A multicentre audit of HDR/PDR brachytherapy absolute dosimetry in association with the INTERLACE trial (NCT015662405).

A UK multicentre audit to evaluate HDR and PDR brachytherapy has been performed using alanine absolute dosimetry. This is the first national UK audit performing an absolute dose measurement at a clinically relevant distance (20 mm) from the source. It was performed in both INTERLACE (a phase III multicentre trial in cervical cancer) and non-INTERLACE brachytherapy centres treating gynaecological tumours. Forty-seven UK centres (including the National Physical Laboratory) were visited. A simulated line source was generated within each centre's treatment planning system and dwell times calculated to deliver 10 Gy at 20 mm from the midpoint of the central dwell (representative of Point A of the Manchester system). The line source was delivered in a water-equivalent plastic phantom (Barts Solid Water) encased in blocks of PMMA (polymethyl methacrylate) and charge measured with an ion chamber at 3 positions (120° apart, 20 mm from the source). Absorbed dose was then measured with alanine at the same positions and averaged to reduce source positional uncertainties. Charge was also measured at 50 mm from the source (representative of Point B of the Manchester system). Source types included 46 HDR and PDR 192Ir sources, (7 Flexisource, 24 mHDR-v2, 12 GammaMed HDR Plus, 2 GammaMed PDR Plus, 1 VS2000) and 1 HDR 60Co source, (Co0.A86). Alanine measurements when compared to the centres' calculated dose showed a mean difference (±SD) of +1.1% (±1.4%) at 20 mm. Differences were also observed between source types and dose calculation algorithm. Ion chamber measurements demonstrated significant discrepancies between the three holes mainly due to positional variation of the source within the catheter (0.4%-4.9% maximum difference between two holes). This comprehensive audit of absolute dose to water from a simulated line source showed all centres could deliver the prescribed dose to within 5% maximum difference between measurement and calculation.

Recent developments and best practice in brachytherapy treatment planning.

Brachytherapy has evolved over many decades, but more recently, there have been significant changes in the way that brachytherapy is used for different treatment sites. This has been due to the development of new, technologically advanced computer planning systems and treatment delivery techniques. Modern, three-dimensional (3D) imaging modalities have been incorporated into treatment planning methods, allowing full 3D dose distributions to be computed. Treatment techniques involving online planning have emerged, allowing dose distributions to be calculated and updated in real time based on the actual clinical situation. In the case of early stage breast cancer treatment, for example, electronic brachytherapy treatment techniques are being used in which the radiation dose is delivered during the same procedure as the surgery. There have also been significant advances in treatment applicator design, which allow the use of modern 3D imaging techniques for planning, and manufacturers have begun to implement new dose calculation algorithms that will correct for applicator shielding and tissue inhomogeneities. This article aims to review the recent developments and best practice in brachytherapy techniques and treatments. It will look at how imaging developments have been incorporated into current brachytherapy treatment and how these developments have played an integral role in the modern brachytherapy era. The planning requirements for different treatments sites are reviewed as well as the future developments of brachytherapy in radiobiology and treatment planning dose calculation.

Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes?

