The pathogenesis of mucositis: updated perspectives and emerging targets.

Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. The MASCC/ISOO Mucositis Study Group regularly assesses available literature relating to pathogenesis, mechanisms, and novel therapeutic approaches and distils this to summary perspectives and recommendations. Reviewers assessed 164 articles published between January 2011 and June 2016 to identify progress made since the last review and highlight new targets for further investigation. Findings were organized into sections including established and emerging mediators of toxicity, potential insights from technological advances in mucositis research, and perspective. Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.

Ethnic Variations in Serum 25(OH)D Levels and Bone Ultrasound Attenuation Measurements in Blacks and Whites.

Vitamin D deficiency is more common in Blacks, yet Blacks have lower prevalence of bone fragility fractures or osteoporosis than Whites. Broadband ultrasound attenuation (BUA) has been used to explore the association between serum 25(OH)D levels and bone quality in White and non-white populations. We investigated serum 25(OH)D status with corresponding BUA measurements assessed cross sectionally in a cohort of 232 Blacks and 260 Whites, aged 30-95 years who were part of the calibration study of the large Adventist Health Study-2 (AHS-2). At the calibration clinics, calcaneal BUA was measured and blood drawn for serum 25(OH)D assessment. In multivariable analyses, BUA was negatively associated with age (ß-coefficient = -0.38; p < 0.0001) and positively associated with body mass index (BMI) (p (trend) < 0.0001) and positively, but non-significantly, associated with serum 25(OH)D levels. Also, as expected, females had lower BUA (ß-coefficient = -5.19; p < 0.05) and Blacks had higher BUA (ß-coefficient = 4.26; p < 0.05). Gender and race modified the relationship of serum 25(OH)D on BUA with a positive association in males (p (trend) ≤ 0.05), but no significant association in females after also controlling for menopausal status and hormone therapy. After also controlling for serum 25(OH)D levels, Black males had higher BUA than White men, but such differences were not found among the females. When stratifying on race, a positive association between serum 25(OH)D levels and BUA (p (trend) ≤ 0.05) was found in Blacks, but not among Whites. Further studies are needed to understand how racial/ethnic differences in serum 25(OH)D levels influence bone health.

Environmental stress in the Gulf of Mexico and its potential impact on public health.

The Deepwater Horizon (DWH) oil spill in the Gulf of Mexico was the largest maritime oil spill in history resulting in the accumulation of genotoxic substances in the air, soil, and water. This has potential far-reaching health impacts on cleanup field workers and on the populations living in the contaminated coastal areas. We have employed portable airborne particulate matter samplers (SKC Biosampler Impinger) and a genetically engineered bacterial reporter system (umu-ChromoTest from EBPI) to determine levels of genotoxicity of air samples collected from highly contaminated areas of coastal Louisiana including Grand Isle, Port Fourchon, and Elmer's Island in the spring, summer and fall of 2011, 2012, 2013 and 2014. Air samples collected from a non-contaminated area, Sea Rim State Park, Texas, served as a control for background airborne genotoxic particles. In comparison to controls, air samples from the contaminated areas demonstrated highly significant increases in genotoxicity with the highest values registered during the month of July in 2011, 2013, and 2014, in all three locations. This seasonal trend was disrupted in 2012, when the highest genotoxicity values were detected in October, which correlated with hurricane Isaac landfall in late August of 2012, about five weeks before a routine collection of fall air samples. Our data demonstrate: (i) high levels of air genotoxicity in the monitored areas over last four years post DWH oil spill; (ii) airborne particulate genotoxicity peaks in summers and correlates with high temperatures and high humidity; and (iii) this seasonal trend was disrupted by the hurricane Isaac landfall, which further supports the concept of a continuous negative impact of the oil spill in this region.

Pulmonary hypertension predicts mortality in infants with omphalocele.

