Response of extreme precipitation to uniform surface warming in quasi-global aquaplanet simulations at high resolution.

Projections of precipitation extremes in simulations with global climate models are very uncertain in the tropics, in part because of the use of parameterizations of deep convection and model deficiencies in simulating convective organization. Here, we analyse precipitation extremes in high-resolution simulations that are run without a convective parameterization on a quasi-global aquaplanet. The frequency distributions of precipitation rates and precipitation cluster sizes in the tropics of a control simulation are similar to the observed distributions. In response to climate warming, 3 h precipitation extremes increase at rates of up to [Formula: see text] in the tropics because of a combination of positive thermodynamic and dynamic contributions. The dynamic contribution at different latitudes is connected to the vertical structure of warming using a moist static stability. When the precipitation rates are first averaged to a daily timescale and coarse-grained to a typical global climate-model resolution prior to calculating the precipitation extremes, the response of the precipitation extremes to warming becomes more similar to what was found previously in coarse-resolution aquaplanet studies. However, the simulations studied here do not exhibit the high rates of increase of tropical precipitation extremes found in projections with some global climate models. This article is part of a discussion meeting issue 'Intensification of short-duration rainfall extremes and implications for flash flood risks'.

Protein and chemotherapy profiling of extracellular vesicles harvested from therapeutic induced senescent triple negative breast cancer cells.

Triple negative breast cancer (TNBC) is an aggressive subtype with relatively poor clinical outcomes and limited treatment options. Chemotherapy, while killing cancer cells, can result in the generation of highly chemoresistant therapeutic induced senescent (TIS) cells that potentially form stem cell niches resulting in metastases. Intriguingly, senescent cells release significantly more extracellular vesicles (EVs) than non-senescent cells. Our aim was to profile EVs harvested from TIS TNBC cells compared with control cells to identify a potential mechanism by which TIS TNBC cells maintain survival in the face of chemotherapy. TIS was induced and confirmed in Cal51 TNBC cells using the chemotherapeutic paclitaxel (PTX) (Taxol). Mass spectrometry (MS) analysis of EVs harvested from TIS compared with control Cal51 cells was performed using Ingenuity Pathway Analysis and InnateDB programs. We demonstrate that TIS Cal51 cells treated with 75 nM PTX for 7 days became senescent (senescence-associated ß-galactosidase (SA-ß-Gal) positive, Ki67-negative, increased p21 and p16, G2/M cell cycle arrest) and released significantly more EVs (P=0.0002) and exosomes (P=0.0007) than non-senescent control cells. Moreover, TIS cells displayed an increased expression of the multidrug resistance protein 1/p-glycoprotein. MS analysis demonstrated that EVs derived from senescent Cal51 cells contained 142 proteins with a significant increased fold change compared with control EVs. Key proteins included ATPases, annexins, tubulins, integrins, Rabs and insoluble senescence-associated secretory phenotype (SASP) factors. A fluorescent analogue of PTX (Flutax-2) allowed appreciation of the removal of chemotherapy in EVs from senescent cells. Treatment of TIS cells with the exosome biogenesis inhibitor GW4869 resulted in reduced SA-ß-Gal staining (P=0.04). In summary, this study demonstrates that TIS cells release significantly more EVs compared with control cells, containing chemotherapy and key proteins involved in cell proliferation, ATP depletion, apoptosis and the SASP. These findings may partially explain why cancer senescent cells remain viable despite chemotherapeutic challenge.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Is point of care testing in Irish hospitals ready for the laboratory modernisation process? An audit against the current national Irish guidelines.

BACKGROUND: The Laboratory modernisation process in Ireland will include point of care testing (POCT) as one of its central tenets. However, a previous baseline survey showed that POCT was under-resourced particularly with respect to information technology (IT) and staffing. AIMS: An audit was undertaken to see if POCT services had improved since the publication of National Guidelines and if such services were ready for the major changes in laboratory medicine as envisaged by the Health Service Executive. METHODS: The 15 recommendations of the 2007 Guidelines were used as a template for a questionnaire, which was distributed by the Irish External Quality Assessment Scheme. RESULTS: Thirty-nine of a possible 45 acute hospitals replied. Only a quarter of respondent hospitals had POCT committees, however, allocation of staff to POCT had doubled since the first baseline survey. Poor IT infrastructure, the use of unapproved devices, and low levels of adverse incident reporting were still major issues. CONCLUSIONS: Point of care testing remains under-resourced, despite the roll out of such devices throughout the health service including primary care. The present high standards of laboratory medicine may not be maintained if the quality and cost-effectiveness of POCT is not controlled. Adherence to national Guidelines and adequate resourcing is essential to ensure patient safety.

