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Abstract Background To describe how frequently harm is reported in the abstract of high impact factor medical journals. Methods Design and population: We carried out a blinded structured review of a random sample of 363 Randomised Controlled Trials (RCTs) carried out on human beings, and published in high impact factor medical journals in 2003. Main endpoint: 1) Proportion of articles reporting harm in the abstract; and 2) Proportion of articles that reported harm in the abstract when harm was reported in the main body of the article. Analysis: Corrected Prevalence Ratio (cPR) and its exact confidence interval were calculated. Non-conditional logistic regression was used. Results 363 articles and 407 possible comparisons were studied. Overall, harm was reported in 135 abstracts [37.2% (CI95%:32.2 to 42.4)]. Harm was reported in the main text of 243 articles [66.9% (CI95%: 61.8 to 71.8)] and was statistically significant in 54 articles [14.9% (CI95%: 11.4 to 19.0)]. Among the 243 articles that mentioned harm in the text, 130 articles [53.5% (CI95% 47.0 to 59.9)] reported harm in the abstract; a figure that rose to 75.9% (CI95%: 62.4 to 86.5) when the harm reported in the text was statistically significant. Harm in the abstract was more likely to be reported when statistically significant harm was reported in the main body of the article [cPR = 1.70 (CI95% 1.47 to 1.92)] and when drug companies (not public institutions) funded the RCTs [cPR = 1.29 (CI95% 1.03 to 1.67)]. Conclusion Abstracts published in high impact factor medical journals underreport harm, even when harm is reported in the main body of the article.

Histone deacetylase 3 (Hdac3) is an epigenetic regulator of gene expression and interacts with skeletal transcription factors such as Runx2. We previously reported that conditional deletion of Hdac3 in Osterix-Cre recombinase-expressing osteoprogenitor cells (Hdac3 CKOOsx) caused osteopenia and increased marrow adiposity, both hallmarks of skeletal aging. We also showed that Runx2+ cells within osteogenic cultures of Hdac3-depleted bone marrow stromal cells (BMSCs) contain lipid droplets (LDs). Cellular senescence, a nonproliferative metabolically active state, is associated with increased marrow adiposity, bone loss, and aging. In this study, we sought to determine if Hdac3 depleted Runx2+ pre-osteoblasts from young mice exhibit chromatin changes associated with early cellular senescence and how these events correlate with the appearance of LDs. We first confirmed that BMSCs from Hdac3 CKOOsx mice have more Runx2 + LD+ cells compared with controls under osteogenic conditions. We then measured senescence-associated distention of satellite (SADS) DNA and telomere-associated foci (TAFs) in Hdac3 CKOOsx and control BMSCs. In situ, Runx2+ cells contained more SADS per nuclei in Hdac3 CKOOsx femora than in controls. Runx2+ BMSCs from Hdac3 CKOOsx mice also contained more SADS and TAFs per nuclei than Runx2+ cells from age-matched control mice in vitro. SADs and TAFs were present at similar levels in Runx2 + LD+ cells and Runx2 + LD- cells from Hdac3 CKOOsx mice. Hdac inhibitors also increased the number of SADS in Runx2 + LD+ and Runx2 + LD- WT BMSCs. Senolytics reduced viable cell numbers in Hdac3 CKOOsx BMSC cultures. These data demonstrate that the depletion of Hdac3 in osteochondral progenitor cells triggers LD formation and early events in cellular senescence in Runx2+ BMSCs through mutually exclusive mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Karl Friston's free-energy principle casts agents as self-evidencing through active inference. This implies that decision-making, planning and information-seeking are, in a generic sense, 'wishful'. We take an interdisciplinary perspective on this perplexing aspect of the free-energy principle and unpack the epistemological implications of wishful thinking under the free-energy principle. We use this epistemic framing to discuss the emergence of biases for self-evidencing agents. In particular, we argue that this elucidates an optimism bias as a foundational tenet of self-evidencing. We allude to a historical precursor to some of these themes, interestingly found in Machiavelli's oeuvre, to contextualise the universal optimism of the free-energy principle.

