Prolonged Interruption Research Articles

Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3

Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1 to 3 that is in clinical development for the treatment of solid tumors. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. Axitinib inhibits cellular autophosphorylation of VEGF receptors (VEGFR) with picomolar IC(50) values. Counterscreening across multiple kinase and protein panels shows it is selective for VEGFRs. Axitinib blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase. Following twice daily oral administration, axitinib produces consistent and dose-dependent antitumor efficacy that is associated with blocking VEGFR-2 phosphorylation, vascular permeability, angiogenesis, and concomitant induction of tumor cell apoptosis. Axitinib in combination with chemotherapeutic or targeted agents enhances antitumor efficacy in many tumor models compared with single agent alone. Dose scheduling studies in a human pancreatic tumor xenograft model show that simultaneous administration of axitinib and gemcitabine without prolonged dose interruption or truncation of axitinib produces the greatest antitumor efficacy. The efficacious drug concentrations predicted in nonclinical studies are consistent with the range achieved in the clinic. Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitinib acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy.

Chronic but not Acute Dopaminergic Transmission Interruption Promotes a Progressive Increase in Cortical Beta Frequency Synchronization: Relationships to Vigilance State and Akinesia

Dopaminergic (DA) denervation results in the appearance of an excessive cortical beta frequency synchronization in parkinsonian patients and animal models of the disease. The present study analyzed electrocorticogram signals in awake rats to further characterize this excessive synchronization in terms of time course, relation to motor activity and state of vigilance. Using substantia nigra pars compacta lesions and both acute and chronic pharmacological interruptions of DA transmission, the present data demonstrated that the appearance of excessive beta synchronization requires a prolonged interruption in DA transmission and builds up progressively. This synchronization was vigilance-state dependent and observed solely during awake-like activity. Furthermore, these data demonstrated for the first time that the appearance of akinesia preceded the excessive cortical beta synchronization. In addition, this synchronization was stronger in the motor than in the somato-sensory cortex and in unilaterally compared with bilaterally lesioned animals. Finally, excessive beta synchronization was accompanied by an increased coherence between motor and somato-sensory cortical activities. These data suggest that excessive beta synchronization is associated with plastic processes whose time course is delayed with respect to the akinesia. Moreover, the expression of this phenomenon, which likely reflects functional changes in the cortico-basal ganglia circuits, requires a specific brain state.

Minimal interruption of cardiopulmonary resuscitation for a single shock as mandated by automated external defibrillations does not compromise outcomes in a porcine model of cardiac arrest and resuscitation

Current automated external defibrillations require interruptions in chest compressions to avoid artifacts during electrocardiographic analyses and to minimize the risk of accidental delivery of an electric shock to the rescuer. The earlier three-shock algorithm, with prolonged interruptions of chest compressions, compromised outcomes and increased severity of postresuscitation myocardial dysfunction. In the present study, we investigated the effect of timing of minimal automated external defibrillation-mandated interruptions of chest compressions on cardiopulmonary resuscitation outcomes, using a single-shock algorithm. We hypothesized that an 8-sec interruption of chest compressions for a single shock, as mandated by automated external defibrillations, would not impair initial resuscitation and outcomes of cardiopulmonary resuscitation. Randomized prospective animal study. University affiliated research laboratory. Domestic pigs. In 24 domestic male pigs weighing 41 +/- 2 kg, ventricular fibrillation was induced by left anterior descending coronary artery occlusion and untreated for 7 min. Cardiopulmonary resuscitation, including chest compressions and ventilation with oxygen, was then performed for an interval of 2 min before attempted defibrillation. Animals were randomized into three groups: A) interruption immediately before defibrillation; B) interruption after 1 min of cardiopulmonary resuscitation; or C) no interruption. Chest compressions were delivered with the aid of a mechanical chest compressor at a rate of 100 compressions/min and compression/ventilation ratio of 30:2. Defibrillation was attempted with a single biphasic 150-J shock. Each animal was successfully resuscitated and survived for >72 hr. No differences in the number of shocks before return of spontaneous circulation, frequency of recurrent ventricular fibrillation, duration of cardiopulmonary resuscitation, and severity of postresuscitation myocardial dysfunction were observed. In this experimental model of cardiac arrest and cardiopulmonary resuscitation, minimal automated external defibrillation-mandated interruption of chest compressions for a single-shock algorithm did not have adverse effects on postresuscitation myocardial or neurologic function. All animals, whether subjected to cardiopulmonary resuscitation interruptions or not, survived.

