation, favoring outside facing sites and disfavoring inward facing sites. A similar pattern of CPD formation in protein-free DNA loops suggests that DNA bending causes the modulation in nucleosomes. To systematically study the cause and effect of nucleosome structure on CPD formation and deamination, we have developed a circular permutation synthesis strategy for positioning a target sequence at different superhelix locations (SHLs) across a nucleosome in which the DNA has been rotationally phased with respect to the histone octamer by TG motifs. We have used this system to show that the nucleosome dramatically modulates CPD formation in a T11-tract that covers one full turn of the nucleosome helix at seven different SHLs, and that the position of maximum CPD formation at all locations is shifted to the 5΄-side of that found in mixed-sequence nucleosomes. We also show that an 80-mer minicircle DNA using the same TG-motifs faithfully reproduces the CPD pattern in the nucleosome, indicating that it is a good model for protein-free rotationally phased bent DNA of the same curvature as in a nucleosome, and that bending is modulating CPD formation.

Purpose Rectal cancer staging with magnetic resonance imaging (MRI) allows accurate assessment and preoperative staging of rectal cancers. Therefore, complete MRI reports are vital to treatment planning. Significant variability may exist in their content and completeness. Template-style reporting can improve reporting standards, but its use is not widespread. Given the implications for treatment, we have evaluated current clinical practice amongst specialist gastrointestinal (GI) radiologists to measure the quality of rectal cancer staging MRI reports. Materials and methods Sixteen United Kingdom (UK) colorectal cancer multi-disciplinary teams (CRC-MDTs) serving a population over 5 million were invited to submit up to 10 consecutive rectal cancer primary staging MRI reports from January 2016 for each radiologist participating in the CRC-MDT. Reports were compared to a reference standard based on recognised staging and prognostic factors influencing case management Results Four hundred ten primary staging reports were submitted from 41 of 42 (97.6%) eligible radiologists. Three hundred sixty reports met the inclusion criteria, of these, 81 (22.5%) used a template. Template report usage significantly increased recording of key data points versus non-template reports for extra-mural venous invasion (EMVI) status (98.8% v 51.6%, p

BACKGROUND: When children with type 1 diabetes approach adolescence, they are encouraged to become more involved in diabetes self-management. This study explored the challenges pre-adolescent children encounter when self-managing diabetes and the factors which motivate and enable them to take on new diabetes-related tasks. A key objective was to inform the support offered to pre-adolescent children.METHODS: In-depth interviews using age-appropriate questioning with 24 children (aged 9-12 years) with type 1 diabetes. Data were analysed using an inductive, thematic approach.RESULTS: Children reported several barriers to taking on self-management tasks. As well as seeking respite from managing diabetes, children described relying on their parents to: perform the complex maths involved in working out carbohydrate content in food; calculate insulin doses if they did not use a bolus advisor; and administer injections or insert a cannula in hard-to-reach locations. Children described being motivated to take on diabetes tasks in order to: minimise the pain experienced when others administered injections; alleviate the burden on their parents; and participate independently in activities with their peers. Several also discussed being motivated to take on diabetes-management responsibilities when they started secondary school. Children described being enabled to take on new responsibilities by using strategies which limited the need to perform complex maths. These included using labels on food packaging to determine carbohydrate contents, or choosing foods with carbohydrate values they could remember. Many children discussed using bolus advisors with pre-programmed ratios and entering carbohydrate on food labels or values provided by their parents to calculate insulin doses. Several also described using mobile phones to seek advice about carbohydrate contents in food.CONCLUSIONS: Our findings highlight several barriers which deter children from taking on diabetes self-management tasks, motivators which encourage them to take on new responsibilities, and strategies and technologies which enable them to become more autonomous. To limit the need to perform complex maths, children may benefit from using bolus advisors provided they receive regular review from healthcare professionals to determine and adjust pre-programmed insulin-to-carbohydrate ratios. Education and support should be age-specific to reflect children's changing involvement in self-managing diabetes.

