Electrophysiological Signs of Neurocognitive Deficits in Long-Term Leukemia Survivors

The long-term effects of disease and treatment on electrophysiologicalmeasures of neurocognitive function were studied in childrenwho had survived acute lymphoblastic leukemia (ALL) for at least4 years and were currently in remission. We report here changesin cognitive processing time as shown by the latency of theP3 wave of the auditory event-related EEG potential (ERP). P3latency was significantly prolonged in long-term ALL surivors,as well as in patients successfully trreated for solid tumors(ST)outside the CNS who received similar chemotherapy but did notreceive prophylactic treatment to the CNS. P3 latencies werestrongly correlated with measures of school performance andIQ in these individuals. The similarity in P3 latency betweenthe ALL and ST groups suggests that the treatments used on thesepateints produce changes in electrophysiological responses thatare associated with mild, but significant, cognitive deficits.     

Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.

PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.     

The association between sidewalk length and walking for different purposes in established neighborhoods

ABSTRACT: BACKGROUND: Walking in neighborhood environments is undertaken for different purposes including for transportation and leisure. We examined whether sidewalk availability was associated with participation in, and minutes of neighborhood-based walking for transportation (NWT) and recreation (NWR) after controlling for neighborhood self-selection. METHOD: Baseline survey data from respondents (n=1813) who participated in the RESIDential Environment (RESIDE) project (Perth, Western Australia) were used. Respondents were recruited based on their plans to move to another neighborhood in the following year. Usual weekly neighborhood-based walking, residential preferences, walking attitudes, and demographics were measured. Characteristics of the respondent's baseline neighborhood were measured including transportation-related walkability and sidewalk length. A Heckman two-stage modeling approach (multivariate Probit regression for walking participation, followed by a sample selection-bias corrected OLS regression for walking minutes) estimated the relative contribution of sidewalk length to NWT and NWR. RESULTS: After adjustment, neighborhood sidewalk length and walkability were positively associated with a 2.97 and 2.16 percentage point increase in the probability of NWT participation, respectively. For each 10km increase in sidewalk length, NWT increased by 5.38 min/wk and overall neighborhood-based walking increased by 5.26 min/wk. Neighborhood walkability was not associated with NWT or NWR minutes. Moreover, sidewalk length was not associated with NWR minutes. CONCLUSION: Sidewalk availability in established neighborhoods may be differentially associated with walking for different purposes. Our findings suggest that large investments in sidewalk construction alone would yield small increases in walking.     

Zidovudine-induced diaphragmatic contractile dysfunction: impact of an antioxidant diet

OBJECTIVE: Zidovudine (AZT) is a primary drug therapy used to treat HIV-infected individuals. While AZT inhibits replication of HIV, it also induces a drug-specific myopathy resulting in altered muscle mitochondria, increased oxidative stress and muscle contractile dysfunction. The purpose of this study was to assess the impact of an antioxidant diet (high in vitamins C and E) on AZT-mediated diaphragmatic contractile dysfunction in rodents. METHODOLOGY: Adult, Sprague-Dawley rats were assigned to feeding groups: control (CON, n = 9), AZT-treatment (AZT, n = 8), antioxidant diet only (Anti-Ox, n = 6), and AZT + antioxidant diet (AZT + Anti, n = 9). Two costal diaphragm strips were removed from each animal (under surgical anaesthesia) and evaluated for force-frequency relationship, maximal specific tension, and fatigue resistance using an in vitro preparation. RESULTS: Results indicate significant reductions in normalized force production (20-200 Hz), including maximal specific tension, between AZT animals and all other groups. While AZT reduced diaphragm contractility, the addition of an antioxidant diet eliminated this decrease. CONCLUSION: These data suggest that an increase in oxidative stress mediated by AZT may contribute to AZT-induced muscle contractile dysfunction, and that antioxidant vitamin supplementation may help ameliorate this effect.     

