The efficacy and safety of probiotics in people with cancer: a systematic review.

BACKGROUND: Probiotics are living microorganisms that are generally thought of as being beneficial to the recipient. They have been shown to be effective in people with acute infectious diarrhoea, and cost-effective in antibiotic-associated diarrhoea. Probiotics may have a role in people with cancer, as various cancer treatments often lead to diarrhoea. However, as people with cancer are often immunocompromised, it is important to assess for adverse events (AEs) such as infection, which could potentially be a consequence of deliberate ingestion of living microorganisms. DESIGN: A systematic review was carried out to collect, analyse and synthesise all available data on the efficacy and safety of probiotics in people with cancer (PROSPERO registration: CRD42012003454). Randomised, controlled trials, identified through screening multiple databases and grey literature, were included for analysing efficacy, while all studies were included for the analysis of safety of probiotics. Primary outcomes were the reduction in duration, severity and incidence of antibiotic-associated diarrhoea and chemotherapy-associated diarrhoea, and AEs, especially probiotic-associated infection. Where possible, data were combined for meta-analysis by a random-effects model, assessing causes of heterogeneity, including differences in strains, dosage and patient characteristics. RESULTS: Eleven studies (N = 1557 participants) were included for assessing efficacy. Results show that probiotics may reduce the severity and frequency of diarrhoea in patients with cancer and may reduce the requirement for anti-diarrhoeal medication, but more studies are needed to assess the true effect. For example comparing probiotic use to control 25 groups on effect on Common Toxicity Criteria ≥2 grade diarrhoea, odds ratio (OR) = 0.32 [95% confidence interval (CI) of 0.13-0.79; P = 0.01]. Seventeen studies (N = 1530) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. CONCLUSIONS: Probiotics may be a rare cause of sepsis. Further evidence needs to be collated to determine whether probiotics provide a significant overall benefit for people with cancer.

The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis.

To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.

Blocking of fetal K antigens on cord red blood cells by maternal anti-K.

A 26-year-old Caucasian female in her second pregnancy grouped as A, D+ R(1)R(1) K- with anti-K (titre: 256) at booking. Her partner was typed as K1 positive. Baby was born with Hb 23.1 g/dl. Cord samples were referred to our laboratory for investigation and were found to be DAT 5+, IgG and anti-K was eluted from the red cells. Cord samples typed as A, R(1)r K- by DiaMed DiaClon Rh subgroups & K card. We report a case of false negative K1 phenotyping due to blocking with maternal anti-K.

High incidence of polyarteritis nodosa in the brains of culled sows.

A total of 307 brains of purebred sows obtained from an abattoir were retrospectively examined. These sows were culled with reasons of reproductive failure, urogenital infections, or locomotor problems. The most common macroscopic lesions were cavitations or lacunae in the basal nuclei (9.1%, 28/307) and coarse and thickened leptomeninges with marked vessels (3.9%, 12/307). The most frequent microscopic lesion was polyarteritis nodosa (21.2%, 65/307), which was found in all 40 brains with the above-mentioned gross lesions and in all 25 brains with microscopic cerebral infarcts or cavitations. The affected arteries of polyarteritis nodosa were distributed primarily in the cerebral leptomeninges, basal nuclei, and internal and external capsules. Histopathologically, a characteristic change of the affected arteries was transmural fibrinoid necrosis with severe infiltration of mixed inflammatory cells; narrowing or occlusion of the lumen. The inflammatory cells were chiefly composed of lymphocytes, macrophages, and plasma cells, with a few eosinophils and occasional multinucleated giant cells. Polyarteritis nodosa was found at a high percentage in the brains from culled sows. It may result in cerebral ischemia, infarcts, and hemorrhage, and possibly play a role in the necessity for culling due to locomotor problems.

Innovative Clinical Trials: The LUNG-MAP Study.

