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7T MRI offers significant benefits to spatial and contrast resolution compared to lower field strengths. This superior image quality can help better delineate targets in stereotactic neurosurgical procedures; however, the potential for increased geometric distortions at 7T has impaired its widespread use for these applications. Image geometric distortions can be due to distortions of BThe purpose of this study was to investigate the use of 7T MRI for neurosurgical frameless stereotactic navigation procedures. Image geometric distortions at the skin surface in 7T images were minimized and compared to results from clinical 3T frameless imaging protocols.A 3D-printed grid phantom filled with oil was designed to perform a fine calibration of the 7T imaging gradients, and an oil-filled head phantom with internal targets was used to determine ground truth (from computed tomography [CT]) positioning errors. Three volunteers and the head phantom were imaged consecutively at 3T and 7T. Ten skin-adhesive fiducial markers were placed on each subject's exposed skin surface at standard clinical placement locations for frameless procedures. Imaging sequences included MPRAGE (three bandwidths at 7T: 400, 690, and 1020 Hz/pixel, and one at 3T: 400 Hz/pixel), T2 SPACE, and T2 SPACE FLAIR acquisitions. An additional GRE field map was acquired on both scanners using a multi-echo GRE sequence. Custom Matlab code was used to perform additional distortion correction of the images using the unwrapped field maps. Fiducial localization was performed with 3D Slicer, with absolute fiducial positioning errors determined in phantom experiments following rigid registration to the CT images. For human experiments, 3T and 7T images were registered and relative differences in fiducial locations were compared using two-tailed paired t-tests.Phantom measurements at 7T yielded gradient distance scaling errors of 1.1%, 2.2%, and 1.0% along the x-, y-, and z-axes, respectively. These system miscalibrations were traced back to phantom manufacturing deviations in the sphericity of the vendor's gradient calibration phantom. Correction factors along each gradient axis were applied, and afterward, geometric distortions of less than 1 mm were obtained in the 7T MR head phantom images for the 1020 Hz/pixel bandwidth MPRAGE sequence. For the human subjects, four fiducial locations were excluded from the analysis due to patient positioning differences. Differences between 3T and 7T MPRAGE with low/medium/high bandwidth were 2.2 /2.6/2.3 mm, respectively, before the correction, reducing to 1.6/1.3/1.0 mm after the correction (p 0.001). T2 SPACE and T2 SPACE FLAIR yielded a similar pattern when the correction was applied, decreasing from 2.1 to 0.8 mm, and 2.6 to 1.0 mm, respectively.7T MRI can be used to perform frameless presurgical planning with skin-adhesive fiducials. Geometric distortions can be reduced to a clinically relevant level (errors ∼1 mm) with no significant susceptibility-related distortions, by using high receiver bandwidth, ensuring gradients are properly calibrated, and placing skin fiducials in areas where distortions from patient positioning are minimal.

OBJECTIVE: The objective of this study was to investigate both the long-term and short-term impact of high fat diet (HFD) or high sucrose diet (HSD) on the normal diurnal pattern of cognitive function, protein expression, and the molecular clock in mice. METHODS: This study utilized both 6-month and 4-week feeding strategies by providing male, C57BL/6J mice access to either standard chow, HFD, or HSD. Spatial working memory and synaptic plasticity were assessed during both day and night, and hippocampal tissue was measured for changes in NMDA and AMPA receptor subunits (GluN2B, GluA1) as well as molecular clock gene expression. RESULTS: HFD and HSD both disrupted normal day-night fluctuations in spatial working memory and synaptic plasticity. Mice fed HFD altered their food intake to consume more calories during the day. Both diets disrupted normal hippocampal clock gene expression, and HFD reduced GluN2B in hippocampal tissue. CONCLUSIONS: Taken together, these results suggest that HFD and HSD induce a loss of day/night performance in spatial working memory and synaptic plasticity as well as triggering a cascade of changes including disruption to the hippocampal molecular clock.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

We discuss alternative estimators of the population total given a dual-frame random-digit-dial (RDD) telephone survey in which samples are selected from landline and cell phone sampling frames. The estimators are subject to sampling and nonsampling errors. To reduce sampling variability when an optimum balance of landline and cell phone samples is not feasible, we develop an application of shrinkage estimation. We demonstrate the implications for survey weighting of a differential nonresponse mechanism by telephone status. We illustrate these ideas using data from the National Immunization Survey-Child, a large dual-frame RDD telephone survey sponsored by the Centers for Disease Control and Prevention and conducted to measure the vaccination status of American children aged 19 to 35 months.

Multiple direct-acting antiviral (DAA)-based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post-treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

In this review of individual patient expanded-access requests to the Center for Drug Evaluation and Research for the period Fiscal Year 2010 to Fiscal Year 2014, we evaluated the number of applications received and the number allowed to proceed. We also evaluated whether drugs and certain biologics obtained under expanded access went on to be approved by the Food and Drug Administration. Finally, we considered concerns that adverse events occurring during expanded access might place sponsors at risk for legal liability. Overall, 98% of individual patient expanded-access requests were allowed to proceed. During the study period, among drugs without a previous approval for any indication or dosage form, 24% of unique drugs (ie, multiple applications for access to the same drug were considered to relate to 1 unique drug), and 20% of expanded-access applications received marketing approval by 1 year after initial submission; 43% and 33%, respectively, were approved by 5 years after initial submission. A search of 3 legal databases and a database of news articles did not appear to identify any product liability cases arising from the use of a product in expanded access. Our analyses seek to give physicians and patients a realistic perspective on the likelihood of a drug's approval as well as certain information regarding the product liability risks for commercial sponsors when providing expanded access to investigational drugs. The US Food and Drug Administration (FDA)'s expanded-access program maintains a careful balance between authorizing patient access to potentially beneficial drugs and protecting them from drugs that may have unknown risks. At the same time, the agency wishes to maintain the integrity of the clinical trials process, ultimately the best way to get safe and effective drugs to patients.

The overlapping roles of the predominant Notch receptors in vascular smooth muscle cells, Notch2 and Notch3, have not been clearly defined in vivo. In this study, we use a smooth muscle-specific deletion of Notch2 together with a global Notch3 deletion to produce mice with combinations of mutant and wild-type Notch2/3 alleles in vascular smooth muscle cells. Mice with complete loss of Notch3 and smooth muscle-expressed Notch2 display late embryonic lethality and subcutaneous hemorrhage. Mice without smooth muscle-Notch2 and only one wild-type copy of Notch3 die within one day of birth and present with vascular defects, most notably patent ductus arteriosus (DA) and aortic dilation. These defects were associated with decreased expression of contractile markers in both the DA and aorta. These results demonstrate that Notch2 and Notch3 have overlapping roles in promoting development of vascular smooth muscle cells, and together contribute to functional closure of the DA.

Pretreating lignocellulosic biomass with certain ionic liquids results in structural and chemical changes that make the biomass more digestible by enzymes. In this study, pine wood was pretreated with 1-ethyl-3-methylimidazolium chloride/acetate ([C2 mim]Cl and [C2 mim][OAc]) at different temperatures to investigate the relative importance of substrate features, such as accessible surface area, cellulose crystallinity, and lignin content, on enzymatic digestibility. The ionic liquid pretreatments resulted in glucan conversions ranging from 23% to 84% on saccharification of the substrates, with [C2 mim][OAc] being more effective than [C2 mim]Cl. The pretreatments resulted in no delignification of the wood, some loss of cellulose crystallinity under certain conditions, and varying levels of increased surface area. Enzymatic digestibility closely correlated with accessible surface area and porosity measurements obtained using Simons' staining and thermoporosimetry techniques. Increased accessible surface area was identified as the principal structural feature responsible for the improved enzymatic digestibility.

PURPOSE To determine interobserver spatial variability in language area localization using three commonly employed language tasks. MATERIALS AND METHODS With institutional review board approval, 125 fMRI time series from 50 different clinical language cases were retrospectively reviewed by three blinded readers who selected 3-dimensional points representing the perceived center of Wernicke's and Broca's areas using three language tasks (semantic decision, SD; sentence comprehension, SC; and silent word generation, WG). Point dispersion values were then calculated using the perimeter of the 3-dimensional triangle defined by the three readers’ selections. RESULTS After resolving interobserver laterality disagreements, there was no difference in spatial variability between the three tasks (P = .069). The SD task had the fewest interobserver laterality disagreements (P = .028) and the SC task had fewer failed localizations for Broca's area (P = .050) and Wernicke's area (P = .013). CONCLUSION While there were no differences between interobserver spatial variability in language area localization between the three tasks, language task choice impacts the accuracy of fMRI language area identification because tasks vary in their rates of interobserver laterality disagreements and failed localizations. A combination of tasks including one with low laterality disagreements (eg, SD) and one with few failed localizations (eg, SC) may offer the best combination.

Plant pathogen effectors encoded by Avirulence (Avr) genes benefit the pathogen by promoting colonization and benefit plants that have a matching resistance (R) gene by constituting a signal that triggers resistance. The Hessian fly,Mayetiola destructor (Say) (Diptera: Cecidomyiidae), resembles a plant pathogen in showing R/Avr interactions. Because of these interactions, a wheat plant with the H13 resistance gene can be resistant or susceptible depending on the genotype of the larva that attacks the plant, being resistant if attack comes from a larva with a functional vH13 gene, but susceptible if attack comes froma larva with a non-functional vH13 gene. In this study we asked: does this susceptible interaction involving plants with H13 look like susceptible interactions with plants lacking H13? Possibly, the H13 plant attacked by a larva with a non-functional vH13 is induced to partial rather than complete resistance. Or the larva, lacking its vH13-encoded effector, is compromised in its ability to induce susceptibility, which includes forcing the plant to create a gall nutritive tissue. Responses of epidermal cells to larval attack were explored using imaging techniques (light microscopy, scanning and transmission electron microscopy). Whole-organism responses were investigated by measuring the growth of plants and larvae.No evidence was found for partial resistance responses by H13 plants or for a compromise in the ability of vH13 loss-of-function larvae to induce susceptibility. It appears that disrupting vH13 function is sufficient for overcoming the induced resistance mediated by the H13 gene.

Regulator of G-protein signaling-10 (RGS10) is a GTPase activating protein for Gαi/q/z subunits that is highly expressed in the immune system and in a broad range of brain regions including the hippocampus, striatum, dorsal raphe, and ventral midbrain. Previously, we reported that RGS10-null mice display increased vulnerability to chronic systemic inflammation-induced degeneration of nigral dopaminergic (DA) neurons. Given that RGS10 is expressed in DA neurons, we investigated the extent to which RGS10 regulates cell survival under conditions of inflammatory stress. Because of the inherent limitations associated with use of primary DA neurons for biochemical analyses, we employed a well-characterized ventral mesencephalon DA neuroblastoma cell line (MN9D) for our studies. We found that stable over-expression of RGS10 rendered them resistant to TNF-induced cytotoxicity; whereas MN9D cells expressing mutant RGS10-S168A (which is resistant to phosphorylation by protein kinase A at a serine residue that promotes its nuclear translocation) showed similar sensitivity to TNF as the parental MN9D cells. Using biochemical and pharmacologic approaches, we identified protein kinase A and the downstream phospho-cAMP response element-binding signaling pathway (and ruled out ERK 1/2, JNK, and NFkB) as key mediators of the neuroprotective effect of RGS10 against inflammatory stress.

The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents.

A cDNA clone encoding the lignin-related enzyme caffeoyl CoA 3-O-methyltransferase (CCoAOMT) was isolated from a Pinus radiata cDNA library derived from differentiating xylem. Suppression of PrCCoAOMT expression in P. radiata tracheary element cultures affected lignin content and composition, resulting in a lignin polymer containing p-hydroxyphenyl (H), catechyl (C) and guaiacyl (G) units. Acetyl bromide-soluble lignin assays revealed reductions in lignin content of up to 20% in PrCCoAOMT-deficient transgenic lines. Pyrolysis-GC/MS and 2D-NMR studies demonstrated that these reductions were due to depletion of G-type lignin. Correspondingly, the proportion of H-type lignin in PrCCoAOMT-deficient transgenic lines increased, resulting in up to a 10-fold increase in the H/G ratio relative to untransformed controls. 2D-NMR spectra revealed that PrCCoAOMT suppression resulted in formation of benzodioxanes in the lignin polymer. This suggested that phenylpropanoids with an ortho-diphenyl structure such as caffeyl alcohol are involved in lignin polymerization. To test this hypothesis, synthetic lignins containing methyl caffeate or caffeyl alcohol were generated and analyzed by 2D-NMR. Comparison of the 2D-NMR spectra from PrCCoAOMT-RNAi lines and synthetic lignins identified caffeyl alcohol as the new lignin constituent in PrCCoAOMT-deficient lines. The incorporation of caffeyl alcohol into lignin created a polymer containing catechyl units, a lignin type that has not been previously identified in recombinant lignin studies. This finding is consistent with the theory that lignin polymerization is based on a radical coupling process that is determined solely by chemical processes.

Questions: Does tree establishment: (1) occur at a treeline depressed by fire, (2) cause the forest line to ascend upslope, and/or (3) alter landscape heterogeneity? (4) What abiotic and biotic local site conditions are most important in structuring establishment patterns? (5) Does the abiotic setting become more important with increasing upslope distance from the forest line? Location: Western slopes of Mount Rainier, USA. Methods: We performed classification analysis of 1970 satellite imagery and 2003 aerial photography to delineate establishment. Local site conditions were calculated from a LIDAR-based DEM, ancillary climate data, and 1970 tree locations in a GIS. We used logistic regression on a spatially weighted landscape matrix to rank variables. Results: Considerable establishment after 1970 caused forest line elevation to increase over 150 m in specific locations. Landscape heterogeneity increased with distance from the 1970 forest line. At a broad spatial context, we found establishment was most common near existing trees (0-50 m) and at low elevations (1250-1350 m). Slope aspect (W, NW, N, NE, and E), slope angle (40-60°), and other abiotic factors emerged as important predictors of establishment with increasing upslope distance from the forest line to restricted spatial extents. Conclusions: Favorable climatic conditions likely triggered widespread tree establishment. Readily available seed probably enhanced establishment rates near sexually mature trees, particularly in the less stressful environment at low elevations. The mass effect of nearly ubiquitous establishment in these areas may have obscured the importance of the abiotic setting to restricted spatial extents. Topographic variability apparently produced favorable sites that facilitated opportunistic establishment with increasing upslope distance from the forest line, thereby enabling additional trees to invade the alpine tundra.

Clients tend to have better treatment outcomes when more counseling sessions (Fiorentine and Anglin 1996, 1997) and case management services (McLellan et al. 1999) are provided and when counselor caseloads are low (McCaughrin and Price 1992; Woodward et al. 2006). While the ideal is to provide appropriate personal contact hours and lower client-to-counselor ratios, programs experience pressures from funding sources and monitoring organizations to do more with less, and cuts are often made in personnel and in nonsubstance abuse specific services (Hubbard et al. 1989; Etheridge et al. 1995). When treatment providers must make do with fewer personnel, the number of counseling sessions available to clients may decrease, and counselors may be required to take on more clients in groups, further impacting personal contact between counselors and clients. Viewing a treatment program as an “open system”—that is, it is not completely self-sufficient, but interacts with its environment (see Pfeffer and Salancik 1978)—provides a framework for understanding the way counselor–client contact is structured. Specifically, the external environment can be a source of uncertainty and a source of resources, which can shape decisions about programs' internal organization and management (Robey and Sales 1994). Accrediting bodies are one such external force, promoting high-quality programming as assessed by an independent, external group. Guidelines applied by accrediting bodies reflect important aspects of treatment, including the frequency of sessions, types of services provided, and amount of direct contact with staff. For instance, accredited agencies provide more treatment hours (Lemak and Alexander 2005), and are more likely than nonaccredited programs to provide mental health (Friedmann, Alexander, and D'Aunno 1999) and medical services (Durkin 2002). An equally important element of a program's environment is its clientele. Clients with different needs may require different treatment plans (National Institute on Drug Abuse 1999), and appropriate services will often be negotiated as part of referral and contract decisions. Programs that admit clients with distinctive needs are more likely to provide specialized services (Olmstead, White, and Sindelar 2004), including case management, which has been found to be predictive of positive posttreatment outcomes (McLellan et al. 1999). Likewise, having a high proportion of criminal justice (CJ) clients can prompt modifications in the way counselors utilize their time with clients. The number of CJ referrals to community-based treatment programs is increasing (Office of Applied Studies 2004), and are often accompanied by funds and mandates. Thus, programs may alter services to meet expectations of CJ referral sources. Program ownership also has implications for contact. Generally speaking, public programs tend to provide more supplemental services than do privately owned programs (Friedmann, Alexander, and D'Aunno 1999; Rogers and Barnett 2000), and the for-profits tend to offer fewer medical and social services (Friedmann, Alexander, and D'Aunno 1999). Lemak and Alexander (2005) found that public programs tend to have higher caseloads, but did not find an association between ownership and counseling hours. It appears that publicly owned programs offer a wider range of supplemental services with fewer staff (as evidenced by higher caseloads) than their privately owned counterparts. Whether or not ownership is associated with counseling hours is unclear. Factors that are internal to the program, reflecting its specific design and operations, are also relevant to understanding counselor–client contact. Programs that are part of a larger “parent” organization often can shift staff from one location to another within the organization to respond to client needs or market demands, or hire specialized personnel who work part-time at multiple locations (Davis-Blake and Uzzi 1993). For these reasons, operating within a parent organization is associated with greater service provision (Durkin 2002), particularly with regard to medical and mental health services (Friedmann, Alexander, and D'Aunno 1999). Affiliation with a mental health center is related to providing more counseling hours and offering smaller caseloads (Lemak and Alexander 2005). However, programs affiliated with a parent organization also tend to serve more clients (Substance Abuse and Mental Health Services Administration 2003). Turnover among staff is a significant problem in substance abuse treatment programs (e.g., Alcoholism & Drug Abuse Weekly 2002; Gurel et al. 2005), and staff changes can have implications for conducting clinical activities. The amount of counselor–client contact can be quite different in programs where the majority of counselors are new to the organization, compared with those where counselors have been with the program for several years. When a counselor quits or is terminated, his or her caseload must be redistributed among staff, resulting in higher caseloads until the position is filled. Time spent locating, hiring, and training replacement or new staff may result in a temporary disruption in contact. The current study extends the existing literature by using a naturalistic design to examine structural correlates of counselor–client contact in outpatient (nonmethadone) substance abuse treatment programs, while simultaneously controlling for geographical differences. Specific aspects of the external environment and internal organization are expected to predict counselor–client contact.

One of the numerous regulatory functions of the Food and Drug Administration (FDA) is the evaluation of drug-drug interactions and the determination of appropriate dose adjustments, if necessary, to ensure the safe and effective use of medications. The FDA considers several data sources when determining the significance of drug-drug interactions. The majority of dose adjustment recommendations are based on specific drug-drug interactions studies. The FDA reviews individual patient pharmacokinetic and safety data from drug interaction studies, determines appropriate dose adjustments, and provides recommendations to update the respective product labeling. Sometimes literature references are submitted to the FDA to support dosing recommendations. Determining an appropriate dose adjustment recommendation based on literature reports is a challenge for the FDA due to the lack of individual patient pharmacokinetic or safety data from these studies. Recently, the FDA encountered a challenging regulatory situation when evaluating literature reports to determine the appropriate dose of efavirenz and rifampin. Although numerous studies were found in the literature about this combination, a dosing recommendation cannot be concluded from the reported data. This article reviews the process the FDA used to evaluate literature to support potential dose adjustments for efavirenz when coadministered with rifampin and the challenges encountered during the process.

