The importance of thinking about the future in culture and cumulative cultural evolution.

Thinking about possibilities plays a critical role in the choices humans make throughout their lives. Despite this, the influence of individuals' ability to consider what is possible on culture has been largely overlooked. We propose that the ability to reason about future possibilities or prospective cognition, has consequences for cultural change, possibly facilitating the process of cumulative cultural evolution. In particular, by considering potential future costs and benefits of specific behaviours, prospective cognition may lead to a more flexible use of cultural behaviours. In species with limited planning abilities, this may lead to the development of cultures that promote behaviours with future benefits, circumventing this limitation. Here, we examine these ideas from a comparative perspective, considering the relationship between human and nonhuman assessments of future possibilities and their cultural capacity to invent new solutions and improve them over time. Given the methodological difficulties of assessing prospective cognition across species, we focus on planning, for which we have the most data in other species. Elucidating the role of prospective cognition in culture will help us understand the variability in when and how we see culture expressed, informing ongoing debates, such as that surrounding which social learning mechanisms underlie culture. This article is part of the theme issue 'Thinking about possibilities: mechanisms, ontogeny, functions and phylogeny'.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: A Dutch pilot study exploring clinical and patient-reported outcomes.

Background: Little is known about pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in adulthood, as the genetic basis of the disorder has only been elucidated 15 years ago. This creates a knowledge gap for physicians, pediatric patients and their parents, which was aimed to address in this study using clinical data as well as patient-reported outcome measures (PROMs) for the patient's perspective. Methods: Dutch, genetically confirmed PDE-ALDH7A1 patients ≥18 years were eligible for inclusion. Clinical data were collected as well as PROMs (PROMIS item banks Anxiety, Depression, Anger, Physical Functioning, Cognitive Functioning, Cognitive Abilities, Ability to Participate and Satisfaction with Social Roles). Results: Ten out of 11 patients agreed to participate (91% response rate). Seizure control at last follow up (median age 25.2 years, range 17.8-29.8 years) was achieved with pyridoxine monotherapy in 70%, 20% with adjunct common-anti epileptic drugs and 10% did not obtain complete seizure control. Neurologic symptoms were present in all but one patient (90%) and included tremors, noted in 40%. Neuro-imaging abnormalities were present in 80%. Intellectual disability was present in 70%. One patient (10%) attended university, three maintained a job without assistance, five maintained a job with assistance or attended social daycare, and one patient never followed regular education. The cohort scored significantly lower on the PROMIS Cognitive Functioning compared to the general (age-related) population. Distribution of scores was wide on all PROMIS item banks. Discussion & conclusion: Outcomes of this young adult cohort are heterogeneous and individualized approaches are therefore needed. Long-term seizure control with pyridoxine was achieved for almost all patients. Neurologic symptoms were noted in the majority, including tremors, as well as neuro-imaging abnormalities and intellectual disability, additionally reflected by the PROMIS Cognitive Functioning. PDE-ALDH7A1 patients scored comparable to the general population on all other PROMs, especially regarding Ability to Participate and Satisfaction with Social Roles this may indicate a positive interpretation of their functioning. The aim is to expand this pilot study to larger populations to obtain more solid data, and to advance the use of PROMs to engage patients in research and provide the opportunity for personalized care.

Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study.

BACKGROUND: Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. METHODS: Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. RESULTS: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ > 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. DISCUSSION: Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed.

Comparison of perinatal outcomes between spontaneous vs. commissioned cycles in gestational carriers for single and same-sex male intended parents.

PURPOSE: To determine whether gestational carrier (GC) in vitro fertilization (IVF) cycles (commissioned cycles) for same-sex or single male intended parents have an increased incidence of adverse perinatal outcomes compared with spontaneous cycles in the same GCs. DESIGN: GC singleton pregnancies were identified from a database of 895 commissioned cycles from a large fertility center. Of these, 78 commissioned cycles met inclusion and exclusion criteria and were compared with 71 spontaneous cycles by the same GCs. The primary outcome was the composite score for adverse perinatal outcomes. Secondary outcomes included mode of delivery, birthweight, and gestational age. Chi-square test of association and Mann-Whitney U tests were used to compare categorical and continuous variables between the cohorts, respectively. Logistic and linear regressions controlling for GC age were constructed to determine the influence of GC cycle type on adverse perinatal outcomes. RESULTS: Commissioned cycles were significantly associated with adverse perinatal outcomes (25.6% vs. 9.9%; p = 0.02) and lower average gestational age (38.7 ± 1.5 vs. 39.4 ± 0.9; p < 0.001) compared with spontaneous cycles. Commissioned cycle increased the likelihood of adverse perinatal outcomes (OR 3.3; p = 0.03) and was a significant independent predictor of a lower average gestational age (ß = 0.897; p < 0.001). There were no significant differences in the incidence of vaginal deliveries or cesarean sections between commissioned and spontaneous cycles. CONCLUSIONS: Commissioned cycles confer a greater incidence of composite perinatal complications and were independently associated with a lower average gestational age when compared with spontaneous pregnancies carried by the same GC despite a confirmed healthy uterine environment, sperm samples, and donor oocytes.