Effects of Airsickness in Male and Female Student Pilots: Adaptation Rates and 4-Year Outcomes

Airsickness (AS) often affects aircrew members, especially at the beginning of their flight careers. In this study the AS incidence in 376 Italian Air Force student pilots (336 men and 40 women) was investigated during their initial flight activity. The study was separated into two parts. In part 1, the AS incidence was analyzed in the whole sample to determine the overall characteristics of AS and the hypothetical differences between men and women during the first flight certification (Basic). Part 2 analyzed a subpopulation of 102 individuals (86 men, 16 women) over 4 subsequent years throughout the first 4 flight certifications (for a total of about 60 flight hours). In all cases, AS was evaluated according to the number of flight missions affected by vomiting episodes. The overall AS incidence during Basic was 34.8%, without significant gender differences. However, within AS individuals, a significantly higher percentage of women were slow adaptors (12.5% of the whole female sample vs. 3.3% in men). AS overall affected the likelihood of reaching Basic certification, but this was not significantly related to the number of AS episodes. The 1-yr interval between two subsequent flight certifications caused a loss of adaptation to the flight environment in most cases. The absolute incidence of AS in our study resulted within the expected range, without significant differences between men and women. In a minor number of individuals (11 out of 336 men and 5 out of 40 women) a slow capability of adaptation to AS was observed. Such a finding was statistically more prevalent in women. In contrast to previous literature data, when prolonged interruptions from flight activity are planned, the retention of adaptation in our study did not play a significant role in avoiding future episodes of AS.

Risk Factors and Mortality Associated with Default from Multidrug‐Resistant Tuberculosis Treatment

Completing treatment for multidrug-resistant (MDR) tuberculosis (TB) may be more challenging than completing first-line TB therapy, especially in resource-poor settings. The objectives of this study were to (1) identify risk factors for default from MDR TB therapy (defined as prolonged treatment interruption), (2) quantify mortality among patients who default from treatment, and (3) identify risk factors for death after default from treatment. We performed a retrospective chart review to identify risk factors for default from MDR TB therapy and conducted home visits to assess mortality among patients who defaulted from such therapy. Sixty-seven (10.0%) of 671 patients defaulted from MDR TB therapy. The median time to treatment default was 438 days (interquartile range, 152-710 days), and 27 (40.3%) of the 67 patients who defaulted from treatment had culture-positive sputum at the time of default. Substance use (hazard ratio, 2.96; 95% confidence interval, 1.56-5.62; P = .001), substandard housing conditions (hazard ratio, 1.83; 95% confidence interval, 1.07-3.11; P = .03), later year of enrollment (hazard ratio, 1.62, 95% confidence interval, 1.09-2.41; P = .02), and health district (P = .02) predicted default from therapy in a multivariable analysis. Severe adverse events did not predict default from therapy. Forty-seven (70.1%) of 67 patients who defaulted from therapy were successfully traced; of these, 25 (53.2%) had died. Poor bacteriologic response, <1 year of treatment at the time of default, low education level, and diagnosis with a psychiatric disorder significantly predicted death after default in a multivariable analysis. The proportion of patients who defaulted from MDR TB treatment was relatively low. The large proportion of patients who had culture-positive sputum at the time of treatment default underscores the public health importance of minimizing treatment default. Prognosis for patients who defaulted from therapy was poor. Interventions aimed at preventing treatment default may reduce TB-related mortality.

