Totally endoscopic cartilage tympanoplasty: a hierarchical task analysis.

BACKGROUND: Totally endoscopic ear surgery is a novel method of conducting otological surgery. Hierarchical task analysis and the systematic human error reduction and prediction approach ('SHERPA') are valuable tools that can effectively deconstruct the technical and non-technical skills required to successfully complete a surgical procedure. METHODS: Twenty-five endoscopic tragal cartilage tympanoplasties were observed, to identify the tasks and subtasks required for completion of totally endoscopic tragal cartilage tympanoplasty. The systematic human error reduction and prediction approach was used to identify the potential risks and methods, to reduce or remediate these risks. RESULTS: A hierarchical task analysis was performed, identifying 8 tasks and 50 subtasks for a safe approach to completing totally endoscopic tragal cartilage tympanoplasty. A risk score for each subtask was calculated to produce a systematic human error reduction and prediction approach and to highlight potential errors. CONCLUSION: This hierarchical task analysis allowed for quick reference to a correct method of endoscopic tympanoplasty. The systematic human error reduction and prediction approach was employed to reduce the risks associated with undergoing endoscopic tympanoplasty, to improve patient safety.

The lady with the dragon tattoo.

BACKGROUND: Though the skin is affected in sarcoidosis in about one-third of cases, granulomatous tattoo reactions are an unusual manifestation of the disease. It is important phenomenon to recognize, as it frequently leads to the diagnosis of systemic sarcoidosis. CASE PRESENTATION: A 35-year-old Caucasian female with multiple tattoos presented with a 5-week history of tenderness of the black dye in a tattoo depicting a dragon. She also described a 15-month history of fatigue, polyarthralgia, and mild dyspnea. Skin biopsy demonstrated multiple dermal non-caseating granulomata with associated tattoo ink. Further investigation revealed the presence of systemic sarcoidosis. Her symptoms and skin changes improved with conservative management. CONCLUSION: Sarcoidal tattoo reactions in those without systemic sarcoidosis are a rare occurrence, and their presence should prompt a search for systemic involvement. The accurate identification of skin involvement in sarcoidosis is important, as it tends to occur early in the course of disease, and the skin is a readily accessible site for biopsy, allowing for prompt diagnosis.

Ageing is a process where the growth effect of neuronal noradrenaline changes progressively in favour of the flow mediated, neurodegenerative and inflammatory effect of plasma noradrenaline.

The noradrenaline stimulus has two components, one excitor, the other inhibitory. Neuronal noradrenaline is the excitor component and plasma noradrenaline is the inhibitory. The balance of effect between the two, the noradrenergic balance, is the controlled variable of the sympathetic system and determines the effect of noradrenaline. Neuronal noradrenaline stimulates tissues by diffusion from their sympathetic nerve endings, plasma noradrenaline does so by diffusion from their microcirculations. Changes in microcirculatory flow, by altering the flow mediated effect of plasma noradrenaline, are mainly responsible for altering the noradrenergic balance in the peripheral tissues; changes in CSF flow are speculated to be mainly responsible for doing the same in the brain, by altering the balance between synaptic noradrenaline in the brain and nonsynaptic noradrenaline in the subarachnoid CSF. When plasma noradrenaline alters the noradrenergic balance it triggers afferent sympathetic activity that alerts hypothalamic neurons to the event and they restore the balance and tissue homeostasis, within milliseconds, by adjusting the level of efferent sympathetic activity they project back to the affected tissue. Because the restoration is so rapid the effect of plasma noradrenaline is normally unobservable and dismissed as not having occurred. Because the hypothalamus is not involved with the responses of isolated canine lateral saphenous vein segments to noradrenaline, the effects of plasma noradrenaline in that preparation are not countered by reactive efferent activity and, consequently, are readily apparent in it. Quantitatively, they have been found to be a function of microcirculatory flow and noradrenaline concentration and, qualitatively, to be inhibitory, dilator, pro inflammatory and neurodegenerative. In life, due to a progressive increase in plasma noradrenaline concentration and, more so, in microcirculatory flow, the noradrenergic balance moves progressively in favour of the neurodegenerative and inflammatory effects of plasma noradrenaline. These observations are the basis of an hypothesis that ageing is caused by a genetically programmed shift in balance away from the growth and anti-inflammatory effects of neuronal noradrenaline, early in life, towards the neurodegenerative and pro-inflammatory effects of plasma noradrenalin, later in life. Death is believed to occur when plasma noradrenaline has damaged the structure of the sympathetic system so much that it can no longer create the minimum quantity of neurotransmitter needed to maintain the level of noradrenergic balance and homeostasis necessary for life.