While causal reasoning is a core facet of our cognitive abilities, its time-course has not received proper attention. As the duration of reasoning might prove crucial in understanding the underlying cognitive processes, we asked participants in two experiments to make probabilistic causal inferences while manipulating time pressure. We found that participants are less accurate under time pressure, a speed-accuracy-tradeoff, and that they respond more conservatively. Surprisingly, two other persistent reasoning errors-Markov violations and failures to explain away-appeared insensitive to time pressure. These observations seem related to confidence: Conservative inferences were associated with low confidence, whereas Markov violations and failures to explain were not. These findings challenge existing theories that predict an association between time pressure and all causal reasoning errors including conservatism. Our findings suggest that these errors should not be attributed to a single cognitive mechanism and emphasize that causal judgements are the result of multiple processes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kolvoort et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) chloride in DMSO were developed using an ultrasound bath to improve reaction homogeneity and mixing. A range of (hetero)aryl sulfonamides bearing a selection of functional groups were prepared, and the mechanism of the transformation was investigated. These investigations have led us to propose the formation of nitrosoarene intermediates, which were established via an independent molecular coupling strategy.

Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKCδ -/- mice displayed reduced tumor progression compared to wild types, with increased response to anti-PD-1. Tumors from PKCδ -/- mice demonstrated T H 1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKCδ -/- mice. Coinjection of PKCδ -/- M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKCδ +/+ controls. PKCδ deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram MPs to augment ICB efficacy.

GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation., (© 2023. Springer Nature Limited.)

Since Tversky argued that similarity judgments violate the three metric axioms, asymmetrical similarity judgments have been particularly challenging for standard, geometric models of similarity, such as multidimensional scaling. According to Tversky, asymmetrical similarity judgments are driven by differences in salience or extent of knowledge. However, the notion of salience has been difficult to operationalize, especially for perceptual stimuli for which there are no apparent differences in extent of knowledge. To investigate similarity judgments between perceptual stimuli, across three experiments, we collected data where individuals would rate the similarity of a pair of temporally separated color patches. We identified several violations of symmetry in the empirical results, which the conventional multidimensional scaling model cannot readily capture. Pothos et al. proposed a quantum geometric model of similarity to account for Tversky's findings. In the present work, we extended this model to a more general framework that can be fit to similarity judgments. We fitted several variants of quantum and multidimensional scaling models to the behavioral data and concluded in favor of the quantum approach. Without further modifications of the model, the best-fit quantum model additionally predicted violations of the triangle inequality that we observed in the same data. Overall, by offering a different form of geometric representation, the quantum geometric framework of similarity provides a viable alternative to multidimensional scaling for modeling similarity judgments, while still allowing a convenient, spatial illustration of similarity., (© 2023 Cognitive Science Society LLC.)

People historically excluded from receiving medical care in the United States, in addition to being at greater risk for SARS-CoV-2 infection, have had slower vaccine uptake due to structural barriers to availability. We present one student-run free clinic's SARS-CoV-2 vaccination program from January 15 to August 1, 2021, in Nashville, Tennessee. We tracked SARS-CoV-2 vaccine primary series completion among 273 free clinic patients with the help of medical student volunteers, who scheduled appointments and answered vaccine-related questions. We worked with our academic medical center partner to host a single-dose vaccination event at our clinic. We compared vaccine series completion in our clinic to adult vaccine completion in Davidson County, Tennessee on August 1, 2021. Of the 273 free clinic participants, 144 identified as Spanish-speaking (52.7%) and 172 (63%) had at least one qualifying comorbidity per the December 30, 2020, Tennessee COVID-19 Vaccination Plan. As such, 183 (67%) were characterized as vaccine eligible in Phase 1a2, 1b, or 1c. On August 1, 2021, 63.1% of free clinic patients had completed their primary SARS-CoV-2 vaccination series compared with 58.9% of adults in Davidson County, Tennessee (RD 4.2%, 95% CI: -1.5% to 9.9%). Spanish-speaking free clinic patients were most likely to have completed their vaccination series. We describe a framework for a patient-centered vaccination effort to reach individuals traditionally missed by large vaccination campaigns. We highlight structural hurdles experienced by vulnerable populations, including language barriers, lack of technology or reliable internet access, inflexible working schedules, lack of transportation, and vaccine misinformation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [ 18 F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [ 64 Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [ 68 Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [ 64 Cu]Cu-DOTATATE and [ 18 F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [ 64 Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUV max 1.3, IQR, 1.2-1.4, N = 4) and remote myocardium (SUV max 0.7, IQR, 0.5-0.8, N = 4, p = 0.0286), and with respect to controls (SUV max 0.6, IQR, 0.5-0.7, N = 4, p = 0.0286), than [ 18 F]F-FDG PET. In atherosclerotic mice, [ 64 Cu]Cu-DOTATATE PET aortic signal, but not [ 18 F]F-FDG PET, was higher compared to controls (SUV max 1.1, IQR, 0.9-1.3 and 0.5, IQR, 0.5-0.6, respectively, N = 4, p = 0.0286). In both models, [ 64 Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [ 18 F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [ 68 Ga]Ga-DOTATATE and [ 18 F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [ 68 Ga]Ga-DOTATATE and [ 18 F]F-FDG in atherosclerotic (SUV max 0.415, IQR, 0.338-0.499, N = 32 and 0.446, IQR, 0.387-0.536, N = 27, respectively) compared to control animals (SUV max 0.253, IQR, 0.197-0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299-0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [ 18 F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [ 18 F]F-FDG., (© 2022. The Author(s).)