Letter by Ristagno and Gullo Regarding Article, “Survival Is Similar After Standard Treatment and Chest Compression Only in Out-of-Hospital Bystander Cardiopulmonary Resuscitation”

To the Editor: We appreciated the elegant study by Bohm et al,1 which has reported equivalency of survival among victims of cardiac arrest who received standard cardiopulmonary resuscitation (CPR) and those who received chest compressions–only (CCo) CPR. According to this study, smaller ventilations are required to maintain optimal ventilation/perfusion ratios during CPR, and in animal models, adverse outcomes followed prolonged interruptions in chest compressions for mouth-to-mouth ventilation.2 During lung inflation, venous return is transiently reduced, with the result that preload and ultimately aortic diastolic pressure is decreased. Systemic blood flow and organ perfusions are correspondingly reduced. The highest priority after “sudden death” is to start …

Quality of CPR during advanced resuscitation training

Previous studies have documented poor quality CPR during real life resuscitation attempts. This study investigated whether poor quality CPR during advanced life support training could be contributing to poor performance in clinical practice. Observational study of quality of CPR during advanced life support training courses before and after the implementation of the European Resuscitation Council Guidelines 2005 into the ALS course. The quality of chest compressions were downloaded from a manikin and direct observations of no-flow time; pre-shock pauses were recorded. 94 cardiac arrest simulations were studied (46 before implementation of Guidelines 2005 and 48 after). Delays in starting CPR, inadequate compression depth, prolonged interruptions of chest compressions and excessive pre-shock pauses were identified. The introduction of Guidelines 2005 resulted in improvements in the number of compressions given per minute and a reduction in no-flow time and duration of pre-shock pauses, but overall the quality of CPR performed during the ALS course remained poor. There was little evidence of performance improving over successive simulations as the course progressed. The implementation of Guidelines 2005 into the ALS course appear to have improved the process of CPR by reducing no-flow time during simulated CPR. However, the quality of CPR during ALS training remains sub-optimal. Delays in starting CPR, inadequate compression depth, excessive interruptions in chest compressions and prolonged pre-shock pauses mirror observations from clinical practice. Strategies to improve CPR performance during ALS training should be explored and potentially may result in improvements in clinical practice.

Parvovirus B19 Infection in Children with Acute Lymphoblastic Leukemia is Associated with Cytopenia Resulting in Prolonged Interruptions of Chemotherapy

Parvovirus B19 infection causes severe cytopenia and can mimic a leukemic relapse or therapy-induced cytopenia in patients with hematologic malignancies. We evaluated the complications of parvovirus B19 infection, including delays in the scheduled course of chemotherapy, in children with acute lymphoblastic leukemia (ALL). Consecutive bone marrow samples were collected from 117 children with ALL and were analyzed for parvovirus B19 DNA by polymerase chain reaction. Clinical and laboratory data were collected from the Nordic Childhood Leukemia Registry and from medical records. Among the 117 children with ALL, 18 (15%) were found to be parvovirus B19 DNA positive. The infection was suspected on clinical grounds in only 1 of these 18 patients. Patients with viremia at diagnosis or during therapy for infection had lower viral loads (median viral load, 7 x 10(4) copies/mL) than did those who became viremic during maintenance therapy (median viral load, 2 x 10(8) copies/mL). The former group also had fewer clinical complications. Indeed, when parvovirus B19 DNA was present during the maintenance treatment, the number of complications (including cytopenia) increased, causing significantly longer periods without chemotherapy (median duration without chemotherapy, 59 days vs. 30 days; P < or = .05) and a higher number of blood transfusions (P = .018) in parvovirus B19 DNA-positive patients than in parvovirus B19 DNA-negative patients. Children with ALL who were infected with parvovirus B19 became cytopenic, leading to reduced treatment intensity and to complications during treatment. Screening for parvovirus B19 DNA by quantitative polymerase chain reaction in pediatric patients with ALL and unexplained cytopenia is suggested.

