Meat and meat-mutagen intake and risk of non-Hodgkin lymphoma: results from a NCI-SEER case-control study

Non-Hodgkin Lymphoma (NHL) incidence has risen dramatically over past decades, but the reasons for most of this increase are not known. Meat cooked well-done using high-temperature cooking techniques produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P). This study was conducted as a population-based case-control study in Iowa, Detroit, Seattle and Los Angeles and was designed to determine whether meat, meat-cooking methods, HCAs or PAHs from meat were associated with NHL risk. This study consisted of 458 NHL cases, diagnosed between 1998 and 2000, and 383 controls. Participants completed a 117-item food frequency questionnaire (FFQ), with graphical aids to assess the meat-cooking method and doneness level, which was linked to a HCA and B[a]P database. Logistic regression, comparing the fourth to the first quartile, found no association between red meat or processed meat intake and risk for NHL [odds ratio (OR) and 95% confidence interval (CI): 1.10 (0.67-1.81) and 1.18 (0.74-1.89), respectively]. A marginally significant elevated risk for NHL was associated with broiled meat [OR and 95% CI: 1.32 (0.99-1.77); P trend = 0.09], comparing those who consumed broiled meat with those who did not. The degree to which meat was cooked was not associated with the risk for NHL, although one of the HCAs, DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline), was associated with an inverse risk. Fat intake was associated with a significantly elevated risk for NHL [OR and 95% CI: 1.60 (1.05-2.45); P trend = 0.12]; in contrast, animal protein was inversely associated with risk for NHL [OR and 95% CI: 0.39 (0.22-0.70); P trend = 0.004]. Overall, our study suggests that consumption of meat, whether or not it is well-done, does not increase the risk of NHL. Furthermore, neither HCAs nor B[a]P from meat increase the risk of NHL.     

Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress

N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in a variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here, we show that 4-HPR and not all-trans retinoic acid and 9-cis retinoic acid effectively induce apoptosis in glioma cells. 4-HPR-induced apoptosis is associated with hydroperoxide production and loss of mitochondrial membrane potential (Delta Psi(m)). Ultrastructural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca(2+) as well as mitochondrial Ca(2+). Chelation of extracellular Ca(2+) by EGTA did not prevent Ca(2+) elevation, thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis; however, blocking the release of Ca(2+) from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca(2+) from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol and nucleus, respectively, along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors, thus suggesting involvement of a caspase-dependent and caspase-independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial-mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.     

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) to drive production of an intracellular photosensitiser, protoporphyrin IX (PpIX), is a promising cancer treatment. However, ALA-PDT is still suboptimal for thick or refractory tumours. Searching for new approaches, we tested a known inducer of cellular differentiation, methotrexate (MTX), in combination with ALA-PDT in LNCaP cells. Methotrexate alone promoted growth arrest, differentiation, and apoptosis. Methotrexate pretreatment (1 mg l(-1), 72 h) followed by ALA (0.3 mM, 4 h) resulted in a three-fold increase in intracellular PpIX, by biochemical and confocal analyses. After exposure to 512 nm light, killing was significantly enhanced in MTX-preconditioned cells. The reverse order of treatments, ALA-PDT followed by MTX, yielded no enhancement. Methotrexate caused a similar relative increase in PpIX, whether cells were incubated with ALA, methyl-ALA, or hexyl-ALA, arguing against a major effect upon ALA transport. Searching for an effect among porphyrin synthetic enzymes, we found that coproporphyrinogen oxidase (CPO) was increased three-fold by MTX at the mRNA and protein levels. Transfection of LNCaP cells with a CPO-expressing vector stimulated the accumulation of PpIX. Our data suggest that MTX, when used to modulate intracellular production of endogenous PpIX, may provide a new combination PDT approach for certain cancers.     

Restoration by aspirin of impaired plasma maspin level in human breast cancer

Maspin, an anti breast cancer protein, is produced in the normal mammary cells but not in malignant cells in breast cancer. We investigated the effect of aspirin induced increase of plasma nitric oxide (NO) on plasma maspin production in breast cancer patients. Fifteen breast cancer patients (35-65 years), who had not yet undergone any cancer therapy, and an equal number of age matched normal female volunteers participated in the study. They were asked not to take any medication for two weeks. All participants then ingested 150 mg of aspirin. Plasma NO and maspin levels were determined before and at 60 min after the ingestion of aspirin. It was found that the maspin level in plasma increased to 4.63+/-0.02 nM from the basal 0.95+/-0.012 nM (p<0.001) with increase of plasma NO from 0.60+/-0.03 microM to 2.08+/-0.030 microM (p<0.001) in breast cancer patients. In normal volunteers the basal maspin increased from 4.76+/-0.041 to 9.36+/-0.036 nM (p<0.001) with increase of NO from 2.15+/-0.08 to 3.36+/-0.04 microM (p<0.001) at the same period. These results indicated that the ingestion of aspirin might be beneficial for breast cancer through increased maspin production.     

