US climate policy yields water quality cobenefits in the Mississippi Basin and Gulf of Mexico.

We utilize a coupled economy-agroecology-hydrology modeling framework to capture the cascading impacts of climate change mitigation policy on agriculture and the resulting water quality cobenefits. We analyze a policy that assigns a range of United States government's social cost of carbon estimates ($51, $76, and $152/ton of CO2-equivalents) to fossil fuel-based CO2 emissions. This policy raises energy costs and, importantly for agriculture, boosts the price of nitrogen fertilizer production. At the highest carbon price, US carbon emissions are reduced by about 50%, and nitrogen fertilizer prices rise by about 90%, leading to an approximate 15% reduction in fertilizer applications for corn production across the Mississippi River Basin. Corn and soybean production declines by about 7%, increasing crop prices by 6%, while nitrate leaching declines by about 10%. Simulated nitrate export to the Gulf of Mexico decreases by 8%, ultimately shrinking the average midsummer area of the Gulf of Mexico hypoxic area by 3% and hypoxic volume by 4%. We also consider the additional benefits of restored wetlands to mitigate nitrogen loading to reduce hypoxia in the Gulf of Mexico and find a targeted wetland restoration scenario approximately doubles the effect of a low to moderate social cost of carbon. Wetland restoration alone exhibited spillover effects that increased nitrate leaching in other parts of the basin which were mitigated with the inclusion of the carbon policy. We conclude that a national climate policy aimed at reducing greenhouse gas emissions in the United States would have important water quality cobenefits.

Projecting global oil palm expansion under zero-deforestation commitments: Direct and indirect land use change impacts.

In the last three decades, global production of oil palm has boomed, which has partly come at the expense of tropical rainforests. Recognizing this, many companies operating in the palm oil industry have committed to eliminate deforestation from their operations, often referred to as zero-deforestation commitments (ZDCs). Here, we estimate that if ZDCs are fully adopted and enforced across all sectors and geographies, the global extent of oil palm plantations may be 11 M ha or 40% smaller in 2030 than in a business-as-usual (BAU) scenario that assumes no compliance with ZDCs. As a result of such land-sparing effects, we estimate that 96 M ha of forests are saved from conversion, of which, 17% would otherwise have been converted (directly or indirectly) due to expanding oil palm plantations. Overall, these figures suggest that ZDCs have the potential to deliver major environmental benefits if they are fully adopted and enforced.

Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes.

Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells, enabling the generation of personalized disease models by differentiating patient-derived iPSCs into disease-relevant cell lines. While genetic variability between different iPSC lines affects differentiation potential, how this variability in somatic cells affects pluripotent potential is less understood. We generated and compared transcriptomic data from 72 dermal fibroblast-iPSC pairs with consistent variation in reprogramming efficiency. By considering equal numbers of samples from self-reported African Americans and White Americans, we identified both ancestry-dependent and ancestry-independent transcripts associated with reprogramming efficiency, suggesting that transcriptomic heterogeneity can substantially affect reprogramming. Moreover, reprogramming efficiency-associated genes are involved in diverse dynamic biological processes, including cancer and wound healing, and are predictive of 5-year breast cancer survival in an independent cohort. Candidate genes may provide insight into mechanisms of ancestry-dependent regulation of cell fate transitions and motivate additional studies for improvement of reprogramming.

Evidence for widespread hydrated minerals on asteroid (101955) Bennu.

Early spectral data from the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission reveal evidence for abundant hydrated minerals on the surface of near-Earth asteroid (101955) Bennu in the form of a near-infrared absorption near 2.7 µm and thermal infrared spectral features that are most similar to those of aqueously altered CM carbonaceous chondrites. We observe these spectral features across the surface of Bennu, and there is no evidence of substantial rotational variability at the spatial scales of tens to hundreds of meters observed to date. In the visible and near-infrared (0.4 to 2.4 µm) Bennu's spectrum appears featureless and with a blue (negative) slope, confirming previous ground-based observations. Bennu may represent a class of objects that could have brought volatiles and organic chemistry to Earth.

Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming.

