A call for a value based approach to laboratory medicine funding.

All areas of healthcare, including pathology, are being challenged by the reality that the days of ever increasing budgets are over and the key debate is about how to provide value for money. As originally described by Porter and Tiesberg, value-based healthcare is defined as maximising outcomes over cost by moving away from fee for service models to ones that reward providers on the basis of outcomes (1). While production efficiencies will continue to evolve, the opportunities for future stepwise improvements in production costs are likely to have diminished. The focus now is on delivering improved testing outcomes in a relatively cost neutral or at least cost effective way. This brings pathology into line with other health services that focus on value for money for payers, and maximising health outcomes for consumers. This would signal a break from the existing pathology funding model, which does not directly recognise or reward the contribution of pathology towards improved health outcomes, or seek to decommission tests that offer little clinical value. Pathology has a direct impact on clinical and economic outcomes that extend from testing and it is important to garner support for a new approach to funding that incentivises improvements of the overall quality and contribution of the pathology service.

Ultrasound is a useful adjunct to mammography in the assessment of breast tumours in all patients.

BACKGROUND: Ultrasound is the first-line breast imaging modality in younger patients and an adjunct to mammography in older patients. The objectives of this study were to evaluate the complementary value of ultrasound to mammography in breast cancer and to investigate the use of ultrasound in patients above and below the age of 50 years. METHODS: Clinical presentation and investigations for consecutive patients undergoing triple assessment at a symptomatic breast clinic were prospectively recorded between January 2000 and August 2003. Clinical data were compared with pathological findings. Patients were divided into two groups, above and below 50 years of age for subgroup analyses. RESULTS: A total of 999 of 2185 patients had both mammography and ultrasound investigations performed and constituted the study population. Subgroup analysis of the 2185 patients demonstrated that 99 of the 127 patients who were diagnosed with breast cancer had both investigations performed (median age 57.0, range: 34-89 years). Mammography was normal/benign in 14.1%, indeterminate in 29.3% and suspicious of cancer in 56.6% of patients. Adjunctive ultrasound was normal/benign in 13.1%, indeterminate in 6.1% and suspicious of cancer in 80.8% of patients. In these 99 patients, adjunctive ultrasound was more sensitive than mammogram alone (80.8% vs. 56.6%, p < 0.001). Ultrasound upgraded nine of 14 mammographically normal and 16 of 29 mammographically indeterminate X-rays to a cancer. Mammography appeared to be more sensitive in patients over 50 years compared with those patients under 50 years (62.5% vs. 45.7%, p = 0.10). The sensitivity of ultrasound was comparable between patients above and below the age of 50 years (82.8% vs. 77.1%, p = 0.60). Further subgroup analysis demonstrated a higher sensitivity with combined mammography and ultrasound compared with mammography alone in either patient group (below 50: 45.7%-->77.1% and above 50: 62.5%-->82.8%). These results also suggested that the difference in the sensitivities of mammography vs. the combined investigation approach was more marked in patients under 50 years of age (below 50 = 31.4% vs. above 50 = 20.3%). CONCLUSION: Adjunctive ultrasound assessment improves breast cancer detection in women of all ages and should be routinely used in symptomatic breast clinics.

Determination of verocytotoxin and eae gene loci by multiplex PCR in Escherichia coli O157:H7 isolated from human faeces in Northern Ireland: a four-year study of trends, 1997-2000.

This study aims to determine the distribution and frequency of verocytotoxin genes in human faecal clinical isolates of Escherichia coli O157 in Northern Ireland during the period 1997-2000, using a special four-target multiplex polymerase chain reaction (PCR) assay. One hundred and thirty two isolates of E. coli O157:H7 cultured during the four-year period (1997 [n=28]; 1998 [n=25]); 1999 (n=43); 2000 [n=36]), representing approximately 79% of total E. coli O157 laboratory isolations throughout N. Ireland, are examined for the presence of verocytotoxin gene loci (VT1, VT2 and eae) using a multiplex PCR assay. These isolates originate from the four Regional Area Health Boards that constitute the healthcare system in N. Ireland as follows: Eastern (53.8%; n=71), Northern (34.1%; n=45), Western (6.8%; n=9) and Southern (5.3%; n=7). Results showed that over 80% of these isolates possessed the VT2 and eae gene loci, with the remainder being predominantly VT1-, VT2- and eae-positive. None possessed the VT1 gene locus alone. Development and adoption of this simple four-target (three virulence and one control gene loci) multiplex PCR assay and subsequent recording of resulting verocytotoxin-typing data in a database, permitted local, rapid determination of carriage of known molecular virulence determinants of E. coli O157 isolates, which may aid in outbreak-related epidemiological investigations or other longitudinal studies.

