The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) - Results of an international collaborative study

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2–5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

A cost-minimization analysis of the societal costs of realtime teledermatology compared with conventional care: results from a randomized controlled trial in New Zealand

A randomized controlled trial was carried out to measure the societal costs of realtime teledermatology compared with those of conventional hospital care in New Zealand. Two rural health centres were linked to a specialist hospital via ISDN at 128 kbit/s. Over 10 months, 203 patients were referred for a specialist dermatological consultation and 26 were followed up, giving a total of 229 consultations. Fifty-four per cent were randomized to the teledermatology consultation and 46% to the conventional hospital consultation. A cost-minimization analysis was used to calculate the total costs of both types of dermatological consultation. The total cost of the 123 teledermatology consultations was NZ$34,346 and the total cost of the 106 conventional hospital consultations was NZ$30,081. The average societal cost of the teledermatology consultation was therefore NZ$279.23 compared with NZ$283.79 for the conventional hospital consultation. The marginal cost of seeing an additional patient was NZ$135 via teledermatology and NZ$284 via conventional hospital appointment. From a societal viewpoint, and assuming an equal outcome, teledermatology was a more cost-efficient use of resources than conventional hospital care.

ENCORE: The effect of nutrient enrichment on coral reefs. Synthesis of results and conclusions

Coral reef degradation resulting from nutrient enrichment of coastal waters is of increasing global concern. Although effects of nutrients on coral reef organisms have been demonstrated in the laboratory, there is little direct evidence of nutrient effects on coral reef biota in situ. The ENCORE experiment investigated responses of coral reef organisms and processes to controlled additions of dissolved inorganic nitrogen (N) and/or phosphorus (P) on an offshore reef(One Tree Island) at the southern end of the Great Barrier Reef, Australia. A multi-disciplinary team assessed a variety of factors focusing on nutrient dynamics and biotic responses. A controlled and replicated experiment was conducted over two years using twelve small patch reefs ponded at low tide by a coral rim. Treatments included three control reefs (no nutrient addition) and three + N reefs (NH4Cl added), three + P reefs (KH2PO4 added), and three + N + P reefs. Nutrients were added as pulses at each low tide (ca twice per day) by remotely operated units. There were two phases of nutrient additions. During the initial, low-loading phase of the experiment nutrient pulses (mean dose = 11.5 muM NH4+; 2.3 muM PO4-3) rapidly declined, reaching near-background levels (mean = 0.9 muM NH4+; 0.5 muM PO4-3) within 2-3 h. A variety of biotic processes, assessed over a year during this initial nutrient loading phase, were not significantly affected, with the exception of coral reproduction, which was affected in all nutrient treatments. In Acropora longicyathus and A. aspera, fewer successfully developed embryos were formed, and in A. longicyathus fertilization rates and lipid levels decreased. In the second, high-loading, phase of ENCORE an increased nutrient dosage (mean dose = 36.2 muM NH4+; 5.1 muM PO4-3 declining to means of 11.3 muM NH4+ and 2.4 muM PO4-3 at the end of low tide) was used for a further year, and a variety of significant biotic responses occurred. Encrusting algae incorporated virtually none of the added nutrients. Organisms containing endosymbiotic zooxanthellae (corals and giant clams) assimilated dissolved nutrients rapidly and were responsive to added nutrients. Coral mortality, not detected during the initial low-loading phase, became evident with increased nutrient dosage, particularly in Pocillopora damicornis. Nitrogen additions stunted coral growth, and phosphorus additions had a variable effect. Coral calcification rate and linear extension increased in the presence of added phosphorus but skeletal density was reduced, making corals more susceptible to breakage. Settlement of all coral larvae was reduced in nitrogen treatments, yet settlement of larvae from brooded species was enhanced in phosphorus treatments. Recruitment of stomatopods, benthic crustaceans living in coral rubble, was reduced in nitrogen and nitrogen plus phosphorus treatments. Grazing rates and reproductive effort of various fish species were not affected by the nutrient treatments. Microbial nitrogen transformations in sediments,were responsive to nutrient loading with nitrogen fixation significantly increased in phosphorus treatments and denitrification increased in all treatments to which nitrogen had been added. Rates of bioerosion and grazing showed no significant effects of added nutrients, ENCORE has shown that reef organisms and processes investigated ill situ were impacted by elevated nutrients. Impacts mere dependent on dose level, whether nitrogen and/or phosphorus mere elevated and were often species-specific. The impacts were generally sub-lethal and subtle and the treated reefs at the end of the experiment mere visually similar to control reefs. Rapid nutrient uptake indicates that nutrient concentrations alone are not adequate to assess nutrient condition of reefs. Sensitive and quantifiable biological indicators need to be developed for coral reef ecosystems. The potential bioindicators identified in ENCORE should be tested in future research on coral reef/nutrient interactions. Synergistic and cumulative effects of elevated nutrients and other environmental parameters, comparative studies of intact vs. disturbed reefs, offshore vs, inshore reefs, or the ability of a nutrient-stressed reef to respond to natural disturbances require elucidation. An expanded understanding of coral reef responses to anthropogenic impacts is necessary, particularly regarding the subtle, sub-lethal effects detected in the ENCORE studies. (C) 2001 Published by Elsevier Science Ltd.