Mechanics of the ventilatory system in sedated infants: forced oscillations versus single-breath method

The real--Re(Z)--and imaginary--Im(Z)--parts of the ventilatory system impedance were measured between 6 and 30 Hz in 18 normal infants and in 19 with airway obstruction. The intercept (R0) and slope (S) of the Re(Z)-frequency function, as well as inertance (I) and compliance (C) estimated from Im(Z), were compared with ventilatory system resistance (Rrs) and compliance (Crs) (single-breath method). R0 correlated significantly with Rrs (r = 0.86), although the slope of the regression equation was significantly lower than 1 (P less than 0.01). Negative frequency dependence of Re(Z) was observed in all subjects and a significant correlation was found between S and Rrs (r = -0.80). "Inertance" was negative in 20 subjects and correlated negatively with Rrs (r = -0.61). C correlated with Crs (r = 0.64) and with 1/Rrs (r = 0.85). The ratio of C to Crs (mean +/- SD = 0.168 +/- 0.082) also correlated with 1/Rrs (r = 0.51). The main characteristics of the total impedance/frequency function could be simulated with a model featuring the upper airway wall (Zuaw) in parallel with the ventilatory system (Zrs). It is suggested that the differential change in Zuaw and Zrs with growth accounts for the marked frequency dependence of Re(Z) as well as the inaccurate estimation of both I and C in this population.     

Switching to darunavir/ritonavir 800/100 mg once‐daily containing regimen maintains virological control in fully suppressed pre‐treated patients infected with HIV‐1

The objective of this study was to evaluate the switch to once‐daily darunavir/ritonavir 800/100 mg in treatment‐experienced patients with suppressed HIV‐1 replication on a twice‐daily ritonavir‐boosted protease‐inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non‐comparative, multicenter study, patients on a bid PI/r‐containing triple combination, with suppressed viral replication, were switched to once‐daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV‐RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty‐five patients were enrolled. All had HIV‐RNA < 50 copies/ml at screening with a pre‐exposure to a median of 2 PI/r (1–5). By intent‐to‐treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV‐RNA < 50 copies/ml at W24. Seven patients experienced protocol‐defined treatment failure between baseline and W24: Two had confirmed low‐level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow‐up. By on‐treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV‐RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration–time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half‐life was 12.2 hr. Tolerability of once‐daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment‐experienced patients can switch safely from a twice‐daily PI/r regimen to a once‐daily darunavir/r 800/100 mg containing regimen. J. Med. Virol. 85:8–15, 2012. © 2012 Wiley Periodicals, Inc.     

Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

Objectives

The aim of the study was to evaluate the long‐term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)‐, darunavir/ritonavir (DRV/r)‐, and lopinavir/ritonavir (LPV/r)‐containing regimens.

Methods

Data were analysed for 5678 EuroSIDA‐enrolled patients starting a DRV/r‐, ATZ/r‐ or LPV/r‐containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART‐naïve subjects (8%) at ritonavir‐boosted protease inhibitor (PI/r) initiation; (2) ART‐experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV‐1 RNA copies/mL; and (3) ART‐experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r‐based regimen. The main analysis was performed with intention‐to‐treat (ITT) ignoring treatment switches.

Results

The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log‐rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART‐naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment‐experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r‐based ART.

Conclusions

Although confounding by indication and calendar year cannot be completely ruled out, in ART‐experienced subjects the long‐term effectiveness of DRV/r‐containing regimens appears to be greater than that of ATZ/r and LPV/r.

     

Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097)

BACKGROUND: Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure. OBJECTIVE: To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures. DESIGN: A randomized comparative controlled trial in 19 university hospitals in France. PATIENTS: Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 x 10(6) cells/l and plasma HIV-1-RNA levels of 50,000 copies/ml or greater. MEASUREMENTS: The primary efficacy outcome was the proportion of patients with at least a 1 log10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy. RESULTS: Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was -1.91 and -0.37 log10 copies/ml (P = 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P = 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir. CONCLUSION: Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus.