Adenocarcinoma arising in a retained esophageal remnant

Fistulation between the trachea and an infected mucocele arising from an excluded retained esophageal segment is an interesting and unusual complication of esophageal bypass surgery. We present such a case in which there was also malignant transformation in the cyst wall, manifested by invasive adenocarcinoma and widespread high-grade glandular dysplasia.     

Abnormal lipid profile of dystrophic cardiac tissue as demonstrated by one- and two-dimensional magic-angle spinning (1)H NMR spectroscopy.

Dystrophin, a protein associated with sarcolemma and cell membranes, is not expressed in sufferers of Duchenne muscular dystrophy (DMD), or in the mdx mouse. DMD is a fatal disorder, with a significant proportion of fatalities associated with cardiac failure ( approximately 40% having dilated cardiomyopathy and >90% clinically significant cardiac defects at death). In this study, the metabolic composition of intact dystrophic cardiac tissue was investigated using high-resolution magic-angle spinning (HRMAS) (1)H NMR spectroscopy with both 1- and 2D pulse sequences coupled with pattern recognition (PR). While conventional solvent presaturation spectra indicated increases in CH(2) chain length in lipids, PR analysis of correlation spectroscopy (COSY) spectra demonstrated that this was also accompanied by an increase in concentration of lactate or threonine along with a relative decrease in CH = CHCH(2)CO groups in these lipids. To investigate the physical environment of these lipids, T(2)- and diffusion-weighted (1)H MAS NMR spectra were acquired on whole-tissue samples. The relatively increased lipid signal intensity in dystrophic tissue was due to an increase in molecules with long T(2) and short diffusion rates. The use of a range of pulse programs allowed the direct probing of the biochemical environment in which the lipid infiltration occurred, and by coupling the experiments to PR the significance of lipid infiltration and accumulation was also assessed.     

High-resolution (1)H NMR and magic angle spinning NMR spectroscopic investigation of the biochemical effects of 2-bromoethanamine in intact renal and hepatic tissue.

The metabolic consequences of xenobiotic-induced toxicity were investigated using high-resolution magic angle spinning (MAS) NMR spectroscopy of intact tissue. Renal papillary necrosis (RPN) was induced in Sprague-Dawley rats (n = 12) via a single i.p. dose of 250 mg/kg 2-bromoethanamine (BEA) hydrobromide. At 2, 4, 6, and 24 h after treatment with BEA, three animals were killed and tissue samples were obtained from liver, renal cortex, and renal medulla. Tissue samples were also removed at 2 and 24 h from matched controls (n = 6). (1)H MAS NMR spectroscopic techniques were used to analyze samples of intact tissue ( approximately 10 mg). Decreased levels of nonperturbing renal osmolytes (glycerophosphocholine, betaine, and myo-inositol) were observed in the renal papilla of BEA-treated animals at 6 and 24 h postdose (p.d.), concomitant with a relative increase in the tissue concentration of creatine. Increased levels of glutaric acid were found in all tissues studied in BEA-treated animals at 4 and 6 h p.d., indicating the inhibition of mitochondrial fatty acyl CoA dehydrogenases and mitochondrial dysfunction. Increased levels of trimethylamine-N-oxide occurred in the renal cortex at 6 h p.d. Changes in the metabolite profile of liver included an increase in the relative concentrations of triglycerides, lysine, and leucine. The novel application of (1)H MAS NMR to the biochemical analysis of intact tissues following a toxic insult highlights the potential of this technique as a toxicological probe in providing a direct link between urinary biomarkers of toxicity and histopathological evaluation of toxicological lesions.     

Interaction of eicosanoids and nitric oxide in renal reperfusion injury.

BACKGROUND: Both the eicosanoids and nitric oxide are known to play an important role in the pathogenesis of postischemic injury. Recent evidence has suggested that the generation of each may affect the other via a feedback loop. This was investigated in an experimental model of renal warm ischemia reperfusion injury. METHODS: Rats underwent bilateral renal warm ischemia (15-60 min) then reperfusion (20 or 80 min) followed by a unilateral nephrectomy to measure renal nitric oxide (as nitroxides) and eicosanoids. Renal function was measured on days 2 and 7 prior to terminal nephrectomy for tissue analysis. RESULTS: Vasodilator eicosanoids (6-KPGF1alpha and PGE2) fell on reperfusion in line with the duration of warm ischemia with a concomitant rise in the vasoconstrictor TxA2. The ratio of vasodilator to vasoconstrictor eicosanoids fell from 8.22 (2.3) in the control to 0.82 (0.1) in the 60-min warm ischemia group (P<0.01). Renal levels of nitroxides rose on reperfusion demonstrating an inverse correlation with the eicosanoid ratio (r2=0.86). Renal function was impaired at both day 2 and day 7 and showed a positive correlation with the eicosanoid ratio (r2=0.67 and 0.62, respectively). CONCLUSIONS: Renal warm ischemic injury is associated with a progressive fall in the ratio of vasodilator-to-vasoconstrictor eicosanoids from early in reperfusion through to day seven although nitric oxide was elevated throughout the same period. There was no evidence of coinduction of nitric oxide synthase and cyclooxygenase in this model.     