Using visual spatial search interface for WWW applications

Most Internet search engines are keyword-based. They are not efficient for the queries where geographical location is important, such as finding hotels within an area or close to a place of interest. A natural interface for spatial searching is a map, which can be used not only to display locations of search results but also to assist forming search conditions. A map-based search engine requires a well-designed visual interface that is intuitive to use yet flexible and expressive enough to support various types of spatial queries as well as aspatial queries. Similar to hyperlinks for text and images in an HTML page, spatial objects in a map should support hyperlinks. Such an interface needs to be scalable with the size of the geographical regions and the number of websites it covers. In spite of handling typically a very large amount of spatial data, a map-based search interface should meet the expectation of fast response time for interactive applications. In this paper we discuss general requirements and the design for a new map-based web search interface, focusing on integration with the WWW and visual spatial query interface. A number of current and future research issues are discussed, and a prototype for the University of Queensland is presented. (C) 2001 Published by Elsevier Science Ltd.

The plausibility of long-wavelength stress correlation or stress magnitude as a mechanism for precursory seismicity: Results from two simple elastic models

Observations of accelerating seismic activity prior to large earthquakes in natural fault systems have raised hopes for intermediate-term eartquake forecasting. If this phenomena does exist, then what causes it to occur? Recent theoretical work suggests that the accelerating seismic release sequence is a symptom of increasing long-wavelength stress correlation in the fault region. A more traditional explanation, based on Reid's elastic rebound theory, argues that an accelerating sequence of seismic energy release could be a consequence of increasing stress in a fault system whose stress moment release is dominated by large events. Both of these theories are examined using two discrete models of seismicity: a Burridge-Knopoff block-slider model and an elastic continuum based model. Both models display an accelerating release of seismic energy prior to large simulated earthquakes. In both models there is a correlation between the rate of seismic energy release with the total root-mean-squared stress and the level of long-wavelength stress correlation. Furthermore, both models exhibit a systematic increase in the number of large events at high stress and high long-wavelength stress correlation levels. These results suggest that either explanation is plausible for the accelerating moment release in the models examined. A statistical model based on the Burridge-Knopoff block-slider is constructed which indicates that stress alone is sufficient to produce accelerating release of seismic energy with time prior to a large earthquake.

ReoPro rules: results from the 'DoTirofiban and ReoPro give similar efficacy trial' (TARGET) - A Key Paper Evaluation (Topol, Ej et al)

In the treatment of atherosclerotic disease, stenting in the presence of a glycoprotein (GP) IIb/IIIa antagonist is becoming an increasingly common procedure. The ‘Do Tirofiban and ReoPro Give Similar Efficacy Trial’ (TARGET) was designed to determine whether the cheaper tirofiban was as effective and safe as abciximab in the prevention of ischaemic events with stenting. Unexpectedly, abciximab was shown to be superior to tirofiban. Tirofiban is a selective GP IIb/IIIa antagonist whereas abciximab has additional anti-inflammatory actions, which may contribute to its superiority.

