Functioning and neurocognition in very early and early-life onset bipolar disorders: the moderating role of bipolar disorder type.

Defining homogeneous subgroups of bipolar disorder (BD) is a major goal in personalized psychiatry and research. According to the neurodevelopmental theory, age at onset may be a key variable. As potential trait markers of neurodevelopment, cognitive and functional impairment should be greater in the early form of the disease, particularly type 1 BD (BD I). The age at onset was assessed in a multicenter, observational sample of 4190 outpatients with BD. We used a battery of neuropsychological tests to assess six domains of cognition. Functioning was measured using the Functioning Assessment Short Test (FAST). We studied the potential moderation of the type of BD on the associations between the age at onset and cognitive and functioning in a subsample of 2072 euthymic participants, controlling for potential clinical and socio-demographic covariates. Multivariable analyses showed cognition to not be impaired in individuals with early (21-30 years) and very early-life (before 14 years) onset of BD. Functioning was equivalent between individuals with early and midlife-onset of BD II and NOS but better for individuals with early onset of BD I. In contrast, functioning was not worse in individuals with very early-onset BD I but worse in those with very early-onset BD II and NOS. Early-life onset BDs were not characterized by poorer cognition and functioning. Our results do not support the neurodevelopmental view that a worse cognitive prognosis characterizes early-life onset BD. This study suggests that functional remediation may be prioritized for individuals with midlife-onset BD I and very early life onset BD 2 and NOS.

Lung Quality and Utilization in Controlled Donation After Circulatory Determination of Death Within the United States.

Although controlled donation after circulatory determination of death (cDCDD) could increase the supply of donor lungs within the United States, the yield of lungs from cDCDD donors remains low compared with donation after neurologic determination of death (DNDD). To explore the reason for low lung yield from cDCDD donors, Scientific Registry of Transplant Recipient data were used to assess the impact of donor lung quality on cDCDD lung utilization by fitting a logistic regression model. The relationship between center volume and cDCDD use was assessed, and the distance between center and donor hospital was calculated by cDCDD status. Recipient survival was compared using a multivariable Cox regression model. Lung utilization was 2.1% for cDCDD donors and 21.4% for DNDD donors. Being a cDCDD donor decreased lung donation (adjusted odds ratio 0.101, 95% confidence interval [CI] 0.085-0.120). A minority of centers have performed cDCDD transplant, with higher volume centers generally performing more cDCDD transplants. There was no difference in center-to-donor distance or recipient survival (adjusted hazard ratio 1.03, 95% CI 0.78-1.37) between cDCDD and DNDD transplants. cDCDD lungs are underutilized compared with DNDD lungs after adjusting for lung quality. Increasing transplant center expertise and commitment to cDCDD lung procurement is needed to improve utilization.

Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

Impact of the lung allocation score on survival beyond 1 year.

Implementation of the lung allocation score (LAS) in 2005 led to transplantation of older and sicker patients without altering 1-year survival. However, long-term survival has not been assessed and emphasizing the 1-year survival metric may actually sustain 1-year survival while not reflecting worsening longer-term survival. Therefore, we assessed overall and conditional 1-year survival; and the effect of crossing the 1-year threshold on hazard of death in three temporal cohorts: historical (1995-2000), pre-LAS (2001-2005) and post-LAS (2005-2010). One-year survival post-LAS remained similar to pre-LAS (83.1% vs. 82.1%) and better than historical controls (75%). Overall survival in the pre- and post-LAS cohorts was also similar. However, long-term survival among patients surviving beyond 1 year was worse than pre-LAS and similar to historical controls. Also, the hazard of death increased significantly in months 13 (1.44, 95% CI 1.10-1.87) and 14 (1.43, 95% CI 1.09-1.87) post-LAS but not in the other cohorts. While implementation of the LAS has not reduced overall survival, decreased survival among patients surviving beyond 1 year in the post-LAS cohort and the increased mortality occurring immediately after 1 year suggest a potential negative long-term effect of the LAS and an unintended consequence of increased emphasis on the 1-year survival metric.

Elevated plasma long pentraxin-3 levels and primary graft dysfunction after lung transplantation for idiopathic pulmonary fibrosis.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Lung function, radiological changes and exposure: analysis of ATSDR data from Libby, MT, USA.