Cardiac Myocyte Progenitors from Adult Hearts for Myocardial Regenerative Therapy

The heart is a highly vascular organ and prolonged interruption of myocardial blood flow initiates events that culminate in cardiac myocyte death. Proposed experimental reparative strategies include harvesting potent cells followed by direct injection into ischemic myocardium to achieve myogenesis and angiogenesis. Accordingly, we set out to isolate and expand a purified population of adult rat putative cardiomyocyte precursors, and to identify their characteristics in vitro. By using an acute myocardial infarction model and direct cell implantation, we further tested the hypothesis that these cells are an ideal cell source for myocardial regeneration and can enhance cardiac repair after implantation into the ischemic rat heart. We describe here the identification of a subpopulation of primitive cells from rat heart, processing stem cell marker, c-kit and myogenic transcriptional factors, GATA-4 and MEF 2C, and cardiac specific proteins, troponin-I, alpha-sarcomeric actinin and connexin-43. They exhibited a high in vitro proliferative potential. These findings strongly suggest that these cells are putative cardiomyocyte precursors. After transplantation, they were able to be retained and proliferate (13.63 +/- 5.97% after 2 weeks) within the ischemic heart. Progeny of implanted cells migrated along the infarcted scar, reconstituted regenerated cardiomyocytes with incorporation into host myocardium, and inhibited cardiac remodeling with decreased scar formation. Our findings suggest that putative cardiomyocyte precursors isolated from adult heart could potentially be an autologous cell source for myocardial regeneration cell therapy.

Evaluation of Delivery of Enteral Nutrition in Critically Ill Patients Receiving Mechanical Ventilation

Published reports consistently describe incomplete delivery of prescribed enteral nutrition. Which specific step in the process delays or interferes with the administration of a full dose of nutrients is unclear. To assess factors associated with interruptions in enteral nutrition in critically ill patients receiving mechanical ventilation. An observational prospective study of 59 consecutive patients who required mechanical ventilation and were receiving enteral nutrition was done in an 18-bed medical intensive care unit of an academic center. Data were collected prospectively on standardized forms. Steps involved in the feeding process from admission to discharge were recorded, each step was timed, and delivery of nutrition was quantified. Patients received approximately 50% (mean, 1106.3; SD, 885.9 Cal) of the prescribed caloric needs. Enteral nutrition was interrupted 27.3% of the available time. A mean of 1.13 interruptions occurred per patient per day; enteral nutrition was interrupted a mean of 6 (SD, 0.9) hours per patient each day. Prolonged interruptions were mainly associated with problems related to small-bore feeding tubes (25.5%), increased residual volumes (13.3%), weaning (11.7%), and other reasons (22.8%). Placement and confirmation of placement of the small-bore feeding tube were significant causes of incomplete delivery of nutrients on the day of admission. Delivery of enteral nutrition in critically ill patients receiving mechanical ventilation is interrupted by practices embedded in the care of these patients. Evaluation of the process reveals areas to improve the delivery of enteral nutrition.

Helping Three Persons with Multiple Disabilities Acquire Independent Dressing through Assistive Technology