AIM: Preoperative radiotherapy has been shown to improve local control in advanced rectal carcinoma compared with surgery alone. Several large randomized trials have confirmed that chemoradiotherapy (CRT) is better than radiotherapy alone. This pilot study was designed to increase the radiation dose using high-dose rate (HDR) brachytherapy boost following preoperative CRT to evaluate whether this strategy improves the outcome of surgery without increase in toxicity. METHOD: Since October 2004, we have used the new rectal HDR applicator for brachytherapy boost in 68 patients following CRT. The patients had CT and MRI Scans as part of staging. All had locally advanced disease either bulky low T2 or T3 with threatened circumferential resection margin and multiple suspicious lymph nodes. They were offered preoperative CRT either by 5-FU infusion 1 g/m(2) day 1-4 (week 1 + 5) or by oral capecitabine 825 mg/m(2) Monday-Friday for 5 weeks together with CT planned external beam RT 45Gy in 25 fractions over 5 weeks (CRT). Those downstage on repeat MRI scan were offered additional HDR Boost 10Gy directly to the tumour followed by surgery 6-8 weeks later [group A]. Four patients proceeded directly to surgery but because of involved resection margin had a HDR brachytherapy boost as postoperative treatment [group B]. Thirty patients were not planned for immediate surgery after CRT and brachytherapy boost, as they were either elderly or considered high risk for anaesthesia [group C]. RESULTS: There were 34 patients (median age 67 (range 39-81) years in group A, including 24 men). The PS was 0-1. The clinical stage at presentation was cT2 in five, cT3 in 23 and T4 in six patients and cN0 in 2, cN1 in 21 and N2 in 11. Thirty-three patients had CRT, and one had radiotherapy alone. All patients completed treatment without interruption. Twenty-nine patients had surgery following CRT and brachytherapy boost including anterior resection in 10 patients, Abdominoperineal excision (APR) in 18 and Hartmann's resection in one. Five patients did not have the intended surgery. Twenty-four (83%) patients had an RO resection compared with 63% having conventional preoperative CRT using bolus 5FU regimes. Pathological complete remission (pCR) was achieved in 9 (31%) compared with 12% patients having conventional CRT. There was no increase in G 3-4 toxicity from RT and no delay in wound healing or increase in anastomotic leakage. One of the four patients in group B developed local recurrence. The thirty patients in group C who had modified radical CRT followed by brachytherapy boost as a definitive treatment will be reported in a further communication. CONCLUSION: Increasing the dose of radiation by HDR brachytherapy boost appears to improve the RO resection and pCR rates compared with conventional CRT. The follow up is too short to judge its effect on disease-free survival. This study will be extended to compare this strategy in a randomized phase III trial with conventional CRT in patients who are not fit for more intensive CRT (HERCULES).

The IPEM code of practice for determination of the reference air kerma rate for HDR (192)Ir brachytherapy sources based on the NPL air kerma standard.

This paper contains the recommendations of the high dose rate (HDR) brachytherapy working party of the UK Institute of Physics and Engineering in Medicine (IPEM). The recommendations consist of a Code of Practice (COP) for the UK for measuring the reference air kerma rate (RAKR) of HDR (192)Ir brachytherapy sources. In 2004, the National Physical Laboratory (NPL) commissioned a primary standard for the realization of RAKR of HDR (192)Ir brachytherapy sources. This has meant that it is now possible to calibrate ionization chambers directly traceable to an air kerma standard using an (192)Ir source (Sander and Nutbrown 2006 NPL Report DQL-RD 004 (Teddington: NPL) http://publications.npl.co.uk). In order to use the source specification in terms of either RAKR, Κ(R) (ICRU 1985 ICRU Report No 38 (Washington, DC: ICRU); ICRU 1997 ICRU Report No 58 (Bethesda, MD: ICRU)), or air kerma strength, S(K) (Nath et al 1995 Med. Phys. 22 209-34), it has been necessary to develop algorithms that can calculate the dose at any point around brachytherapy sources within the patient tissues. The AAPM TG-43 protocol (Nath et al 1995 Med. Phys. 22 209-34) and the 2004 update TG-43U1 (Rivard et al 2004 Med. Phys. 31 633-74) have been developed more fully than any other protocol and are widely used in commercial treatment planning systems. Since the TG-43 formalism uses the quantity air kerma strength, whereas this COP uses RAKR, a unit conversion from RAKR to air kerma strength was included in the appendix to this COP. It is recommended that the measured RAKR determined with a calibrated well chamber traceable to the NPL (192)Ir primary standard is used in the treatment planning system. The measurement uncertainty in the source calibration based on the system described in this COP has been reduced considerably compared to other methods based on interpolation techniques.

Physical fitness and carotid atherosclerosis in men.