Although the proportion of patients with squamous cell carcinoma of the lung has declined over the last two decades, the disease is still fatal for tens of thousands of patients each year. The treatment of non-small cell lung cancer has advanced rapidly over the past decade, providing novel, targeted therapeutic options to patients, but has mostly been limited to the adenocarcinoma histology. Efforts are currently underway to bring squamous cell carcinoma of the lung into this new era of targeted therapy. This article reviews the rationale and trial design for the "LUNG-MAP: S1400 Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer" study. This multi-institutional, multi-cooperative group trial aims to individualize treatment for patients with metastatic squamous cell carcinoma to one of five arms based on the genomic profile of the tumor. The goal of this clinical trial is to rapidly identify new active drugs and bring them as soon as possible through a registration process for patients with squamous cell lung cancer by utilizing a novel trial design and involving all key stakeholders in drug development in a national effort. This could serve as a paradigm for drug development for malignancies with wide molecular heterogeneity.

Detection of Chlamydia trachomatis in general practice urine samples.

BACKGROUND: Chlamydia trachomatis is frequently overlooked as a cause of dysuria and urinary frequency in general practice patients. AIM: This study set out to determine the impact of performing chlamydial antigen detection on sterile pyuria samples from patients aged 16-65 years and which were submitted to a hospital microbiology laboratory by general practitioners in the Winchester health district for routine microbiological investigations. METHOD: Chlamydial antigen detection was performed by enzyme immunoassay and direct immunofluorescence. The cost of performing the test was estimated. In the first year of the study (1991) questionnaires were sent to general practitioners whose patients had a positive test result. RESULTS: A total of 1025 samples of sterile pyuria were received at the laboratory between January 1991 and March 1993. Chlamydial antigen was detected in 54 samples (5%); 22 men and 32 women aged between 16 and 57 years (mean 25 years). The detection rate was highest in the 16-20 years age group (22% of men had a positive sample and 7% of women). Completed questionnaires from 27 general practitioners revealed that 59% of their patients were referred to the genitourinary clinic for treatment and contact tracing. The others were treated by the general practitioner. The cost of the screening programme per cure in this population was estimated to be 246 pounds. CONCLUSION: C trachomatis is a significant pathogen which may go unrecognized and untreated. The cost, medically and financially, of screening for this pathogen and treating infected patients and contacts is likely to be less than ignoring it, particularly if screening is confined to the 16-30 years age group. General practitioners should consider the diagnosis of chlamydial infection in young adult patients with sterile pyuria, and microbiology laboratories should screen sterile pyuria samples for chlamydial antigen.

Severe pre-eclampsia remote from term: what to expect of expectant management.

OBJECTIVE: To describe the duration of expectant management and the indications for termination of expectant management of pregnancies complicated by severe pre-eclampsia remote from term. STUDY DESIGN: We identified pregnancies complicated by severe pre-eclampsia diagnosed between 24 weeks and 31 weeks 6 days at our institution in 1991-98. Pertinent clinical data were obtained from review of maternal and neonatal charts. Comparison of patients was based on the duration of time from admission to delivery: < 48 h (group 1), 48 h to 7 days (group 2), and > or = 7 days (group 3). RESULTS: A total of 142 women met all study criteria. Seventy-nine (55.6%) women were delivered within 48 h, 42 (29.6%) between 48 h and 7 days, and 21 (14.8%) at > or = 7 days from diagnosis. Of group 1 patients (< 48 h), 59 (74.7%) were delivered for maternal indications while 20 (25.3%) were delivered for fetal indications. Of group 2 patients (48 h to 7 days), 35 (83.3%) were delivered for maternal indications while seven (16.7%) were delivered for fetal indications. Of group 3 patients (> or = 7 days), 16 (76.2%) were delivered for maternal indications while five (23.8%) were delivered for fetal indications. There were no significant differences in the indications for delivery based on the duration from admission to delivery. CONCLUSIONS: Despite an aggressive approach towards expectant management of preterm pregnancies complicated by severe pre-eclampsia, most patients were delivered within 48 h for maternal indications.

The effect of intrapartum magnesium sulfate therapy on fetal cardiac troponin I levels at delivery.