Multiple myeloma: a review of imaging features and radiological techniques.

The recently updated Durie/Salmon PLUS staging system published in 2006 highlights the many advances that have been made in the imaging of multiple myeloma, a common malignancy of plasma cells. In this article, we shall focus primarily on the more sensitive and specific whole-body imaging techniques, including whole-body computed tomography, whole-body magnetic resonance imaging, and positron emission computed tomography. We shall also discuss new and emerging imaging techniques and future developments in the radiological assessment of multiple myeloma.

A comparative study of faecal occult blood kits in a colorectal cancer screening program in a cohort of healthy construction workers.

BACKGROUND: The incidence of colorectal cancer (CRC) has been increasing. We evaluated uptake rates and outcomes of faecal immunochemical test (FIT) and Guaiac test (gFOBT) kits as part of a two-step CRC screening. METHODS: A 3-year CRC screening program for a defined population of construction workers was conducted. Those satisfying the inclusion criteria were provided with gFOBT or FIT kits. Individuals testing positive were invited for a colonoscopy. RESULTS: A total of 909 faecal testing kits were distributed. Age range was 53-60 years. Compliance rate was higher for FIT (58.3%) as compared to gFOBT (46.7%) (p = 0.0006). FIT detected adenomatous polyps and CRC in 37.5 and 25%, respectively, whereas; gFOBT detected 23.5 and 18%. Colonoscopies were normal in 53 and 25% tested positive by gFOBT and FIT, respectively (p = 0.016). CONCLUSION: The FIT was more cost-effective when compared with gFOBT with higher return rate, sensitivity and specificity. A comparative study of faecal occult blood kits in a CRC screening program in a healthy cohort of construction workers.

A survey of point of care testing in Irish hospitals: room for improvement.

BACKGROUND: "Guidelines for safe and effective management and use of point of care testing" have been recently launched in Ireland. AIMS: To survey point of care testing (POCT) services in the Republic of Ireland. METHODS: A questionnaire covering accreditation status, existence of POCT committees, quality management systems, and staff resources was distributed by the Irish External Quality Assessment Scheme (IEQAS). RESULTS: Of those that returned completed questionnaires, 56% had assigned specific POCT responsibilities to designated staff. Most support was for blood gases and glucose analysis. Compared with other published studies, Irish laboratories gave similar support for blood gases, less for glucose and much less for urinalysis. CONCLUSIONS: This survey demonstrated poor IT support for POCT. The majority of the respondents (78%) were dissatisfied with the quality of the POCT service in their institution.

Multicentric Castleman's disease & HIV infection.

We report the case of a 35 year patient from Nigeria who presented with fever and splenomegaly. The initial diagnosis was Salmonellosis. However, relapsing symptoms lead to a re-evaluation and ultimately a diagnosis of Multicentric Castleman's Disease (MCD). There is no gold standard treatment but our patient responded to Rituximab and Highly active anti-retroviral therapy. MCD is a rare, aggressive disease that should be considered in a HIV positive patient presenting with fever and significant lymphadenopathy.

Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions, and correlation of disease distribution with whole-body MRI (WBMRI).

AIM: The aim of the study is to assess the feasibility of whole-body low-dose computed tomography (WBLDCT) in the diagnosis and staging of multiple myeloma and compare to skeletal survey (SS), using bone marrow biopsy and whole-body magnetic resonance imaging (WBMRI; where available) as gold standard. MATERIALS AND METHODS: Patients referred over an 18-month period for investigation of suspected multiple myeloma or restaging of myeloma were randomized to undergo one of two WBLDCT protocols using high kVp, low mAs technique (140 kVp, 14 mAs; or 140 kVp, 25 mAs). Recent WBMRI scans were reviewed in 23 cases. Each imaging modality was assessed by two radiologists in consensus and scored from 0-3 (0 = normal, 1 = 1-4 lesions, 2 = 5-20 lesions, 3 >or= 20 lesions/diffuse disease) in ten anatomical areas. Overall stage of disease, image quality score, and the degree of confidence of diagnosis were recorded. Diagnostic accuracy of skeletal survey and WBLDCT were determined using a gold standard of bone marrow biopsy and distribution of disease was compared to WBMRI. RESULTS: Thirty-nine patients were evaluated. WBLDCT identified more osteolytic lesions than skeletal survey with a greater degree of diagnostic confidence and led to restaging in 18 instances (16 upstaged, two downstaged). In those with recent WBMRI, distribution of disease on WBLDCT showed superior correlation with WBMRI when compared with SS. Overall reader impression of stage on WBLDCT showed significant correlation with WBMRI (kappa = 0.454, p < 0.05). WBLDCT provided complementary information to WBMRI in nine patients with normal marrow signal following treatment response, but which were shown to have diffuse residual cortical abnormalities on CT. CONCLUSION: WBLDCT at effective doses lower than previously reported, is superior to SS at detecting osteolytic lesions and at determining overall stage of multiple myeloma, and provides complementary information to WBMRI.