In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR; Atlanta, GA, USA) investigated lung disease in those exposed to the tremolite-contaminated vermiculite mine in Libby, MT, USA. Previously unreported spirometric results are presented here in relation to exposure and radiographic findings. 4,524 study participants were assigned to one of seven mutually exclusive exposure categories. Associations among radiographic findings, spirometric results and exposure were investigated, along with the effect of a reduction in exposure potential when production was moved to a wet process mill in the mid 1970s. Spirometry data for the total population by smoking status and age were within the normal range. Prevalence of pleural plaque increased with age, but was lowest in the environmentally exposed group (0.42-12.74%) and greatest in the W.R. Grace & Co. mineworkers (20-45.68%). For males, there was a significant (4.5%) effect of pleural plaques on forced vital capacity. For W.R. Grace & Co. workers and household contacts, a reduction in plaque (0.11 versus 1.64%) and in diffuse pleural thickening or costophrenic angle obliteration (1.94 and 0.13%) was noted for those exposed after 1976. These analyses do not support a clinically important reduction in spirometry of this cohort. The 1976 reductions in exposure have led to decrease in radiographic changes.

Increasing lung allocation scores predict worsened survival among lung transplant recipients.

Implemented in 2005, the lung allocation score (LAS) aims to distribute donor organs based on overall survival benefits for all potential recipients, rather than on waiting list time accrued. While prior work has shown that patients with scores greater than 46 are at increased risk of death, it is not known whether that risk is equivalent among such patients when stratified by LAS score and diagnosis. We retrospectively evaluated 5331 adult lung transplant recipients from May 2005 to February 2009 to determine the association of LAS (groups based on scores of < or =46, 47-59, 60-79 and > or =80) and posttransplant survival. When compared with patients with LAS < or = 46, only those with LAS > or = 60 had an increased risk of death (LAS 60-79: hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.21-1.90; LAS > or = 80: HR, 2.03; CI, 1.61-2.55; p < 0.001) despite shorter median waiting list times. This risk persisted after adjusting for age, diagnosis, transplant center volume and donor characteristics. By specific diagnosis, an increased hazard was observed in patients with COPD with LAS > or = 80, as well as those with IPF with LAS > or = 60.

A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients.

BACKGROUND: Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can cause significant morbidity and mortality in lung and heart-lung transplant recipients. We evaluated the utility of a multi-drug protocol for the treatment of RSV- and PIV-related infections. PATIENTS AND METHODS: RSV or PIV was identified in 25 patients with a total of 29 infectious episodes between January 2006 and December 2007. The study included 20 women and 5 men, mean age 42 +/- 13 years. Fifteen patients had received bilateral lung transplant and the remainder either received single lung or heart-lung transplant. Mean time from transplant to infection was 1192 days. RSV was identified in 23 cases, PIV in 7 cases. Patients underwent treatment with inhaled ribavirin, methylprednisolone, and intravenous immunoglobulin (IVIG). RSV-positive patients were also treated with palivizumab. We retrospectively evaluated their clinical status and pulmonary function for a 1-year interval before and after the date of infection. RESULTS: Average baseline forced expiratory volume in 1 s (FEV(1)) before infection was 2.14 +/- 0.68 L/min. Average decline in FEV(1) was 5.7% at the time of infection. Average FEV(1) during post-treatment follow-up was not significantly different than baseline (2.16 +/- 0.80 L/min). Among patients with bronchiolitis obliterans syndrome (BOS) stages 1, 2, or 3 at the time of infection, average FEV(1) declined by 14.8% and remained lower at 9.1% during follow-up when compared with patients with BOS stages 0 or 0p. No complications resulted from treatment. One patient died during follow-up as a result of pre-existing liver failure. CONCLUSIONS: This study of lung and heart-lung transplant recipients infected with RSV and PIV shows that a multi-drug regimen including inhaled ribavirin, corticosteroids, and IVIG (with or without palivizumab) is safe and effective. Prompt diagnosis and therapy for patients with RSV or PIV infections are critical for maintaining lung function.

Europium anomaly in plagioclase feldspar: experimental results and semiquantitative model.

The partition of europium between plagioclase feldspar and magmatic liquid is considered in terms of the distribution coefficients for divalent and trivalent europium. A model equation is derived giving the europium anomaly in plagioclase as a function of temperature and oxygen fugacity. The model explains europium anomalies in plagioclase synthesized under controlled laboratory conditions as well as the variations of the anomaly observed in natural terrestrial and extraterrestrial igneous rocks.

Breccias from the lunar highlands: preliminary petrographic report on apollo 16 samples 60017 and 63335.

Lunar samples 60017,4 and 63335,14 are composed of microbreccias and devitrified glass. These components are predominantly anorthositic, with the exception of a cryptocrystalline clast found in the microbreccia portion of 63335,14 which contains 2.7 percent potassium oxide and 66.7 percent silicon dioxide. The samples have been subjected to extreme shock and thermal metamorphism. The parent materials of the microbreccias include both a coarse-grained anorthosite and a fine-grained subophitic anorthositic gabbro.

Petrology of a fine-grained igneous rock from the sea of tranquillity.