OBJECTIVE: To determine whether intrapartum magnesium sulfate (MgSO4) therapy for seizure prophylaxis in pre-eclampsia-eclampsia is associated with biochemical evidence of subacute fetal myocardial damage at delivery. STUDY DESIGN: Troponin I, a cardiac-specific protein used to detect myocardial injury, was measured from the umbilical vein at delivery in term pregnancies complicated by pre-eclampsia and uncomplicated control pregnancies. Women with pre-eclampsia received intravenous MgSO4 as a 6-g load followed by 2 g/hour until delivery. Clinical characteristics and fetal troponin levels were compared between groups. RESULTS: There was no difference in troponin I concentrations between term patients with intrapartum MgSO4 therapy and controls who did not receive MgSO4 (median 0.86 ng/ml, range 0.72-1.10 vs. 0.89 ng/ml, range 0.68-1.50; p = 1.0). There was also no statistically significant difference in the number of patients with a troponin I level of > or = 1.0 ng/ml between groups (30.8% (4/13) vs. 15.4% (4/26); p = 0.4). CONCLUSIONS: Our findings suggest that, in term fetuses that are not growth impaired, exposure to intrapartum MgSO4 is not associated with subacute myocardial injury.

Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes.

OBJECTIVE: Neutrophil defensins (HNP 1-3), bactericidal/permeability-increasing protein (BPI) and calprotectin (MRP8/14) are antimicrobial peptides stored in leukocytes that act as effector molecules of the innate immune response. The purpose of this study was to determine whether parturition, premature rupture of the membranes (PROM) and microbial invasion of the amniotic cavity (MIAC) are associated with changes in amniotic fluid concentrations of these antimicrobial peptides. STUDY DESIGN: Amniotic fluid was retrieved by amniocentesis from 333 patients in the following groups: group 1, mid-trimester with a subsequent normal pregnancy outcome (n = 84); group 2, preterm labor and intact membranes without MIAC who delivered at term (n = 36), or prematurely (n = 52) and preterm labor with MIAC (n = 26); group 3, preterm PROM with (n = 26) and without (n = 26) MIAC; and group 4, term with intact membranes in the absence of MIAC, in labor (n = 52) and not in labor (n = 31). The concentrations of HNP 1-3, BPI and calprotectin in amniotic fluid were determined by specific and sensitive immunoassays. Placentae of patients in both preterm labor with intact membranes and preterm PROM groups who delivered within 72 h of amniocentesis were examined. Non-parametric statistics, receiver-operating characteristic (ROC) curves and Cox regression models were used for analysis. A p value of < 0.05 was considered statistically significant. RESULTS: Intra-amniotic infection was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin in both women with preterm labor and intact membranes, and women with preterm PROM. Preterm PROM was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin. Preterm parturition was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin, while parturition at term was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3. Among patients with preterm labor and intact membranes, elevation of amniotic fluid HNP 1-3, BPI and calprotectin concentrations was associated with intra-amniotic inflammation, histological chorioamnionitis and a shorter interval to delivery. CONCLUSION: MIAC, preterm parturition and preterm PROM are associated with increased amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin. Moreover, elevated amniotic fluid concentrations of BPI, immunoreactive HNP 1-3 and calprotectin are associated with intra-amniotic inflammation, histological chorioamnionitis and shorter amniocentesis-to-delivery interval in patients presenting with preterm labor with intact membranes.

Influence of Age on the Electrocardiographic Waves in Taiwanese Lan-Yu Miniature Pigs.

The purpose of the study reported here was to determine baseline information of the electrocardiogram (ECG) and the influence of age on cardiac function in Taiwanese Lan-Yu (TLY) miniature pigs. Non-anesthetized TLY minipigs (from birth to 6 months of age) were placed on a webbed stanchion, simulating a standing position, for acquisition of an ECG, using six limb leads (I, II, III, aVR, aVL, and aVF), with each as a single-channel ECG recorder. The P and T waves obtained from leads I, III, and aVL were useful in determining the subtle cardiac changes during maturation of TLY minipigs. Interestingly, changes in the QT interval analyzed from all 6 leads were almost indistinguishable. Shortening of the QT interval was induced (p < 0.05) between days 1 and 7 of postnatal life. The QT interval lengthened to a steady state at day 60, and paralleled pigs' physical maturation. The longer QT interval was conversely correlated to heart rate as pigs matured. In the QRS complex interval, only lead aVR was significantly decreased at day 7 (p < 0.05). Further changes in the QRS interval from day 21 were not observed in any lead. Because the duration of the ventricular complex represents the period required for the excitation front to reach the terminals of the Purkinje fibers in the ventricular myocardium, the increase in QRS interval observed within 21 days of birth could be attributed to an increase in the thickness of ventricular myocardium. The data suggest that cardiac maturation was achieved at 60 days of age, although the body weight of minipigs continued to increase beyond 60 days of age. Because the body weight of these newly developed TLY minipigs can be maintained within 25 to 30 kg at one year of age and their major ECG findings did not significantly differ from those of domestic pigs and humans, they may be useful as a model for cardiovascular and pharmacologic research. The similarity of ECG profiles between pigs and humans also was evaluated.

