Purpose: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-α-2a in which IFN-α is attached to a branched methoxypolyethylene
glycol (PEG) moiety of large molecular weight (40 kDa). Such ...molecular modification results in sustained absorption after
s.c. drug administration and a prolonged half-life. A phase I study of PEG-IFN was conducted in patients with chronic myelogenous
leukemia (CML) who were previously treated with IFN-α to evaluate the effect of sustained exposure to IFN on patients with
CML.
Experimental Design: Twenty-seven patients with long-term or IFN-refractory CML were enrolled in cohorts of three or six patients. PEG-IFN was
given once weekly by s.c. injections starting at a dose of 270 μg/wk to a maximum dose of 630 μg/wk. Sixteen additional patients
were treated with escalating doses of PEG-IFN ranging from 450 to 540 μg/wk in combination with two different schedules of
low-dose cytarabine (1-β- d -arabinofuranosylcytosine, ara-C). Serial venous blood samples were collected to evaluate the pharmacokinetic and pharmacodynamic
characteristics of PEG-IFN in these patients.
Results: The dose-limiting toxicity (DLT) as defined by the protocol was not achieved at the highest dose tested of 630 μg/wk. With
the addition of ara-C, the DLT was reached at 540 μg/wk. The safety profile was similar to that of unmodified IFNs. Of 27
patients treated with PEG-IFN, 14 (52%) achieved or maintained a complete hematologic response and three (11%) achieved a
complete cytogenetic response. Among 16 patients treated with the combination of PEG-IFN and ara-C, 11 (69%) achieved or maintained
complete hematologic remission and two (13%) achieved complete cytogenetic remission. The mean serum peak concentration ( C max ) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 μg/wk, with no further increases in C max at higher dose levels. Serum concentration reached peak value starting about 48 hours after drug administration and was maintained
at close to peak value throughout the dosing interval. The mean ± SD area under the serum concentration-time curve (AUC) calculated
after the first dose also increased from 1,022 ± 694 to 3,343 ± 2,728 ng hour/mL as dose was increased from 270 to 450 μg/wk,
showing a dose-related increase in systemic exposure of PEG-IFN. As with C max , the AUC did not increase at higher dose levels. The maximum induction ( E max ) of neopterin, the surrogate marker of the pharmacodynamic activity of PEG-IFN, increased from 120% to 361% over baseline
values as the dose was increased from 270 to 540 μg/wk. On the once-weekly multiple dosing schedule, both the PEG-IFN and
neopterin concentration seemed to reach steady state by week 5 and the steady-state values were maintained with chronic dosing
over 6 months.
Conclusion: Pegasys provided a significant advantage over standard IFN-α by enabling once-weekly dosing while maintaining acceptable
safety, tolerability, and activity profiles. This branched 40-kDa PEG-IFN was well tolerated both as a monotherapy as well
as in combination with ara-C. Demonstration of its sustained exposure, pharmacodynamic activity, hematologic response, and
evidence of cytogenetic response in several patients in this limited study with either IFN-refractory or INF-intolerant patients
provides a promise for further investigation in combination with new agents like imatinib.
Abstract Premenstrual syndrome (PMS) is a serious condition that is still poorly understood and accepted. It is a psychological and somatic disorder of unknown aetiology. It is quoted that 95% of ...women suffer from premenstrual symptoms and 5% of these suffer from PMS. Symptoms of PMS must arise in the luteal phase of a woman’s cycle, be relieved by menstruation, and be recurrent and severe enough to have a major impact on normal functioning. There are no tests to diagnose PMS; instead, a careful history must be taken, ruling out differentials. However, the diagnosis should be made following prospective symptom rating using validated tools. Several treatment options have been suggested for PMS, including behavioural therapies, committing to a regular exercise programme, simple dietary alterations, and pharmacological and surgical interventions. However, the most effective treatments tend to fall into one of two categories: suppressing ovulation or correcting a speculated neuroendocrine anomaly.
To conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high ...circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses.
Fifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m(2) for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m(2).
Toxicity with the first dose (375 mg/m(2)) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m(2) was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P <.001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m(2), 43% for those treated at 1,000 to 1,500 mg/m(2), and 75% for those treated at the highest dose of 2,250 mg/m(2) (P =.007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon.
Rituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.
We describe how the multimode spectrum of a Fabry-Perot diode laser can be tailored using a non-periodic patterning of the cavity effective index. The cavity geometry is obtained from the solution of ...an inverse problem based on a perturbative calculation of the threshold gain of the longitudinal modes of the cavity. Experimental measurements are presented that demonstrate an all-optical memory element based on the injection locking bistability of a two-mode device. We also demonstrate passive harmonic mode-locking of a device designed to support a comb of six modes. Near-transform limited pulsed output with 2
ps pulse duration at 100
GHz repetition rate was obtained. Prospects for the extension of our approach to locking of larger numbers of modes over wider bandwidths are discussed. Similarities between the effective index profiles found in these devices and those of related devices and grating structures are also highlighted.
Sequencing of the human genome is nearing completion and biologists, molecular biologists, and bioinformatics specialists have teamed up to develop global genomic technologies to help decipher the ...complex nature of pathophysiologic gene function. This review will focus on differential gene expression in ischemic stroke. It will discuss inheritance in the broader stroke population, how experimental models of spontaneous stroke might be applied to humans to identify chromosomal loci of increased risk and ischemic sensitivity, and also how the gene expression induced by stroke is related to the poststroke processes of brain injury, repair, and recovery. In addition, we discuss and summarise the literature of experimental stroke genomics and compare several approaches of differential gene expression analyzes. These include a comparison of representational difference analysis we have provided using an experimental stroke model that is representative of stroke evolution observed most often in man, and a summary of available data on stroke differential gene expression. Issues regarding validation of potential genes as stroke targets, the verification of message translation to protein products, the relevance of the expression of neuroprotective and neurodestructive genes and their specific timings, and the emerging problems of handling novel genes that may be discovered during differential gene expression analyses will also be addressed.