We investigated the association between cardiorespiratory fitness (CRF) and carotid atherosclerosis in 9 871 Korean men aged 40-81 years. We measured carotid intima-media thickness by using B-mode ultrasonography, and cardiorespiratory fitness was measured by a maximal treadmill exercise test using the Bruce protocol. Carotid atherosclerosis was defined as an intima-media wall thickness greater than 1.2 mm or stenosis >25% of carotid arteries, while CRF was classified as low fit (<20%), moderately fit (20-<60%), or high fit (> or =60%) categories based on age-specific VO (2peak) (ml/kg/min) percentiles. The presence of carotid atherosclerosis across CRF categories was 11.7% (low fit), 9.6%, and 7.7%, respectively. After adjustment for age, cigarette smoking, body mass index, physical activity, there was an inverse association between CRF and carotid atherosclerosis (p for trend <0.001). The odds ratio of presence of carotid atherosclerosis in the high-fit men versus the low-fit men was 0.67 (95% CI, 0.55, 0.80). After additional adjustment for high cholesterol, hypertension, and diabetes mellitus, the results remain unchanged and the odds ratios across CRF levels were (95% CI): 1.00 (low fit, referent), 0.85 (0.71, 1.01), 0.71 (0.59, 0.85) (p for trend <0.001), respectively. High levels of cardiorespiratory fitness were associated with a lower risk of having carotid atherosclerosis in middle-aged and elderly men.

Survey of complementary and alternative medicine practitioners regarding cancer management and research.

The primary purpose of this survey was to assess the interest and concerns of a group of cancer complementary and alternative medicine (CAM) practitioners regarding CAM research issues. These issues include the CAM modalities used most often by CAM practitioners in the treatment of cancer patients, cancer CAM practitioners' perceptions of the most promising areas of cancer CAM research, the perceived obstacles to carrying out research objectives in the emerging field of cancer CAM research, the extent of awareness of the National Cancer Institute (NCI) Best Case Series Program, and CAM practitioners' level of interest in research collaboration with CAM researchers. A cross-sectional survey of a convenience sample of cancer CAM practitioners was conducted. One hundred thirty-four respondents completed the survey. About 72% of the respondents were involved in the care of cancer patients, and these were considered the informative respondents. All results were from the informative respondent group. Respondent practitioners provided care using interventions from all seven of the predefined CAM categories. This care was provided to improve both quality of life and survival. Over two-thirds of the respondents rated research in pharmacologic and biologic treatments, alternative medical systems and nutritional therapeutics for cancer treatment, and symptom/side-effect management as high-priority areas. Although no single obstacle to research predominated as the most significant, the most frequently encountered obstacle was lack of awareness of appropriate funding sources (75.4%). More than 83% of respondents expressed some interest in or willingness to establish research collaboration with a cancer researcher. The results from this survey indicate that many cancer CAM practitioners have shared interests, perceived obstacles, and desired research opportunities. Despite a small sample size and lack of a feasible process for random sampling, this survey highlights avenues to promote and support collaborative research. The NCI/Office of Cancer Complementary and Alternative Medicine will continue to respond to the concerns elucidated by the survey by developing strategies for future program opportunities within the NCI.

High dose rate brachytherapy as a boost after preoperative chemoradiotherapy for more advanced rectal tumours: the Clatterbridge experience.

