Objective comparison of image quality and dose between conventional and synchrotron radiation mammography.

The shape of the energy spectrum produced by an x-ray tube has a great importance in mammography. Many anode-filtration combinations have been proposed to obtain the most effective spectrum shape for the image quality-dose relationship. On the other hand, third generation synchrotrons such as the European Synchrotron Radiation Facility in Grenoble are able to produce a high flux of monoenergetic radiation. It is thus a powerful tool to study the effect of beam energy on image quality and dose in mammography. An objective method was used to evaluate image quality and dose in mammography with synchrotron radiation and to compare them to standard conventional units. It was performed systematically in the energy range of interest for mammography through the evaluation of a global image quality index and through the measurement of the mean glandular dose. Compared to conventional mammography units, synchrotron radiation shows a great improvement of the image quality-dose relationship, which is due to the beam monochromaticity and to the high intrinsic collimation of the beam, which allows the use of a slit instead of an anti-scatter grid for scatter rejection.

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir.

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study.

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369.

A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial.

BACKGROUND: The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). METHODS: Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m(2), paclitaxel at 175 mg/m(2), and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. RESULTS: Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade > or = 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. CONCLUSIONS: The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

My older sibling was drunk - younger siblings' drunkenness in relation to parental monitoring and the parent-adolescent relationship.

This study explored the links between having older siblings who get drunk, satisfaction with the parent-adolescent relationship, parental monitoring, and adolescents' risky drinking. Regression models were conducted based on a national representative sample of 3725 8th to 10th graders in Switzerland (mean age 15.0, SD = .93) who indicated having older siblings. Results showed that both parental factors and older siblings' drinking behaviour shape younger siblings' frequency of risky drinking. Parental monitoring showed a linear dose-response relationship, and siblings' influence had an additive effect. There was a non-linear interaction effect between parent-adolescent relationship and older sibling's drunkenness. The findings suggest that, apart from avoiding an increasingly unsatisfactory relationship with their children, parental monitoring appears to be important in preventing risky drinking by their younger children, even if the older sibling drinks in such a way. However, a satisfying relationship with parents does not seem to be sufficient to counterbalance older siblings' influence.

Variability of a peripheral dose among various linac geometries for second cancer risk assessment.

Second cancer risk assessment for radiotherapy is controversial due to the large uncertainties of the dose-response relationship. This could be improved by a better assessment of the peripheral doses to healthy organs in future epidemiological studies. In this framework, we developed a simple Monte Carlo (MC) model of the Siemens Primus 6 MV linac for both open and wedged fields that we then validated with dose profiles measured in a water tank up to 30 cm from the central axis. The differences between the measured and calculated doses were comparable to other more complex MC models and never exceeded 50%. We then compared our simple MC model with the peripheral dose profiles of five different linacs with different collimation systems. We found that the peripheral dose between two linacs could differ up to a factor of 9 for small fields (5 × 5 cm(2)) and up to a factor of 10 for wedged fields. Considering that an uncertainty of 50% in dose estimation could be acceptable in the context of risk assessment, the MC model can be used as a generic model for large open fields (≥10 × 10 cm(2)) only. The uncertainties in peripheral doses should be considered in future epidemiological studies when designing the width of the dose bins to stratify the risk as a function of the dose.

Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

A Dose-Response Strategy Reveals Differences between Normal-Weight and Obese Men in Their Metabolic and Inflammatory Responses to a High-Fat Meal.

A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (iAUC) = 22.9 ± 6.8 pg/mL × 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 ± 0.5 mmol/L × 6 h vs. 6.0 ± 0.5 mmol/L × 6 h; P = 0.015) but not in the normal-weight group (4.3 ± 0.5 mmol/L × 6 h vs. 4.8 ± 0.5 mmol/L × 6 h; P = 0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068.

Transgenic expression of Ly49A on T cells impairs a specific antitumor response.

Inhibitory MHC receptors determine the reactivity and specificity of NK cells. These receptors can also regulate T cells by modulating TCR-induced effector functions such as cytotoxicity, cytokine production, and proliferation. Here we have assessed the capacity of mouse T cells expressing the inhibitory MHC class I receptor Ly49A to respond to a well-defined tumor Ag in vivo using Ly49A transgenic mice. We find that the presence of Ly49A on the vast majority of lymphocytes prevents the development of a significant Ag-specific CD8+ T cell response and, consequently, the rejection of the tumor. Despite minor alterations in the TCR repertoire of CD8+ T cells in the transgenic lines, precursors of functional tumor-specific CD8+ T cells exist but could not be activated most likely due to a lack of appropriate CD4+ T cell help. Surprisingly, all of these effects are observed in the absence of a known ligand for the Ly49A receptor as defined by its ability to regulate NK cell function. Indeed, we found that the above effects on T cells may be based on a weak interaction of Ly49A with Kb or Db class I molecules. Thus, our data demonstrate that enforced expression of a Ly49A receptor on conventional T cells prevents a specific immune response in vivo and suggest that the functions of T and NK cells are differentially sensitive to the presence of inhibitory MHC class I receptors.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Protein kinase C-zeta mediates retinal degeneration in response to TNF.