Previously either regarded as insignificant or feared as potential sources of infection, the bacteria living on our skin are increasingly recognized for their role in benefitting human health. Skin commensals modulate mucosal immune defenses and directly interfere with pathogens; however, their contribution to the skin's physical integrity is less understood. Here, we show that the abundant skin commensal Staphylococcus epidermidis contributes to skin barrier integrity. S. epidermidis secretes a sphingomyelinase that acquires essential nutrients for the bacteria and assists the host in producing ceramides, the main constituent of the epithelial barrier that averts skin dehydration and aging. In mouse models, S. epidermidis significantly increases skin ceramide levels and prevents water loss of damaged skin in a fashion entirely dependent on its sphingomyelinase. Our findings reveal a symbiotic mechanism that demonstrates an important role of the skin microbiota in the maintenance of the skin's protective barrier., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

T cell metabolism is dynamic and highly regulated. While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns, the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways. T cells must function in a wide variety of tissue settings, and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance. Both in inflamed and cancer tissues, a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity. These include fever and increased temperatures, depletion of critical micro and macro-nutrients, and accumulation of inhibitory waste products. Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity., (© 2022. The Author(s), under exclusive licence to CSI and USTC.)

Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor β (LXRβ) as the target. Binding of the small molecule ligand stabilized LXRβ, as shown by cellular thermal shift assay (CETSA). In addition, we identified a probe-modified peptide by mass spectrometry and proposed a model where the photoaffinity probe is bound in the ligand-binding pocket of LXRβ. Taken together, our findings demonstrated that the lead chemical matter bound directly to LXRβ, and our results highlight the power of chemical proteomic approaches to identify the target of a phenotypic screening hit. Additionally, the LXR photoaffinity probe and lead compound described herein may serve as valuable tools to further evaluate the LXR pathway., Competing Interests: Declaration of Interests All authors of this manuscript are (or were at the time of their involvement with the apoE project) employees of Pfizer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP 10 -HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP 10 -HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP 10 -HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs., Competing Interests: Declaration of Interests W.J.M.M., L.A.B.J., J.O., Z.A.F., and M.G.N. are scientific co-founders of and have equity in Trained Therapeutix Discovery. W.J.M.M. and Z.A.F. have consulting agreements with Trained Therapeutix Discovery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Herein we describe the 2,2,2-trifluoroethoxy group as an alternative leaving group for hydrolytically unstable heteroaryl chlorides. This group provides improved shelf stability by years while maintaining reactivity toward nucleophiles in S N Ar reactions. A highlighted trifluoroethyl ether was shown to be tolerant to aqueous Suzuki conditions, permitting sequential Suzuki/S N Ar processes inaccessible to the heterocyclic chlorides. The strategic use of trifluoroethyl ethers enables storage of otherwise unstable heterocyclic chlorides and limits costly decomposition.

Probiotic nutrition is frequently claimed to improve human health. In particular, live probiotic bacteria obtained with food are thought to reduce intestinal colonization by pathogens, and thus to reduce susceptibility to infection. However, the mechanisms that underlie these effects remain poorly understood. Here we report that the consumption of probiotic Bacillus bacteria comprehensively abolished colonization by the dangerous pathogen Staphylococcus aureus in a rural Thai population. We show that a widespread class of Bacillus lipopeptides, the fengycins, eliminates S. aureus by inhibiting S. aureus quorum sensing-a process through which bacteria respond to their population density by altering gene regulation. Our study presents a detailed molecular mechanism that underlines the importance of probiotic nutrition in reducing infectious disease. We also provide evidence that supports the biological significance of probiotic bacterial interference in humans, and show that such interference can be achieved by blocking a pathogen's signalling system. Furthermore, our findings suggest a probiotic-based method for S. aureus decolonization and new ways to fight S. aureus infections.