In a systemic review of 8507 patients from 22 randomised trials, radiotherapy has been shown to reduce the risk of local recurrence and death from rectal cancer compared with surgery alone. Recent large randomised trials confirmed that chemoradiotherapy was better than radiotherapy alone. Contact radiotherapy as a boost after external beam radiotherapy (without chemotherapy) has also been shown to improve local control and sphincter preservation in the Lyon 092 trial. Brachytherapy has now been used as preoperative treatment for rectal cancer and showed similar results. The Swedish and Dutch trial results of short-course preoperative radiotherapy have shown improved local control in favour of the radiotherapy group. Similar to the Scandinavian group, investigators from McGill University in Montreal adopted a short course using brachytherapy instead of external beam radiotherapy. However, surgery was delayed for 4-8 weeks to achieve downstaging. The radiation dose was delivered directly on to the tumour and the surrounding normal tissues were spared the effects of radiation. This approach has been shown to reduce the side-effects seen with external beam short-course radiotherapy, but maintains the benefit of improved local control. The Danish group used brachytherapy as a boost after external beam chemoradiotherapy for more advanced rectal tumours and have shown improved pathological complete remission and R0 resection rates. The Mount Vernon group used a similar rectal applicator for inoperable rectal cancer patients and achieved good local and symptom control. The brachytherapy group at Clatterbridge used the same approach as the Danish group, but reduced the external beam radiotherapy dose and increased the brachytherapy dose to lower the side-effects. All 16 patients (100%) had R0 resection compared with 63% with conventional preoperative chemoradiotherapy using a bolus 5-fluorouracil regimen. Pathological complete remission was achieved in seven (44%) patients compared with 2-12% with conventional chemoradiotherapy. There was no increase in grade 3-4 toxicity from radiotherapy and no delay in wound healing or anastamotic leakage. The inclusion of high dose rate brachytherapy seems to increase the pathological complete remission rates and improves the R0 resection rates with no detriment to the side-effects as the increased dose of radiation from the high dose rate boost is confined mainly to the tumour. This treatment may be particularly suitable for elderly patients where intensive chemoradiotherapy regimens are not suitable. Several trials are planned to define the role of preoperative high dose rate brachytherapy in rectal cancer and the results are awaited with interest.

Role of hippocampal M2 muscarinic receptors in the estrogen-induced enhancement of working memory.

We have previously demonstrated that acetylcholine, acting at M2 muscarinic receptors, mediates the estradiol-induced increase in hippocampal N-methyl-d-aspartate receptor binding and the associated enhancement in working memory. The goal of present experiment was to investigate the role of hippocampal M2 receptors in the behavioral aspects of these effects. Ovariectomized rats were trained to locate a hidden escape platform on a matching-to-place version of the water maze in which the platform was moved to a new location for each session of four daily trials. Following 18 days of training, rats were randomly assigned to receive one of the following treatments: 1) injections of oil vehicle delivered 72 and 48 h before testing and continuous delivery of vehicle into the dorsal hippocampus via bilateral cannulae implants connected to osmotic minipumps; 2) injections of estradiol benzoate (EB) delivered 72 and 48 h before testing and continuous delivery of vehicle into the hippocampus; 3) injections of EB delivered 72 and 48 h before testing and continuous delivery of the M2 muscarinic receptor antagonist, AFDX 116, into the hippocampus; and 4) injections of EB delivered 72 and 48 h before testing and continuous delivery of AFDX 116 into a control site in the cortex. Chronic administration of AFDX 116 into the hippocampus, but not the cortex, significantly attenuated an estrogen-induced enhancement in performance on a working memory task in the water maze as indicated by increased latency and increased path length to locate an escape platform during a test trial when a 90 min delay was imposed between the first and second trials. These results indicate that acetylcholine acts at M2 muscarinic receptors located in the hippocampus to mediate the positive effects exerted by estrogen on working memory.

Two cases of steakhouse syndrome associated with nutcracker esophagus.

The most common type of esophageal food-related foreign body is the meat bolus, which is frequently associated with underlying esophageal stenosis. Herein, we report two cases of meat bolus impaction associated with nutcracker esophagus. In the first case, the 63-year-old male patient had chest discomfort and swallowing difficulty after ingestion of butcher's meat. In the second case, the 55-year-old male patient had complained of swallowing difficulty after ingestion of chicken. In both cases, no pathologic findings were observed endoscopically after removal of the esophageal meat bolus. We performed esophageal manometry, which showed very high amplitudes of esophageal pressure in the mid- and distal esophagus. These findings were consistent with nutcracker esophagus. These cases show that esophageal motility disorder may be the cause of esophageal foreign body impaction, and esophageal manometry should be performed for evaluation of the cause of foreign body, especially in an endoscopically normal patient.

Ultrastructural changes of hepatic stellate cells in the space of Disse in alcoholic fatty liver.