Epigenetic enzymes regulate higher-order chromatin architecture and cell-type specific gene expression. The ATPase BRG1 and the SWI/SNF chromatin remodeling complex are epigenetic enzymes that regulate chromatin accessibility during steady and transitional cell states. Experiments in mice show that the loss of BRG1 inhibits cellular reprogramming, while studies using human cells demonstrate that the overexpression of BRG1 enhances reprogramming. We hypothesized that the variation of SWI/SNF subunit expression in the human population would contribute to variability in the efficiency of induced pluripotent stem cells (iPSC) reprogramming. To examine the impact of an individual's sex, ancestry, and age on iPSC reprogramming, we created a novel sex and ancestry balanced cohort of 240 iPSC lines derived from human dermal fibroblasts (DF) from 80 heathy donors. We methodically assessed the reprogramming efficiency of each DF line and then quantified the individual and demographic-specific variations in SWI/SNF chromatin remodeling proteins and mRNA expression. We identified BRG1, BAF155, and BAF60a expression as strongly correlating with iPSC reprogramming efficiency. Additionally, we discovered that high efficiency iPSC reprograming is negatively correlated with donor age, positively correlated with African American descent, and uncorrelated with donor sex. These results show the variations in chromatin remodeling protein expression have a strong impact on iPSC reprogramming. Additionally, our cohort is unique in its large size, diversity, and focus on healthy donors. Consequently, this cohort can be a vital tool for researchers seeking to validate observational results from human population studies and perform detailed mechanistic studies in a controlled cell culture environment. Stem Cells 2018;36:1697-1708.

Water flow modulates the response of coral reef communities to ocean acidification.

By the end of the century coral reefs likely will be affected negatively by ocean acidification (OA), but both the effects of OA on coral communities and the crossed effects of OA with other physical environmental variables are lacking. One of the least considered physical parameters is water flow, which is surprising considering its strong role in modulating the physiology of reef organisms and communities. In the present study, the effects of flow were tested on coral reef communities maintained in outdoor flumes under ambient pCO2 and high pCO2 (1300 µatm). Net calcification of coral communities, including sediments, was affected by both flow and pCO2 with calcification correlated positively with flow under both pCO2 treatments. The effect of flow was less evident for sediments where dissolution exceeded precipitation of calcium carbonate under all flow speeds at high pCO2. For corals and calcifying algae there was a strong flow effect, particularly at high pCO2 where positive net calcification was maintained at night in the high flow treatment. Our results demonstrate the importance of water flow in modulating the coral reef community response to OA and highlight the need to consider this parameter when assessing the effects of OA on coral reefs.

Global market integration increases likelihood that a future African Green Revolution could increase crop land use and CO2 emissions.

There has been a resurgence of interest in the impacts of agricultural productivity on land use and the environment. At the center of this debate is the assertion that agricultural innovation is land sparing. However, numerous case studies and global empirical studies have found little evidence of higher yields being accompanied by reduced area. We find that these studies overlook two crucial factors: estimation of a true counterfactual scenario and a tendency to adopt a regional, rather than a global, perspective. This paper introduces a general framework for analyzing the impacts of regional and global innovation on long run crop output, prices, land rents, land use, and associated CO2 emissions. In so doing, it facilitates a reconciliation of the apparently conflicting views of the impacts of agricultural productivity growth on global land use and environmental quality. Our historical analysis demonstrates that the Green Revolution in Asia, Latin America, and the Middle East was unambiguously land and emissions sparing, compared with a counterfactual world without these innovations. In contrast, we find that the environmental impacts of a prospective African Green Revolution are potentially ambiguous. We trace these divergent outcomes to relative differences between the innovating region and the rest of the world in yields, emissions efficiencies, cropland supply response, and intensification potential. Globalization of agriculture raises the potential for adverse environmental consequences. However, if sustained for several decades, an African Green Revolution will eventually become land sparing.

Expression and cellular localization of the classical progesterone receptor in healthy and amyotrophic lateral sclerosis affected spinal cord.