Evaluation of the reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index and the Cutaneous Assessment Tool-Binary Method in juvenile dermatomyositis among paediatric dermatologists, rheumatologists and neurologists.

BACKGROUND: The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and Cutaneous Assessment Tool-Binary Method (CAT-BM) have been shown to be reliable and valid outcome measures to assess cutaneous disease in adult dermatomyositis (DM) and juvenile DM (JDM), respectively. OBJECTIVES: This study compared the CDASI and CAT-BM for use by paediatric dermatologists, paediatric rheumatologists and paediatric neurologists in patients with JDM. METHODS: Five paediatric dermatologists, five paediatric rheumatologists and five paediatric neurologists each evaluated 14 patients with JDM using the CDASI, CAT-BM, and skin Physician Global Assessment (PGA) scales. Inter-rater reliability, intra-rater reliability, construct validity and completion time were compared. RESULTS: Inter-rater reliability for CDASI activity and damage scores was good to moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists. The inter-rater reliability for CAT-BM activity scores was moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists and poor across all specialties for damage scores. Intra-rater reliability for the CDASI and CAT-BM activity and damage scores was moderate to excellent for paediatric dermatologists, rheumatologists and neurologists. Strong associations were found between skin PGA activity and damage scores and CDASI or CAT-BM activity and damage scores, respectively (P < 0·002). The CDASI had a mean completion time of 5·4 min compared with that for the CAT-BM of 3·1 min. CONCLUSIONS: Our data confirm the reliability of the CDASI activity and damage scores and the CAT-BM activity scores when used by paediatric dermatologists and rheumatologists in assessing JDM. Significant variation existed in the paediatric neurologists' scores.

RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma.

Cell-based vaccination strategies to induce functional tumor-specific T cells in cancer patients have focused on using autologous dendritic cells. An alternative approach is to use RNA-loaded CD40 activated B cells (CD40-B) that are highly efficient antigen-presenting cells capable of priming naive T cells, boosting memory T-cell responses and breaking tolerance to tumor antigens. The use of tumor RNA as the antigenic payload allows for gene transfer without viruses or vectors and permits major histocompatibility complex (MHC)-independent, multiple-antigen targeting. Here, we use CD40L transfected K562 cells to generate functional CD40-B cells from the peripheral blood of humans and dogs. Testing of RNA-loaded CD40-B cells in dogs allows not only for its development in veterinary medicine but also for determination of its safety and efficacy in a large animal model of spontaneous cancer prior to initiation of human clinical trials. We found that CD40-B cells from healthy humans, healthy dogs and tumor-bearing dogs express increased levels of immune molecules such as MHC and CCR7. Moreover, RNA-loaded CD40-B cells induce functional, antigen-specific T cells from healthy dogs and dogs with lymphoma. These findings pave the way for immunotherapy trials using tumor RNA-loaded CD40-B cells to stimulate antitumor immunity in a large animal model of spontaneous neoplasia.

Care centered organizations, Part 2. The changing role of the nurse executives.

In the first (February 2001) of a three-part series on the role of nursing in care centered organizations, the rationale for establishing service lines, the process for determining governance structure, and the changing role of nurse executives in a large academic medical center reorganized around service-line care delivery were discussed. In this second article, the author describes the nursing governance structure in two academic healthcare institutions after their redesign into care centers.

Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate.

