Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients

High-dose or dose-intensive cytotoxic chemotherapy often causes myelosuppression and severe neutropenia among cancer patients. Severe neutropenia accompanied by fever, named febrile neutropenia (FN), is the most serious manifestation of neutropenia usually requiring hospitalization and intravenous antibiotics. FN and neutropenia can lead to chemotherapy treatment delays or dose reductions, which potentially compromises the effectiveness of cancer treatment and prospects for a cure. Granulocyte-macrophage (GM) and granulocyte colony-stimulating factors (G-CSFs) are administered during chemotherapy in order to prevent or reduce the incidence or the duration of FN and neutropenia.

Dog bites man or man bites dog? The enigma of the amino acid conjugations

The proposition posed is that the value of amino acid conjugation to the organism is not, as in the traditional view, to use amino acids for the detoxication of aromatic acids. Rather, the converse is more likely, to use aromatic acids that originate from the diet and gut microbiota to assist in the regulation of body stores of amino acids, such as glycine, glutamate, and, in certain invertebrates, arginine, that are key neurotransmitters in the central nervous system (CNS). As such, the amino acid conjugations are not so much detoxication reactions, rather they are homeostatic and neuroregulatory processes. Experimental data have been culled in support of this hypothesis from a broad range of scientific and clinical literature. Such data include the low detoxication value of amino acid conjugations and the Janus nature of certain amino acids that are both neurotransmitters and apparent conjugating agents. Amino acid scavenging mechanisms in blood deplete brain amino acids. Amino acids glutamate and glycine when trafficked from brain are metabolized to conjugates of aromatic acids in hepatic mitochondria and then irreversibly excreted into urine. This process is used clinically to deplete excess nitrogen in cases of urea cycle enzymopathies through excretion of glycine or glutamine as their aromatic acid conjugates. Untoward effects of high-dose phenylacetic acid surround CNS toxicity. There appears to be a relationship between extent of glycine scavenging by benzoic acid and psychomotor function. Glycine and glutamine scavenging by conjugation with aromatic acids may have important psychosomatic consequences that link diet to health, wellbeing, and disease.

Acute Encephalopathy with Unilateral Cortical-Subcortical Lesions in Two Unrelated Kindreds Treated with Glucocorticoids Prenatally for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Established Facts and Novel Insight

Background: Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. Case Reports: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. Conclusion: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed.

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis

This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

Effects of low abdominal blood flow and dobutamine on blood flow distribution and on the hepatic arterial buffer response in anaesthetized pigs

Low cardiac output impairs the hepatic arterial buffer response (HABR). Whether this is due to low abdominal blood flow per se is not known. Dobutamine is commonly used to increase cardiac output, and it may further modify hepatosplanchnic and renal vasoregulation. We assessed the effects of isolated abdominal aortic blood flow changes and dobutamine on hepatosplanchnic and renal blood flow. Twenty-five anesthetized pigs with an abdominal aorto-aortic shunt were randomized to 2 control groups [zero (n = 6) and minimal (n = 6) shunt flow], and 2 groups with 50% reduction of abdominal blood flow and either subsequent increased abdominal blood flow by shunt reduction (n = 6) or dobutamine infusion at 5 and 10 microg kg(-1) min(-1) with constant shunt flow (n = 7). Regional (ultrasound) and local (laser Doppler) intra-abdominal blood flows were measured. The HABR was assessed during acute portal vein occlusion. Sustained low abdominal blood flow, by means of shunt activation, decreased liver, gut, and kidney blood flow similarly and reduced local microcirculatory blood flow in the jejunum. Shunt flow reduction partially restored regional blood flows but not jejunal microcirculatory blood flow. Low-but not high-dose dobutamine increased gut and celiac trunk flow whereas hepatic artery and renal blood flows remained unchanged. Neither intervention altered local blood flows. The HABR was not abolished during sustained low abdominal blood flow despite substantially reduced hepatic arterial blood flow and was not modified by dobutamine. Low-but not high-dose dobutamine redistributes blood flow toward the gut and celiac trunk. The jejunal microcirculatory flow, once impaired, is difficult to restore.