BACKGROUND AND PURPOSE: Previous studies have suggested that elevated progesterone levels are associated with a slower disease course in amyotrophic lateral sclerosis (ALS). Given that the effects of progesterone are mediated in part by the classical progesterone receptor (PR), the expression and cellular localization of the A and B isoforms (PR-A and PR-B, respectively) of the PR in control (neuropathologically normal) and ALS-affected spinal cord (SC) were examined. METHODS: Semi-quantitative RT-PCR, immunohistochemistry and immunofluorescence analyses of the cervical and lumbar SC of post-mortem ALS patients (n = 19) and control subjects (n = 10) were performed. Primers and antibodies used allowed the detection of both PR-A and PR-B isoforms together (PR-A+B) or PR-B isoform alone. RESULTS: Lumbar PR-A+B and cervical PR-B mRNA expression were significantly higher in ALS than controls. In both ALS and controls, PR-A+B immunoreactivity (IR) was occasionally detected in motor neurons. In contrast, PR-A+B IR was prominent in axonal processes and vessels. This was more evident in nerve roots and large arteries in ALS compared with controls. Colocalization of PR-A+B with markers of neurons, axonal processes and vascular endothelium was also observed. CONCLUSIONS: Evidence that both PR-A and PR-B isoforms are expressed in the human SC is provided, with some regional variation in isoform expression between ALS and controls. The IR was more prominent in nerve roots and large arteries in ALS, suggesting a potential role in the degenerative process.

α(1,3)-Fucosyltransferases FUT4 and FUT7 control murine susceptibility to thrombosis.

The α(1,3)-fucosyltransferases, types IV and VII (FUT4 and FUT7, respectively), are required for the synthesis of functional selectin-type leukocyte adhesion molecule ligands. The selectins and their ligands modulate leukocyte trafficking, and P-selectin and its ligand, P-selectin glycoprotein ligand-1, can modulate hemostasis and thrombosis. Regulation of thrombosis by FUT4 and/or FUT7 activity was examined in mouse models of carotid artery thrombosis and collagen/epinephrine-induced thromboembolism. Mice lacking both FUT4 and FUT7 (Fut(-/-) mice) had a shorter time to occlusive thrombus formation in the injured carotid artery and a higher mortality due to collagen/epinephrine-induced pulmonary thromboemboli. Mice lacking P-selectin or P-selectin glycoprotein ligand-1 did not have a prothrombotic phenotype. Whole blood platelet aggregation was enhanced, and plasma fibrinogen content, clot weight, and clot strength were increased in Fut(-/-) mice, and in vitro clot lysis was reduced compared with wild type. Fut4(-/-), but not Fut7(-/-), mice had increased pulmonary thromboembolism-induced mortality and decreased thromboemboli dissolution in vivo. These data show that FUT4 and FUT7 activity regulates thrombosis in a P-selectin- and P-selectin glycoprotein ligand-1-independent manner and suggest that FUT4 activity is important for thrombolysis.

Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance.

BACKGROUND & AIMS: Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish. METHODS: Germ-free, wild-type, and interleukin (Il)10(-/-) mice and germ-free zebrafish embryos were colonized with specific pathogen-free (SPF) microbiota. Germ-free or SPF-raised wild-type and Il10(-/-) mice were given intraperitoneal injections of cobalt(III) protoporphyrin IX chloride (CoPP), which up-regulates HO-1, the CO-releasing molecule Alfama-186, or saline (control). Colitis was induced in wild-type mice housed in SPF conditions by infection with Salmonella typhimurium. RESULTS: In colons of germ-free, wild-type mice, SPF microbiota induced production of HO-1 via activation of nuclear factor erythroid 2-related factor 2-, IL-10-, and Toll-like receptor-dependent pathways; similar observations were made in zebrafish. SPF microbiota did not induce HO-1 in colons of germ-free Il10(-/-) mice. Administration of CoPP to Il10(-/-) mice before transition from germ-free to SPF conditions reduced their development of colitis. In Il10(-/-) mice, CO and CoPP reduced levels of enteric bacterial genomic DNA in mesenteric lymph nodes. In mice with S typhimurium-induced enterocolitis, CoPP reduced the numbers of live S typhimurium recovered from the lamina propria, mesenteric lymph nodes, spleen, and liver. Knockdown of HO-1 in mouse macrophages impaired their bactericidal activity against E coli, E faecalis, and S typhimurium, whereas exposure to CO or overexpression of HO-1 increased their bactericidal activity. HO-1 induction and CO increased acidification of phagolysosomes. CONCLUSIONS: Colonic HO-1 prevents colonic inflammation in mice. HO-1 is induced by the enteric microbiota and its homeostatic function is mediated, in part, by promoting bactericidal activities of macrophages.

Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish.