Epizootic activity of Murray Valley encephalitis virus in an aboriginal community in the southeast Kimberley region of western Australia: Results of cross-sectional and longitudinal serologic studies

Murray Valley encephalitis (MVE) virus is a mosquito-borne flavivirus causing severe encephalitis with a resultant high morbidity and mortality. In the period 1989-1993. we undertook a cross-sectional and longitudinal studs by annually screening members of a small remote Aboriginal community in northwestern Australia for MVE virus antibodies. Of the estimated 250-300 people in the community. 249 were tested, and 52.6% had positive serology to MVE. The proportion testing positive increased with increasing age group. and males were slightly more likely to be positive than females. During the study period. a high proportion of the population seroconverted to MVE: the clinical/subclinical ratio seems to be lower than previously reported. Although MVE is mostly asymptomatic, the devastating consequences of clinical illness indicate that advice should be provided regarding the avoidance of mosquito bites. Our longitudinal study showed that the risk of seroconversion was similar for each age group. not just the young.

Pamidronate results in symptom control of hypertrophic pulmonary osteoarthropathy in cystic fibrosis

Hypertrophic pulmonary osteoarthropathy (HPOA) may complicate the advanced lung disease that is associated with cystic fibrosis, resulting in severe joint pain and early-morning stiffness. Symptoms are usually controlled with the administration of nonsteroidal anti-inflammatory drugs, physiotherapy, and, on occasions, oral corticosteroids. I This report describes a case of refractory HPOA with complete remission following the administration of IV pamidronate, which is a potent inhibitor of osteoclastic bone resorption. Symptom relief resulted for up to 3 months, but repeated courses of pamidronate have been required to maintain symptom control.

Vibration instability in rolling mills: Modeling and experimental results

Models for the occurrence of the vibrational instability during rolling known as third octave chatter are presented and discussed. An analysis of rolling mill chatter was performed for the purpose of identifying characteristics of the vibrations and to determine any dependency on the rolling schedule. In particular, a stability criterion for the critical rolling speed is used to predict the maximum rolling speed without chatter instability on schedules from a 5 stand tandem mill rolling thin steel product. The results correlate well with measurements of critical speed occurring on the mill using a vibration monitor: This research provides significant insights into the chatter phenomena and has been used to investigate control methods for suppression of the instability.

A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (Part 1 of 2): clinical results

Objective: First, to assess the clinical effectiveness of hylan G-F 20 in an appropriate care treatment regimen (as defined by the American College of Rheumatology (ACR) 1995 guidelines) as measured by validated disease-specific outcomes and health-related quality of life endpoints for patients with osteoarthritis (OA) of the knee. Second, to utilize the measures of effectiveness and costs in an economic evaluation (see accompanying manuscript). Design: A total of 255 patients with OA of the knee were enrolled by rheumatologists or orthopedic surgeons into a prospective, randomized, open-label, 1-year, multi-centred trial, conducted in Canada. Patients were randomized to 'Appropriate care with hylan G-F 20' (AC+H) or 'Appropriate care without hylan G-F 20' (AC). Data were collected at clinic visits (baseline, 12 months) and by telephone (1, 2, 4, 6, 8, 10, and 12 months). Results: The AC+H group was superior to the AC group for all primary (% reduction in mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale: 38% vs 13%, P=0.0001) and secondary effectiveness outcome measures. These differences were all statistically significant and exceeded the 20% difference between groups seta priori by the investigators as the minimum clinically important difference. Health-related quality of life improvements in the AC+H group were statistically superior for the WOMAC pain, stiffness and physical function (all P

Occult Axillary Lymph Node Metastases in Breast Cancer Do Matter: Results of 10-Year Survival Analysis

Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens. In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients. Histologic features of the primary tumor and immunohistochemical staining for estrogen receptor, progesterone receptor, Her-2, and p53 were also evaluated. With multivariate analysis, both occult metastases and higher histologic grade of the primary tumor were independent predictors of disease-free survival. Histologic grade was the only significant independent predictor of overall survival. Estrogen receptor, progesterone receptor, Her-2, and p53 status did not predict the presence of metastases or survival when all tumor types were considered together. Metastases >0.5 mm significantly predicted a poorer disease-free survival when invasive ductal carcinomas were considered alone. Histologic grade was significantly associated with disease-free survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients. The presence of occult metastases approached significance for overall survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.