BackgroundWhile pre‐adolescent children with type 1 diabetes receive most support from their parents/caregivers, others also contribute to their care. This study explored pre‐adolescent children's experiences of receiving diabetes‐related support from friends and peers. The objective was to identify how children could be better supported by their friends and peers to undertake diabetes self‐management.MethodsIn‐depth interviews with 24 children (aged 9‐12 years) with type 1 diabetes. Data were analysed using an inductive, thematic approach.ResultsChildren gave mixed accounts of their experiences of speaking to their school/class about diabetes with some indicating that this had resulted in unwanted attention. Most individuals reported that other children had a limited understanding of diabetes and sometimes acted in insensitive ways or said things they found upsetting. Virtually all children described having a small number of close friends who were interested in learning about diabetes and provided them with support. These friends provided support in three overlapping ways, as “monitors and prompters,” “helpers” and “normalizers.” While some children described benefiting from meeting peers with type 1 diabetes, most indicated that they would prefer to develop friendships based on shared interests rather than a common disease status.Discussion and conclusionsFriends and peers provide several kinds of support to pre‐adolescent children with diabetes. Health professionals could consider ways to assist small friendship groups to undertake monitoring and prompting, helping and normalizing roles. Parents, schools and health professionals could explore ways to normalize self‐management practices to better support children with diabetes in school settings.

While is it well known that human telomeric DNA sequences can adopt G-quadruplex structures, some promoters sequences have also been found to form G-quadruplexes, and over 40% of promoters contain putative G-quadruplex forming sequences. Because UV light has been shown to crosslink human telomeric G-quadruplexes by cyclobutane pyrimidine dimer (CPD) formation between T’s on adjacent loops, UV light might also be able to photocrosslink G-quadruplexes in promoters. To investigate this possibility, fifteen potentially UV-crosslinkable G-quadruplex forming sequences found in a search of human DNA promoters, were UVB irradiated in vitro, and three were confirmed to have formed non-adjacent CPDs by mass spectrometry. In addition to non-adjacent T=T CPDs found in human telomeric DNA, a non-adjacent T=U CPD was discovered that presumably arose from deamination of a non-adjacent T=C CPD. Analysis of the three sequences by circular dichroism, melting temperature analysis, and chemical footprinting confirmed the presence of G-quadruplexes that could explain the formation of the non-adjacent CPDs. The formation of non-adjacent CPDs from the sequences in vitro, suggests that they might be useful probes for the presence of non-B DNA structures, such as G-quadruplexes, in vivo, and if they were to form in vivo, might also have significant biological consequences.

Purpose People with macular degeneration (MD) experience difficulties in reading due to central-field loss. Two new fonts, Eido and Maxular Rx, have been designed specifically for individuals with MD. We have compared reading performance of these new fonts with three mainstream fonts (Times-Roman, Courier, and Helvetica). Methods Subjects with MD (n = 19) and normally sighted subjects (n = 40) were tested with digital versions of the MNREAD test using the five fonts. Maximum reading speed (MRS), critical print size (CPS), and reading acuity (RA) were estimated to characterize reading performance. Physical properties of the fonts were quantified by interletter spacing and perimetric complexity. Results Reading with MD showed font differences in MRS, CPS, and RA. Compared with Helvetica and Times, Maxular Rx permitted both smaller CPS and RA, and Eido permitted smaller RA. However, the two new fonts presented no advantage over Courier. Spacing, but not Complexity, was a significant predictor of reading performance for subjects with MD. Conclusions The two fonts, designed specifically for MD, permit smaller print to be read, but provide no advantage over Courier.

Dentofacial disharmony in patients with cerebral palsy (CP) can lead to low self-esteem and functional limitations. However, medical and behavioral challenges in patients with developmental disorders often prevent dental practitioners from offering the necessary treatment. This report describes the clinical interdisciplinary management of a 20-year-old man with CP, including orthodontic, periodontal, and orthognathic surgery therapy. The patient presented with the chief complaint of having difficulty chewing, was wheelchair dependent, had poor orofacial muscle control, and exhibited a Class III malocclusion with a skeletal anterior open bite. The lower midline was shifted 3 mm to the right, there was severe maxillary spacing, and the patient had gingival overgrowth. A combined orthodontic, periodontal, and orthognathic surgery treatment approach was chosen to meet the patient's interdisciplinary needs. Because of his physical limitations, it was necessary to avoid complicated and prolonged orthodontic treatment mechanics. Interdisciplinary therapy improved the patient's oral function, periodontal health, and facial esthetics and led to a good occlusion, which remained stable 1 year after treatment. Regardless of the treatment challenges, combined orthodontic and surgical therapy in the present patient with CP led to favorable treatment results and improved the patient's self-esteem, confidence in social interactions, and speaking and chewing abilities.