The Staphylococcus aureus enterotoxins are a superfamily of secreted virulence factors that share structural and functional similarities and possess potent superantigenic activity causing disruptions in adaptive immunity. The enterotoxins can be separated into two groups; the classical (SEA-SEE) and the newer (SEG-SE l Y and counting) enterotoxin groups. Many members from both these groups contribute to the pathogenesis of several serious human diseases, including toxic shock syndrome, pneumonia, and sepsis-related infections. Additionally, many members demonstrate emetic activity and are frequently responsible for food poisoning outbreaks. Due to their robust tolerance to denaturing, the enterotoxins retain activity in food contaminated previously with S. aureus . The genes encoding the enterotoxins are found mostly on a variety of different mobile genetic elements. Therefore, the presence of enterotoxins can vary widely among different S. aureus isolates. Additionally, the enterotoxins are regulated by multiple, and often overlapping, regulatory pathways, which are influenced by environmental factors. In this review, we also will focus on the newer enterotoxins (SEG-SE l Y), which matter for the role of S. aureus as an enteropathogen, and summarize our current knowledge on their prevalence in recent food poisoning outbreaks. Finally, we will review the current literature regarding the key elements that govern the complex regulation of enterotoxins, the molecular mechanisms underlying their enterotoxigenic, superantigenic, and immunomodulatory functions, and discuss how these activities may collectively contribute to the overall manifestation of staphylococcal food poisoning.

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 ( 2 ) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery., Competing Interests: The authors declare no competing financial interest.

Hoarseness is a common presentation in primary care practices. Combined with other voice-related changes, it falls under the umbrella diagnosis of dysphonia. Hoarseness has a number of causes, ranging from simple inflammatory processes to less common psychiatric disorders to more serious systemic, neurologic, or cancerous conditions. Medication-induced hoarseness is common and should be considered. The initial evaluation begins with a targeted history and physical examination, while also looking for signs of potential systemic etiologies. Treatment should begin with voice rest, especially avoidance of whispering, and conservative management directed toward a presumptive cause. For example, proton pump inhibitors are appropriate for hoarseness due to reflux, and proper vocal hygiene is recommended for vocal abuse-related indications. In the absence of a clear indication, antibiotics, oral corticosteroids, and proton pump inhibitors should not be used for the empiric treatment of hoarseness. Direct visualization of the larynx and vocal folds, commonly mislabeled as vocal cords, should be performed within three months if an etiology has not been determined or if conservative management has been ineffective. Patients who experience symptoms lasting longer than two weeks and who have risk factors for dysplasia (e.g., tobacco use, heavy alcohol use, hemoptysis) may require earlier laryngoscopic evaluation. Voice therapy is effective for improving voice quality in patients with dysphonia if conservative measures are unsuccessful, and it can also be helpful for prophylaxis in high-risk individuals (e.g., vocalists, public speakers). Surgical management is indicated for laryngeal or vocal fold dysplasia or malignancy, airway obstruction, or benign pathology resistant to conservative treatment.

Bacterial sepsis is a major killer in hospitalized patients. Coagulase-negative staphylococci (CNS) with the leading species Staphylococcus epidermidis are the most frequent causes of nosocomial sepsis, with most infectious isolates being methicillin-resistant. However, which bacterial factors underlie the pathogenesis of CNS sepsis is unknown. While it has been commonly believed that invariant structures on the surface of CNS trigger sepsis by causing an over-reaction of the immune system, we show here that sepsis caused by methicillin-resistant S. epidermidis is to a large extent mediated by the methicillin resistance island-encoded peptide toxin, PSM-mec. PSM-mec contributed to bacterial survival in whole human blood and resistance to neutrophil-mediated killing, and caused significantly increased mortality and cytokine expression in a mouse sepsis model. Furthermore, we show that the PSM-mec peptide itself, rather than the regulatory RNA in which its gene is embedded, is responsible for the observed virulence phenotype. This finding is of particular importance given the contrasting roles of the psm-mec locus that have been reported in S. aureus strains, inasmuch as our findings suggest that the psm-mec locus may exert effects in the background of S. aureus strains that differ from its original role in the CNS environment due to originally "unintended" interferences. Notably, while toxins have never been clearly implied in CNS infections, our tissue culture and mouse infection model data indicate that an important type of infection caused by the predominant CNS species is mediated to a large extent by a toxin. These findings suggest that CNS infections may be amenable to virulence-targeted drug development approaches., Competing Interests: The authors have declared that no competing interests exist.