OBJECTIVE: The objective of this study was to identify predictors of mortality in infants with omphalocele. METHODS: Medical records of infants with omphalocele born between January 1992 and June 2012, with follow-up toDecember 2012, were retrospectively reviewed. Survivors and non-survivors were compared. Evidence for pulmonary hypertension was sought between the second and seventh day after birth. All included infants had increased right ventricular pressures (RVP >40 mmhg) on echocardiogram on the second day of life with increased oxygen requirements, therefore, the finding of increased pressure was not considered a result of the transitional circulation. Logistic regression was used to evaluate the importance and independence of various factors. RESULTS: Of 51 infants whose records were reviewed, 13 died (25%) and 38 survived (75%). The median time to death was 34 days (range: 4 -408 days). The median follow-up time for those who died was 1.5 years (range: 0.01-15 years) and for survivors was 2.6 years (range: 0.08-15 years). Logistic regression revealed that respiratory insufficiency at birth (OR: 14.8; 95% CI: 2.5-85.0) and pulmonary hypertension (OR: 6.4; 95% CI: 1.1-39.0) were independently associated with mortality. CONCLUSION: Respiratory insufficiency after birth and pulmonary hypertension are independent predictors of mortality in infants with omphalocele.

Cytological follow-up after hysterectomy: is vaginal vault cytology sampling a clinical governance problem? The University Hospital of North Staffordshire approach.

OBJECTIVES: Vaginal vault cytology sampling following hysterectomy is recommended for specific indications in national guidelines. However, clinical governance issues surround compliance with guidance. Our first study objective was to quantify how many patients undergoing hysterectomy at the University Hospital of North Staffordshire (UHNS) had vault cytology advice in their histology report and, if indicated, whether it was arranged. The second was to devise a vault cytology protocol based on local experience and national guidance. METHODS: The local cancer registry was searched. Clinical, clerical and histological data for all patients undergoing hysterectomy were collected. RESULTS: In total, 271 patients were identified from both the gynae-oncology and benign gynaecology teams. Of these, 24% (65/271) were gynae-oncology patients with a mean age of 69 years. The benign gynaecology team had 76% (206/271) of patients with a mean age of 55 years. Subsequently, 94% (256/271) had cytology follow-up advice in their histopathology report. Ultimately, from both cohorts, 39% (18/46) had follow-up cytology performed when indicated. CONCLUSION: A high proportion of cases complied with national guidance. However, a disappointingly high number did not have vault cytology sampling when this was indicated. This is probably a result of the complex guidance that is misunderstood in both primary and secondary care. Vault follow-up of patients after hysterectomy rests with the team performing the surgery. Vault cytology, if indicated, should be performed in secondary care and follow-up should be planned. The protocol set out in this article should be followed to avoid unnecessary clinical governance failings.

Vigorous physical activity and cytokines in adolescents.

Habitual physical activity and chronic exercise may positively influence circulating cytokines in youth as in adults. The purpose of this study was to determine if adolescents reporting higher amounts of physical activity had a better cytokine profile independent of weight status. We compared the concentrations of cytokines in highly active (n = 60) and less active adolescents (n = 60) of different weight status [normal weight (BMI < 75th percentile), and overweight (BMI > 95th percentile)]. Vigorous physical activity (VPA) was obtained through a questionnaire and included activities with a MET level of > or =6. Adiponectin, resistin, TNF-alpha and IL-6 were measured in fasting plasma samples. Anovas indicated that girls with high VPA had higher adiponectin than girls with low VPA (P < 0.05), but similar resistin, TNF-alpha and IL-6 concentrations (P > 0.05). Boys with high VPA had only a trend to lower resistin than those with low VPA (P = 0.052). Differences between VPA groups were independent of weight status. In adolescents, higher amounts of accumulated habitual VPA may improve some cytokines, reducing the risk of inflammation associated with increased adiposity and insulin resistance. The effect of physical activity appears to be independent of weight status.

Dietary supplements of soya flour lower serum testosterone concentrations and improve markers of oxidative stress in men.