All phases in a thin section of sample 10022 have been analyzed by electron microprobe. Augite grains show strong iron enrichment in the outer 15 to 20 microns. Pigeonite cores occur within augite grains. The plagioclase has an anorthite content of between 73 and 81 mole percent and is high in Si and low in Al compared to stoichiometric feldspar. Residual phases include microcrystalline Fe-rich "pyroxene," plagioclase, K-rich alkali feldspar, silica, and rare areas rich in P and Zr with concentrations of Ba, Y, and rare earth elements. The density, viscosity, and crystallization history of the lava of sample 10022 are discussed.

Heart and lung transplantation in the United States, 1997-2006.

This article highlights trends in heart and lung transplantation between 1997 and 2006, drawing on data from the OPTN and SRTR. The total number of candidates actively awaiting heart transplantation declined by 45% over the last decade, dropping from 2414 patients in 1997 to 1327 patients in 2006. The overall death rates among patients awaiting heart transplantation declined over the same period. The distribution of recipients among the different status groups at the time of heart transplantation changed little between the inception of the new classification system in 1999 and 2005. Deaths in the first year after heart transplantation have steadily decreased. At the end of 2006, 2885 candidates were awaiting a lung transplant, up 10% from the 1997 count. The median time-to-transplant for listed patients decreased by 87% over the decade, dropping from 1053 days in 1997 to 132 days in 2006. Selection for listing and transplantation has shifted toward more urgent patients since the May 2005 implementation of a new lung allocation system based on survival benefit and urgency rather than waiting time. Only 31 heart-lung transplants were performed in 2006, down from a high of 62 in 1997.

Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.

BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Relative content of isoaccepting tRNAs for glycine and proline in avian tendon cells with different rates of procollagen synthesis.

The relative amounts of iso-tRNAsGly and iso-tRNAsPro existing in chick embryo tendon are indicative of a specialization of the tRNA population for collagen synthesis. These amounts are not modified (i) in primary avian tendon (PAT) cells in culture for which the procollagen production varies from about 10% of total protein synthesis to 60% and (ii) in tendons from immature chicks, which show a 3-fold decrease of procollagen production with increasing age. The characteristic tRNA pattern was not maintained in cells which had lost the ability to make high levels of collagen as observed in the cases of: (i) PAT cells reaching confluency; (ii) virus-transformed PAT cells and (iii) tendon from adult chick. Our data are consistent with the idea that tendon tRNA specialization for collagen synthesis is a differentiation feature independent of the expression level of the collagenic function but related to its maintenance.

Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer.

PURPOSE: To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS: Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION: Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Direct signal transduction via functional interferon-alphabeta receptors in CD34+ hematopoietic stem cells.

Affinity purified, freshly isolated CD34+ progenitors were shown to express low levels of type I interferon (IFN) receptors (740 +/- 60 binding sites/cell, K(d) 0.7 +/- 0.04 nM) determined by Scatchard's analysis using a radiolabelled, neutralizing, monoclonal antibody directed against the IFNAR1 chain of the human type I IFN receptor. Treatment of freshly isolated (day 0), highly purified (>95% pure) CD34+ cells with recombinant IFN-alpha resulted in rapid tyrosine phosphorylation and activation of STAT1, Tyk2 and JAK1 as shown by Western immunoblotting. Similarly, IFN treatment was shown by confocal microscopy to result in rapid nuclear localization of the transcription factors IRF1 and STAT2, demonstrating the presence of functional IFN receptors on freshly isolated (day 0) CD34+ cells. The number of specific type I IFN receptor binding sites expressed on hematopoietic progenitor cells increased to some 1440 +/- 40 per cell after 11 days of cultivation of CD34+ cells in vitrosuggesting that receptor expression increases with cell differentiation. IFN-mediated signal transduction and the inhibitory effect of IFN-alpha on 7 or 14 days CFU-GM and BFU-E colony formation was abrogated in the presence of the anti-IFNAR1 mAb, indicating that IFN-alpha acts directly on the proliferation of human hematopoietic progenitor cells via receptor activated signal transduction without excluding the induction of other cytokines or growth factors by residual accessory cells.

Induction of tumor necrosis factor alpha expression in human T lymphocytes following ionizing gamma irradiation.