Dietary vitamin B12 deficiency in an adolescent white boy.

Dietary deficiency of cobalamin resulting in tissue deficiency in white individuals is unusual. However, several patients with dietary deficiency who were neither vegan nor Hindu have been described. This report describes the case of a 14 year old boy who was a white non-Hindu with a very low intake of cobalamin, which was not apparent until a detailed dietary assessment was performed. The patient responded rapidly to a combination of oral and parenteral B12. This case illustrates the fact that severe dietary vitamin B12 deficiency can occur in non-Hindu white individuals. Inadequate dietary content of B12 may not be apparent until a detailed dietary assessment is performed. This patient is likely to have had subclinical vitamin B12 deficiency for several years. Increased vitamin B12 requirements associated with the adolescent growth spurt may have provoked overt tissue deficiency.

In vitro cold activation of complement shown by an overestimation of total complement 4: a study in patients with hepatitis C virus infection.

Total complement 4 (C4) levels, when analysed on the Beckman Array nephelometer, were found to increase number of serum specimens [predominantly from patients with hepatitis C virus (HCV) infection] after overnight storage at 4 degrees C. In order to investigate whether the phenomenon of in vitro cold-dependent activation of complement (CDAC) was the explanation for this increase, paired specimens were collected from 63 patients with HCV infection in tubes with no anticoagulant (serum) and in tubes containing EDTA (which inhibits complement activation). C4 levels increased after overnight storage at 4 degrees C in 33 serum specimens (52%). In contrast, no increase in C4 levels was observed in any of the 63 EDTA specimens. Immunofixation of intact and activated C4 products confirmed that complement activation had taken place in the serum specimens in which C4 levels had increased after storage. There was a higher frequency of hepatitis C viraemia (P<0.0001), HCV antibody positivity (P<0.05) and the presence of rheumatoid factor (P<0.05) in the group of patients in whose serum samples CDAC had occurred (n = 33) than in the other group (n = 30). As a result of our findings on C4 analysis in stored serum specimens, we would recommend potassium EDTA plasma as the specimen of choice for complement analysis on the Beckman Array.

Continuous infusion of porcine factor VIII in patients with haemophilia A and high-responding inhibitors: stability and clinical experience.

A multicentre retrospective survey was conducted to assess the efficacy and side-effect profile of porcine factor VIII (pFVIII:C) given by continuous infusion (CI) to patients with congenital haemophilia A and inhibitors. Twenty-nine episodes in 18 patients were treated by CI of pFVIII:C. Efficacy was graded as good in 79% of infusions and fair in 17%. There was a failed response in only one episode. Fourteen percent of patients experienced transfusion reactions with bolus doses, but no reactions were observed in patients given CI. There were no severe reactions. All the reactions resolved following interruption of the infusion and administration of steroids. Premedication did not prevent reactions. In this series the median decrease in platelet count after bolus injection of pFVIII:C was -67 X 10(9) L(-1) compared with a median decrease of -2 x 109 L(-1) during the course of CI, thus, continuous infusion of pFVIII:C appears to have less effect on platelet count than bolus injection. An anamnestic response was associated with 77% of infusions. This high rate of anamnesis reflects patient selection, in that they were all known to have high-level high-responding FVIII inhibitors with cross-reactivity to pFVIII. After reconstitution, the pFVIII:C showed little loss in factor VIII activity in solution over a 24-h period. We conclude that pFVIII:C may be effectively administered by CI to patients with haemophilia A and high-responding FVIII inhibitors. CI is the probably the mode of administration of choice for intensive replacement therapy with pFVIII.

Albumin concentrations are primarily determined by the body cell mass and the systemic inflammatory response in cancer patients with weight loss.