Antiphospholipid syndrome is an antiphospholipid antibody-mediated prothrombotic state leading to arterial and venous thrombosis. This condition alters routine in-vitro coagulation tests, making results unreliable. Antiphospholipid syndrome patients requiring cardiac surgery with cardiopulmonary bypass present a unique challenge in perioperative anticoagulation management. We describe 3 patients with antiphospholipid syndrome who had successful heart valve surgery at our institution. We have devised an institutional protocol for antiphospholipid syndrome patients, and all 3 patients were managed according to this protocol. An algorithm-based approach is recommended because it improves team work, optimizes treatment, and improves patient outcome.

In this paper, we present our cross-wire assist concept, for assisting a single joint in multiple degrees of freedom. It is comprised of four motor driven Bowden cable actuators (wires) per assisted joint, with the wires crossed over each other at the front and rear. Simulation results show that selectively actuating a subset of these wires allows torque to be generated in 6 directions, with the torque magnitude dependent on joint angle. We have built a fully wearable prototype of our assistance device for both hip joints, with 8 high-speed and independently controllable actuators each providing force up to 100 N. The prototype has a total mass of 9.3 kg, and is shown in motion capture testing to generate movement in 6 directions around the users joint, including internal and external rotation. Mobile, multi-degree of freedom assistance cross-wire system will enable assistive devices to better match human movement, allowing support and rehabilitation in tasks beyond straight line walking.

It was theorized that when a society exploits a shared resource, the system can undergo extreme phase transition from full cooperation in abiding by a social agreement, to full defection from it. This was shown to happen in an integrated society with complex social relationships. However, real-world agents tend to segregate into communities whose interactions contain features of the associated community structure. We found that such social segregation softens the abrupt extreme transition through the emergence of multiple intermediate phases composed of communities of cooperators and defectors. Phase transitions thus now occur through these intermediate phases which avert the instantaneous collapse of social cooperation within a society. While this is beneficial to society, it nonetheless costs society in two ways. First, the return to full cooperation from full defection at the phase transition is no longer immediate. Community linkages have rendered greater societal inertia such that the switch back is now typically stepwise rather than a single change. Second, there is a drastic increase in social disharmony within the society due to the greater tension in the relationship between segregated communities of defectors and cooperators. Intriguingly, these results on multiple phases with its associated phenomenon of social disharmony are found to characterize the level of cooperation within a society of Balinese farmers who exploit water for rice production. Published version

Background Panniculus morbidus is a large abdominal apron found in morbidly obese patients. This condition creates a vicious cycle of weight gain and functional incapacity. Our study assessed the functional improvement in patients undergoing massive panniculectomy. Methods A retrospective review of panniculectomies performed from 1994 to 2012 was conducted. Twenty-seven patients with resections >20 lbs were selected. Data on demographics, operative details, complications, and pre- and postoperative functional capacity (using the Steinbrocker Functional Classification) were collected. Results The preoperative mean body mass index was 58 kg/m 2 , with a mean resection weight of 33 lbs. The overall complication rate was 74%. A statistically significant improvement in functional capacity (preop mean 3.7 vs postop mean 2.0; P Conclusions Panniculus morbidus is a functionally debilitating condition and massive panniculectomy is often the only treatment available. Our data suggest that massive panniculectomy is a viable option for patients functionally incapacitated by panniculus morbidus.

Detailed analyses of the electron spin resonance (ESR) spectra, cell viability, and DNA degradation studies are presented for the photolyzed Type I phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates. The ESR studies provided evidence that copious free radicals can be generated from these N-H, N-S, and S-O containing compounds upon photoirradiation with UV/visible light. The analyses of spectral data allowed us to identify the free radical species. The cell viability studies showed that these agents after exposure to light exert cytotoxicity to kill cancer cells (U937 leukemia cell lines HTC11, KB, and HT29 cell lines) in a dosage- and time-dependent manner. We examined a possible pathway of cell death via DNA degradation by a plasmid cleavage assay for several compounds. The effects of photosensitization with benzophenone in the presence of oxygen were examined. The studies indicate that planar tricyclic amines and sulfenamides tend to form π-electron delocalized aminyl radicals, whereas nonplanar ones tend to yield nitroxide radicals resulting from the recombination of aminyl radicals with oxygen. The ESR studies coupled with the results of cell viability measurements and DNA degradation reveal that planar N-centered radicals can provide higher potency in cell death and allow us to provide some insights on the reaction mechanisms. We also found the formation of azatropylium cations possessing high aromaticity derived from azepines can facilitate secondary electron transfer to form toxic O2(•-) radicals, which can further exert oxidative stress and cause cell death.