Enabling persons with intellectual or multiple disabilities to carry out personal care tasks (such as washing and dressing) independent of guidance from parents or staff members and without prolonged interruptions is a relevant educational objective (King-Sears & Carpenter, 2005; Lancioni, O'Reilly, Campodonico, & Mantini, 2001; Sewell, Collins, Hemmeter, & Schuster, 1998). Achieving such an objective is often difficult, particularly with persons whose disabilities also include visual impairments (Lancioni et al., 2006), and staff or parental guidance may continue to be needed (King-Sears & Carpenter, 2005). This guidance can be time consuming for staff members or parents and negative for the social image of individuals because it emphasizes their dependence on others (Lancioni, O'Reilly, & Campodonico, 2002). Attempts were recently made to curb the problem of dependency in personal care tasks with the use of assistive technology, which ensured a combination of verbal prompting and preferred stimuli that were automatically delivered on positive performance (see Lancioni et al., 2002, 2006). Three participants were involved in the intervention programs described in these studies, and they all learned to dress themselves. Although these results are encouraging, two aspects of the technology that was used in the interventions raise some questions. First, prompts were delivered at preset intervals, rather than upon the failure to respond of participants. The latter condition would appear preferable in terms of effectiveness and respect for the dignity of participants (Lancioni, O'Reilly, Seedhouse, Furniss, & Cunha, 2000). Second, the prompts and reinforcing stimuli were all auditory. The possibility of using various types of prompts and reinforcing events would be essential for the generalizability of the approach. The goal of the study presented here was to help three new participants with multiple disabilities acquire independent dressing through an upgraded version of the technology. This technology provided prompts only for the failure to respond and included auditory, visual, and vibratory stimuli as reinforcing events or prompts. METHOD Participants The participants, Sylvie, Floyd, and Alan (all names are pseudonyms), were 37, 27, and 29 years old, respectively. They had encephalopathy with a level of functioning estimated to be in the profound range of intellectual disability. Their age equivalents for their daily living skills were about 3 years or younger on the Vineland Adaptive Behavior Scales-Interview Edition (Sparrow, Balla, & Cicchetti, 1984). Sylvie was deaf and had minimal residual vision that allowed her to enjoy light displays and find fairly large objects within about 1 meter (about 39 inches) in front of her and at the center of her visual field. Floyd was totally blind and had typical hearing. Alan was totally blind and deaf and, contrary to the other participants, nonambulatory. These differences in sensory-motor conditions (representative of common variations among individuals with multiple disabilities) allowed for adaptations and a broader evaluation of the assistive technology used in the intervention presented here. All three participants were considered capable of performing the steps of the dressing task, even though Alan needed some physical support to complete the responses of putting on his underpants and pants because of his physical condition. In spite of their general abilities, the three participants still tended to have breaks in performance that required interventions by staff members. Approval for this research was granted by the Scientific and Ethics Committee of the Lega F. D'Oro, Osimo, Italy. The participants were not capable of signing an informed consent form, so their parents did it for them in accordance with Italian law. Setting, dressing task, recording, and reliability The study was carried out in the participants' bedrooms by research assistants who were familiar with the topic of personal care tasks and the delicate issue of respect for the participants' dignity. …

Control of HIV-1 RNA load after HAART interruption: Relationship with CCR5 co-receptor density and proviral DNA load in HIV-infected patients

Background CCR5 co-receptor density has been reported to play a role in the level of HIV production. In addition, reports about the relationship between proviral DNA load and plasma HIV load are controversial. Objectives To analyse the role of CCR5 co-receptor density and proviral DNA load in the control of plasma HIV-viral load after HAART interruption, comparing patients whose plasma HIV load was persistently below 4 log 10 RNA copies/mL, defined as “HIV controllers”, with patients who showed a viral load higher than 4 log 10 RNA copies/mL, defined as “non-controllers”. Study design Proviral DNA load quantification ( N = 55) and CCR5 co-receptor density ( N = 29) were determined in HIV-infected patients on prolonged HAART interruption. Results Twenty-three percent of our HAART interruption cohort were classified as HIV controllers, while 77% were classified as non-controllers. CCR5 co-receptor density was statistically higher in HIV controllers than in non-controllers, while proviral DNA load was not different between them. CCR5 co-receptor density in activated CD4 cells was independently associated with HIV plasma load after interruption. Conclusions The observation of a higher CCR5 co-receptor expression in HIV controllers suggests that HIV infection leads to the selection of CD4 cells with low CCR5 co-receptor density after HAART interruption.

Invasive fungal infection in children undergoing chemotherapy for cancer

In children with cancer, invasive fungal infection is a serious complication of anticancer therapy. Successful treatment is a major challenge for clinical oncologists. The records of all episodes of invasive fungal infection occurring in children with cancer undergoing chemotherapy at Mackay Memorial Hospital, Taipei between January 1987 and October 2005 were reviewed. The following were documented: general characteristics, clinical presentation, predisposing factors, pathogens, antifungal treatment, association with anticancer therapy and outcome. We endeavoured to preserve renal function by administration of new antifungal agents. Anticancer therapy was given as soon as possible after diagnosis and the dose of chemotherapeutic agents was adjusted as required to prevent unduly prolonged interruption of chemotherapy and minimise the risk of leukaemia relapse. Twenty-six patients with 29 episodes of invasive fungal infection were reviewed. Candida species were the leading pathogens (14/29) followed by Aspergillus species (11/29). In six episodes there was both visceral dissemination and fungaemia. In 23/29 patients, antibiotic therapy preceded fungal infection with a median of 11 days. Three children died from extensive fungal infection and four from progression of malignancy; the remainder survived with a median follow-up of 40 months (range 12-233). The actuarial 12-month survival rate was 87%; in patients with invasive candidiasis and aspergillosis the rates were 75% and 100%, respectively. In children with cancer, most invasive fungal infections can be treated successfully. Current antifungal prophylaxis should protect patients from fungal infection.

