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.

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.

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.

Identification and characterization of pro-T lymphocytes and lineage-uncommitted lymphocyte precursors from mice with three novel surface markers.

The study of prethymic stages of T cell development has been limited because specific markers for mouse pro-T lymphocytes were not available. We developed a panel of rat monoclonal antibodies (mAbs) that bind to our pro-T lymphocyte clones obtained from bone marrow of young adult mice and the thymus of 14-d-old embryos. The mAbs, called Joro 30-8, Joro 37-5, and Joro 75, were found to bind to all pro-T clones tested but not to cell lines representing later stages of T cell development, B lymphocyte, or myeloid lineages. We determined the frequency and tissue distribution in normal and immunodeficient mouse strains as well as the ontogeny in liver and thymus of cells positive for these mAbs. The results were consistent with the pattern of reactivity observed with cell lines. We isolated Joro 30-8+, Joro 37-5+, and Joro 75+ bone marrow cells by cell sorter and found that: (a) phenotypically, they are Thy-1+, CD4-, CD8-, CD3-, B-220-, IgM-, F4/80-, and PgP-1+; (b) they grew in response to the combination of interleukin 3 (IL-3) + IL-4 or IL-3 + IL-4 + IL-6; and (c) Joro 37-5+ and Joro 75+ marrow cells gave rise to mature T lymphocytes but not to B lymphocytes, while Joro 30-8+ marrow cells generated both T and B lymphocytes after 8-12 wk of transfer into severe combined immunodeficient (Scid) mice. In normal mice subjected to 600 rad of irradiation to induce a wave of thymus recolonization, we found by flow fluorocytometry analysis that Joro+ cells entered the thymus 2 d after irradiation, expanded during the next 4 d, and underwent further differentiation, and from day 8 up to day 21, post-irradiation Joro+ cells were no longer detectable in the thymuses. Immunohistochemical analysis of normal thymus shows the presence of very few Joro 30-8+, Joro 37-5+, and Joro 75+ lymphoid cells in the subcapsular area and outer cortex but not in the medulla. The kinetic analysis of tissue sections from thymuses at various days post-irradiation suggests that Joro+ cells enter the thymus via blood vessels through the subcapsular and outer cortex areas; subsequently, these cells seem to migrate to the inner cortex without reaching the medulla, and give rise to Joro- thymocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

Recurrent breeding seasons in pinealectomized or optic-nerve-sectioned ferrets.

The breeding seasons of two groups of pinealectomized ferrets and one group of blind ferrets, with appropriate controls, were observed for up to 5 years after the operations. All animals showed recurrent breeding seasons. Both pinealectomized and blind animals became increasingly asynchronous after the first season, but showed no evidence of a free-running, endogenous circannual periodicity nor of synchronization to light or other environmental cues.

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.

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.

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.

Peptides associated with eggs: mechanisms of interaction with spermatozoa.

Speract (Gly-Phe-Asp-Leu-Asn-Gly-Gly-Gly-Val-Gly), a peptide obtained from the culture medium of Strongylocentrotus purpuratus eggs, stimulates the respiration and motility of S. purpuratus spermatozoa under appropriate conditions. Resact (Cys-Val-Thr-Gly-Ala-Pro-Gly-Cys-Val-Gly-Gly-Gly-Arg-LeuNH2), a peptide obtained from Arbacia punctulata eggs also stimulates the metabolism and motility of A. punctulata spermatozoa, however, it fails to stimulate S. purpuratus spermatozoa. Early biochemical responses of the spermatozoa to the egg peptides include a net H+ efflux and elevations of cyclic AMP and cyclic GMP concentrations. In addition, in A. punctulata spermatozoa, a major plasma membrane protein is modified in response to resact such that its apparent molecular weight shifts from 160,000 to 150,000. If cells are incubated with 32P, the 160,000 molecular weight form of the protein becomes radiolabeled; subsequent addition of resact causes a rapid loss of 32P from the protein. The plasma membrane protein appears to be the enzyme, guanylate cyclase; coincident with the shift in apparent molecular weight, enzyme activity decreases by as much as 90%. Since speract fails to cause these responses in A. punctulata, it can be concluded that the events are receptor-mediated.

Oncology nurses' attitudes regarding voluntary, physician-assisted dying for competent, terminally ill patients.

Euthanasia and "voluntary dying" are among the most controversial issues involved in cancer care. The purpose of this descriptive study was to explore oncology nurses' attitudes about physician-assisted death (PAD) for competent, terminally ill adults who request this assistance. Questionnaires were sent to 2,000 randomly selected members of the Oncology Nursing Society. The questionnaires included demographic questions, four vignettes describing patient care situations and possible responses based on beliefs about PAD, and questions that explored awareness of organizations and legislation that promote legalization of PAD. The response rate was 61% (1,210). Findings indicate that oncology nurses hold diverse views regarding the acceptability of PAD. Although many nurses favored PAD, they also expressed a reluctance to administer the medication that would cause death. Given that PAD is an ethical and legal issue in the United States for terminally ill patients, nurses are encouraged to become informed about the concept of PAD and be prepared to actively respond to the policy-making ramifications of the assisted-death movement.

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.

Measuring medical students' reluctance to prescribe opioids for cancer pain.

Among 644 senior medical students a 14-item scale which was internally consistent indicated no change over the 6 years of testing in intent to reserve opioids for terminally ill.

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.