The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline.

Experiments on canine lateral saphenous vein segments have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates a segment by diffusion from its microcirculation (vasa vasorum). The effects it causes contrast with those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected - star patterns need darkness, sound patterns, quietness - has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance is believed to be responsible for inflammatory and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia. Finally, the shift in the balance caused by the slow physiological increase in plasma noradrenaline concentration in life is believed to be responsible for ageing.

Diacylglycerol kinase η modulates oncogenic properties of lung cancer cells.

PURPOSE: Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase η (DGKη), an enzyme that phosphorylates diacylglycerol to form phosphatidic acid, has been shown to modulate MAPK signaling downstream of EGFR, which is an oncogenic driver in some lung cancers. Since mutations in EGFR and K-Ras are common in lung cancer, we hypothesized that limiting the function of DGKη would attenuate oncogenic properties of lung cancer cells. METHODS: We determined the expression levels of DGKη in a mouse models of mutant EGFR and K-Ras lung cancer and in human lung cancer cell lines with activating mutations in either EGFR or K-Ras. We also tested the effects of shRNA-mediated depletion of DGKη in lung cancer cells and tested if DGKη depletion augmented the effects of afatinib, a new generation EGFR inhibitor. RESULTS: DGKη was expressed in malignant epithelium from mice with mutant EGFR or K-Ras lung cancer. It was also expressed in human lung cancer cell lines with EGFR or K-Ras mutations. Depleting DGKη in lung cancer cell lines, harboring mutant EGFR, reduced their growth on plastic and in soft agar and also augmented the effects of afatinib, an EGFR inhibitor. DGKη depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras. CONCLUSIONS: Our data indicate that DGKη is a potential therapeutic target in lung cancers, especially those harboring EGFR mutations. Our findings warrant further studies to examine the effects of limiting its function in vivo.

Imbalances in the neurotrophic effects of noradrenaline, favouring the positive in the child and the negative in the mother, are the cause of preeclampsia.

Preeclampsia is an inflammatory condition, involving the pregnant mother and complicated by the presence of a growing child and a disfunctional placenta; such is its complexity that so far no one has been able to fully elucidate its pathophysiology. Varicose veins are an inflammatory condition also, but far simpler and localised, whose pathophysiology has recently been virtually fully established by a combination of clinical observation, animal experiment and analysis of stripped veins. They have indicated the immediate cause of inflammation is stimulation of a tissue by increased levels of plasma noradrenaline, at basal concentration, diffusing into it from its microcirculation. The hypothesis offered here applies that information and proposes the changes in the uteroplacental tissues in preeclampsia are a result of a decreased level of microcirculatory noradrenaline stimulation, and the changes in the maternal tissues are a result of an increased level. The dichotomy means any treatment likely to benefit the mother in preeclampsia is likely to harm the child and vice versa. That may explain why the spectacular therapeutic advances of the past 50-60 years have had, relatively, so little impact on the treatment of preeclampsia. However, experiments aimed at finding tissue specific drugs to treat different aspects of HIV and individual types of cancer offer some slight hope that in the long term it may be possible to at least alleviate preeclampsia, if not cure it.

Successful use of combined high cut-off haemodialysis and bortezomib for acute kidney injury associated with myeloma cast nephropathy.