OBJECTIVE: We examined the effects on serum sex steroids, lipids and markers of oxidative stress of supplementing the diets of healthy male volunteers with scones made with soya flour. DESIGN: A randomized placebo controlled cross-over trial. SETTING: University Hospital of Wales. SUBJECTS: Twenty volunteers recruited by advertisement. INTERVENTIONS: Male volunteers ate three scones a day in addition to their normal diet for a period of 6 weeks. The scones were made with either wheat or soya flour (containing 120 mg/day of isoflavones). Blood was analysed for sex steroids (testosterone, dihydro-testosterone, oestradiol, oestrone, sex hormone binding globulin, albumin and the concentration of non-protein bound sex steroids were calculated), lipid profile (total cholesterol, high density lipoprotein cholesterol and triglycerides) and measures of oxidative stress (hydroperoxides, susceptibility of LDL to oxidation with copper and myeloperoxidase). RESULTS: The volunteers' mean age was 35.6 (s.d. 11.2) y. Total serum testosterone fell in volunteers taking the soya scones (19.3-18.2 nmol/l; 95% CI 1.01, 1.12; P=0.03). No significant changes were seen in the concentrations of the other serum sex steroids, albumin or sex hormone binding globulin throughout the study. Significant improvements in two of the three markers of oxidative stress were seen in volunteers taking soya scones. Lag time for myeloperoxidase rose from 55.0 to 68.0 min (95% CI -16.0, -3.5; P=0.009) and the presence of hydroperoxides decreased from 2.69 to 2.34 micro mol/l (95% CI 0.12, 0.71; P=0.009). There were no changes seen in serum triglycerides or cholesterol. CONCLUSIONS: We have shown that soya supplements reduce serum testosterone and improve markers of oxidative stress. These findings provide a putative mechanism by which soya supplements could protect against prostatic disease and atherosclerosis. Further dietary studies with clinical end points are warranted.

Management of opioid-induced constipation.

Constipation is an expected side effect of opioid use and as such should be treated prophylactically. However, because it is often overlooked and under-appreciated it is one of the most common reasons patients avoid or abandon opioid use and, as a result, suffer pain needlessly. Thorough assessment, ongoing evaluation, and patient teaching are key factors in establishing an effective bowel regimen. A bowel clean-out is indicated for patients who have not had a bowel movement in more than 5 days. Once any impactions have been eliminated, a regular regimen of senna and docusate is recommended. Dietary modifications, fluids, and exercise are important but usually not sufficient to overcome opioid-induced constipation. Although many of the medicines that are used to treat pain and related symptoms come with a significant potential for distressing side effects, it is important to understand that most side effects, especially constipation, can be managed and quality of life can be preserved without sacrificing needed analgesia.

Why provider-sponsored health plans don't work.

Integrated delivery systems (IDSs) that assume risk directly by starting their own health plans need to ensure that they have set realistic goals. Many provider-health plan integrations fail because either the conditions under which they are started are not optimal or the integration is faulty. Successful provider-plan integrations generally have developed in rural areas where they faced limited competition, had higher utilization rates, and enjoyed greater profit margins because of lower price competition and employers' acceptance of premium rates. These factors are uncommon today. IDDSs sponsoring health plans can face problems in partnering with physicians, who may not demonstrate concern for the success of the healthcare system as a whole. For these and other reasons, IDDSs should consider partnering with existing health plans rather than starting their own plans.

Forecasting roles of combinatorial chemistry in the age of genomically derived drug discovery targets.

Genomics has caused an explosion in the number of potential therapeutic targets with varying degrees of validated pathophysiology. Among the first applications of combinatorial chemistry in genomics-driven drug discovery is the search for surrogate ligands or substrates. In the event that no surrogate is found for molecular assays, more exotic functional screens in whole cells or model organisms are used. Protein-protein interaction mapping by yeast and mammalian two-hybrid systems dominates empirical functional genomics, and this will lead to a bias for screening projects targeting this type of interaction. Drug discovery for protein-protein interactions has a poor track record, and this will challenge prevailing views on the design of combinatorial libraries. Genomics based on structural homology will yield many putative kinases, receptors, enzymes, transporter proteins, ion channels and GPCRs. Most of these projects will require new surrogate agonists, ligands or substrates, and then pharmaceutically useful agonists or antagonists will need to be found. Again, combinatorial chemistry might be essential to these studies. Given the need to screen hundreds of targets at great risk of irrelevance to pathophysiology, combined with the challenge of finding surrogate or natural ligands for these new targets, there is an urgent need for efficiency. Different groups are addressing these concerns by developing biologically-driven combinatorial libraries in order to achieve a higher density of bioactivity. Early efforts in this regard will be described.

