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'.

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.

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.

Serum enzyme levels in alcoholism and drug dependency.

Serum gamma glutamyl transpeptidase (GGTP), isocitrate dehydrogenase (ICD), ornithine carbamoyl transferase (OCT), alanine aminotransferase (AlT), aspartate aminotransferase (AsT), and alkaline phosphatase (ALP) activities were assayed in 67 alcoholics and 40 drug dependent patients. Bilirubin, total protein, albumin, and globulin were also measured. GGTP elevation was observed in 48% of alcoholics and in 50% of drug dependents. The incidences of elevated levels of other enzymes were: ICD 39 and 38-7%; OCT 23-7 and 36-1%; AlT 30 and 33%; AsT 24-2 and 21-7%; ALP 10-4 and 5% respectively. Measurement of GGTP is thus more useful as a screening test for involvement of the liver in alcoholics and drug dependent patients than that of the other enzymes.

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.

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.

Plasma urea and creatinine status in chronic alcoholics.

Plasma urea and creatinine concentrations were estimated by Auto-Analyzer in 128 chronic alcoholics (103 males, 25 females; mean age +/- SD = 42.73 +/- 6.53; age range 20-60 years). Plasma levels of both urea (mean +/- SD = 3.46 +/- 1.31; normal range 2.0-6.5 mmol/l) and creatinine (mean +/- SD = 87.86 +/- 15.45; normal range 60-120 mumol/l) were found to be within normal limits. It is concluded from our observations that chronic ethanol ingestion per se is not nephrotoxic. The kidney seems to be the only vital organ generally spared in chronic alcoholics without advanced alcoholic liver disease or hepato-renal syndrome.

The effect of Naftidrofuryl on ethanol-induced liver damage in chronic alcoholic patients.

A prospective double-blind placebo-controlled trial of intramuscular Naftidrofuryl was carried out on 32 randomly selected hospitalized male alcoholic patients with clinical, biochemical and histological evidence of hepatic damage. Seventeen patients received the drug (40 mg in 5 ml i.m. three times daily for 6 days) and 15 patients received a placebo (5 ml in normal saline i.m. three times daily for 6 days). The drug was well tolerated and there were no adverse side-effects. Naftidrofuryl significantly improved the physiological function of the liver cells as reflected by indocyanine green (ICG) clearance by the liver (t = 2.61; p less than or equal to 0.02) and also caused a larger fall in raised serum levels of gamma glutamyl transpeptidase (GGT) than did the placebo injections. Overall clinical improvement (e.g. appetite, body weight, reduced liver size, general sense of well-being) was more clearly evident in patients of the treated group than in those of the placebo group. Naftidrofuryl, therefore, appears to be of benefit in ethanol-induced liver damage and more extensive long-term trials are suggested in patients with alcoholic liver disease (ALD).

Assessment of a new enzyme reaction rate analyser, the Vitatron AKES.

We have assessed the function of the Vitatron AKES (Automatic Kinetic Enzyme System) in terms of three enzymes, alpha-hydroxybutyrate dehydrogenase, alanine transaminase and asparate transaminase, and have compared the results with our existing techniques. Overall a good precision and correlation with routine laboratory methods was found. The machine is entirely automatic in operation and is economical in its use of sample and reagents.

A method for the preparation of human thyroxine-binding globulin; its importance in the establishment of an accurate and specific radioimmunoassay.

Pure thyroxine-binding globulin (TBG) is required in radioimmunoassay to prepare monospecific antisera, [125I]TBG and as primary standard. Homogeneous TBG was prepared by a three-stage affinity chromatography procedure; it could not be dissociated into subunits and its molecular weight by SDS polyacrylamide gel electrophoresis was 59 000. The amino acid composition was in agreement with two earlier reports. The secondary structure determined by circular dichroism in the far U.V. showed it to contain 24% each of alpha-helix and beta-pleated sheet. Serum TBG was determined by a 24-h radioimmunoassay using polyethyleneglycol to separate bound and free TBG. Serum TBG (mg/l, mean +/- S.D.) was: normal men 15.3 +/- 2.11 (n = 34), normal women 18.4 +/- 2.72 (n = 32) (P less than 0.005), in women on oral oestrogens 24.0 +/- 5.0 (n = 23), in normal pregnancy 38.6 +/- 3.0 (n =37), in cord blood 21.7 +/- 3.5 (n = 25) (P less than 0.001) and in euthyroid subjects aged over 60 years 17.8 +/- 4.5 (P n.s.). In women with thyroid disease TBG was reduced in hyperthyroidism: 15.5 +/- 2.5 (n = 28) and elevated in hypothyroidism: 21.0 +/- 4.0 (n = 25). Wider use in TBG-assay of non-denatured TBG of proven composition and structure should decrease the scatter in reference ranges and improve its value as a routine thyroid function test as both a primary measurement and as the T4 : TBG ratio.

Doppler index perfusion in the detection of hepatic metastases secondary to gastric carcinoma.