A test of behavioral family therapy to augment exposure for combat-related posttraumatic stress disorder.

This study tested a family-based skills-building intervention in veterans with chronic combat-related posttraumatic stress disorder (PTSD). Veterans and a family member were randomly assigned to 1 of 3 conditions: (a) waiting list, (b) 18 sessions of twice-weekly exposure therapy, or (c) 18 sessions of twice-weekly exposure therapy followed by 16 sessions of behavioral family therapy (BFT). Participation in exposure therapy reduced PTSD positive symptoms (e.g., reexperiencing and hyperarousal) but not PTSD negative symptoms. Positive symptom gains were maintained at 6-month follow-up. However, participation in BFT had no additional impact on PTSD symptoms.

Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging.

A wide variety of neuroendocrine tumours express somatostatin receptors, and can be visualized by radiolabelled somatostatin analogue scintigraphy. To investigate the value of [111In]-octreotide scintigraphy (Octreoscan), 48 patients (37 with proven carcinoid, pancreatic endocrine and medullary carcinoma of thyroid tumours, 11 with neuroendocrine syndromes multiple endocrine neoplasia (MEN-I) and Zollinger-Ellison syndrome (ZES) were examined with 111In-DTPA-D-Phe1-octreotide. Scintigrams were obtained at 24 and 48 h, and the results were compared with CT and magnetic resonance imaging (MRI). Thirty-five of 48 patients had positive [111In]-octreotide scintigraphy (23/25 (92%) carcinoids, 8/9 (89%) PETs, 4/11 (36%) MEN-I & ZES). Of the 42 lesions located by conventional imaging techniques, 37 (88%) were also identified by Octreoscan. Unexpected lesions (40 sites), not detected by CT or MR imaging were found in 24/48 (50%) patients. [111In]-octreotide scintigraphy has a higher sensitivity for tumour detection, and is superior to MR imaging and CT scanning in the identification of previously unsuspected extraliver and lymph node metastases. It may also be helpful for the localization of clinically suspected tumours in patients with MEN-I and ZES.

Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity.

Helicobacter pylori is involved in gastritis, gastric and duodenal ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. Earlier studies already suggested a role for autoimmune phenomena in H. pylori-linked disease. We now report that lipopolysaccharides (LPS) of H. pylori express Lewis y, Lewis x, and H type I blood group structures similar to those commonly occurring in gastric mucosa. Immunization of mice and rabbits with H. pylori cells or purified LPS induced an anti-Lewis x or y or anti-H type I response, yielding antibodies that bound human and murine gastric glandular tissue, granulocytes, adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma cells. Experimental oral infections in mice or natural infection in humans yielded anti-Lewis antibodies also. The beta chain of gastric (H+,K+)-ATPase, the parietal cell proton pump involved in acid secretion, contained Lewis y epitopes; gastric mucin contained Lewis x and y antigenic determinants. Growth in mice of a hybridoma that secretes H. pylori-induced anti-Lewis y monoclonal antibodies resulted in histopathological evidence of gastritis, which indicates a direct pathogenic role for anti-Lewis antibodies. In conclusion, our observations demonstrate that molecular mimicry between H. pylori LPS and the host, based on Lewis antigens, and provide understanding of an autoimmune mechanism for H. pylori-associated type B gastritis.

In vivo trafficking of nascent H(+)-K(+)-ATPase in rabbit parietal cells.