Assessment of Fracture Risk: Value of Random Population-Based Samples-The Geelong Osteoporosis Study

Fracture risk is determined by bone mineral density (BMD). The T-score, a measure of fracture risk, is the position of an individual's BMD in relation to a reference range. The aim of this study was to determine the magnitude of change in the T-score when different sampling techniques were used to produce the reference range. Reference ranges were derived from three samples, drawn from the same region: (1) an age-stratified population-based random sample, (2) unselected volunteers, and (3) a selected healthy subset of the population-based sample with no diseases or drugs known to affect bone. T-scores were calculated using the three reference ranges for a cohort of women who had sustained a fracture and as a group had a low mean BMD (ages 35-72 yr; n = 484). For most comparisons, the T-scores for the fracture cohort were more negative using the population reference range. The difference in T-scores reached 1.0 SD. The proportion of the fracture cohort classified as having osteoporosis at the spine was 26, 14, and 23% when the population, volunteer, and healthy reference ranges were applied, respectively. The use of inappropriate reference ranges results in substantial changes to T-scores and may lead to inappropriate management.     

Stuff you think you can handle as a parent and stuff you can’t’. Understanding parental health‐seeking behaviour when accessing unscheduled care: A qualitative study

BackgroundUnscheduled health care constitutes a significant proportion of health‐care utilization. Parental decision making when accessing unscheduled care for their children is multifaceted and must be better understood to inform policy and practice.DesignNineteen semi‐structured interviews and one focus group (n = 4) with parents of children younger than twelve in Ireland were conducted. Participants had accessed unscheduled care for their children in the past. Data were thematically analysed.ResultsParents accessed unscheduled care for their children after reaching capacity to manage the child''s health themselves. This was informed by factors such as parental experience, perceived urgency and need for reassurance. Parents considered the necessity to access care and situated their health‐seeking behaviour within a framework of ‘appropriateness’. Where parents sought unscheduled care was largely determined by timely access, and inability to secure a general practitioner (GP) appointment often led parents to access other services. Parents expressed a need for more support in navigating unscheduled care options.ConclusionsBetter resources to educate and support parents are required, and structural issues, such as accessibility to GPs, need to be addressed to enable parents to better navigate the unscheduled health system and manage their children''s health. The discourse around ‘appropriate’ and ‘inappropriate’ access to health care has permeated parental decision making when accessing unscheduled health care for their children. What constitutes appropriate access should be examined, and a shift away from this framing of health‐seeking behaviour may be warranted.Patient or Public ContributionThere was no explicit patient or public involvement. All authors hold experience as users of the health system.     

Certified causes of death in patients with mesothelioma in South East England

Background  

Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.     

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

Acquired resistance to endocrine therapies presents a major obstacle to the successful treatment of breast cancer patients. Previously, we have shown that acquisition of resistance to tamoxifen in breast cancer cells is accompanied by an elevation in Src kinase activity which promotes an aggressive, invasive phenotype in vitro. Here, we have explored the potential therapeutic effects of combining Src inhibition with anti-oestrogen treatment on the development of endocrine insensitivity in breast cancer cells. Treatment of MCF7 and T47D cells with tamoxifen alone resulted in an initial growth inhibitory phase followed by the eventual development of tamoxifen resistance together with an elevation of Src kinase activity, which was central to their increased invasive capacity. Chronic exposure of both cell types to the Src inhibitor, AZD0530, as a monotherapy resulted in outgrowth of AZD0530-resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasive nature. Treatment of both MCF7 and T47D cells with AZD0530 in combination with tamoxifen resulted in a reduction of Src activity together with inhibition of focal adhesion kinase phosphorylation and a complete abrogation of their in vitro invasive behaviour. Furthermore, combination therapy significantly suppressed expression of cyclinD1 and c-myc and prevented cell proliferation and the subsequent emergence of a resistant phenotype, with total cell loss occurring by 12 weeks. These data demonstrate that pharmacological targeting of Src kinase, in conjunction with antihormone therapies, effectively prevents antihormone resistance in breast cancer cells in vitro and suggests a potential novel therapeutic benefit of Src kinase inhibitors clinically.     

Derivation of a subtype-specific biochemical signature of endometrial carcinoma using synchrotron-based Fourier-transform infrared microspectroscopy

Endometrial carcinoma consists of endometrioid (type I) and serous papillary (SP; type II) subtypes; a rarer form is malignant mixed müllerian tumours (MMMT; type II/mixed). We set out to determine whether one might be able to biochemically signature these subtypes using Fourier-transform infrared (FTIR) microspectroscopy and distinguish non-tamoxifen associated from tamoxifen-associated cases. Paraffin-embedded blocks were obtained from non-tamoxifen associated cases reported as endometrioid (n=7), SP (n=4) or MMMT (n=4). From tamoxifen-associated cases, endometrioid (n=1), SP (n=3) and MMMT (n=4) blocks were retrieved; benign tissues (n=3) were also analysed. Exploiting synchrotron-based radiation, sections (10-microm thick) on BaF(2) windows were interrogated through a 10 microm x 10 microm aperture. Point spectra were derived from >or=10 locations in each of six glandular elements per tissue; a further 20 stromal spectra were obtained. Following normalisation to Amide I, average spectra (1800-900 cm(-1)) per gland or stroma were analysed for variance using principal component analysis (PCA) and linear discriminant analysis (LDA). In scores plots, segregation of spectra from different subtypes or benign tissues was noted and it proved possible to distinguish tamoxifen-associated cases. In the PCA-LDA loadings plots, the wavenumbers that highlighted variance for benign or endometrioid carcinoma tissues were in the protein region (1800-1480 cm(-1)) whereas those contributing most to SP or MMMT segregation were primarily in the DNA/RNA region (1425-900 cm(-1)) of the vibrational spectrum. Our results suggest that the application of FTIR microspectroscopy is a powerful new approach in disease diagnosis and characterisation.     

Predicting breast cancer risk: implications of a “weak” family history

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk ≥1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40–56, with family histories placing them below the “moderate” level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that “low penetrance” alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them. All the authors are from the Scottish Cancer Family Clinical Centres.