Background:The design of new nuclear reactors and transmutation devices requires to reduce the present neutron cross section uncertainties of minor actinides. Purpose: Reduce the ...\(^{243}\)Am(n,\(\gamma\)) cross section uncertainty. Method: The \(^{243}\)Am(n,\(\gamma\)) cross section has been measured at the n_TOF facility at CERN with a BaF\(_{2}\) Total Absorption Calorimeter, in the energy range between 0.7 eV and 2.5 keV. Results: The \(^{243}\)Am(n,\(\gamma\)) cross section has been successfully measured in the mentioned energy range. The resolved resonance region has been extended from 250 eV up to 400 eV. In the unresolved resonance region our results are compatible with one of the two incompatible capture data sets available below 2.5 keV. The data available in EXFOR and in the literature has been used to perform a simple analysis above 2.5 keV. Conclusions: The results of this measurement contribute to reduce the \(^{243}\)Am(n,\(\gamma\)) cross section uncertainty and suggest that this cross section is underestimated up to 25% in the neutron energy range between 50 eV and a few keV in the present evaluated data libraries.
Abstract only
7026
Background: CML-AP is often associated with imatinib-resistance and the occurrence of BCR-ABL mutations. This phase II open-label study was designed to evaluate the safety and ...efficacy of Nilotinib, a potent novel tyrosine kinase inhibitor, in imatinib-resistant or - intolerant CML-AP pts. Methods: Imatinib-resistance and -intolerance were defined using standard criteria, and all resistant pts failed imatinib >/= 600mg/day. Primary endpoint was a confirmed hematologic response (HR) determined by conventional ITT analysis. Nilotinib was started at 400mg BID and escalated to 600mg BID for inadequate responses. Results: Safety and efficacy are reported for first 64 consecutively enrolled pts completing >/= 8 mos treatment. 52 (81%) were imatinib-resistant; 12 (19%) -intolerant. Median duration of CML was 74 mos; median duration of prior imatinib use was 28 mos. Median duration of nilotinib exposure was 208 days; median average dose intensity (mg/days) was 787. Median cumulative duration of dose interruption was 23 days. Treatment is ongoing for 27 (42%) pts; 37 (58%) have discontinued (9 for AEs; 17 for disease progression). HR occurred in 38 (59%) pts, of which 15 (23%) were complete, 8 (13%) were marrow responses, and 15 (23%) returned to chronic phase. MCyR occurred in 23 (36%) pts; 14 (22%) were complete and 9 (14%) were partial. 6 (9%) pts did not respond; 5 (8%) pts had disease progression. Median time to HR was 1.0 (1–3) mos and to MCyR was 2.0 (1–8) mos. Estimated 1-yr survival rate was 69% and median duration of HR has not been reached. The most common Grade 3/4 AEs included neutropenia (45%), thrombocytopenia (40%), asymptomatic lipase elevations (17%), and anemia (16%) pts. No pts experienced Grade 3/4 peripheral edema, or pleural/pericardial effusions; 2 pts had pulmonary edema. Conclusion: In pts with CML-AP, nilotinib is an effective therapeutic option in CML-AP pts with imatinib-resistance or -intolerance and is generally well tolerated with acceptable rates of myelosuppression and minimal non- hematologic toxicities.
No significant financial relationships to disclose.
Rumble Strip Gaps for High-Speed Bicycles O'Brien, Sarah Worth; Jackson, Kristy N.; Vosburgh, Erik ...
Transportation research record,
01/2015, Letnik:
2520, Številka:
1
Journal Article
Recenzirano
Shoulder rumble strips (SRSs) are a proven safety countermeasure that reduces motor vehicle lane departures; however, they may be seen as an impediment to bicycle travel because they decrease comfort ...for bicyclists and can affect riders' control while bicycling. Existing literature provides recommendations for the placement of regular gaps in SRSs, but the supporting research is limited to low and moderate bicycle speeds. Roads with SRSs along long, steep grades present a unique set of risks for cyclists because of the possibility of higher bicycle speeds. This study evaluated how variations in SRS gap lengths and shoulder widths affected bicyclists' ability to maneuver through these gaps when riding at higher than average speeds. The findings suggest that as gap length increases, bicyclists may increase downhill speed while reporting fewer instances of discomfort when attempting to cross larger gaps. The likelihood of a bicyclist hitting a simulated rumble strip while crossing a gap decreases modestly as the gap size increases. Shoulder widths in excess of 4 ft do not appear to significantly influence bicyclists' capability of maneuvering across different gap lengths and had only a minor effect on bicyclists' speeds.
This study responded to a unique opportunity to determine behavioral changes that resulted from the construction of a critical link of the American Tobacco Trail (ATT) in Durham, North Carolina. ...Observational data were collected both before and after construction of a bicycle-and-pedestrian bridge that linked two separate segments of the regional greenway. Before construction of the bridge and trail connections, the two segments of the ATT were separated by Interstate 40. Heavy traffic on local streets as well as a lack of bicycle and pedestrian facilities in the area provided additional barriers to active travel between the two ATT segments. The Institute of Transportation Research and Education conducted intercept surveys and manual counts on the two trail segments before and after construction of the bridge. The before-and-after data were compared to determine the changes that occurred in the use of the ATT and the accompanying social, public health, transportation, and economic effects.
PDF