Regulation of intestinal dietary fat absorption is critical to maintaining energy balance. While intestinal microbiota clearly impact the host's energy balance, their role in intestinal absorption and extraintestinal metabolism of dietary fat is less clear. Using in vivo imaging of fluorescent fatty acid (FA) analogs delivered to gnotobiotic zebrafish hosts, we reveal that microbiota stimulate FA uptake and lipid droplet (LD) formation in the intestinal epithelium and liver. Microbiota increase epithelial LD number in a diet-dependent manner. The presence of food led to the intestinal enrichment of bacteria from the phylum Firmicutes. Diet-enriched Firmicutes and their products were sufficient to increase epithelial LD number, whereas LD size was increased by other bacterial types. Thus, different members of the intestinal microbiota promote FA absorption via distinct mechanisms. Diet-induced alterations in microbiota composition might influence fat absorption, providing mechanistic insight into how microbiota-diet interactions regulate host energy balance.

Microbial colonization induces dynamic temporal and spatial patterns of NF-κB activation in the zebrafish digestive tract.

BACKGROUND & AIMS: The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) transcription factor pathway is activated in response to diverse microbial stimuli to regulate expression of genes involved in immune responses and tissue homeostasis. However, the temporal and spatial activation of NF-κB in response to microbial signals have not been determined in whole living organisms, and the molecular and cellular details of these responses are not well understood. We used in vivo imaging and molecular approaches to analyze NF-κB activation in response to the commensal microbiota in transparent gnotobiotic zebrafish. METHODS: We used DNA microarrays, in situ hybridization, and quantitative reverse transcription polymerase chain reaction analyses to study the effects of the commensal microbiota on gene expression in gnotobiotic zebrafish. Zebrafish PAC2 and ZFL cells were used to study the NF-κB signaling pathway in response to bacterial stimuli. We generated transgenic zebrafish that express enhanced green fluorescent protein under transcriptional control of NF-κB, and used them to study patterns of NF-κB activation during development and microbial colonization. RESULTS: Bacterial stimulation induced canonical activation of the NF-κB pathway in zebrafish cells. Colonization of germ-free transgenic zebrafish with a commensal microbiota activated NF-κB and led to up-regulation of its target genes in intestinal and extraintestinal tissues of the digestive tract. Colonization with the bacterium Pseudomonas aeruginosa was sufficient to activate NF-κB, and this activation required a functional flagellar apparatus. CONCLUSIONS: In zebrafish, transcriptional activity of NF-κB is spatially and temporally regulated by specific microbial factors. The observed patterns of NF-κB-dependent responses to microbial colonization indicate that cells in the gastrointestinal tract respond robustly to the microbial environment.

Tau protein hyperphosphorylation in sporadic ALS with cognitive impairment.

The authors have characterized frontal cortical tau protein in cognitively intact (4) and cognitively impaired (ALSci, 4) ALS patients and compared it with control (2) or Alzheimer disease (AD, 1)- derived tau. The authors observed expression of both 3R and 4R tau isoforms; increased insoluble tau protein; phosphatase resistance; and hyperphosphorylation at T175, S208, and S210. Soluble tau from both AD and ALSci was also phosphorylated at S237. Tau hyperphosphorylation is associated with ALS.

Development of the Muscle Dysmorphia Inventory (MDI).

AIM: The development of the 6-factor, 27-item Muscle Dysmorphia Inventory (MDI) was based on Lantz et al. proposed model of characteristics associated with Muscle Dysmorphia. EXPERIMENTAL DESIGN: quantitative procedures including item-to-total correlations, exploratory and confirmatory factor analyses, and structure equation modeling confirmed the construct validity of the scale. Convergent validity was also tested. SETTING: bodybuilding and powerlifting competition venues, weight training facilities, and university athletic venues. PARTICIPANTS: the 1(st) study consisted of 77 experienced male free weight lifters. The 2(nd) study consisted of 156 male non-competitive bodybuilders and weight lifters and 168 elite level powerlifters and bodybuilders. The 3(rd) study consisted of 151 male and female bodybuilders and weight lifters. MEASURES: each participant completed demographic information, the MDI, Drive for Thinness subscale of the Eating Disorder Inventory, and the Training Dependency subscale of the Bodybuilding Dependence Scale. RESULTS: Reliability estimates (Cronbach's a) ranged from 0.72 to 0.94. Factor loadings in all 3 studies supported the 6-factor structure (size/symmetry, supplement use, exercise dependence, pharmacological use, dietary behavior, and physique protection). Much of the scale validation was focused on construct validity, however, correlations with the MDI's subscales and the Training Dependency subscale of the Bodybuilding Dependence Scale and the Drive for Thinness subscale of the Eating Disorder Inventory provided evidence of convergent validity also. CONCLUSIONS: From these preliminary results, the MDI appears to contribute to the identification of a newly formed disorder by offering a multi-dimensional measure of factors related to Muscle Dysmorphia.