Metronomic chemotherapy: an antiangiogenic scheduling

Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.

Motor learning induces astrocytic hypertrophy in the cerebellar cortex

Motor skill learning, but not mere motor activity, is associated with an increase in both synapse number and glial cell volume within the cerebellar cortex. The increase in synapse number has been shown to persist for at least 4 weeks in the absence of continued training. The present experiment similarly examined how a prolonged interruption in training affects the training-induced increase in astrocytic volume. Adult female rats were randomly allocated to either an acrobatic motor learning condition (AC) or a motor control condition (MC). The AC animals were trained to traverse a complex series of obstacles and each AC animal was pair matched with an MC animal that traversed an obstacle-free runway. These groups were further assigned to one of three training conditions. Animals in the early condition were trained for 10 consecutive days, animals in the delay condition received the same 10 days of training followed by a 28-day period without training, and animals in the continuous condition were trained for the entire 38 days. Unbiased stereological techniques were used to determine that AC animals had a significantly greater volume of astrocytes per Purkinje cell in the cerebellar paramedian lobule than the MC animals, a difference which was reduced (and not statistically detectable) among animals in the delay condition. These findings demonstrate that learning triggers the hypertrophy of astrocytic processes and furthermore that, unlike learning-induced synaptogenesis, astrocytic growth is reduced in the absence of continued training.

Neutralizing anti-Tat antibodies prolonged HAART interruption in vaccines in a prospective structured interruption study

Anti-Tat therapeutic vaccination has been clinically investigated by different groups [1-4], given that 1) extracellular Tat protein induces T cell apoptosis and cellular immune suppression, 2) epidemiological data showed that LTNP exhibit high level of serum anti-Tat Ab, negatively correlated with p24 antigenemia, 3) in Tat immunized macaques, viremia decreased following SHIV challenge. Anti-Tat therapeutic vaccination using Tat Toxoid adjuvanted either with Seppic [1,2] or with alum or DcChol (Aventis Pasteur) proved to be safe. A prospective structured treatment interruption study (STI) monitored according to EU guidelines was conducted at Hospital St-Pierre, Brussels (Pr. N. Clumeck) on 31 vaccinees who received a DcChol adjuvanted Tat Toxoid (n = 12), a DcChol placebo (n = 8) or non adjuvanted Tat toxoid (n = 11). The 2 year study follow-up showed that vaccinees developing high titer of Abs neutralizing Tat bioactivity prolonged HAART-interruption.

Thymic Volume Predicts CD4 T-Cell Decline in HIV-Infected Adults Under Prolonged Treatment Interruption

To analyze the predictive capacity of thymic volume in CD4 T-cell loss after treatment interruption in HIV-infected patients with high nadir CD4 count. Thirty-nine HIV-infected patients with CD4 counts greater than or equal to 500 cells/microL, nadir CD4 counts greater than or equal to 250 cells/microL, and plasma viral loads less than 50 copies/mL for at least the past 12 months began a treatment interruption program. The event of interest for this study was the decrease of CD4 count below 350 cells/microL. Kaplan-Meier curves were used for all time-to-event analyses, and log-rank tests were used for comparison between groups in the univariate analysis. All variables with statistical association with CD4 T-cell loss were analyzed using multivariate Cox proportional hazards regression models. Twenty-three percent of the patients had a decrease in CD4 count to less than 350 cells/microL. In the univariate analysis, only thymic volume was statistically significant with this event (P = 0.02). Nadir CD4 count nearly reached statistical significance. However, age, sex, HCV coinfection, CD4 count, T-cell receptor excision circle-bearing cells, and early viral load rebound did not show statistical differences. Thymic volume and CD4 T-cell loss were independently associated using Cox proportional hazards regression model (P = 0.04; relative risk, 0.76; 95% confidence interval, 0.59-0.99). In this study, we demonstrate for the first time that thymic volume predicts CD4 T-cell loss in patients with nadir CD4 count greater than or equal to 250 cells/muL under treatment interruption.

