Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R(max)) of PD effects was increased, and the time to reach R(max) shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.     

Comparison of stroke volume estimation for non-steady-state and steady-state graded exercise testing

The stroke volume (SV) during exercise is an important index of the heart's functional capacity. A new method has been developed for the non-invasive estimation of exercise SV (SVex). It requires the determination of the slope for the oxygen uptake versus heart rate relationship in the steady state of graded exercise testing (GXT). The product of the slope and a constant (reciprocal of an assumed value of the arterial oxygen content) equals an estimated value for SVex. It was validated in a previous study using invasive measurements while subjects were performing steady-state GXT. However, currently the most commonly used GXT protocols are non-steady state, e.g. protocols with 1-min increment durations. We tested the hypothesis that SVex is the same for steady-state and non-steady-state GXT. A total of 30 subjects (15 males and 15 females) served as subjects for the study. Each subject performed two GXTs on different days with different increment durations - 1 and 4 min. Ventilation and gas exchange were measured with the Vacumed metabolic cart. For the male subjects, the mean (SD) SVex values for the 1- and 4-min GXTs were 155.4 (39.5) and 134.6 (27.5) ml, respectively. The corresponding values for the female subjects were 151.6 (37.6) and 134.3 (36.4) ml. Paired t-test analysis demonstrated that for both genders the mean SVex for the 1-min GXT was significantly larger than the 4-min GXT mean value (P<0.05). Hence, the commonly used 1-min GXT does not yield the same values for SVex as the steady-state GXT.     

Features of Childhood Maltreatment and Resilience Capacity in Adulthood: Results from a Large Community-Based Sample

Childhood maltreatment is consistently associated with poor outcomes. However, few epidemiological studies have examined the association between childhood maltreatment and adult resilience capacity, defined as one's perceived ability to cope successfully with challenges. This study aimed to determine associations between adult resilience capacity and specific types and features of childhood maltreatment. Participants were African American adults recruited from a public urban hospital in Atlanta, GA (N = 1,962) between 2005 and 2013. Childhood maltreatment, including witnessing domestic violence or physical, emotional, and sexual abuse, was assessed retrospectively using the Traumatic Events Inventory. Perceived resilience capacity was assessed using the Connor-Davidson Resilience Scale. Linear regressions were performed assessing the association between resilience capacity and childhood maltreatment exposure in general, as well as specific dimensions of exposure, including type, co-occurrence, and developmental timing, adjusting for covariates. Participants exposed to any maltreatment reported lower resilience capacity than unexposed peers, B = −0.38, SE = 0.04, p < .001. All maltreatment types were negatively associated with resilience capacity, even after adjusting for other lifetime trauma exposure. Only emotional abuse remained significantly associated with resilience capacity after accounting for current psychological distress, B = −0.11, SE = 0.05, p = .022. Maltreatment co-occurrence followed an inverse dose–response relationship with resilience capacity: For each additional maltreatment type, scores decreased by 0.18 units (SD = 0.02), p < .001. Finally, the developmental timing of maltreatment did not reveal any differential influences on resilience capacity. The results suggest that childhood emotional abuse and co-occurrence of maltreatment types may be particularly deleterious to adult resilience capacity.     

Residual Symptoms of Posttraumatic Stress Disorder and Alcohol Use Disorder Following Integrated Exposure Treatment Versus Coping Skills Treatment

Although some studies have demonstrated residual symptoms in patients who have participated in posttraumatic stress disorder (PTSD) treatment, no studies to date have assessed residual PTSD symptoms following treatment for comorbid alcohol use disorder (AUD) and PTSD (PTSD/AUD). We examined residual symptoms of PTSD and AUD in 73 veterans with PTSD/AUD who completed a posttreatment assessment after being randomized to receive either Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) or Seeking Safety (SS). We used logistic regression to identify differences (a) in residual PTSD and AUD symptoms among participants randomized to COPE versus SS and (b) among those with versus without a posttreatment PTSD/AUD diagnosis within both treatment conditions. Participants randomized to SS were more likely to report persistent avoidance, inability to experience positive emotions, hypervigilance, difficulty concentrating, and difficulty sleeping, ORs = 3.74–6.21. There were no differences between COPE and SS regarding the likelihood of persistent AUD symptoms. Participants without a posttreatment PTSD diagnosis had lower conditional probabilities of most symptoms, although exaggerated startle, OR = 0.71, and irritability/aggression, OR = 0.58, were most likely to persist. Participants without a posttreatment AUD diagnosis had lower conditional probabilities of most symptoms, although withdrawal, OR = 0.21; unsuccessful quit attempts, OR = 0.04; and higher intake, OR = 0.01, were most likely to persist. Findings indicate hyperarousal may warrant additional intervention following PTSD treatment. Residual AUD symptoms may relate to the enduring nature of some AUD symptoms rather than a lack of treatment efficacy.     

Refrigerated storage of lyophilized and rehydrated, lyophilized human red cells

Human red cells (RBCs) were collected in CPDA-1 and then freeze-dried in lyoprotective solution. The lyophilized RBCs were then stored at -20 degrees C for 7 days. At the end of the storage period, the lyophilized RBCs were rehydrated and washed in dextrose saline. The washed, reconstituted, lyophilized RBCs were resuspended in final wash solutions of ADSOL, CPDA-1, or a special additive solution containing glucose, citrate, phosphate, adenine, and mannitol, and then they were stored at 4 degrees C for an additional 7 days. The main purpose of this study was to determine whether human RBCs can be lyophilized in such a manner that normal metabolic, rheologic, and cellular properties are maintained during rehydration and subsequent storage in standard blood bank preservative solutions. Our results show that reconstituted, lyophilized RBCs maintained levels of ATP, 2,3 DPG, lactate, and cellular properties that are equal to or better than those in control nonlyophilized RBCs stored for a comparable period in CPDA-1. Reconstituted, lyophilized RBCs stored at 4 degrees C after rehydration also show better maintenance of ATP, 2,3 DPG, and lactate than do control RBCs stored in the same preservative solutions for comparable periods.     

Genetic association signal near NTN4 in Tourette syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10⁻³) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry‐matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10⁻⁴) remained significant after Bonferroni correction. Meta‐analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10⁻⁷). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case–control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. Ann Neurol 2014;76:310–315