DNA polymerase λ (Pol λ) is a novel X-family DNA polymerase that shares 34% sequence identity with DNA polymerase β. Pre-steady-state kinetic studies have shown that the Pol λ–DNA complex binds both correct and incorrect nucleotides 130-fold tighter, on average, than the DNA polymerase β–DNA complex, although the base substitution fidelity of both polymerases is 10 − 4 to 10 − 5 . To better understand Pol λ's tight nucleotide binding affinity, we created single-substitution and double-substitution mutants of Pol λ to disrupt the interactions between active-site residues and an incoming nucleotide or a template base. Single-turnover kinetic assays showed that Pol λ binds to an incoming nucleotide via cooperative interactions with active-site residues (R386, R420, K422, Y505, F506, A510, and R514). Disrupting protein interactions with an incoming correct or incorrect nucleotide impacted binding to each of the common structural moieties in the following order: triphosphate ≫ base > ribose. In addition, the loss of Watson–Crick hydrogen bonding between the nucleotide and the template base led to a moderate increase in K d . The fidelity of Pol λ was maintained predominantly by a single residue, R517, which has minor groove interactions with the DNA template.

BACKGROUND: Syndromic case management remains the cornerstone for STI (sexually transmitted infection) treatment in many countries. We undertook this study to better understand the etiology of STIs in adults in south India and to inform STI management guidelines. METHODS: Adult males and females presenting with genital complaints were recruited from clinics in Karnataka state south India. A questionnaire was administered physical examination performed and blood collected for herpes simplex virus-type 2 (HSV-2) and syphilis serology. Men with urethral discharge (UD) and women with vaginal discharge were tested for Neisseria gonorrhoeae (NG) Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV). Vaginal swabs were also tested for bacterial vaginosis and yeast infection. Participants with genital ulcers were tested for Treponema pallidum (TP) Haemophilus ducreyi (HD) and HSV-2. human immunodeficiency virus (HIV) testing was offered to all individuals. RESULTS: There were 401 male and 412 female participants and rates of HIV infection were high (men 17%; women 15%). HSV-2 was significantly associated with HIV in men and women. Among men with the complaint of UD NG was identified in 35% CT in 10.5% and TV in 8.5%. Very little NG or CT was detected among women with vaginal discharge. However bacterial vaginosis was identified in approximately 40% of women with significant amounts of TV and Candida also detected. HSV-2 was the most commonly identified pathogen among participants with genital ulcer disease and the clinical distinction of herpetic versus nonherpetic lesions was not helpful. CONCLUSIONS: Current STI management guidelines should be reevaluated in south India. Consideration should be given to treating all persons with GUD for both HSV-2 and syphilis and to adding initial treatment for TV for men with UD in areas of high background prevalence of HSV-2 and TV respectively. This population is at high risk for HIV and should be counseled and tested appropriately.

SUMMARY Heme is the prosthetic group for cytochromes, which are directly involved in oxidation/reduction reactions inside and outside the cell. Many cytochromes contain heme with covalent additions at one or both vinyl groups. These include farnesylation at one vinyl in hemes o and a and thioether linkages to each vinyl in cytochrome c (at CXXCH of the protein). Here we review the mechanisms for these covalent attachments, with emphasis on the three unique cytochrome c assembly pathways called systems I, II, and III. All proteins in system I (called Ccm proteins) and system II (Ccs proteins) are integral membrane proteins. Recent biochemical analyses suggest mechanisms for heme channeling to the outside, heme-iron redox control, and attachment to the CXXCH. For system II, the CcsB and CcsA proteins form a cytochrome c synthetase complex which specifically channels heme to an external heme binding domain; in this conserved tryptophan-rich “WWD domain” (in CcsA), the heme is maintained in the reduced state by two external histidines and then ligated to the CXXCH motif. In system I, a two-step process is described. Step 1 is the CcmABCD-mediated synthesis and release of oxidized holoCcmE (heme in the Fe +3 state). We describe how external histidines in CcmC are involved in heme attachment to CcmE, and the chemical mechanism to form oxidized holoCcmE is discussed. Step 2 includes the CcmFH-mediated reduction (to Fe +2 ) of holoCcmE and ligation of the heme to CXXCH. The evolutionary and ecological advantages for each system are discussed with respect to iron limitation and oxidizing environments.