We present the case of a 58-year old female with de novo dialysis-dependent acute kidney injury (AKI) secondary to myeloma cast nephropathy. The patient underwent extended high cut-off haemodialysis (HCO-HD), in conjunction with bortezomib-based chemotherapy, and soon became dialysis independent with normal renal function. To our knowledge, this is the first time this treatment strategy has been employed successfully in an Irish centre.

Removal of multiple sentinel lymph nodes in patients with breast cancer: defining the "correct" node.

PURPOSE: Sentinel node biopsy is routinely used for axillary staging in patients with clinical and radiological node negative breast cancer. The number of nodes removed at surgery is highly variable. A mean of 2.4 nodes is frequently seen in the larger series. Removal of multiple (3 or more) nodes does not improve the accuracy but increases both operative time and pathological analysis. The aim of the current study was to define the correct sentinel node based on uptake of blue dye and radioactive counts. METHODS: The sentinel node was identified in 121 consecutive patients using isosulfan blue dye and radioisotope. Nodes were labelled sequentially as (i) Hot (ii) Blue or (iii) Hot and Blue and submitted for pathological analysis. Data pertaining to blue dye uptake and radioisotope counts were recorded prospectively. This was correlated with pathological and scintigraphy findings. RESULTS: Thirty eight (32%) patients had a positive sentinel node. "Hot and Blue" nodes were found in 105 cases. The number of hot and blue nodes correlated exactly with the number seen on scintigraphy. "Blue" nodes were found in one case. "Hot" nodes were found in 15 cases. In cases where a "hot and blue" node was positive there were no further "hot" or "blue" nodes found to be positive. CONCLUSION: Removal of multiple sentinel nodes can be avoided by removing all hot and blue nodes and correlating with findings on lymphoscintigraphy. When present (87% of cases), the "hot and blue" node accurately predicts the pathological burden of the axilla.

The significance of immunohistochemistry positivity in sentinel nodes which are negative on haematoxylin and eosin in breast cancer.

INTRODUCTION: Sentinel lymph node (SLN) biopsy allows a more detailed examination of a smaller number of lymph nodes in patients with clinically node negative breast cancer. Immunohistochemistry detects small tumour burden not routinely seen on haematoxylin and eosin (H&E). The significance of such findings remains to be fully elucidated. AIM: To assess the axillary disease burden of patients in whom the sentinel lymph node biopsy was positive on immunohistochemistry and negative on H and E. METHODS: An analysis of patients who underwent SLN mapping for breast cancer at St Vincent's University Hospital from January 1st, 2000 to December 31st, 2006 was conducted. All SLNs were assessed by serial H&E and IHC sections. Patients with micrometastases (0.2-2mm) underwent a completion axillary lymph node dissections (CLND). Patients with ITC (<0.2mm) were individually discussed and a CLND was performed selectively based on additional clinicopathological criteria and patient preference. Analysis of the additional nodes from CLND was performed. Patients were followed for a median of 27 months (range 12-72 months). RESULTS: 1076 patients who underwent SLN were included for analysis. 211 (20%) had a positive SLN biopsy using H&E. Forty-nine patients (5%) had a negative SLN on H&E which was positive on IHC. Of these, 15 had micrometastases and underwent a CLND. Two had further axillary nodal disease. ITC were found in the remaining 34 patients. Sixteen of these patients underwent a CLND. Five of this group had further nodal disease. CONCLUSION: Micrometastases and isolated tumour cells, detected only by immunohistochemical analysis of sentinel lymph nodes, are associated with further positive nodes in the axilla in up to 15% of patients. This upstaging of disease may impact upon patient outcome.

Radical pancreaticoduodenectomy for benign disease.