The association between hypoalbuminemia and poor prognosis in patients with cancer is well recognized. However, the factors that contribute to the fall in albumin concentrations are not well understood. In the present study, we examined the relationship between circulating albumin concentrations, weight loss, the body cell mass (measured using total body potassium), and the presence of an inflammatory response (measured using C-reactive protein) in male patients (n = 40) with advanced lung or gastrointestinal cancer. Albumin concentrations were significantly correlated with the percent ideal body weight (r = 0.390, p < 0.05), extent of reported weight loss (r = -0.492, p < 0.01), percent predicted total body potassium (adjusted for age, height, and weight, r = 0.686, p < 0.001), and log10 C-reactive protein concentrations (r = -0.545, p < 0.001). On multiple regression analysis, the percent predicted total body potassium and log10 C-reactive protein concentrations accounted for 63% of the variation in albumin concentrations (r2 = 0.626, p < 0.001). The interrelationship between albumin, body cell mass, and the inflammatory response is consistent with the concept that the presence of an ongoing inflammatory response contributes to the progressive loss of these vital protein components of the body and the subsequent death of patients with advanced cancer.

Prognostic factors in advanced gastrointestinal cancer patients with weight loss.

There are few reports on factors that determine survival in advanced gastrointestinal cancer with weight loss. In these patients (n = 91, median weight loss 16.6%), we prospectively examined the importance of metastatic spread, anthropometry, blood parameters, Karnofsky performance status, appetite, and the acute-phase response as predictors of survival. Survival was calculated from date of assessment to the most recent clinic attendance (> or = 30 mo) or until death. On multivariate analysis, metastatic spread (p < 0.05), Karnofsky performance status (p < 0.01), and C-reactive protein concentration (p < 0.001) had independent prognostic value. In locally advanced disease (n = 64), Karnofsky performance status and C-reactive protein concentration remained significant. There was a significantly lower survival in patients with an acute-phase response (median 136 days) than in patients with no response (median 466 days; p < 0.01). Performance status and the acute-phase response are associated, independent of weight loss, with survival duration in advanced gastrointestinal cancer patients.

Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine.

BACKGROUND: There is a need for systematic evaluation of methods before their release to the market. We addressed this problem in novel homocysteine assays as part of an European Demonstration Project involving six centers in four countries. METHODS: Two immunological methods for measurement of plasma total homocysteine (P-tHcy), the fluorescence polarization immunoassay (FPIA) and the enzyme immunoassay (EIA), were compared with two comparison methods, HPLC and gas chromatography-mass spectrometry (GC-MS). All laboratories performed the following procedures: (a) familiarization; (b) determination of linearity and precision by analyzing five plasma samples with interrelated concentrations for 20 days; (c) correlation using patients' samples; and (d) assessment of long-term performance. RESULTS: Both immunological methods were linear for P-tHcy between 5 and 45 micromol/L. The intralaboratory imprecision (CV) was <5% for FPIA and <9% for EIA used with a sample processor. The bias was -2% to 3% for FPIA and 2-4% for EIA used with a sample processor. CONCLUSIONS: The immunological methods provide results with little bias compared with HPLC and GC-MS. The imprecision of the assays must be considered in the context of their intended use(s).

Optimization of routine plasma homocysteine monitoring.

An elevated plasma homocysteine (Hcy) level is now considered to be an important risk factor in arterial and venous thromboembolic events. As a result of this relatively recent finding, there has been a dramatic increase in the number of requests for Hcy measurement. In our laboratory, this demand has been met by employing an automated immunoassay and improving the pre-analytical handling of blood samples. An automated fluorescent polarization immunoassay (FPIA) gave similar results to a reference high-pressure chromatographic (HPLC) method (r2 = 0.98, enzyme immunoassay = 0.998 HPLC - 0.3) and excellent between-run reproducibility (coefficient of variation <3%). The new assay also required less specialized technical input, and improved the sample throughput two-fold. Pre-analytical stability of plasma Hcy concentrations in blood samples is crucial to the accuracy of Hcy monitoring. This stability was improved 10-fold by adopting the anticoagulant acidic citrate instead of ethylenediamine tetraacetic acid for Hcy screening by FPIA. Acidic citrate dramatically inhibits time-related plasma contamination by red-cell Hcy, resulting in improved accuracy and a reduced number of 'spoiled' specimen discards.

A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss.

The use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the combination of megestrol acetate and placebo with megestrol acetate and ibuprofen in the treatment of weight loss in such patients. At baseline, 4-6 weeks and 12 weeks, patients underwent measurements of anthropometry, concentrations of albumin and C-reactive protein and assessment of appetite, performance status and quality of life using EuroQol-EQ-5D and EORTC QLQ-C30. Thirty-eight and 35 patients (median weight loss 18%) were randomized to megestrol acetate/placebo or megestrol acetate/ibuprofen, respectively, for 12 weeks. Forty-six (63%) of patients failed to complete the 12-week assessment. Of those evaluable at 12 weeks, there was a decrease in weight (median 2.8 kg) in the megestrol acetate/placebo group compared with an increase (median 2.3 kg) in the megestrol acetate/ibuprofen group (P<0.001). There was also an improvement in the EuroQol-EQ-5D quality of life scores of the latter group (P<0.05). The combination of megestrol acetate/ibuprofen appeared to reverse weight loss and appeared to improve quality of life in patients with advanced gastrointestinal cancer. Further trials of this novel regimen in weight-losing patients with hormone-insensitive cancers are warranted.