BACKGROUND: Hepatic stellate cell (HSC) has been suggested to play a role in fibrogenesis in alcoholic liver disease. We evaluate the correlation with fibrogenesis and ultrastructure of hepatic stellate cells in alcoholic fatty liver. METHODS: We studied 6 patients with alcoholic fatty liver and 5 non-alcoholic fatty liver. The numbers of fat droplets in hepatic stellate cell was determined by electron microscopy. We also studied the grading of deposition of collagen fibers in the space of Disse. We were to evaluate the structure of hepatic stellate cells in the space of Disse by light and electron microscopy. RESULTS: Wider distribution of fat droplets in hepatic stellate cells in alcoholic fatty liver than in normal liver. The hypertrophied endoplasmic reticulum in hepatic stellate cells is a prominent findings in alcoholic fatty liver. We observed basement membrane-like materials in patients with alcoholic fatty liver with hepatic fibrosis. CONCLUSION: The results demonstrate that, in patients with alcoholic fatty liver by alcoholic liver injury, the hepatic stellate cells may play an important role in the fibrogenesis of perisinusoidal spaces in the liver.

The relationship between virological characteristics of hepatitis C virus (HCV) and reactivity to the regional specific proteins of HCV.

BACKGROUND: Although the polyproteins of hepatitis C virus(HCV) are processed and formed in nearly equimolar amounts, individual functional proteins have a discrepancy in their time of appearance following HCV infection and eliciting immune response. This study was conducted to compare the reactivity toward regional specific HCV protein in relation to virological characteristics, including HCV genotype and HCV replication. METHODS: Sera from forty-five patients with chronic HCV infection were analyzed through the experiments of the recombinant immunoblot assay(RIBA-2), HCV genotyping and HCV RNA quantitation. RESULTS: The frequencies of seropositivity to C22-3, C33C, C100-3 and 5-1-1 proteins were 91.1%, 91.1%, 64.4% and 53.3%, respectively, of all the patients, and thus the antibodies to C22-3 and C33C proteins were found more frequently (p < 0.05). The antibody responses between core or NS3 proteins and NS4 proteins showed more discrepancy in the HCC group than that in the CH group, implying a possibility of oncogenic potential of core or NS3 gene in hepatocarcinogenesis. The detection rate of antibodies to C22-3 and C33C, in accordance with serum HCV RNA levels, was significantly higher in highly viremic patients than that in low viremic patients (p < 0.05). Antibodies to C22-3, C33C, C100-3 and 5-1-1 were also found more frequently in patients with HCV genotype 1b, compared to those with HCV genotype 2a (p < 0.05). CONCLUSION: These results suggest that antibody detection of HCV may depend on the virological characteristics of HCV, the levels of HCV replication and HCV genotype and, therefore, HCV RNA detection using RT-PCR technique is essential for confirmatory diagnosis for HCV infection. Furthermore, the HCV core or NS3 Protein may play important role in hepatocarcinogenesis.

Bilateral radical radiotherapy in a patient with uterus didelphys.

We report a case of congenital abnormality of uterus didelyphys in a patient who developed invasive carcinoma of the cervix. She received radical radiotherapy by a combination of external beam pelvic radiotherapy and high dose rate brachytherapy by insertion of afterloading catheters into both uterine canals. A newly defined prescription point was used midway between the two catheters and 2 cm above the mean cervical os position. The classical point A was regarded as inappropriate in this patient with a rare condition. Acute toxicity was minor and the patient is tumour free with no significant normal tissue late effects after follow-up of nearly 3 years.

Mutations of hepatitis C virus 1b NS5A 2209-2248 amino acid sequence is not a predictive factor for response to interferon-alpha therapy and development of hepatocellular carcinoma.

Genetic changes between codons 2209 and 2248 of NS5A of genotype 1b hepatitis C virus (HCV-1b) have been reported to be associated with the sensitivity to interferon-alpha (IFN-alpha). The present study was performed to analyze such relationship in Korean patients with chronic hepatitis C and HCV-1b (n=19), including 12 chronic hepatitis C patients treated with IFN-alpha, 3 chronic hepatitis C patients without treatment as controls, and 4 patients with hepatocellular carcinoma (HCC). Two serum samples, before and after the treatment, were analyzed for the mutations by reverse transcription-polymerase chain reaction, cloning and sequencing. The mutations were identified in 32% (6/19), including five intermediate type (1-3 mutations) and one mutant type (4 or more). In 12 patients treated with IFN-alpha, the number of amino acid substitutions in NS5A2209-2248 was not associated with outcome of the treatment. Two HCV isolates with NS5A2209-2248 mutations from HCC patients were intermediate type. These results do not support that the NS5A2209-2248 determines interferon sensitivity of HCV-1b and that the mutations is associated with development of HCC.