Rating specific chiropractic technique procedures for common low back conditions.

OBJECTIVE: To rate specific chiropractic technique procedures used in the treatment of common low back conditions. DESIGN AND METHODS: A panel of chiropractors rated specific chiropractic technique procedures for their effectiveness in the treatment of common low back conditions, based on the quality of supporting evidence after systematic literature reviews and expert clinical opinion. Statements related to the rating process and clinical practice were then developed through a facilitated nominal consensus process. RESULTS: For most low back conditions presented in this study, the three procedures rated most effective were high-velocity, low- amplitude (HVLA) with no drop table (side posture), distraction technique, and HVLA prone with drop table assist. The three rated least effective were upper cervical technique, non-thrust reflex/low force, and lower extremity adjusting. The four conditions rated most amenable to chiropractic treatment were noncomplicated low back pain, sacroiliac joint dysfunction, posterior joint/subluxation, and low back pain with buttock or leg pain. CONCLUSIONS: The ratings for the effectiveness of chiropractic technique procedures for the treatment of common low back conditions are not equal. Those procedures rated highest are supported by the highest quality of literature. Much more evidence is necessary for chiropractors to understand which procedures maximally benefit patients for which conditions.

Non-stationary distributed source approximation: an alternative to improve localization procedures.

Localization of the generators of the scalp measured electrical activity is particularly difficult when a large number of brain regions are simultaneously active. In this study, we describe an approach to automatically isolate scalp potential maps, which are simple enough to expect reasonable results after applying a distributed source localization procedure. The isolation technique is based on the time-frequency decomposition of the scalp-measured data by means of a time-frequency representation. The basic rationale behind the approach is that neural generators synchronize during short time periods over given frequency bands for the codification of information and its transmission. Consequently potential patterns specific for certain time-frequency pairs should be simpler than those appearing at single times but for all frequencies. The method generalizes the FFT approximation to the case of distributed source models with non-stationary time behavior. In summary, the non-stationary distributed source approximation aims to facilitate the localization of distributed source patterns acting at specific time and frequencies for non-stationary data such as epileptic seizures and single trial event related potentials. The merits of this approach are illustrated here in the analysis of synthetic data as well as in the localization of the epileptogenic area at seizure onset in patients. It is shown that time and frequency at seizure onset can be precisely detected in the time-frequency domain and those localization results are stable over seizures. The results suggest that the method could also be applied to localize generators in single trial evoked responses or spontaneous activity.

Effect of chiropractic intervention on small scoliotic curves in younger subjects: a time-series cohort design.

BACKGROUND: Chiropractors have long claimed to affect scoliotic curves, and case studies abound reporting on successful outcomes. No clinical trials exist, however, that evaluate chiropractic's effectiveness in the management of scoliotic curves. OBJECTIVE: To assess the effectiveness of chiropractic intervention in the management of adolescent idiopathic scoliosis in curves less than 20 degrees. DESIGN: Cohort time-series trial with all subjects electing chiropractic care. Entry-level Cobb angle was compared with postmanagement curve. METHODS: Forty-two subjects completed the program of chiropractic intervention. Age range at entry was 6 to 12 years, and patients were included if their entry-level x-ray films revealed curves of 6 degrees to 20 degrees. Participants had adjustments performed for 1 year before follow-up. Full-spine osseous adjustments were the major form of intervention, but heel lifts and postural and lifestyle counseling were used as well. RESULTS: There was no discernable effect on the severity of the curves as a function of age, initial curve severity, frequency of care, or attending physician. CONCLUSION: Full-spine chiropractic adjustments with heel lifts and postural and lifestyle counseling are not effective in reducing the severity of scoliotic curves.