Medical students' attitudes toward pain and the use of opioid analgesics: implications for changing medical school curriculum.

BACKGROUND: Barriers to pain management include physicians' lack of knowledge and attitudes. Our aim was to investigate future physicians' knowledge and attitudes toward pain and the use of opioid analgesics. METHODS: We tested a medical school class during their freshman and senior years. Stepwise regression analysis was used to identify the personal traits that predicted opiophobia. RESULTS: The professionalization process of medical training may reinforce negative attitudes. Psychologic characteristics were associated with reluctance to prescribe opioids, and fears of patient addiction and drug regulatory agency sanctions. CONCLUSIONS: Consistent attitudes were found in senior medical students with preferences for certain specialty areas and the practitioners of their future specialties, suggesting a "preselection" effect. Higher scores on reliance on high technology, external locus of control, and intolerance of clinical uncertainty were associated with higher scores on one or more of the three dimensions of opiophobia. Implications for medical education are discussed.

Physicians' attitudes toward pain and the use of opioid analgesics: results of a survey from the Texas Cancer Pain Initiative.

BACKGROUND: Despite extensive progress in the scientific understanding of pain in humans, serious mismanagement and undermedication in treating acute and chronic pain is a continuing problem. This study was designed to examine the barriers to adequate pain management, especially as they might be associated with community size and medical discipline. METHODS: A 59-item survey was used to measure physicians' attitudes, knowledge, and psychologic factors that contribute to pain management practices. RESULTS: Overall, a significant number of physicians in this survey revealed opiophobia (prejudice against the use of opioid analgesics), displayed lack of knowledge about pain and its treatment, and had negative views about patients with chronic pain. There were significant differences among groups of physicians based on size of geographic practice area and medical discipline. CONCLUSIONS: New educational strategies are needed to overcome these barriers and to improve pain treatment in routine medical practice. The effect of practice milieu must be taken into consideration.

Mammary hibernoma.

Hibernomas are rare benign tumours of brown fat. We report the first account in the English literature of a mammary hibernoma, presenting in the post-lactational period.

Combinatorial chemistry defines general properties of linkers for the optimal display of peptide ligands for binding soluble protein targets to TentaGel microscopic beads.

Affinity chromatography and the binding of soluble target proteins to novel or known ligands attached to solid supports are important phenomena to basic and applied research. Satisfactory display of a ligand for the acceptor protein is critical for successful binding to occur. Here we describe the application of combinatorial chemistry to systematically explore the properties of linkers used to present peptide ligands to various protein targets. Our main interest is in drug discovery, and our results probably explain, in large part, the disappointing efficiency of an early drug discovery method known as the "Selectide Process" (Lam, K. S., et al. (1991) Nature 358, 82-84). Interestingly, for all seven protein targets studied, a cationic feature was found to be a common theme for optimal linkers displaying peptide ligands on TentaGel beads, and this is not likely to be caused by ionic exchange mechanisms.

Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules.

Living systems are mainly composed and regulated by compounds in four biochemical classes and their polymers-nucleotides, carbohydrates, lipids, and amino acids. Early combinatorial chemistry libraries consisted of peptides. The present report describes the general bioactivity and biophysical properties of a combinatorial chemical library that used glyco, nucleotidyl, and lipid building blocks. The resulting chimeric combinatorial library of 361 compounds had a confirmed cumulative hit rate of 0.16%, which is 8-fold higher than a commonly claimed industrial benchmark of 0. 02%. It produced 7 structurally confirmed hits for a third of 12 proprietary drug discovery projects, and these comprised a variety of molecular targets. Diversity analyses demonstrated that despite the small number of compounds, a wider range of diversity space was covered by this library of biochemical chimeras than by a branched tripeptide library of the same size and similar generic formula.

A genomic screen of autism: evidence for a multilocus etiology.

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying

A reliable technique for radiographic imaging of the pisotriquetral joint.

We report a novel technique for radiographic imaging of the pisotriquetral joint. This technique has proved useful for five consecutive patients presenting with pisotriquetral osteoarthritis. It is consistently reliable in imaging the joint and reduces the number of unsuccessful radiographic attempts.