This mini-review highlights developments that have been made over the past year to advance the construction of well-defined nanoscale objects to serve as devices for cell transfection. Design of the nanoscale objects originated from biomimicry concepts, using histones as the model, to afford cationic shell crosslinked knedel-like (cSCK) nanoparticles. Packaging and delivery of plasmid DNA, oligonucleotides, and peptide nucleic acids were studied by dynamic light scattering, transmission electron microscopy, gel electrophoresis, biological activity assays, RT-PCR measurements, flow cytometry, and confocal fluorescence microscopy. With the demonstration of more efficient cell transfection in vitro than that achieved using commercially-available transfection agents, together with the other features offered by the robust nanostructural framework, work continues toward the application of these cSCKs for in vivo molecular recognition of genetic material, for imaging and therapy targeted specifically to pulmonary injury and disease.

Peptide nucleic acids (PNAs) have a number of attractive features that have made them an ideal choice for antisense and antigene-based tools, probes, and drugs, but their poor membrane permeability has limited their application as therapeutic or diagnostic agents. Herein, we report a general method for the synthesis of phospholipid-PNAs (LP-PNAs) and compare the effect of noncleavable lipids and bioreductively cleavable lipids (L and LSS) and phospholipid (LP) on the splice-correcting bioactivity of a PNA bearing the cell penetrating Arg9 group (PNA-R9). While the three constructs show similar and increasing bioactivity at 1-3 microM, the activity of LP-PNA-R9 continues to increase from 4-6 microM, while the activity of L-PNA-R9 remains constant and that of LSS-PNA-R9 decreases rapidly in parallel with their relative cytotoxicity. The activity of both LP-PNA-R9 and L-PNA-R9 dramatically increased in the presence of chloroquine, as expected for an endocytotic entry mechanism. The constructs were also found to have CMC values of 1.0 and 4.5 microM, respectively, in 150 mM NaCl, pH 7 water, suggesting that micelle formation may play a hitherto unrecognized role in modulating toxicity and/or facilitating endocytosis.

The unusual structural forms of telomere DNA, which protect the ends of chromosomes during replication, may render it vulnerable to unprecedented photodamage, possibly involving nonadjacent bases that are made proximate by folding. The G-quadruplex for the human telomere sequence consisting of a repeating d(TTAGGG) is one unusual form. Tel22, d[AGGG(TTAGGG) 3 ], forms a basket structure in the presence of Na + and may form multiple equilibrating structures in the presence of K + with hybrid-type structures predominating. UVB irradiation of d[AGGG(TTAGGG) 3 ] in the presence of Na + results in a cis,syn thymine dimer between two adjacent Ts in a TTA loop and a mixture of nonadjacent anti thymine dimers between various loops. Irradiation in the presence of K + , however, produces, in addition to these same products, a large amount of specific anti thymine dimers formed between either T in loop 1 and the central T in loop 3. These latter species were not observed in the presence of Na + . Interloop-specific anti thymine dimers are incompatible with hybrid-type structures, but could arise from a chair or basket-type structure or from triplex intermediates involved in interconverting these structures. If these unique nonadjacent anti thymine dimer photoproducts also form in vivo, they would constitute a previously unrecognized type of DNA photodamage that may interfere with telomere replication and present a unique challenge to DNA repair. Furthermore, these unusual anti photoproducts may be used to establish the presence of G-quadruplex or quadruplex-like structures in vivo.

One particular aspect of the literature on preferences for female body shapes has focused on the purported universality of preferences for a low waist-to-hip ratio (WHR), despite substantial evidence of cross-cultural variability in such preferences. In the present study, we examined the effects of manipulating women's profile WHR, breast size, and ethnicity on men's ratings of physical attractiveness and health. A total of 51 African men in South Africa, 56 British Africans, and 114 British Caucasians rated 12 line drawings that varied in two levels of ethnicity, three levels of WHR, and two levels of breast size. Overall, the results suggested that there were cross-cultural differences in preferred body shape, with the preferred body configuration varying as a function of the ethnicity of the figure being rated. In addition, there was a strong positive correlation between ratings of attractiveness and health. These findings are discussed in relation to the interplay between culture and evolution in determining ideals of attractiveness.