Predictive factors of treatment interruption duration in a cohort of HIV-1 infected patients with CD4 count greater than 350 cells per mm 3

Objective To determine predictive factors of treatment interruption (TI) duration within a cohort of HIV-1 infected patients having stopped their treatment with CD4 above 350 cells per mm 3. Design Data were collected from computerized medical records. Patients were selected if they were HIV-1 positive, 18 years of age or older, and had stopped their treatment between January 1st, 1999 and July 1st, 2003, with CD4 count above 350 cells per mm 3. The study period was censored on October 1st, 2003. Patients were assessed every 3 months from inclusion to censure. A survival analysis using the Cox proportional hazard model was performed. Results One hundred eighty-five patients were included. The median duration of TI was 43 weeks. Sixty-three patients remained off-treatment at censure. In the multivariate analysis, TI duration was shorter if CD4 nadir was below 250 cells per mm 3 before TI (relative hazard, 2.10), age superior to 40 (relative hazard, 1.72), viral load higher than 2.3 log.copies per ml (relative hazard, 1.52), and CDC class C (relative hazard, 1.78) at TI. Neither CD4 cell count at TI, numbers of treatments, nor duration of treatment and infection before TI were independent predictive factors of early treatment resumption (TR). Conclusion Some clinical and biological data may be used as predictive factors of early TR. Our results can have implications on future therapeutic strategies, in which the goal of therapy is to maintain CD4 cell count above a predetermined threshold using cycles of therapy followed by prolonged interruption according to CD4 count.

Potential output pathways for agonistic-like responses resulting from the GABA A blockade of the torus semicircularis dorsalis in weakly electric fish, Gymnotus carapo

The purpose of this study is to examine the pathways involved in the electromotor (electric organ discharge interruptions) and skeletomotor responses (defense-like) observed by blockade of GABAergic control of the torus semicircularis dorsalis (TSd) of the awake weakly electric fish Gymnotus carapo, described in a former study. Microinjection of NMDA (5 mM) into the pacemaker nucleus (PM) through a guide cannula previously implanted caused a prolonged interruption of the electric organ discharge (EOD) intermingled with reduction in frequency, similar to that described for TSd GABA A blockade, but without noticeable skeletomotor effects. The EOD alterations elicited by bicuculline microinjections (0.245 mM) into the TSd could be blocked or attenuated by a previous microinjection of AP-5 (0.5 mM), an NMDA antagonist, into the PM. Labeled terminals are found in the nucleus electrosensorius (nE) after injection of the biotinylated dextran amine (BDA) tracer into the TSd and into the sublemniscal prepacemaker nucleus (SPPn) subsequent to the tracer injection into the nE. Defense-like responses but not EOD interruptions are observed after microinjections of NMDA (5 mM) into the rhombencephalic reticular formation (RF), where labeled terminals are seen after BDA injection into the TSd and somata are filled after injection of the tracer into the spinal cord. In this last structure, marked fibers are seen subsequent to injection of BDA into the RF. These results suggest that two distinct pathways originate from the torus: one for EOD control, reaching PM through nE and SPPn, and the other one for skeletomotor control reaching premotor reticular neurons. Both paths could be activated by toral GABA A blockade.

Simulation of resonance over-voltage during energization of high voltage power network

Under network equipment outage conditions, the system has to be restored to normal operating conditions as fast as possible to ensure the supply security and avoid prolonged interruption of power supply. In the development of the restoration strategy under different contingencies, a wide range of issues are needed to be studied. For different contingencies, it is important that appropriate approaches, tools and study models are selected and used to meet different objectives. The extraordinary system conditions during restoration require special electromagnetic transient analysis with different system modelling methods and system parameters. All these are very different from those studies conducted for normal operating conditions. Field tests of various restoration arrangements also play an important role in calibrating the study models and parameters in order to verify the study results. With all these studies, CLP Power is able to establish practical and reliable system restoration plans.