Protein metabolic labeling in vivo was used to determine a time course for trafficking of nascent H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase) from endoplasmic reticulum (ER) to mature tubulovesicles in parietal cells. Stomachs of cimetidine-treated rabbits were taken 15-90 min after injection of [35S]methionine/cysteine, and mucosal microsomes were fractionated on sucrose gradients for analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot, and autoradiography. After 15 min, labeled alpha-subunit peaked at approximately 1.14 g/ml, matching the distribution of the high-mannose beta-subunit precursor, "pre-beta." After 30 min, most labeled alpha-subunit was in a peak at approximately 1.10 g/ml, considered to be Golgi. By 90 min, most labeled alpha-subunit was in a light peak, at approximately 1.07 g/ml, aligned with the major peak of total H(+)-K(+)-ATPase previously characterized as mature tubulovesicles. From material enriched in pre-beta, alpha-subunit was coprecipitated with pre-beta by a terminal mannose-specific lectin, Galanthus nivalis agglutinin, in the same ratio as the mature alpha:beta ratio. Thus alpha- and beta-subunits associated early in the ER. This is the first use of protein metabolic labeling to study early trafficking of the H(+)-K(+)-ATPase in vivo. The techniques may be usefully applied to examining changes in H(+)-K(+)-ATPase synthetic rate in response to various pharmacological treatments and studying the divergent pathways for nascent H(+)-K(+)- and Na(+)-K(+)-ATPases.

Direct measurement of extracellular proton flux from isolated gastric glands.

We used the microphysiometer, a sensitive extracellular pH sensor, to resolve luminal (or apical) H+ secretion and basolateral release of OH- as well as liberation of acidic metabolites in rabbit gastric glands. Stimulation of glands via the adenosine 3',5'-cyclic monophosphate pathway produced a biphasic change in the extracellular acidification rate (EAR): after an initial transient decrease below the unstimulated baseline (-40.9 +/- 3.4%), the EAR increased to a steady-state maximal plateau (+98.1 +/- 5.3%) within 30 min (n = 37). We interpret the biphasic EAR profile as an initial excess of basolaterally released OH- followed by delayed luminal efflux of simultaneously produced H+. The elevated EAR at steady state reflected liberation of metabolic acid attributed to H(+)-K(+)-ATPase enzymatic activity. The presence of H2-4,4'-diisothiocyanostilbene-2,2'-disulfonic acid prevented OH- release and reduced steady-state EAR. Basolateral OH- release and steady-state EAR were also inhibited by the H(+)-K(+)-ATPase inactivators omeprazole and SCH-28080. Inhibition of Na+/H+ exchange did not reduce steady-state EAR and did not affect apical H+ production, as judged by the accumulation of the weak base aminopyrine. Sodium thiocyanate (1 mM), which short circuits intraluminal H+ accumulation, blocked OH- release, demonstrating its dependence on H(+)-OH- separation at the apical membrane. A computerized model was developed to illustrate how the observed biphasic EAR profile would result from a delayed luminal efflux of H+ due to transitory intraluminal compartmentalization.

Omeprazole decreases H(+)-K(+)-ATPase protein and increases permeability of oxyntic secretory membranes in rabbits.

Amounts and fractional distributions of gastric H(+)-K(+)-adenosinetriphosphatase (ATPase) activity and H(+)-K(+)-ATPase protein as well as properties of H(+)-K(+)-ATPase-containing membranes were studied in rabbits injected with omeprazole (OM; 1 mg/kg sc twice daily for 5 days). Total H(+)-K(+)-ATPase activity decreased to 22 +/- 2% of control (n = 4). Densitometry of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blots showed H(+)-K(+)-ATPase protein was decreased to 60-70% of control. In vitro reduction of the enzyme-OM disulfide bond with 0.1 M 2-mercaptoethanol increased microsomal H(+)-K(+)-ATPase activity to 56 +/- 7% of control (n = 3), consistent with a substantial decrease in enzyme protein. Incorporation of 35S-labeled methionine for 30 min before death resulted in 2.2-fold more label per unit of microsomal alpha-subunit protein (5 days OM vs. control). Thus the decrease in enzyme protein resulted from increased breakdown rather than decreased synthesis. A striking shift in distribution of H(+)-K(+)-ATPase-containing microsomes (tubulovesicles) on sucrose gradients reflected slow equilibration of most control vesicles with the gradient medium and faster equilibration after 5 days OM, indicating increased permeability. After 5 days OM, microsomal vesicle acidification (by acridine orange uptake assay) was negligible, even with 2-mercaptoethanol treatment, and H+ leakage on sudden delta pH was faster than control. We conclude that extended OM treatment not only inhibits H(+)-K(+)-ATPase but accelerates its breakdown and renders H(+)-K(+)-ATPase-containing membranes more permeable. It is thus possible that increased backward H+ flux contributes to profound inhibition of acid secretion during extended omeprazole treatment. In parallel experiments, H(+)-K(+)-ATPase activity and density gradient sedimentation of tubulovesicles returned to near normal 3 days after OM withdrawal.