Introduction Herpes zoster ophthalmicus (HZO) is characterized by a typical vesicular eruption affecting the distribution of the ophthalmic division of the trigeminal nerve which can be of varying severity. The correlation of eruption severity and ocular involvement and subsequent visual loss is still to be established. In this prospective longitudinal study we evaluated the correlation of eruption severity with ocular complications, visual outcome and postherpetic neuralgia. Methods Patients with HZO underwent detailed ophthalmological and dermatological examination at presentation and follow-up on 1st , 2nd and 4th week and 3rd and 6th month. Eruption severity was graded as mild, moderate and severe based on the number of vesicles. The correlation of eruption severity and distribution with ocular complications, visual outcome and postherpetic neuralgia was statistically evaluated. Results Severe eruption was seen in 14(28%), moderate eruption in 21(42%) and mild eruption in 15(30%). Severe eruption was significantly associated with increased incidence and severity of ocular involvement (p = 0.04 and p = 0.04 respectively), occurrence of uveitis (p = 0.004), reduced visual outcome (p = 0.002) and the occurrence of PHN (p = 0.05). Lacrimal nerve involvement was also associated with increased incidence (p = 0.03) and severity (p = 0.02) of ocular complications and visual loss (p = 0.01). Conclusion Increasing eruption severity is a good predictor of occurrence of ocular complications and subsequent visual loss in HZO. Presence of a severe eruption is an indication for early ophthalmic intervention. Nasociliary nerve and lacrimal nerve involvement are also good predictors of ocular complications.

Peptide nucleic acids have a number of features that make them an ideal platform for the development of in vitro biological probes and tools. Unfortunately, their inability to pass through membranes has limited their in vivo application as diagnostic and therapeutic agents. Herein, we describe the development of cationic shell-cross-linked knedel-like (cSCK) nanoparticles as highly efficient vehicles for the delivery of PNAs into cells, either through electrostatic complexation with a PNA * ODN hybrid, or through a bioreductively cleavable disulfide linkage to a PNA. These delivery systems are better than the standard Lipofectamine/ODN-mediated method and much better than the Arg(g)-mediated method for PNA delivery in HeLa cells, showing lower toxicity and higher bioactivity. The cSCKs were also found to facilitate both endocytosis and endosomal release of the PNAs, while themselves remaining trapped in the endosomes.

Inhibitors of heat-induced heat shock protein 70 (HSP70) expression have the potential to enhance the therapeutic effectiveness of heat-induced radiosensitization of tumors. Among known small molecule inhibitors, quercetin has the advantage of being easily modified for structure-activity studies. Herein, we report the ability of five monomethyl and five carbomethoxymethyl derivatives of quercetin to inhibit heat-induced HSP70 expression and enhance HSP27 phosphorylation in human cells. While quercetin and several derivatives inhibit HSP70 induction and enhance HSP27 phosphorylation at Ser78, other analogues selectively inhibit HSP70 induction without enhancing HSP27 phosphorylation that would otherwise aid in cell survival. We also show that good inhibitors of HSP70 induction are also good inhibitors of both CK2 and CamKII, kinases that are known to activate HSP70 expression by phosphorylation of heat shock transcription factor 1. Derivatives that show poor inhibition of either or both kinases are not good inhibitors of HSP70 induction, suggesting that quercetin's effectiveness is due to its ability to inhibit both kinases.

In order to probe the nanoparticle shape/size effect on cellular uptake, a spherical and two cylindrical nanoparticles, whose lengths were distinctively varied, were constructed by the selective crosslinking of amphiphilic block copolymer micelles. Herein, we demonstrate that, when the nanoparticles were functionalized with the protein transduction domain of human immunodeficiency virus type 1 Tat protein (HIV Tat PTD), the smaller, spherical nanoparticles had a higher rate of cell entry into Chinese Hamster Ovary (CHO) cells than did the larger, cylindrical nanoparticles. It was also found that nanoparticles were released after internalization, and that the rate of cell exit was dependent on both the nanoparticle shape and the amount of surface-bound PTD.