Behavioral and anatomical abnormalities in a sodium iodate-induced model of retinal pigment epithelium degeneration

We characterized changes in the visual behavior of mice in which a loss of the retinal pigment epithelium (RPE) was experimentally induced with intravenous (i.v.) administration of sodium iodate (NaIO3). We compared and correlated these changes with alterations in neural retinal structure and function. RPE loss was induced in 4-6 week old male C57BL/6 mice with an i.v. injection of 1% NaIO3 at three concentrations: 35, 50, or 70 mg/kg. At 1, 3, 7, 14, 21, and 28 days (d) as well as 6 months post injection (PI) a behavioral test was performed in previously trained mice to evaluate visual function. Eye morphology was then assessed for changes in both the RPE and neural retina. NaIO3-induced RPE degeneration was both dose and PI time dependent. Our low dose showed no effects, while our high dose caused the most damage, as did longer PI times at our intermediate dose. Using the intermediate dose, no changes were detectable in either visual behavior or retinal morphology at 1 d PI. However, at 3 d PI visual behavior became abnormal and patchy RPE cell loss was observed. From 7 d PI onward, changes in retinal morphology and visual behavior became more severe. At 6 months PI, no recovery was seen in any of these measures in mice administered the intermediate dose. These results show that NaIO3 dosage and/or time PI can be varied to produce different, yet permanent deficits in retinal morphology and visual function. Thus, this approach should provide a unique system in which the onset and severity of RPE damage, and its consequences can be manipulated. As such, it should be useful in the assessment of rescue or mitigating effects of retinal or stem cell transplantation on visual function.

Multicentre evaluation of a new point-of-care test for the determination of NT-proBNP in whole blood

BACKGROUND: The Roche CARDIAC proBNP point-of-care (POC) test is the first test intended for the quantitative determination of N-terminal pro-brain natriuretic peptide (NT-proBNP) in whole blood as an aid in the diagnosis of suspected congestive heart failure, in the monitoring of patients with compensated left-ventricular dysfunction and in the risk stratification of patients with acute coronary syndromes. METHODS: A multicentre evaluation was carried out to assess the analytical performance of the POC NT-proBNP test at seven different sites. RESULTS: The majority of all coefficients of variation (CVs) obtained for within-series imprecision using native blood samples was below 10% for both 52 samples measured ten times and for 674 samples measured in duplicate. Using quality control material, the majority of CV values for day-to-day imprecision were below 14% for the low control level and below 13% for the high control level. In method comparisons for four lots of the POC NT-proBNP test with the laboratory reference method (Elecsys proBNP), the slope ranged from 0.93 to 1.10 and the intercept ranged from 1.8 to 6.9. The bias found between venous and arterial blood with the POC NT-proBNP method was < or =5%. All four lots of the POC NT-proBNP test investigated showed excellent agreement, with mean differences of between -5% and +4%. No significant interference was observed with lipaemic blood (triglyceride concentrations up to 6.3 mmol/L), icteric blood (bilirubin concentrations up to 582 micromol/L), haemolytic blood (haemoglobin concentrations up to 62 mg/L), biotin (up to 10 mg/L), rheumatoid factor (up to 42 IU/mL), or with 50 out of 52 standard or cardiological drugs in therapeutic concentrations. With bisoprolol and BNP, somewhat higher bias in the low NT-proBNP concentration range (<175 ng/L) was found. Haematocrit values between 28% and 58% had no influence on the test result. Interference may be caused by human anti-mouse antibodies (HAMA) types 1 and 2. No significant influence on the results with POC NT-proBNP was found using volumes of 140-165 muL. High NT-proBNP concentrations above the measuring range of the POC NT-proBNP test did not lead to false low results due to a potential high-dose hook effect. CONCLUSIONS: The POC NT-proBNP test showed good analytical performance and excellent agreement with the laboratory method. The POC NT-proBNP assay is therefore suitable in the POC setting.

Osseointegration of hollow cylinder based spinal implants in normal and osteoporotic vertebrae: a sheep study