Longitudinal study of weight, appetite, performance status, and inflammation in advanced gastrointestinal cancer.

There is increasing evidence that, in most patients with advanced cancer, weight loss is associated with an inflammatory response. To examine the temporal relationship between weight loss, appetite, performance status, and the inflammatory response, 50 patients with advanced gastrointestinal cancer with weight loss were observed for six weeks. Patients were grouped according to whether they had lost weight (> 3%, n = 16), were weight stable (< 3% change, n = 25), or gained weight (> 3%, n = 9). At baseline, the group that subsequently lost weight had lower albumin and higher C-reactive protein concentrations (p < 0.05). On follow-up, there was an increase in C-reactive protein concentration and reductions in triceps skinfold thickness and Karnofsky performance status in the weight-losing group (p < 0.05). In contrast, Karnofsky performance status was improved in the group that gained weight (p < 0.05). Over the six to eight weeks, there was a difference in the changes of triceps skinfold thickness (p < 0.05) and Karnofsky performance status (p < 0.01) between the two groups. These results suggest that loss or gain of > 2.5 kg over a six- to eight-week period is required to produce a significant alteration in performance status in weight-losing patients with gastrointestinal cancer. Moreover, the results suggest that the presence of an inflammatory response is associated with further weight loss and the deterioration of performance status.

Impact of weight loss, appetite, and the inflammatory response on quality of life in gastrointestinal cancer patients.

The relationship between weight loss, appetite, the inflammatory response, and quality of life in patients with advanced gastrointestinal cancer was examined. Height, weight, and skinfold anthropometry were measured in 119 patients. Blood was taken for analysis of C-reactive protein and albumin. Appetite, performance status, and quality of life were assessed using EuroQol EQ-5D and EORTC QLQ-C30 questionnaires. Weight loss was > 5% (median 17.1%) of their preillness weight in 97 patients; the remaining 22 patients were weight stable. Anthropometric measurements and circulating albumin concentrations were significantly lower (p < 0.01) and circulating concentrations of C-reactive protein were significantly higher in the weight-losing than in the weight-stable group (p < 0.001). Appetite scores, performance status, and EuroQol EQ-5D and EORTC QLQ-C30 scores were also lower in the weight-losing group (p < 0.01). When the weight-losing cancer patients were divided on the basis of whether they had a marked inflammatory response, albumin concentrations, appetite, and Karnofsky performance status were significantly lower (p < 0.05) in the group with a marked inflammatory response. The results of the present study are consistent with weight loss, reduction of appetite, and an elevated inflammatory response being important related factors in lowering the quality of life of gastrointestinal cancer patients.

Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden.

Patients with inflammatory bowel disease have an increased frequency of thromboembolism, and microvascular thrombosis has been proposed as a contributory pathogenic factor. The mechanism of enhanced procoagulant activity is not understood. We examined the clinical setting of thromboembolic events in 52 patients with Crohn's disease or ulcerative colitis, and assessed the procoagulant laboratory profile, including Factor V Leiden, in a subset of 20 patients to identify procoagulant risk factors. Patients who developed thrombosis tended to be young; 60% of thrombotic events occurred in patients under 50 years. Multiple thromboembolic episodes occurred in 13% and unusual sites of thrombosis (e.g. intracardiac, cerebral, inominate veins) in 11%. No risk factor was identifiable in 52% of cases and two-thirds of thromboses occurred in an out-patient setting. The mortality rate was 8%. Evidence for inflammatory disease activity was found in only 45% of patients with ulcerative colitis at the time of the thromboembolic event, in contrast to 89% of those with Crohn's disease. Assays for specific coagulation defects were negative in all cases tested (protein S, C were normal in 17/17; anti-thrombin III, anti-phospholipid antibodies and activated protein C resistance were negative in 20/20, and only 1/20 patients was found to be heterozygous for Factor V leiden. Thrombosis in inflammatory bowel disease is important because it occurs in a young population, often in unusual sites, and has a high mortality. The development of thrombosis is related to active inflammatory disease in most patients with Crohn's disease but apparently not in those with ulcerative colitis. Since approximately half of the patients had no other identifiable risk factor, there remains a substantial group of patients with IBD who develop thrombosis for unknown reasons.