Accurate hip joint center (HJC) location is critical when studying hip joint biomechanics. The HJC is often determined from anatomical methods, but functional methods are becoming increasingly popular. Several studies have examined these methods using simulations and in vivo gait data, but none has studied high-range of motion activities, such a chair rise, nor has HJC prediction been compared between males and females. Furthermore, anterior superior iliac spine (ASIS) marker visibility during chair rise can be problematic, requiring a sacral cluster as an alternative proximal segment; but functional HJC has not been explored using this approach. For this study, the quality of HJC measurement was based on the joint gap error (JGE), which is the difference in global HJC between proximal and distal reference segments. The aims of the present study were to: (1) determine if JGE varies between pelvic and sacral referenced HJC for functional and anatomical methods, (2) investigate which functional calibration motion results in the lowest JGE and if the JGE varies depending on movement type (gait versus chair rise) and gender, and (3) assess whether the functional HJC calibration results in lower JGE than commonly used anatomical approaches and if it varies with movement type and gender. Data were collected on 39 healthy adults (19 males and 20 females) aged 14–50 yr old. Participants performed four hip “calibration” tests (arc, cross, star, and star-arc), as well as gait and chair rise (activities of daily living (ADL)). Two common anatomical methods were used to estimate HJC and were compared to HJC computed using a published functional method with the calibration motions above, when using pelvis or sacral cluster as the proximal reference. For ADL trials, functional methods resulted in lower JGE (12–19 mm) compared to anatomical methods (13–34 mm). It was also found that women had significantly higher JGE compared to men and JGE was significantly higher for chair rise compared to gait, across all methods. JGE for sacrum referenced HJC was consistently higher than for the pelvis, but only by 2.5 mm. The results indicate that dynamic hip range of movement and gender are significant factors in HJC quality. The findings also suggest that a rigid sacral cluster for HJC estimation is an acceptable alternative for relying solely on traditional pelvis markers.

How DNA damaged is formed, recognized, and repaired in chromatin is an area of intense study. To better understand the structure activity relationships of damaged chromatin, mono and dinucleosomes containing site-specific damage have been prepared and studied. This review will focus on the design, synthesis, and characterization of model systems of damaged chromatin for structural, physical, and enzymatic studies.

Sunlight-induced C to T mutation hot spots in skin cancers occur primarily at methylated CpG sites that coincide with sites of UV-induced cyclobutane pyrimidine dimer (CPD) formation. The C and 5-methyl-C in CPDs are not stable and deaminate to U and T, respectively, which leads to the insertion of A by the DNA damage bypass polymerase η, thereby defining a probable mechanism for the origin of UV-induced C to T mutations. Deamination rates for T(m)CG CPDs have been found to vary 12-fold with rotational position in a nucleosome in vitro. To determine the influence of nucleosome structure on deamination rates in vivo, we determined the deamination rates of CPDs at TCG sites in a stably positioned nucleosome within the FOS promoter in HeLa cells. A procedure for in vivo hydroxyl radical footprinting with Fe-EDTA was developed, and, together with results from a cytosine methylation protection assay, we determined the translational and rotational positions of the TCG sites. Consistent with the in vitro observations, deamination was slower for one CPD located at an intermediate rotational position compared with two other sites located at outside positions, and all were much faster than for CPDs at non-TCG sites. Photoproduct formation was also highly suppressed at one site, possibly due to its interaction with a histone tail. Thus, it was shown that CPDs of TCG sites deaminate the fastest in vivo and that nucleosomes can modulate both their formation and deamination, which could contribute to the UV mutation hot spots and cold spots.

AimsTo explore the difficulties parents encounter in trying to achieve clinically recommended blood glucose levels and how they could be better supported to optimize their child's glycaemic control.MethodsIn-depth interviews were conducted with 54 parents of children with Type 1 diabetes (≤ 12 years). Data were analysed thematically.ResultsParents described being reluctant and finding it difficult to keep their child's blood glucose levels consistently within clinically recommended ranges. As well as worrying about their child's ability to detect/report hypoglycaemia, parents highlighted a multitude of factors that had an impact on their child's blood glucose levels and over which they could exercise little control. These included: leaving their child with other caregivers who could not be trusted to detect hypoglycaemia; difficulties remotely monitoring and regulating their child's food consumption and activity; and physical and social changes accompanying childhood development. Most parents used two sets of blood glucose targets, with clinically recommended targets employed when their child was in their immediate care and higher targets when in the care of others. Parents described health professionals as lacking understanding of the difficulties they encountered keeping blood glucose within target ranges and needing more empathetic, tailored and realistic advice.ConclusionIt is not parents' fear of hypoglycaemia in isolation that leads to decisions to raise their child's blood glucose but, rather, parental fear in conjunction with other factors and considerations. Hence, to improve diabetes management in children, these factors may need to be addressed; for instance, by training others in diabetes management and using new technologies. Changes to consultations are also recommended.

Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPD), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. Here we show that in melanocytes, CPD are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These “dark CPD” constitute the majority of CPD and include the cytosine-containing CPD that initiate UV-signature C→T mutations. Dark CPD arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but that induces CPD by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically-generated excited electronic states are relevant to mammalian biology.