Whipple's procedure is the treatment of choice for pancreatic and periampullary malignancies. Preoperative histological confirmation of malignancy is frequently unavailable and some patients will subsequently be found to have benign disease. Here, we review our experience with Whipple's procedure for patients ultimately proven to have benign disease. The medical records of all patients who underwent Whipple's procedure during a 15-year period (1987-2002) were reviewed; 112 patients underwent the procedure for suspected malignancy. In eight cases, the final histology was benign (7.1%). One additional patient was known to have benign disease at resection. The mean age was 50 years (range: 30-75). The major presenting features included jaundice (five), pain (two), gastric outlet obstruction (one), and recurrent gastrointestinal haemorrhage (one). Investigations included ultrasound (eight), computerised tomography (eight), endoscopic retrograde cholangiopancreatography (seven; of these, four patients had a stent inserted and three patients had sampling for cytology), and endoscopic ultrasound (two). The pathological diagnosis included benign biliary stricture (two), chronic pancreatitis (two), choledochal cyst (one), inflammatory pseudotumour (one), cystic duodenal wall dysplasia (one), duodenal angiodysplasia (one), and granular cell neoplasm (one). There was no operative mortality. Morbidity included intra-abdominal collection (one), anastomotic leak (one), liver abscess (one), and myocardial infarction (one). All patients remain alive and well at mean follow-up of 41 months. Despite recent advances in diagnostic imaging, 8% of the patients undergoing Whipple's procedure had benign disease. A range of unusual pathological entities can mimic malignancy. Accurate preoperative histological diagnosis may have allowed a less radical operation to be performed. Endoscopic ultrasound-guided fine needle aspirate (EUS-FNA) may reduce the need for Whipple's operation in benign pancreaticobiliary disease in the future.

Sentinel lymph node biopsy in elderly irish patients with malignant melanoma.

In patients with malignant melanoma, Breslow depth increases with age. However, studies suggest that the frequency of sentinel lymph node metastases in malignant melanoma decreases with age. We investigated whether this applied to the cohort of patients undergoing sentinel lymph node biopsy (SLNB) in our institution. In a prospectively accrued database we identified 149 patients undergoing SLNB from 1997 to 2005. Tumour thickness as measured by Breslow depth was assessed in stratified age groups. We assessed the relationship between SLNB positivity and age using the Chi-square for trend. We directly examined the relationship between SLNB positivity in patients aged less than 65 and aged 65 years of age and over. Disease-free and overall survival in patients aged less than 65 and aged 65 years of age and over were also assessed. Comparing the age groups, there was no significant difference identified in Breslow depth (<65 years, median Breslow > or = 1.2 mm (range 0.2-9.7); > or =65 years, median Breslow > or = 1.4 mm (range 0.12-8.5); p > or = 0.06, Mann-Whitney U). Chi-square for trend identified no significant relationship between SLNB positivity and age. We found n=120 patients <65 had SLNB, of which 26 (21.7%) were positive. In patients =65, n=29 had SLNB of which 3 (10.3%) were positive. These differences were not statistically significant (Fisher's exact test, p > or = 0.2). There was no difference in disease-free or overall survival between patients aged <65 or > or =65 who had SLNB (median follow-up 37.5 months (range 5-70); disease-free survival, p > 0.08; overall survival, p > or = 0.3, Logrank test). We did not find that elderly patients with malignant melanoma had a demonstrable difference in tumour thickness when compared to younger patients. In those patients who underwent SLNB there was no significant difference in node positivity between the age groups. Disease-free and overall survival were not significantly different between the age groups. Further study and longer follow-up will help establish the relationship between age and SLNB positivity.

Changing patterns of thyroid carcinoma.