Chiropractic technique procedures for specific low back conditions: characterizing the literature.

BACKGROUND: Many original clinical trials and several review papers have come to the conclusion that manipulation is safe and effective for the treatment of low back pain. However, it is necessary to determine which specific types of manipulation and nonmanipulative types of chiropractic adjustive care are most effective for particular types of low back pain across both tissue-specific and functional classifications. OBJECTIVE: To characterize the quantity and quality of literature gathered for an Expert Panel that was convened to rate various specific chiropractic adjustive procedures for the treatment of common types of low back pain, drawing on the clinical expertise of the panel members and the relevant literature. STUDY DESIGN: Systematic review of treatment-specific, condition-specific trials, studies, and case reports of chiropractic care for low back pain. METHODS: Computerized searching and hand searching were used to identify references in the medical and chiropractic literature pertaining to the chiropractic treatment of low back pain in which both the condition and specific treatment procedures were adequately described. This literature was then categorized according to a variety of characteristics and used by a panel to evaluate the specific procedures. RESULTS: The 3 most studied adjustive procedures are side-posture high-velocity, low-amplitude; distraction (mostly flexion distraction); and mobilization, respectively. The clinical condition most commonly addressed by the included studies is low back pain. The procedure with the widest base of evidence support is side posture manipulation for low back pain.

Errors in precise examiner head placement during cervical range-of-motion measurements.

OBJECTIVE: To quantify errors associated with examiner-assisted neutral head placement in cervical range of motion measurements in normal subjects and to investigate the influence of these errors on range of motion measurements. DESIGN: Repeated-measures design with cervical range of motion and errors in placement measured in 20 volunteers with no symptoms with the OSI CA-6000. METHODS: Examiner placement of head position was achieved with inclinometers and triangulation. Subjects estimated pain experienced during measurements with numeric pain scales. Angular data around 3 axes were analyzed with descriptive statistics. Possible correlations between errors and other variables were investigated. RESULTS: Drift, defined as displacement from original head positioning at first data acquisition and before initiation of motion, was negligible (+/-0.8 degrees ). Standard errors in neutral head placement ranged from 1.0 degrees in axial rotation to 3.2 degrees in flexion/extension. Within-trial variability of neutral position did not correlate with between-trial differences in ranges of motion. CONCLUSION: Head position errors were not the primary sources of variability for between-trial measurements of cervical range of motion. The largest errors were in flexion/extension, and least, in axial rotation. Neutral position errors up to approximately 5 degrees for lateral bending, 3 degrees for rotation, and 9 degrees for flexion and extension fall within 95% CI and are the recommended lower limits for significant changes in clinical settings.

The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study.

BACKGROUND: Few studies have approached the subject of polypharmacotherapy systematically. This retrospective review of 178 patients with refractory bipolar disorder or unipolar depression (Research Diagnostic Criteria or DSM-III-R criteria) discharged from the National Institute of Mental Health (NIMH) Biological Psychiatry Branch between 1974 and 1996 was conducted to assess the degree and efficacy of "add-on" pharmacotherapy. METHOD: Following completion of formal structured blinded research protocols, patients entered a treatment phase (often again on a blind basis) in which all agents available in the community could be utilized. Each patient's retrospective life chart and all prospective double-blind nurse- and self-rated NIMH data were reviewed. The overall degree of improvement at discharge was assessed by rating on the Clinical Global Impressions scale (CGI) as modified for bipolar illness (CGI-BP). RESULTS: A 78% improvement rate (moderate or marked on the CGI) was achieved at the time of discharge. There was a significant relationship between number of medications utilized at discharge as a function of discharge date (r = 0.45, p < .0001). The percentages of patients discharged on treatment with 3 or more medications were 3.3% (1974-1979), 9.3% (1980-1984), 34.9% (1985-1989), and 43.8% (1990-1995). No correlation was found between polypharmacy and age (r = -0.03, p = .66). Patients more recently discharged from the NIMH had an earlier age at illness onset, more lifetime weeks depressed, and a higher rate of rapid cycling than patients in the earlier cohorts. CONCLUSION: Increasing numbers of medications in more recent NIMH cohorts were required to achieve the same degree of improvement at hospital discharge. More systematic approaches to the complex regimens required for treatment of patients with refractory mood disorder are clearly needed.