CRTs--cluster randomized trials or "courting real troubles": challenges of running a CRT in rural Gujarat, India

This paper addresses the logistical challenges of implementing public health interventions in the setting of cluster randomized trials (CRTs), drawing on the experience of carrying out a CRT within a community-based health insurance (CBHI) scheme in rural India. Our CRT is seeking to improve the equity impact--i.e., reduce the differential in claims submission for hospitalization between poor and less poor--of this CBHI in rural areas. Five main challenges are identified and discussed: 1) assigning control clusters, 2) blinding, 3) implementing interventions simultaneously, 4) minimizing leakage, and 5) piggy-backing on a changing scheme. These challenges are not likely to be unique to low-income settings, although the fifth challenge is particularly likely when working with relatively small and resource-constrained programs. While compromises to methodological best-practice may reduce internal validity, they make the intervention more 'real', and potentially more applicable, to other programs and settings. Further, careful documentation of compromises allows them to be considered in the final analysis.     

Safe removal of LMA in children – at what BIS?

Background:  Removal of an LMA without producing untoward complications has remained a matter of concern to all anesthesiologists; more so in pediatric practice where the margin of safety is narrow. Most work on LMA in adults supports its removal following return of airway reflexes. The situation regarding its removal in children is, however, less clear.
Methods:  We conducted a randomized, prospective study to compare incidence of airway complications after removal of the LMA at deep or awake planes in 120 children, ASA I or II, aged 1–8 years and to objectively determine the most appropriate Bispectral index (BIS) to allow safe removal of an LMA in children. They were studied in two groups of 60 and depth of anesthesia (whether awake-Gp A or deep-Gp D) for LMA removal was decided by random distribution from sealed envelopes. BIS was recorded continuously for all the patients until 2 min after removal of LMA.
Results:  Mean SpO₂ after removal of LMA was 93% Gp A and 98% in Gp D. The mean duration of surgery in Gp A was 53.9 ± 10 and in Gp D 46.7 ± 4 min. P_ESev at removal in Gp A was 0.20 ± 0.16 and in Gp D was 0.59 ± 0.1. BIS median in Gp A was 79 with a maximum of 86 and minimum of 66. In Gp D BIS, median was 60 with maximum of 76 and minimum of 58. The number of patients with airway complications in awake removal group was 21 (35%) and in deep removal group was 4 (6.6%).
Conclusions:  Bispectral index scoring should prove a useful adjunct to the present monitoring and can be used to achieve smoother emergence conditions. We suggest that LMA removal should be attempted in children when a BIS value of approximately 60 is reached.     

Prediction of successful epidural catheter placement by a 'cold test'

We tested the hypothesis that the patients' feeling of cold sensation down the back during epidural drug administration through the epidural catheter was a reliable predictor of correct epidural catheter placement. In a prospective study of 80 patients, an epidural catheter was placed in the lumbar epidural space. During epidural drug injection, patients were asked to report feeling of the cold sensation in their back by pressing a bell. After 15 minutes, the patients were assessed for cold sensation in the thoracic to sacral dermatomes bilaterally and the dermatomal block recorded. Of 80 patients, three had inadvertent dural puncture. Seventy-two of 77 patients reported feeling cold sensation in their back during local anaesthetic injection, and all had successful epidural blockade. Of the five patients who did not report any cold sensation, three had failed epidural block and two successful epidural block. There were no false positive results. Of three patients who had inadvertent dural puncture and had normal saline 5 ml injected through the Tuohy needle, none reported cold sensation. The perception of cold sensation in the back during epidural administration of a test dose and/or subsequent full dose of local anaesthetic is useful in predicting successful epidural catheter placement.     

Platelet counts are persistently increased following simultaneous pancreas and kidney transplantation

BACKGROUND: Increased platelet counts has been reported to be a sequela of pancreas transplantation and even incriminated in the increased rate of thrombosis of pancreas grafts. The aim of the study was to measure the platelet counts after simultaneous kidney-pancreas transplantations compared to kidney transplants alone in diabetic patients. METHODS: This retrospective case-control study included 57 patients who received simultaneous pancreas and kidney transplants (SPK), from 1985 to 2000 and had functioning grafts for more than 1 month. The control patients were 38 type I diabetic recipients of kidney transplants alone (KTA), matched for sex, era, and immunosuppression. The platelet counts, white cell counts, and hemoglobin were analyzed on the preoperative day, weeks 1 to 6, 3 months, 6 months and 1 year. RESULTS: The mean age of the SPK group was significantly lower than that of the KTA group (39.8+/-8.3 versus 48.2+/-11.7, P<.01). Significantly higher platelet counts were demonstrated during weeks 2 to 6, which persisted at 3 months and at 1 year among the SPK compared to the KTA group. Although significantly higher white cell counts and lower hemoglobin levels were seen among the SPK versus KTA group during weeks 3 to 6, it did not persist after 3 months. CONCLUSION: The mean platelet counts of patients with simultaneous pancreas and kidney transplantation was significantly higher than that of diabetic patients with kidney transplants alone. This thrombocytosis persisted up to the first year and cannot be explained by an increased amount of blood loss or higher infectious complications in the SPK group. Routine antiplatelet prophylaxis is recommended in this group of patients.