BACKGROUND: The early detection of liver metastases in patients with gastric carcinoma is important for determining the appropriate therapy; however conventional imaging techniques are limited for detecting "occult" liver metastases. Previous studies have shown that the measurement of the Doppler perfusion index (DPI)-ratio of hepatic arterial to total liver blood flow-can detect the presence of even small hepatic tumors. In this study, we compared the measurement of DPI with computed tomography (CT) for detecting gastric liver metastases. METHODS: At presentation, 43 patients with gastric carcinoma underwent CT scanning of the liver and after 12 hours of fasting, DPI measurement was carried out using Doppler sonography. RESULTS: Both techniques detected overt liver metastases in 9 of the 43 patients. Of the 34 remaining patients with an apparently disease-free liver on the basis of CT, laparotomy, or laparoscopy, 14 subsequently develop liver metastases over a follow-up period of 4 years, 13 of which had been predicted by DPI at the time of presentation. CONCLUSION: The data suggest that the measurement of the DPI is more sensitive than a CT scan for detecting liver metastases secondary to gastric carcinoma.

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.

An intra-erythrocytic low molecular weight lead-binding protein in acute and chronic lead exposure and its possible protective role in lead toxicity.

A low-molecular-weight protein was measured in erythrocytes from workers with chronic and recent lead exposure, with and without clinical lead toxicity, and from a group of control subjects not exposed to undue environmental lead. The protein was detected in all the workers, but in significantly smaller amounts in those with symptoms, and was absent from controls. The synthesis of the protein is induced at blood lead concentrations above 1.9 mumol/L, but is reduced in workers susceptible to clinical lead toxicity at blood lead concentrations below 4.0 mumol/L. The activity of the red blood cell dithiothreitol (DTT)--activated 5-aminolaevulinate dehydratase (ALA-D) was correlated with the concentration of the low-molecular-weight protein, with both being particularly low in the symptomatic workers. Previous studies have shown that the protein binds lead. By sequestrating excess lead into a non-toxic form, the protein may have a protective role in preventing clinical, and reducing biochemical, lead toxicity.

delta-Aminolaevulinic acid dehydratase as an index of the presence and severity of lead poisoning in acute and chronic lead exposure.

The activity of delta-aminolaevulinic acid dehydratase (ALA-D; porphobilinogen synthase) was measured in whole blood from a group of workers with acute exposure to lead and with low blood lead levels, a group of workers with chronic lead exposure and high blood lead levels, and a group of people without undue environmental lead exposure. The activity of ALA-D was reduced significantly at low blood lead levels only if undue exposure to lead had occurred, and was thus a reflection of low level lead poisoning. In chronic lead exposure the enzyme was not invariably reactivated fully with dithiothreitol, indicating more severe enzyme poisoning. The one lead worker with symptomatic lead poisoning had the most marked enzyme suppression. Measurement of both ALA-D activity and blood lead levels was more useful than the measurement of blood lead levels alone in the diagnosis and assessment of the severity of lead poisoning.

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.

Vitamin C utilization status in chronic alcoholic patients after short-term intravenous therapy.

Blood (leukocytic) ascorbic acid (vitamin C) levels were estimated in 25 chronic alcoholics (M = 21; F = 4; Age: mean +/- S.D. = 46.28 +/- 8.78; range 28-61 years) on admission before starting any treatment and on the sixth day following intravenous therapy with vitamin C -- 500 mg daily for 5 days. Twenty-four out of 25 patients (96%) were found to be deficient in blood vitamin C (mean +/- S.D. = 68.44 +/- 28.13; range = 28-148; normal range for control population = 120-300 nmol/10(8) W.B.C.). The status of blood vitamin C was significantly improved after the replenishment therapy with I/V vitamin C 500 mg daily for 5 days (mean +/- S.D. = 108.32 +/- 34.98 nmol/10(8) W.B.C.: range = 54-282.5; t = 3.76; P = less than 0.001). Still the levels did not return to within the normal range in 16 patients out of 25 (64%). In view of the biochemical deficiency of vitamin C in chronic alcoholics, it is suggested that conventional detoxification therapy for ethanol withdrawal syndrome should include polyvitamins including ascorbic acid. It is further suggested that more prolonged replenishment therapy with vitamin C, preferably by intravenous route, may be needed to normalize its blood levels in some chronic alcoholic patients.

Blood vitamin status (B1, B2, B6, folic acid and B12) in patients with alcoholic liver disease.

Blood vitamin status (B1, B2, B6, folic acid and B12) was assessed in 41 patients (M = 39; F = 2) with alcoholic liver disease. Biochemical evidence of thiamine deficiency was observed in all groups of patients. Deficiency of riboflavin was detected in patients with histologically normal liver but not in other groups. All the groups were found to be deficient in pyridoxal-5-phosphate--the active form of vitamin B6 (pyridoxine). Serum folate was decreased in all groups except in those with alcoholic hepatitis: red cell folate was, of course within normal limits in all the groups. Vitamin B12 levels were within normal limits in all groups except the cirrhotic one where it was raised. Clinico-biochemical implications of the findings are discussed. Biochemical changes in blood vitamin status may precede clinical manifestations of a disease process and may have prognostic value.

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.