The National Breast Screening Programme: the first 5,000 women screened in Northern Ireland.

The National Breast Screening Programme is an ongoing public health programme. Women between 50 and 64 years are being invited to attend for screening at three yearly intervals. The results of the first 5,000 women screened in the Eastern Health and Social Services Board's unit are presented. The breast cancer detection rate was 7.8 per thousand women screened. The malignant to benign biopsy rate was greater than 1:1.

Ontogeny of gastric H(+)-K(+)-ATPase in suckling rabbits.

Gastric mucosal homogenates were prepared from resting and stimulated stomachs of rabbits, age 3-57 days postnatal, and fractionated by differential centrifugation. Total H(+)-K(+)-adenosinetriphosphatase (ATPase) (assayed as K(+)-dependent ouabain-insensitive hydrolysis of p-nitrophenyl phosphate) was low in the first 3 wk but rapidly accumulated between days 20 and 43. Specific activity rose eightfold from day 3 to a typically adult level of 2 mumol.mg-1.h-1 by day 43. The microsomal fraction (P3) was subfractionated on sucrose gradients (20, 27, and 33% steps or 10-40% continuous gradient). H(+)-K(+)-ATPase from P3 of resting stomachs was distributed bimodally on the continuous gradients, with activity mainly in the denser peak (or on the 33% sucrose step) before day 20, but accumulating mainly in the lighter peak (or in the lighter step-gradient fractions) after day 20. Throughout the age range tested, in vivo stimulation with histamine just before removal of the stomach caused a loss of most H(+)-K(+)-ATPase from P3 and an increase in H(+)-K(+)-ATPase in a lower-speed fraction P1. Thus, even in the 1st postnatal wk, when H(+)-K(+)-ATPase is low, most of the enzyme occurs in cells with histamine H2 receptors and all the intracellular mechanisms for fusion of oxyntic cell tubulovesicles (enriched in P3) with the apical membrane (enriched in P1). These studies delineate a 3-wk period of sharply accelerated synthesis of H(+)-K(+)-ATPase before weaning. Age-related changes in distribution of H(+)-K(+)-ATPase among microsomal density subfractions suggest maturational changes either in the intracellular partitioning of the enzyme or in properties of the membranes containing the enzyme.

Fibroadenolipoma of the breast.

Fibroadenolipoma is a well recognised but unusual benign tumour of the breast. It is a circumscribed lesion composed of fat and other breast tissues which may be normal or which may show various benign changes. The presence of smooth muscle has been recorded but was not found in our cases. A series of eight cases is described, occurring over a period of 10 years in a series of 20 000 mammograms. Radiological and pathological correlation is made and histological changes are described. Our findings are compared with other reviews in the literature. The lesions are usually diagnosed radiologically.

Dyspnea in divers at 49.5 ATA: mechanical, not chemical in origin.

Pulmonary function was studied in six divers living in a hyperbaric chamber at a pressure nearly fifty times normal (49.5 atmospheres absolute (ATA), equivalent to 488 m or 1600 ft seawater (fsw)). As expected, ventilatory function was reduced. At 49.5 ATA, maximum voluntary ventilation (MVV) was 45% less than the control value. Instantaneous rates of gas flow during forced expiration were similarly reduced, especially those flow rates measured high in the lung volume. These reductions occurred despite an apparent increase in functional residual capacity (FRC) and the use of transpulmonary pressures considerably greater than those exerted during the same maneuvers at normal (sea-level) pressure. During underwater work at 49.5 ATA, the divers rapidly became exhausted at moderate levels of oxygen consumption (1.9 liters/min), showing severe dyspnea and impending syncope. These symptoms were not due to retention of carbon dioxide, nor to hemodynamic or metabolic causes. Thus, dense gas breathing, like asthma, exemplifies a state in which severe dyspnea may occur with normal or low arterial carbon dioxide and normal oxygen transport. The physiological adjustments the divers employed were similar to those seen in acute asthma, imposing an elastic load in addition to the flow-resistive work of breathing a gas mixture eight times as dense as air. Although men can do moderate work under conditions similar to those of this experiment, they will have only a limited physiological reserve available to meet the possibilities of emergencies or respiratory infections.