BACKGROUND: To assess changing trends in histological types of thyroid cancer in an Irish hospital over the past 30 years. METHODS: Biographical data, tumour characteristics, treatment and outcome from 190 patients with thyroid carcinoma from 1970 to 2000 were reviewed retrospectively. RESULTS: Detailed records of 190 patients with thyroid cancer were identified with a mean age at presentation of 50 years. From 1970 to 1979 the distribution of histological types was: papillary carcinoma; 9 patients (4.7%), follicular; 17 patients (8.9%), anaplastic; 9 patients (4.7%), medullary; 1 patient (0.5%) and lymphoma; 1 patient (0.5%). From 1980 to 1989 papillary carcinoma accounted for 32 patients (16.8%), follicular; 14 patients (7.3%), anaplastic; 13 patients (6.8%), medullary; 7 patients (3.7%) and lymphoma; 5 patients (2.6%). From 1990 to 1999 papillary cancer accounted for 48 patients (25.2%), follicular; 14 patients (7.3%), anaplastic; 8 patients (4.2%), medullary; 7 patients (3.7%) and lymphoma; 5 patients (2.6%). Survival rates were significantly better for those aged less than 45 years (P < 0.0001), female sex (P < 0.01) and those with papillary carcinoma (P < 0.01). CONCLUSIONS: This study demonstrated a significant increase in the incidence of papillary carcinoma. This may be related to increasing dietary iodine intake and may be significant as papillary carcinoma is associated with a more favourable prognosis.

The venous valve agger and plasma noradrenaline-mediated venodilator feedback.

OBJECTIVE: To investigate the structure and function of the venous valve agger, a fibroelastic structure located at the base of every valve in veins that are responsive to noradrenaline (NA). DESIGN: Constant flow perfusion studies of the responses of in situ and in vitro canine lateral saphenous vein segments to NA and electrical stimulation, supplemented by histological studies of the segments. SETTING: University Departments of Physiology and Histology. MATERIALS: Segments of canine lateral saphenous vein. In vitro=84, in situ=60 plus. RESULTS: The agger is a crescentic fibroelastic sleeve, spanning the vein wall very obliquely through which the local vasa venarum network drains. It has a dedicated musculature which, when the tone rises, contracts and stretches the fibroelastic of the agger and opens the drainage channels to reflux. Each agger has four muscles, two each of which insert on the concave and convex margins of the agger. They pull in opposite directions when they contract. CONCLUSIONS: The agger forms part of a complex that, in conjunction with its dedicated musculature, a reversible transmural pressure gradient and physiological turbulence in the valve sinuses, positively facilitates drainage from the local segment of the vasa venarum network when venous tone is normal; and when venous tone is elevated it pumps and sucks blood from the lumen of the vein to perfuse the vasa venarum network. When the plasma NA in the perfusate diffuses from the network, it causes a localized venodilator feedback effect that restores the elevated tone of the vein to normal. The feedback effect is potent, being estimated to reduce the venonstrictor effect of neuronal NA by about 50% when flow is laminar and considerably more when flow is turbulent. There is evidence that plasma NA may constitute the lateral inhibitory component of the NA chemostimulus of the smooth muscle cell, neuronal NA constituting the excitor component. A chronic breakdown in agger function is believed to be the cause of varicose veins.

A quantitative study of enamel acid etch patterns on surfaces used for retention of resin-bonded fixed prostheses.

This study investigated the quality of in vivo etch patterns on the bonding surfaces of 46 abutment teeth following acid etching with 37% phosphoric acid for 30 seconds. Two-stage putty and light bodied addition cured silicone impressions of the etched lingual surfaces were used to form replicas that were then viewed using the scanning electron microscope. Over 69% of the lingual bonding surface area of incisors, canine and premolars were unetched, 16% barely etched, 7% etched and less than 2% ideally etched. There was no significant difference in the quality of etch between different tooth types. There was a significantly greater proportion of poorly etched enamel towards the cervical margin in comparison with the occlusal half. This may have implications in retention of resin bonded bridges.

Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer.

The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-alpha and ER-beta. Although ER-alpha has been well characterized, the role of ER-beta as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-alpha, ER-beta and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n=150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of beta-oestradiol and tamoxifen was assessed using Western blotting (n=14). Oestrogen receptor-beta protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P=0.0008 and P<0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (P<0.0001 and P<0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to beta-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-beta and SRC-1 was inversely associated (P=0.0001). The association of ER-beta protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.

Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1.

BACKGROUND: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. AIM: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. METHODS: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. RESULTS: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p<0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). CONCLUSION: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.

Factors affecting metastases to non-sentinel lymph nodes in breast cancer.

AIMS: Because sentinel lymph node (SLN) biopsy for breast cancer has become well established, one of the challenges now is to determine which patients require a completion axillary dissection following a positive SLN biopsy. METHODS: A prospective database of patients who underwent SLN biopsy for invasive breast cancer from July 1999 to November 2002 (n = 180) was analysed. Fifty four patients (30%) had one or more positive SLN, and all underwent a completion axillary dissection. This subgroup was further analysed to delineate which factors predicted non-SLN metastasis. RESULTS: Twenty six of the 54 patients with a positive SLN had additional metastases in non-SLNs. Significant variables that predicted non-SLN metastasis included extranodal extension (odds ratio (OR), 17.399; 95% confidence interval (CI), 1.69 to 178.96) and macrometastasis within the SLN (OR, 6.985; 95% CI, 1.291 to 37.785). CONCLUSIONS: In patients with invasive breast cancer and a positive SLN, extranodal extension or macrometastasis within the SLN were both independent predictors of non-SLN involvement.

The corrupted feedback hypothesis.

This paper argues that varicose veins are caused by a feedback malfunction. The feedback in question regulates the tone of the vein by dilating it as needed, using noradrenaline (NA), tapped from the circulating pool, for the purpose. The drug, though conventionally classified as a venoconstrictor, dilates the vein when it diffuses from the vasa venarum of the vein into the vein's media; the drug having reached the vasa by reflux from the vein lumen. A varicosity is created when a factor increases the volume of reflux, and, therefore, the quantity of NA, perfusing a unit of the vasa network, selectively. The resultant, exaggerated, localised, dilator effect that the NA has on a section of the vein, constitutes the varicosity radix. In brief, a varicosity, when first created, is seen as being an exaggerated, but appropriate, dilator response of a section of a normal vein to an inappropriate, corrupted, feedback signal. The acute varicosity is believed to transform into the permanent type seen in varicose veins if the factor responsible for it persists long enough.

Objective measurement of breast cancer oestrogen receptor status through digital image analysis.

AIMS: The authors have previously described quantitative, computer-assisted analysis of oestrogen receptor status in immuno-histochemically stained sections in patients with primary breast cancer. The aim of this study was to validate the aforementioned system against the commonly used methods of assessing oestrogen receptor status. METHODS: Paraffin embedded sections from 156 patients with primary breast carcinoma were stained with anti-alpha-oestrogen receptor monoclonal antibody (1D5) using a standard immunohistochemical protocol. Images from 10 high-powered fields were captured from each section using a digital camera mounted on a microscope and analyzed using Adobe Photoshop image analysis software. A nuclear mask was obtained by digitally selecting the nuclear area. Staining intensity in the nuclear mask was then analyzed using red-scale absorption characteristics. Manual assessment of oestrogen receptor status was performed through counting the percentages of cells that are positive from 200 randomly sampled nuclei from ten high powered fields HPF. Cut off value for positivity was taken as 10%. Cytosolic oestrogen receptor concentration was measured through enzyme immunisation. Cut off value for ER positivity was taken as 200 fmol/g (wet tissue). RESULTS: One hundred and fifty-six sections were studied of which 41 were ER negative. Median percentage positivity in the remainder was 90% (17-100) by manual assessment. The median red scale value was 108 (58-156). A close correlation was observed between median optical density of the nuclear mask and percentage positivity assessed manually (P<0.0001). There was a significant correlation between the optical density of the nuclear mask and cytosolic oestrogen receptor concentration (P<0.001). CONCLUSION: Oestrogen receptor positivity can be accurately assessed through digital image analysis. This process offers objective data regarding the amount of oestrogen receptors within the nuclei as well as the percentage of nuclei, which express oestrogen receptors.