The relationship between personal religiousness and substance abuse treatment outcomes has emerged as an important issue in the public health arena. Using the "moral community" perspective, a conceptual framework developed by Stark, Kent, and Doyle (1982) to analyze the contextual effects of religion, we explore the degree to which religion influences two drug treatment outcome measures-critical retention and commitment to treatment. The data are derived from the Drug Abuse Treatment Outcome Studies (DATOS), a national study of 10,010 clients enrolled in 70 drug treatment programs. Three research questions were addressed: (1) What is the relationship between an individual's level of religiosity and retention in treatment and commitment to treatment? (2) How does the ecological context of treatment programs shape the individual-level relationships ? (3) To what extent are program practices and characteristics directly linked to outcome level? The findings are supportive of the literature that shows a weak to moderate relationship between religiosity and treatment outcomes. However, the findings did not show strong support for the "moral community" hypothesis. Although there was a wide variation in the size of the individual-level religiosity-treatment correlations, the variation could not be conclusively attributed to the overall religious emphasis of the programs. The findings suggest that further research is needed in order to understand fully the role of religion in substance abuse treatment.

Ice storms (major freezing rain events) periodically disturb forests in eastern North America. The damage may vary spatially, especially in complex terrain. This study uses satellite imagery to investigate spatial heterogeneity of forest damage caused by ice storms that affected the Appalachian Mountains, Virginia during 1994. The results display a region-scale (southwest-to-northeast) gradient in damage that apparently corresponds to a gradient in the depth of ice that accumulated during the storms. Damage also varied topographically, particularly by aspect. Damage was most extensive on east-, southeast- and south-facing slopes; at middle elevations; and on slopes of moderate steepness.

Recent studies in our lab identified a mutant mouse model of obstructive nephropathy designated mgb for megabladder. Homozygotic mgb mice (mgb−/−) develop lower urinary tract obstruction in utero due to a lack of bladder smooth muscle differentiation. This defect is the result of a random transgene insertion/translocation into chromosomes 11 and 16. Transcriptional profiling identified a significantly over-expressed cluster of gene products located on the translocated fragment of chromosome 16 including urotensin II-related peptide (Urp), which was shown to be preferentially over-expressed in developing mgb−/− bladders. Pathway analysis of mgb microarray data indicated dysregulation of at least 60 gene products associated with smooth muscle development. In conclusion, the results of this study indicate that the molecular pathways controlling normal smooth muscle development are severely altered in mgb−/− bladders, and provide the first evidence that Urp may play a critical role in bladder smooth muscle development. Developmental Dynamics 237:170–186, 2008. © 2007 Wiley-Liss, Inc.

Amphetamines and their methylenedioxy derivatives generically display similar behavioral, physiologic and toxic effects. Inconsistent pharmacokinetic and toxicity data for methylenedioxymethamphetamine (MDMA) may suggest that active drug transporters are interacting with these compounds, and thus altering drug absorption and tissue distribution. In vitro models of CNS accumulation and intestinal drug transport were used to assess efflux transport of MDMA. Madin-Darby kidney cell epithelial (MDCK) monolayers displayed a 4-fold increase in accumulation in the basolateral to apical orientation relative to the apical to basolateral orientation, although no differential accumulation was noted between MDCK-WT and MDCK-MDR1 monolayers. Caco-2 monolayers demonstrated an approximate 2-fold increase in accumulation of MDMA. Exposure of various inhibitors of active drug transporters demonstrated mixed results; ritonavir, progesterone and indomethacin produced an approximately 50% reduction of MDMA transport, while verapamil, MK-571 and probenecid had no effect. Based on these data, it is concluded that MDMA efflux is mediated via the activity of a transporter distinct from P-glycoprotein. The possible inhibitory effects of amphetamines on rhodamine-123 transport were also assessed. MDMA, methylenedioxyamphetamine, amphetamine and methamphetamine, at physiologically relevant concentrations, did not significantly alter the transport of rhodamine-123 in Caco-2 monolayers or the LS180 cell line, suggesting that these compounds do not alter the function of P-glycoprotein.