The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men.

BACKGROUND: Several studies show an inverse association between self-reported physical activity and type 2 diabetes. It is not known whether physical activity or cardiorespiratory fitness is associated with the onset of objectively determined impaired fasting glucose and type 2 diabetes. OBJECTIVE: To determine whether cardiorespiratory fitness, an objective marker of physical activity, is associated with risk for impaired fasting glucose and type 2 diabetes. DESIGN: Population-based prospective study. SETTING: Preventive medicine clinic. PATIENTS: 8633 nondiabetic men (of whom 7511 did not have impaired fasting glucose) who were examined at least twice. MEASUREMENTS: Cardiorespiratory fitness (determined by a maximal exercise test on a treadmill), fasting plasma glucose level, and other clinical and personal characteristics and incidence of impaired fasting glucose and type 2 diabetes. RESULTS: During an average follow-up of 6 years, 149 patients developed type 2 diabetes and 593 patients developed impaired fasting glucose. After age, cigarette smoking, alcohol consumption, and parental diabetes were considered, men in the low-fitness group (the least fit 20% of the cohort) at baseline had a 1.9-fold risk (95% CI, 1.5- to 2.4-fold) for impaired fasting glucose and a 3.7-fold risk (CI, 2.4- to 5.8-fold) for diabetes compared with those in the high-fitness group (the most fit 40% of the cohort). The risk for impaired fasting glucose was elevated in older men and those with a higher body mass index. Age, body mass index, blood pressure, triglyceride level, and a history of parental diabetes were also directly related to risk for type 2 diabetes. CONCLUSIONS: Low cardiorespiratory fitness was associated with increased risk for impaired fasting glucose and type 2 diabetes. A sedentary lifestyle may contribute to the progression from normal fasting glucose to impaired fasting glucose and diabetes. Risk for type 2 diabetes was elevated in older persons and those with higher body mass index, blood pressure, and triglyceride levels and a parental history of diabetes.

Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men.

BACKGROUND: Cardiorespiratory fitness and body fatness are both related to health, but their interrelation to all-cause and cardiovascular disease (CVD) mortality is unknown. OBJECTIVE: We examined the health benefits of leanness and the hazards of obesity while simultaneously considering cardiorespiratory fitness. DESIGN: This was an observational cohort study. We followed 21925 men, aged 30-83 y, who had a body-composition assessment and a maximal treadmill exercise test. There were 428 deaths (144 from CVD, 143 from cancer, and 141 from other causes) in an average of 8 y of follow-up (176742 man-years). RESULTS: After adjustment for age, examination year, cigarette smoking, alcohol intake, and parental history of ischemic heart disease, unfit (low cardiorespiratory fitness as determined by maximal exercise testing), lean men had double the risk of all-cause mortality of fit, lean men (relative risk: 2.07; 95% CI: 1.16, 3.69; P = 0.01). Unfit, lean men also had a higher risk of all-cause and CVD mortality than did men who were fit and obese. We observed similar results for fat and fat-free mass in relation to mortality. Unfit men had a higher risk of all-cause and CVD mortality than did fit men in all fat and fat-free mass categories. Similarly, unfit men with low waist girths (<87 cm) had greater risk of all-cause mortality than did fit men with high waist girths (> or =99 cm). CONCLUSIONS: The health benefits of leanness are limited to fit men, and being fit may reduce the hazards of obesity.

Late development of umbilical metastasis after laparoscopic cholecystectomy for a gallbladder carcinoma.