Obesity prevention in defined (high school) populations.

BACKGROUND: A challenge for the widespread dissemination of Internet-based programs designed to produce weight maintenance/loss in defined (high school) populations is to adapt them to local needs and interests, whereas demonstrating effectiveness and salience for both universal and targeted populations. OBJECTIVE: The objective of this study is to examine the feasibility of providing an inexpensive, Internet-based universal (healthy weight regulation) and targeted (weight maintenance/loss) health program to all ninth-grade students in a high school serving a lower socioecnomic status, diverse population. DESIGN: A total of 118 normal-weight and 64 overweight/obese students in the same ninth-grade class completed a baseline screen and were allocated to a healthy weight regulation program or a weight-loss maintenance program. Both groups simultaneously received a 10-week Internet-based intervention. Program implementation required minimal teacher time. Measurement included self-reported fruit, vegetable and high-fat/-calorie food consumption, self-reported change in body mass index (BMI), weight and shape concerns, as well as program engagement. RESULTS: The program was successfully implemented in nine classes, with minimal help from the investigators. There was a significant increase in self-reported consumption of fruits and vegetables (P=0.001). There was a significant reduction in self-reported BMI in the overweight/obese group (P=0.001). Students found the program helpful and engaging. There was a significant reduction in weight and shape concerns in the high-risk female students, consistent with a reduced risk for the development of an eating disorder. Providing a universal and targeted online healthy weight regulation program to ninth-grade students is feasible and inexpensive. The results suggest the program can serve as 'core' for future studies using adaptive, continuous quality-improvement designs.

A prospective study of the incidence of red cell allo-immunisation following transfusion.

To establish the incidence and timing of red cell allo-immunisation following transfusion, pretransfusion and serial post-transfusion samples were screened for allo-antibodies in a total of 452 patients who had undergone elective surgery. Antibody screening was performed by 2-stage papain, manual polybrene and indirect antiglobulin techniques (IAT). Red cell allo-antibodies were found in 42 patients and 38 of these (8.4% overall) demonstrated antibodies only after transfusion; 76% of them had Rh specificity. This rate of red cell allo-immunisation is higher than what would be expected if transfused patients were tested only once post-transfusion, as has been the case in several previous studies. For the type of patients studied, this finding may not be of clinical relevance at present because most patients undergoing elective surgery do not require further transfusion in their lifetime. However, this is changing with the longer life expectancy of the population and the increased probability of repeat surgery. Twenty-two (58%) of the antibodies were initially detected by the 2-stage papain and/or polybrene techniques, when the IAT was negative, although later 19 became positive by IAT; this added sensitivity of techniques other than the IAT, to detect early allo-immunisation may be relevant in pretransfusion testing to prevent haemolytic transfusion reactions in patients requiring repeated transfusions.

Comparison of IgM and IgG anti-A and anti-B levels in Asian, Caucasian and Negro donors in the North West Thames Region.

This study was undertaken to test the widely held belief that higher levels of immune anti-A and anti-B are characteristic of Negro and Asian populations with a corresponding increased risk factor for AB0 haemolytic disease of the newborn. Overall, 300 serum samples from male and female Asian. Caucasian and Negro blood donors in the North West Thames Region of groups A, B and 0 were collected. The sera were titrated in microplates against pooled group A1 and pooled group B red blood cells. Although the results show that the highest levels for IgG anti-A and anti-B were found in group 0 female Negro donors, statistically these levels are not significantly higher than those of the other group 0 donors tested. We suggest that the potent anti-A and anti-B reported by others in Negro and Asian populations may arise from environmental rather than genetic factors.

Effect of breathing frequency and airflow on pulmonary function in high-intensity equine exercise.