Tumor necrosis factor-alpha (TNF) has been implicated in retinal ganglion cells (RGC) degeneration in glaucoma. Atypical protein kinase C (PKC) zeta is involved in cell protection against various stresses. The aim of this study was to investigate the potential proapoptotic effects of intravitreal injections of TNF with or without PKCzeta specific inhibitor on the rat retina. TNF was injected in the vitreous of rat eyes alone or in combination with specific PKCzeta inhibitor. PKCzeta and NF-kappaB were studied by immunohistochemistry and western-blotting analysis on retina, and apoptosis quantified by the TUNEL assay. While low basal PKCzeta was observed in the control eyes, TNF induced intense expression of PKCzeta mostly in bipolar cells processes. PKCzeta staining became nuclear when TNF was coinjected with PKCzeta inhibitor. TNF alone did not induce apoptosis in the retina. Coinjection of the PKCzeta-specific inhibitor and TNF, however, induced apoptosis in the inner nuclear and ganglion cell layers. The PKCzeta-specific inhibitor unmasks retinal cells to TNF cytotoxicity showing a link between the proapoptotic effects of TNF and the antiapoptotic PKCzeta signaling pathway.

The PPARgamma agonist pioglitazone modifies the vascular sodium-angiotensin II relationship in insulin-resistant rats.

Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (ANG II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of ANG II. Whether glitazones interfere with the interaction between sodium and the response to ANG II is not known. Therefore, we investigated the effects of pioglitazone on the relationship between sodium and the systemic and renal effects of ANG II in rats. Pioglitazone, or vehicle, was administered for 4 wk to 8-wk-old obese Zucker rats. Animals were fed a normal-sodium (NS) or a high-sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to ANG II, and the renal ANG II binding and expression of ANG II type 1 (AT(1)) receptors were measured. The results of our study were that food intake and body weight increased, whereas blood pressure, heart rate, filtration fraction, and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to ANG II and abolished the increased responsiveness to ANG II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with ANG II perfusion. These effects were associated with a decrease in the number and expression of the AT(1) receptor in the kidney. In conclusion, these data demonstrate that the peroxisome proliferator-activated receptor-gamma agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to ANG II in insulin-resistant rats.

Dose and time effects of treatment with low doses of a LRH agonist on testicular axis and accessory sex organs in rats.

LRH and its agonists have been shown to exert both stimulatory and inhibitory effects on testicular function. In the present study, the dose and length of treatment were tested to determine the appearance of the stimulatory and inhibitory effects of LRH agonist on testicular axis including the three levels. Two doses of an agonist of LRH, 40 and 100 ng/100 g body weight (buserelin, 'agonist'), were administered daily for 1 to 15 days to adult male rats. Control rats received the vehicle only. On day 1, 2, 4, 8 and 15 of treatment, the pituitary, testicular and peripheral levels (weight of accessory sex organs and androgen receptors in ventral prostate) were tested 6 h after the last injection. For the 15 days of treatment with both doses, a stimulatory effect of the 'agonist' was observed on LH and FSH release. A short exposure (1-2 days) to the low dose of the 'agonist' had a stimulatory effect on the density of LH/hCG testicular receptors (326 +/- 49 vs control 185 +/- 21 fmol/mg protein, mean +/- SEM), on the weights of seminal vesicles and ventral prostate and exposure to both doses led to high plasma testosterone levels (13.8 +/- 0.5 and 13.7 +/- 0.7 ng/ml, respectively, vs control 2.6 +/- 0.3 ng/ml), and to an increased density of nuclear androgen receptors in the ventral prostate (142 +/- 9 and 144 +/- 15 fmol/mg protein respectively vs control 97 +/- 12 fmol/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations.

For the general practitioner to be able to prescribe optimal therapy to his individual hypertensive patients, he needs accurate information on the therapeutic agents he is going to administer and practical treatment strategies. The information on drugs and drug combinations has to be applicable to the treatment of individual patients and not just patient study groups. A basic requirement is knowledge of the dose-response relationship for each compound in order to choose the optimal therapeutic dose. Contrary to general assumption, this key information is difficult to obtain and often not available to the physician for many years after marketing of a drug. As a consequence, excessive doses are often used. Furthermore, the physician needs comparative data on the various antihypertensive drugs that are applicable to the treatment of individual patients. In order to minimize potential side effects due to unnecessary combinations of compounds, the strategy of sequential monotherapy is proposed, with the goal of treating as many patients as possible with monotherapy at optimal doses. More drug trials of a crossover design and more individualized analyses of the results are badly needed to provide the physician with information that he can use in his daily practice. In this time of continuous intensive development of new antihypertensive agents, much could be gained in enhanced efficacy and reduced incidence of side effects by taking a closer look at the drugs already available and using them more appropriately in individual patients.