A periumbilical mass developed 47 months after laparoscopic cholecystectomy. Pathologic examination of this mass showed features of moderately differentiated papillary adenocarcinoma, similar to that identified within the previously removed early stage (pT1b) gallbladder carcinoma. The cause of this at the laparoscope port is unclear. after laparoscopic cholecystectomy for gallbladder carcinoma has not been reported previously. We reported a case with late periumbilical tumor seeding at the navel trocar insertion site in a 65-year-old female. A review of the preventative information of tumor recurrence and management is discussed. The use of gasless laparoscopy, slow desufflation, trocar site washout, wound protector and specimen bags are recommended.

US weight guidelines: is it also important to consider cardiorespiratory fitness?

BACKGROUND: The health consequences of weight ranges across low to moderate and high levels of cardiorespiratory fitness are unknown. OBJECTIVE: To evaluate the validity of the 1995 US weight guidelines, while considering cardiorespiratory fitness. METHODS: We followed 21,856 men, aged 30-83 y, who had a complete preventive medical examination, including a maximal treadmill exercise test and body composition assessment. There were 427 deaths (144 cardiovascular disease (CVD); 143 cancer; 140 others) during an average of 8.1 y of follow-up. We used Cox proportional hazards regression to examine the relations among cardiorespiratory fitness, body mass index (BMI, kg/m2), and all-cause and CVD mortality. RESULTS: After adjustment for age, examination year, cigarette smoking and alcohol intake, we observed that men with a BMI of 19.0 to < 25.0 and who were unfit had 2.3 times the risk of all-cause mortality (95% confidence interval (95% CI), 1.59-3.17, P < 0.001) compared with fit men in this BMI group (reference category). Unfit men with a BMI of 25.0 to < 27.8 also had a greater risk of all-cause mortality than fit men in the same BMI category. Fit but overweight men (BMI > or = 27.8) had a similar rate of all-cause mortality as physically fit men of normal weight (BMI 19.0 to < 25.0) and had a lower risk of all-cause mortality than unfit and normal weight men. Fit men of normal weight had the lowest CVD mortality, while unfit and overweight men experienced the highest CVD mortality. Unfit men had substantially higher CVD mortality than fit men in each BMI group. CONCLUSIONS: Unfit men had higher all-cause and CVD mortality than fit men. The health benefits of normal weights appear to be limited to men who have moderate or high levels of cardiorespiratory fitness. These data suggest that the 1995 US weight guidelines may be misleading unless cardiorespiratory fitness is taken into account.

Cardiorespiratory fitness determined by exercise heart rate as a predictor of mortality in the Aerobics Center Longitudinal Study.

This paper reviews the association of cardiorespiratory fitness to all-cause and cardiovascular disease mortality. Data are presented from the Aerobics Center Longitudinal Study (ACLS), which is a prospective study of 25,341 men and 7080 women. These individuals completed a health screening examination and were followed for more than 8 years for mortality. Low cardiorespiratory fitness was one of the strongest predictors of mortality in this study, with the risk of low fitness being comparable to smoking. Risk of low fitness persisted after adjustment for a long list of other risk factors and other potential confounders. Previously unpublished data on metabolic and cardiovascular responses to the exercise test used in the ACLS are also provided. This additional information further characterizes this cohort, and gives additional data and methods that can be used by others for risk assessment and stratification.

Phyllanthus amarus down-regulates hepatitis B virus mRNA transcription and replication.

The Phyllanthus amarus plant shows potential for treating hepatitis B virus. To define the mechanism of action of P. amarus, we used HepG2 2.2.15 cells, which support hepatitis B virus replication. P. amarus inhibited hepatitis B virus polymerase activity, decreased episomal hepatitis B virus DNA content and suppressed virus release into culture medium. To examine transcriptional control mechanisms, we used G26 hepatitis B virus transgenic mice, which produce serum HBsAg but neither HBcAg nor virion particles. When P. amarus was administered to transgenic mice, hepatic HBsAg mRNA levels decreased, indicating transcriptional or post-transcriptional down-regulation of the transgene. Increase in hepatitis B virus mRNA expression after stimulation of the glucocorticoid responsive element was also suppressed by P. amarus, suggesting involvement of the hepatitis B virus enhancer in this response. Disruption by P. amarus of hepatitis B virus polymerase activity, mRNA transcription and replication supports its role as an antiviral agent.