PURPOSE: To determine the potential advantage of androgen ablation following standard external-beam radiation therapy in patients with locally advanced (clinical or pathologic T3; clinical or pathologic node positive) carcinoma of the prostate. METHODS AND MATERIALS: In 1987 the RTOG initiated a Phase III trial of long-term adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients were accrued to the study of which 945 remain analyzable: 477 on the adjuvant hormone arm (Arm I); and 468 on the radiation only arm (Arm II) with hormones initiated at relapse. The initial results were reported in the Journal of Clinical Oncology in 1997. RESULTS: With a median follow up of 5.6 years for all patients and 6.0 years for living patients local failure at 8 years was 23% for Arm I and 37% for Arm II (p < 0.0001). Distant metastasis was likewise favorably impacted with the immediate use of hormonal manipulation with a distant metastasis rate in Arm I of 27% and 37% in Arm II (p < 0.0001). Disease-free survival (NED survival) and NED survival with PSA of 1.5 ng/mL (bNED) or less were both statistically significant in favor of the immediate hormone arm (both p < 0.0001). Cause-specific failure was not statistically different with a cause-specific failure of 16% for Arm I and 21% in Arm II (p = 0.23). Overall survival was likewise not statistically different between two arms, with a 49% overall survival at 8 years in Arm I and 47% in Arm II (p = 0.36). Subset analysis of centrally reviewed Gleason 8-10 patients who did not undergo prostatectomy showed that for patients receiving radiation therapy plus adjuvant hormones there was a statistically significant improvement in both absolute (p = 0.036) and cause-specific survival (p = 0.019). CONCLUSIONS: Use of long-term adjuvant androgen deprivation in addition to definitive radiation therapy results in a highly significant improvement in regards to local control, freedom from distant metastasis, and biochemical free survival in unfavorable prognosis patients with carcinoma of the prostate.

Care-centered organizations: Part 1: Nursing governance.

In the first of a three-part series on the role of nursing in care-centered organizations, the authors describe the thinking and process that lead to the creation of care centers and related governance structures. They explore the rationale for the establishment of care centers, describe the process for determining governance structures, and examine the changing role of nurse executives in a large academic medical center reorganized around care centers.

Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507.

PURPOSE: A phase I trial was conducted by the Radiation Therapy Oncology Group (RTOG) to determine the maximum-tolerated dose of topotecan that could be safely combined with standard cranial radiation for glioblastoma multiforme. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and radiation. PATIENTS AND METHODS: Forty-seven patients with histologically confirmed glioblastoma multiforme were entered onto this phase I trial. Three cycles of topotecan were administered at 21-day intervals commencing at day 1 of cranial radiotherapy (60 Gy/30 fractions). Each cycle consisted of daily 30-minute intravenous (IV) infusions for 5 days. The dose of topotecan was escalated in three-dose increments from 0.5 mg/m(2)/d to 1.0 mg/m(2)/d to 1.5 mg/m(2)/d in different patient groups. RESULTS: The majority of patients were over age 50. Three dose levels of topotecan were tested. Fifteen patients accrued to level 1 (topotecan dose 0.5 mg/m(2)/d). No grade 4 toxicities were seen. Sixteen patients accrued to level 2 (topotecan dose 1.0 mg/m(2)/d), five of whom had brief episodes of grade 4 neutropenia. Seventeen patients accrued to level 3 (1.5 mg/m(2)/d). Six of these patients had brief episodes of grade 4 neutropenia and four developed grade 3 thrombocytopenia. No serious nonhematologic or late toxicities were seen. Median survival for all patients was 9.7 months. There was no apparent difference in survival by topotecan dose schedule. CONCLUSION: Toxicity was acceptable at an IV topotecan dose of 1.5 mg/m(2)/d administered daily for 5 days every 21 days for three cycles. A phase II trial has been performed using this dose of topotecan.

Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or < or = 20 cm(2), respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients.

PURPOSE: To compare survivorship, and acute and delayed toxicities following radiation therapy (RT) of radiosurgery-ineligible glioblastoma multiforme (GBM) patients treated with tumor volume-influenced, high-dose accelerated, hyperfractionated RT plus bischloroethyl-nitrosourea (BCNU), using prior RTOG malignant glioblastoma patients as historical controls. METHODS AND MATERIALS: One hundred four of 108 patients accrued from June 1994 through May 1995 from 26 institutions were analyzable. Patients were histologically confirmed with GBM, and previously untreated. Treatment assignment (52 patients/arm) was based on tumor mass (TM), defined as the product of the maximum diameter and greatest perpendicular dimension of the titanium-gadolinium-enhanced postoperative MRI: Arm A, 64 Gy, TM > 20 cm(2); or Arm B, 70.4 Gy, TM < or = 20 cm(2). Both Arms A and B received BCNU (80 mg/m(2), under hyperhydration) days 1-3, 56-58, then 4 cycles, each 8 weeks, for a total of 6 treatment series. RESULTS: During the 24 months immediately post-treatment, the overall median survival was 9.1 months in Arm A (64 Gy) and 11.0 months in Arm B (70.4 Gy). Median survival in recursive partitioning analysis (RPA) Class III/IV was 10.4 months in Arm A and 12.2 months in Arm B, while RPA Class V/VI was 7.6 months in Arm A and 6.1 months in Arm B. There were no grade 4 neurological toxicities in Arm A; 2 grade 4 neurological toxicities were observed in Arm B (1 motor deficit, 1 necrosis at 157 days post-treatment). CONCLUSION: This strategy of high-dose, accelerated hyperfractionated radiotherapy shortens overall RT treatment times while allowing dose escalation, and it provides the potential for combination with currently available, as well as newer, chemotherapy agents. Survival is comparable with previously published RTOG data, and toxicities are within acceptable limits.