In this work, we present evidence that enriched human peripheral blood T lymphocytes, depleted of contaminating monocytes, rapidly express tumor necrosis factor alpha (TNF-alpha) mRNA when exposed to low doses of gamma-irradiation. In total PBL, TNF-alpha mRNA accumulation increased threefold as early as 30 minutes following exposure to 4 Gy and then declined to the baseline level by 3-5 h, as measured by the reverse transcriptase-polymerase chain reaction (RT-PCR). The increase in TNF-alpha mRNA was also observed in populations of enriched T cells and decreased when the dose of irradiation was increased to 10 Gy, strongly suggesting that T lymphocytes, the most radiosensitive cells of the body, contributed directly to the increase of TNF-alpha mRNA. A good correlation was found between mRNA expression and TNF-alpha protein secretion. Interestingly, a eightfold increase in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA accumulation was also detected in both PBL and enriched T cells irradiated at 4 Gy for 3 h compared with unirradiated cells. This irradiation effect was almost completely abolished, however, following exposure to 10 Gy. Together these data suggest that T cells are responsible for the irradiation-induced expression of TNF-alpha and GAPDH.

Oromucosal interferon therapy: pharmacokinetics and pharmacodynamics.

Oromucosal administration of [125I]-labeled recombinant human interferon-alpha1-8 (IFN-alpha1-8), which is biologically active in the mouse, resulted in readily detectable levels of radioactivity in the serum of animals within 5 min. Biologically active IFN could not be detected in the serum at any time after oromucosal administration, however, and SDS-PAGE analysis showed that the material present in the serum was of low molecular weight and most probably reflected absorption of degradation products following digestion of IFN in the stomach and small intestine. Furthermore, oromucosal administration of murine IFN-alpha/beta (MuIFN-alpha/beta) had no significant effect on the expression of IFN-responsive genes in either peripheral blood mononuclear cells or splenic lymphocytes even though in the same animals IFN treatment activated gene transcription locally in the lymphoid tissue of the oropharyngeal cavity and caused a marked systemic antiviral activity. Oromucosal administration of MuIFN-alpha/beta had no significant effect on either the number of circulating peripheral blood leukocytes or the number of granulocyte-macrophage colonies recovered from the bone marrow of IFN-treated animals. These results suggest that the mechanism of action of oromucosal IFN therapy is distinct from that of parenterally administered IFN and may involve, in the abundant lymphoid or epithelial tissue of the oropharyngeal cavity, either production of a soluble factor or activation of a specific cell population that enters the circulation to mediate the elimination of virus-infected or neoplastic cells.

A versatile ELISA-PCR assay for mRNA quantitation from a few cells.

Gene expression studies require a sensitive and quantitative assay of mRNA amounts present in small samples. We describe a general method of quantifying specific mRNA quickly and easily from purified RNA or directly from a few cells by PCR and enzyme-linked immunosorbent assay (ELISA) revelation of the resulting products (sensitivity of the last step: < 0.1 fmol). Cells are digested and the total cellular RNA is reverse-transcribed and then amplified with 5' and 3' primers; the former being 5' biotinylated. The amplification product is captured on avidin-coated microplates and quantified by hybridization with a digoxigenin-labeled internal oligonucleotide probe. After revelation with an anti-digoxigenin alkaline phosphatase coupled antibody (anti-DIG-AP1), the amount of hybridized probe is determined by optical reading. The results can be easily converted to absolute values by comparison with an external DNA standard curve. An internal DNA or RNA standard can also be used. The method we describe can be adapted to any cellular or viral gene of known sequence in a matter of days. Since it uses nonradioactive probes, commercially available reagents and standard microplate readers, it is inexpensive and could be automated easily. In this study, interleukin-2 mRNA expression could be studied in as few as 40 Jurkat cells. It was also possible to quantify human immunodeficiency virus (HIV) DNA from 1500 to 1.5 copies out of 1.5 x 10(5) human genomic DNA copies.

Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement.

A double blind randomized trial comparing subcutaneous enoxaparin (40 mg once daily) with standard unfractionated calcium heparin administered at a dose of 5,000 units every 8 hours in patients undergoing elective hip replacement has been performed. Treatment regimens began 12 hours preoperatively with enoxaparin, 2 hours preoperatively with standard unfractionated calcium heparin, and were continued for 15 days or until discharge. Venography was performed in all patients. Two hundred thirty-seven patients were included in the study: 113 received unfractionated heparin and 124 received enoxaparin. The incidence of proximal deep vein thrombosis was reduced from 18.5% in the unfractionated heparin group to 7.5% in the enoxaparin group (p = 0.014), and the incidence of total deep vein thrombosis was similarly reduced from 25% to 12.5% (p = 0.03). There were two major bleeding episodes and one minor bleed in the enoxaparin group compared to two minor bleeds in the unfractionated heparin group. Patients who received enoxaparin required fewer red blood cell transfusions and had a significantly higher hemoglobin on postoperative days 3 and 4. Thus prophylaxis with enoxaparin, 40 mg once daily, is simple, safe and more effective than standard low dose unfractionated heparin in preventing deep vein thrombosis in patients undergoing elective hip replacement.