We have recently shown that an MCF-7 tumor can be imaged in a mouse by PET with 64Cu-labeled Peptide nucleic acids (PNAs) tethered to the permeation peptide Lys4 that recognize the uniquely overexpressed and very abundant upstream of N-ras or N-ras related gene (unr mRNA) expressed in these cells. Herein we describe how the high affinity antisense PNAs to the unr mRNA were identified and characterized. First, antisense binding sites on the unr mRNA were mapped by an reverse transcriptase random oligonucleotide library (RT-ROL) method that we have improved, and by a serial analysis of antisense binding sites (SAABS) method that we have developed which is similar to another recently described method. The relative binding affinities of oligodeoxynucleotides (ODNs) complementary to the antisense binding sites were then qualitatively ranked by a new Dynabead-based dot blot assay. Dissociation constants for a subset of the ODNs were determined by a new Dynabead-based solution assay and were found to be 300 pM for the best binders in 1 M salt. PNAs corresponding to the ODNs with the highest affinities were synthesized with an N-terminal CysTyr and C-terminal Lys4 sequence. Dissociation constants of these hybrid PNAs were determined by the Dynabead-based solution assay to be about 10 pM for the highest affinity binders.

Hidradenitis suppurativa (HS) is a distressing condition for which no satisfactory treatment is available. Studies on hormonal mechanisms responsible for HS point towards altered end-organ sensitivity, probably related to the enzyme 5a reductase that converts testosterone to dihydrotestosterone. Finasteride, an inhibitor of type II 5a reductase, has been reported to be effective in recalcitrant HS.To study the effectiveness and tolerability of finasteride in patients with HS in a preliminary trial.Seven patients (five women and two men) with HS that was not responding well to antibiotics were treated with finasteride at a dose of 5 mg/day as monotherapy. Clinical response was assessed at regular intervals. Patients were followed up for periods varying from 8 months to 2 years.Six patients improved significantly and three of them had complete healing of lesions. Two patients who were followed up for more than 1 year experienced remissions lasting 8-18 months. The drug was generally well tolerated; however, two women complained of breast enlargement.The results of this preliminary study suggest that finasteride is an effective therapeutic option in HS.

Background Sporotrichosis is a granulomatous infection caused by Sporothrix schenkii. Although world-wide in distribution, only four cases have been reported from southern India to date. Methods The medical records of all cases seen at the Department of Dermatology at St John's Medical College Hospital, Bangalore, over the last 15 years were reviewed. Results A total of seven cases of sporotrichosis were seen in this 15-year period. Conclusion Sporotrichosis is considered to occur only sporadically in southern India. Our findings suggest that this may be a result of reporting bias.

DNA polymerase mu (Polmu) is a newly discovered member of the polymerase X family with unknown cellular function. The understanding of Polmu function should be facilitated by an understanding of its biochemical activities. By using purified human Polmu for biochemical analyses, we discovered the lesion bypass activities of this polymerase in response to several types of DNA damage. When it encountered a template 8-oxoguanine, abasic site, or 1,N(6)-ethenoadenine, purified human Polmu efficiently bypassed the lesion. Even bulky DNA adducts such as N-2-acetylaminofluorene-adducted guanine, (+)- and (-)-trans-anti-benzo[a]pyrene-N(2)-dG were unable to block the polymerase activity of human Polmu. Bypass of these simple base damage and bulky adducts was predominantly achieved by human Polmu through a deletion mechanism. The Polmu specificity of nucleotide incorporation indicates that the deletion resulted from primer realignment before translesion synthesis. Purified human Polmu also effectively bypassed a template cis-syn TT dimer. However, this bypass was achieved in a mainly error-free manner with AA incorporation opposite the TT dimer. These results provide new insights into the biochemistry of human Polmu and show that efficient translesion synthesis activity is not strictly confined to the Y family polymerases.

A scintigraphic pattern of increased uptake was observed in the pedicles of the affected segment and a triangular pattern of uptake in the sagittal projection of tomographic studies of pars fractures. It was hypothesised that these observations were specific for pars fractures. A retrospective study of 25 young athletes (age 9-16 years) with a variety of spinal disorders was undertaken. Back pain was present for an average of 4 months. Diagnosis was confirmed by radiologic studies and/or response to treatment. All 15 children with spondylolysis had evidence of increased uptake in the ipsilateral or contralateral pedicle. None of the other causes of back pain showed this pattern. A specific triangular pattern of uptake was seen in the sagittal view in these patients. The authors describe two unique features of spondylolysis that add to the confidence with which the scintigraphic diagnosis may be made.