An unusual complication of intracranial electrodes.

This report describes two patients who developed persistent neurologic deficits during intracranial EEG recording without clear evidence of intracranial edema or infarction. Both patients had previously received high-dose brain radiation therapy and chemotherapy. Because of this experience, we strongly caution the use of intracranial electrodes in patients with similar profiles.

Is the asthma quality of life questionnaire a useful measure for low-income asthmatics?

The purpose of this study was to evaluate the reliability and validity of the Asthma Quality of Life Questionnaire (AQLQ) in a population-based sample of low-income adults with asthma. A total of 112 subjects (46 African American, 66 Caucasian; mean age = 33 +/- 9 yr; 26% male) were recruited from the Baltimore County, Maryland and Atlanta, Georgia metropolitan areas. Internal consistency reliability (Cronbach's alpha) was high for the overall scale (0. 96); 2-wk reproducibility (intraclass correlation, ICC) was 0.82 (n = 38). Overall score was significantly correlated with FEV1 percentage of predicted (r = 0.20), and the Asthma Disease Severity Scale (r = -0.38). Correlations between overall score and the SF-36 Physical Component Summary (r = 0.49), SF-36 Mental Component Summary (r = 0.37), Cantril's Ladder (r = 0.23), and the Health Utilities Index (r = 0.22) supported the validity of the AQLQ in this sample. Comparison of reliability and validity estimates across racial groups found few substantive differences. Internal consistency, reproducibility, and validity estimates found in this sample were consistent with those of a reliable and valid measure and were comparable to those found in other populations. These results suggest the AQLQ is a useful indicator of health- related quality of life in low-income asthmatics.

Tumor cell responses to IFNgamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis.

Expression of a dominant negative mutant IFNgammaR1 in murine SCK and K1735 tumor cells rendered them relatively unresponsive to IFNgamma in vitro and more tumorigenic and less responsive to IL-12 therapy in vivo. IL-12 induced histologic evidence of ischemic damage only in IFNgamma-responsive tumors, and in vivo Matrigel vascularization assays revealed that while IFNgamma-responsive and -unresponsive tumor cells induced angiogenesis equally well, IL-12 and its downstream mediator IFNgamma only inhibited angiogenesis induced by the responsive cells. IL-12 induced angiogenesis inhibitory activity in the responsive cells, which may be attributable to production of the chemokine IP-10. Thus, IL-12 and IFNgamma inhibit tumor growth by inducing tumor cells to generate antiangiogenic activity.

Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.

The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70% of mice from concurrently injected distant SCK cells and 30% of mice from SCK cells established 3 d earlier. Antibody neutralization studies revealed that the antitumor effects of secreted mIL-12 and mIL-18 required IFN-gamma. Interestingly, half the survivors of SCK.12 and/or SCK.18 cells developed protective immunity suggesting that anti-SCK immunity is unlikely to be responsible for protection. Instead, angiogenesis inhibition, assayed by Matrigel implants, appeared to be a property of both SCK.12 and SCK.18 cells and the two cell types together produced significantly greater systemic inhibition of angiogenesis. This suggests that inhibition of tumor angiogenesis is an important part of the systemic antitumor effect produced by mIL-12 and mIL-18.

Psychometric performance of the Asthma Quality of Life Questionnaire in a US sample.

The purpose of this study was to examine the psychometric characteristics of the Juniper Asthma Quality of Life Questionnaire (AQLQ) in a sample of asthmatics from the USA, employing data from the Asthma Symptom Utility Index (ASUI) validation study. One hundred and sixty-one adults (66 men) undergoing standard care in an asthma clinic participated in the study (mean age = 34.7 +/- 10.7 years, mean duration of illness = 17.3 +/- 11.22 years and mean FEV1% predicted = 85.6% +/- 17.1%). The internal consistency reliability (infinity) ranged from 0.90 (environment subscale) to 0.95 (overall score) and the 2 week reproducibility (ICC) ranged from 0.81 (activities subscale) to 0.93 (symptoms subscale). The AQLQ was significantly correlated with an asthma disease severity scale and the Health Utilities Index (p < 0.001). No relationship was found between the AQLQ score and FEV1% predicted. Men reported better overall quality of life (QoL), fewer activity limitations and less environmental exposure than women (p < 0.01), while patients with a high school education or less had more severe asthma and poorer QoL across all subscales (p < 0.001). This may reflect the differential experiences of asthma across gender and socioeconomic groups. The results suggest that the AQLQ may be a useful outcome measure for clinical trials conducted in the USA.