INTRODUCTION: Osteoporosis is not only responsible for an increased number of metaphyseal and spinal fractures but it also complicates their treatment. To prevent the initial loosening, we developed a new implant with an enlarged implant/bone interface based on the concept of perforated, hollow cylinders. We evaluated whether osseointegration of a hollow cylinder based implant takes place in normal or osteoporotic bone of sheep under functional loading conditions during anterior stabilization of the lumbar spine. MATERIALS AND METHODS: Osseointegration of the cylinders and status of the fused segments (ventral corpectomy, replacement with iliac strut, and fixation with testing implant) were investigated in six osteoporotic (age 6.9 +/- 0.8 years, mean body weight 61.1 +/- 5.2 kg) and seven control sheep (age 6.1 +/- 0.2 years, mean body weight 64.9 +/- 5.7 kg). Osteoporosis was introduced using a combination protocol of ovariectomy, high-dose prednisone, calcium and phosphor reduced diet and movement restriction. Osseointegration was quantified using fluorescence and conventional histology; fusion status was determined using biomechanical testing of the stabilized segment in a six-degree-of-freedom loading device as well as with radiological and histological staging. RESULTS: Intact bone trabeculae were found in 70% of all perforations without differences between the two groups (P = 0.26). Inside the cylinders, bone volume/total volume was significantly higher than in the control vertebra (50 +/- 16 vs. 28 +/- 13%) of the same animal (P<0.01), but significantly less (P<0.01) than in the near surrounding (60 +/- 21%). After biomechanical testing as described in Sect. "Materials and methods", seven spines (three healthy and four osteoporotic) were classified as completely fused and six (four healthy and two osteoporotic) as not fused after a 4-month observation time. All endplates were bridged with intact trabeculae in the histological slices. CONCLUSIONS: The high number of perforations, filled with intact trabeculae, indicates an adequate fixation; bridging trabeculae between adjacent endplates and tricortical iliac struts in all vertebrae indicates that the anchorage is adequate to promote fusion in this animal model, even in the osteoporotic sheep.

Intravenous magnesium for acute myocardial infarction

BACKGROUND: Mortality and morbidity from acute myocardial infarction (AMI) remain high. Intravenous magnesium started early after the onset of AMI is thought to be a promising adjuvant treatment. Conflicting results from earlier trials and meta-analyses warrant a systematic review of available evidence. OBJECTIVES: To examine the effect of intravenous magnesium versus placebo on early mortality and morbidity. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library Issue 3, 2006), MEDLINE (January 1966 to June 2006) and EMBASE (January 1980 to June 2006), and the Chinese Biomedical Disk (CBM disk) (January 1978 to June 2006). Some core Chinese medical journals relevant to the cardiovascular field were hand searched from their starting date to the first-half year of 2006. SELECTION CRITERIA: All randomized controlled trials that compared intravenous magnesium with placebo in the presence or absence of fibrinolytic therapy in addition to routine treatment were eligible if they reported mortality and morbidity within 35 days of AMI onset. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trial quality and extracted data using a standard form. Odds ratio (OR) were used to pool the effect if appropriate. Where heterogeneity of effects was found, clinical and methodological sources of this were explored. MAIN RESULTS: For early mortality where there was evidence of heterogeneity, a fixed-effect meta-analysis showed no difference between magnesium and placebo groups (OR 0.99, 95%CI 0.94 to 1.04), while a random-effects meta-analysis showed a significant reduction comparing magnesium with placebo (OR 0.66, 95% CI 0.53 to 0.82). Stratification by timing of treatment (< 6 hrs, 6+ hrs) reduced heterogeneity, and in both fixed-effect and random-effects models no significant effect of magnesium was found. In stratified analyses, early mortality was reduced for patients not treated with thrombolysis (OR=0.73, 95% CI 0.56 to 0.94 by random-effects model) and for those treated with less than 75 mmol of magnesium (OR=0.59, 95% CI 0.49 to 0.70) in the magnesium compared with placebo groups.Meta-analysis for the secondary outcomes where there was no evidence of heterogeneity showed reductions in the odds of ventricular fibrillation (OR=0.88, 95% CI 0.81 to 0.96), but increases in the odds of profound hypotension (OR=1.13, 95% CI 1.09 to 1.19) and bradycardia (OR=1.49, 95% CI 1.26 to 1.77) comparing magnesium with placebo. No difference was observed for heart block (OR=1.05, 95% CI 0.97-1.14). For those outcomes where there was evidence of heterogeneity, meta-analysis with both fixed-effect and random-effects models showed that magnesium could decrease ventricular tachycardia (OR=0.45, 95% CI 0.31 to 0.66 by fixed-effect model; OR=0.40, 95% CI 0.19 to 0.84 by random-effects model) and severe arrhythmia needing treatment or Lown 2-5 (OR=0.72, 95% CI 0.60 to 0.85 by fixed-effect model; OR=0.51, 95% CI 0.33 to 0.79 by random-effects model) compared with placebo. There was no difference on the effect of cardiogenic shock between the two groups. AUTHORS' CONCLUSIONS: Owing to the likelihood of publication bias and marked heterogeneity of treatment effects, it is essential that the findings are interpreted cautiously. From the evidence reviewed here, we consider that: (1) it is unlikely that magnesium is beneficial in reducing mortality both in patients treated early and in patients treated late, and in patients already receiving thrombolytic therapy; (2) it is unlikely that magnesium will reduce mortality when used at high dose (>=75 mmol); (3) magnesium treatment may reduce the incidence of ventricular fibrillation, ventricular tachycardia, severe arrhythmia needing treatment or Lown 2-5, but it may increase the incidence of profound hypotension, bradycardia and flushing; and (4) the areas of uncertainty regarding the effect of magnesium on mortality remain the effect of low dose treatment (< 75 mmol) and in patients not treate...

Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 x 10(9)/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 x 10(9)/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 x 10(9)/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Histopathological alterations, EROD activity, CYP1A protein and biliary metabolites in gilthead seabream Sparus aurata exposed to benzo(a)pyrene

This study compared for seabream, Sparus aurata exposed to benzo(a)pyrene-B(a)P-, the response of molecular cytochrome P450 1A (CYP1A) and cellular histopathology biomarkers. Male gilthead seabream, Sparus aurata specimens were exposed for 20 days via water to a series of high B(a)P concentrations. CYP1A was assessed by measuring enzymatic activity (EROD) and CYP1A protein content, and cellular responses were evaluated by routine histopathological methods. In addition, biliary metabolites were measured in order to verify that B(a)P was absorbed and metabolised. Histological lesions, both in liver and gills, increased in parallel to B(a)P concentrations, with the majority of changes representing rather non-specific alterations. Hepatic EROD and CYP1A proteins data showed a concentration-dependent induction, while in the gills, EROD activity but not CYP1A proteins showed a non-monotonous dose response, with a maximum induction level at 200 microg B(a)P.L-1 and decreasing levels thereafter. The findings provide evidence that short-term, high dose exposure of fish can result in significant uptake and metabolism of the lipophilic B(a)P, and in pronounced pathological damage of absorptive epithelia and internal organs.

Role of calcium-independent phospholipase A2 in cortex striatum thalamus cortex circuitry-enzyme inhibition causes vacuous chewing movements in rats

RATIONALE: High levels of calcium independent phospholipase A2 (iPLA2) are present in certain regions of the brain, including the cerebral cortex, striatum, and cerebellum (Ong et al. 2005). OBJECTIVES: The present study was carried out to elucidate a possible role of the enzyme in the motor system. METHODS: The selective iPLA2 inhibitor bromoenol lactone (BEL), the nonselective PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), and an antisense oligonucleotide were used to interfere with iPLA2 activity in various components of the motor system. Control animals received injections of carrier (phosphate buffered saline, PBS) at the same locations. The number of vacuous chewing movements (VCM) was counted from 1 to 14 days after injection. RESULTS: Rats that received BEL and high-dose MAFP injections in the striatum, thalamus, and motor cortex, but not the cerebellum, showed significant increase in VCM, compared to those injected with PBS at these locations. BEL-induced VCM were blocked by intramuscular injections of the anticholinergic drug, benztropine. Increased VCM was also observed after intrastriatal injection of antisense oligonucleotide to iPLA2. The latter caused a decrease in striatal iPLA2 levels, confirming a role of decreased enzyme activity in the appearance of VCM. CONCLUSIONS: These results suggest an important role for iPLA2 in the cortex-striatum-thalamus-cortex circuitry. It is postulated that VCM induced by iPLA2 inhibition may be a model of human parkinsonian tremor.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Sitosterolaemia in Switzerland: molecular genetics links the US Amish-Mennonites to their European roots

Sitosterolaemia is a rare autosomal recessive disease characterized by increased intestinal absorption of plant sterols, decreased hepatic excretion into bile and elevated concentrations in plasma phytosterols. Homozygous or compound heterozygous loss of function mutations in either of the ATP-binding cassette (ABC) proteins ABCG5 and ABCG8 explain the increased absorption of plant sterols. Here we report a Swiss index patient with sitosterolaemia, who presented with the classical symptoms of xanthomas, but also had mitral and aortic valvular heart disease. Her management over the last 20 years included a novel therapeutic approach of high-dose cholesterol feeding that was semi-effective. Mutational and extended haplotype analyses showed that our patient shared this haplotype with that of the Amish-Mennonite sitosterolaemia patients, indicating they are related ancestrally.

Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

BACKGROUND: Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 microl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. RESULTS: Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16-25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60-31.8]; (P = NS) and 9.8 [1.7-27.3] (controls: 10.5 [2.4-21.75]) in animals treated with high dose RO 25-6981 (P = NS). CONCLUSIONS: Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.