It has been postulated that the hypoxaemia and hypercapnoea that characterize strenuous equine exercise are partly due to flow limitations imposed by high breathing frequencies (fb), and that gas exchange would be improved if fb could be lowered. To evaluate this possibility, 6 Thoroughbred horses underwent 4 incremental treadmill exercise tests at inclines of 0, 5, 10 and 25%, respectively. In the test, horses were given a warm-up for 2 min, then ran sequentially for 1 min each at 60, 100 and 115% VO2max. Oxygen consumption (VO2), blood gas tensions (PaO2, PaCO2), fb, tidal volume (VT), minute ventilation (Ve), transpulmonary pressure (Ptp), peak inspiratory and expiratory airflows (VI, VE) and work of breathing (Wrm) were determined during the last 15 s of exercise at each intensity. The only effect of fb on PaO2 was seen at 60% VO2max. Also, maximal transpulmonary pressure difference (delta Ptpmax), and peak VI, and VE on a 25% slope were lower than those recorded at the other 3 inclines at 60% VO2max. At 100 and 115% VO2max, the effect of fb was less clear. While fb still differed, the only effects of fb at 100% VO2max were on delta Ptpmax. At 115% VO2max, fb on a 25% incline was lower than that for 0 and 5% slopes. The only other difference noted at this intensity was in VT on 10% slope. However, there was no difference between VTS recorded at inclines of 0, 5 or 25% at 115% VO2max. There was no effect of fb or exercise intensity on Ve at 100 or 115% VO2max. There was no change in PaO2, fb, VT, delta Ptpmax or VI and VE as exercise intensity increased from 60-115% VO2max on slopes of 0, 5 or 10%. However, for exercise on the 25% incline (i.e. with lower fb), each of these parameters increased (or decreased for PaO2) from 60-100%, but not from 100-115% VO2max. Failure of peak airflow and VT to increase when intensity increased was associated with the development of hypoxaemia and hypercapnoea, regardless of slope or fb. It is concluded that while a low fb may have some beneficial effect on gas exchange during submaximal exercise at approximately 60% VO2max, this effect disappears as exercise intensity increases. There appear to be limits to the peak airflows that can be generated by horses during strenuous exercise, and these limits may be reached regardless of fb. Flow limitation per se may play a greater role in the development of exercise-induced hypoxaemia and hypercapnoea in horses than dose fb.

New reference reagent for the quality assurance of anti-D antibody detection.

A UK BTS-NIBSC freeze-dried anti-D preparation has been prepared and used to monitor the performance of routine antibody detection tests and of the test operators. With the day-to-day use of this preparation, adverse changes in test performance and in test operator may be detected and appropriate action taken before the effect becomes significant. Two dilutions of this preparation have been defined, one which should be detected unequivocally in every test; the other, more dilute, may not be detected in every test but is used to monitor changes in performance. Experience with the use of this preparation is reported from three test centres undertaking routine antibody detection tests. By monitoring results over a series of working days, significant differences were noted in operator performance within one test centre, as was a reduced sensitivity of a given test system within one test centre compared with the same system in the other test centres. These differences were detected only by monitoring the results obtained with this preparation.

Relationship between the sonographic pattern of intrauterine growth restriction and acid-base status at the time of cordocentensis.

OBJECTIVE: To determine whether there is a difference in acid-base status at the time of cordocentesis between fetuses with symmetric and asymmetric intrauterine growth restriction (IUGR). STUDY DESIGN: Non-anomalous singleton fetuses with IUGR who underwent fetal blood sampling for rapid karyotype analysis from 1992-1995 were retrospectively identified. Cases with gestational age <24 weeks, abnormal karyotype, or evidence of congenital infection were excluded. Fetuses were divided into two groups based on Head Circumference/ Abdominal Circumference Ratio (HC/AC). The asymmetric-IUGR group had HC/AC > or = 95% tile for GA, and the symmetric-IUGR group had HC/AC <95% tile. GA adjusted values of umbilical venous pH, pCO2, pO2, HCO3, hemoglobin and reticulocyte count were calculated by subtracting the mean values for GA from the observed and compared between groups. RESULTS: Both symmetric-IUGR (n = 7) and asymmetric-IUGR (n = 9) had umbilical venous pH and pO2, levels lower than GA normative values. However, there were no differences between groups for any of the parameters studied. CONCLUSIONS: Fetuses with symmetric and asymmetric IUGR due to UPI display a similar degree of acid-base impairment.