Mucolipidosis Type IV (ML IV) is an autosomal recessive genetic disorder characterized by severe psychomotor impairments and ophthalmologic abnormalities. Reports on the cognitive development of people with ML IV are limited, but suggest that achievement of language and cognitive milestones varies between a 3- and 18-month level. There is also variability in reports of whether people with ML IV make developmental progress, regress, or remain static after infancy. This study examines the longitudinal development of a young child with ML IV who participated in an augmentative and alternative communication (AAC) intervention.At 26 months, the child displayed significant developmental delays on direct assessment, with the exception of a possible relative strength in receptive language. An examination of adaptive behavior over time indicated improvements in raw scores but declines in standard scores across all domains. She learned to use 13 new words with a speech generating device (SGD) by the end of intervention.These results add to literature on the clinical manifestations of ML IV and indicate that although children with this disorder have deficits in many domains, they may be most severely affected in gross motor or oral motor development and have a relative strength in receptive language. Moreover, this child made progress in all domains of adaptive functioning, but at a slower pace than typically developing children. She also gained expressive vocabulary in the AAC intervention, and this may have supported her development in other areas.

A facile protocol for the synthesis of 1,2-dibromoarenes is described. A standard ortho-lithiation/bromination procedure, when applied to bromoarenes, resulted in poor yields of the corresponding 1,2-dibromoarenes (13-62% yield). However, transmetalation of the transient aryllithium intermediate to an arylzinc species with ZnCl2, followed by bromination, resulted in dramatically improved yields of the synthetically useful 1,2-dibromoarenes (68-95% yield).

Expression of rat glucose transporter-5 (GLUT5) is tightly regulated during development. Expression and activity are low throughout the suckling and weaning stages, but perfusion of the small intestinal lumen with fructose solutions during weaning precociously enhances GLUT5 activity and expression. Little is known, however, about the signal transduction pathways involved in the substrate-induced precocious GLUT5 development. We found that wortmannin and LY-294002, inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) specifically inhibited the increase in fructose uptake rate and brush-border GLUT5 protein abundance but not GLUT5 mRNA abundance. Perfusion of EGF, an activator of PI3-kinase, also resulted in a marked wortmannin-inhibitable increase in fructose uptake. Perfusion of fructose for 4 h increased cytosolic immunostaining of phosphatidylinositol-3,4,5-triphosphate (PIP(3)), the primary product of PI3-kinase, mainly in the mid- to upper-villus regions in which the brush-border membrane also stained strongly with GLUT5. Perfusion of glucose for 4 h had little effect on fructose or glucose uptake and PIP(3) or GLUT5 staining. SH-5, an Akt inhibitor, prevented the increase in fructose uptake and GLUT5 protein induced by fructose solutions, and had no effect on glucose uptake. The PI3-kinase/Akt signaling pathway may be involved in the synthesis and/or recruitment to the brush border of GLUT5 transporters by luminal fructose in the small intestine of weaning rats. Increases in fructose transport during the critical weaning period when rats are shifting to a new diet may be modulated by several signaling pathways whose cross talk during development still needs to be elucidated.

This study was undertaken to determine if dissolution of 226Radium from pipe-scale deposits contributes to enhanced waterborne 226Radium concentrations at the point of use. Water samples were collected from residential water customers of a small rural Iowa town. Sites were evenly divided between new and old water main connections. Daily samples were collected from the point-of-entry water. Point-of-use 226Radium concentrations ranged from 0.4 to 12.9 pCi L-1 (0.01 to 0.5 Bq L-1). The mean 226 Radium concentration for homes connected to old water mains was significantly higher than the mean 226Radium concentration of homes connected to new water mains, mean(standard deviation) equal 8.3(1.1) and 5.3(0.8) pCi L-1 [0.3(1.1) and 0.2(0.8) Bq L-1], respectively. 226Radium concentrations of the point-of-entry water ranged from 5.0 pCi L-1 to 10.3 pCi L-1 (0.2 Bq L-1 to 0.4 Bq L-1). This study indicates considerable variability of 226Radium exposure from drinking water among residents of the same water supply and has implications for regulatory compliance and exposure assessment in epidemiologic studies.

Exposure to high concentrations of radon progeny (radon) produces lung cancer in both underground miners and experimentally exposed laboratory animals. To determine the risk posed by residential radon exposure, the authors performed a population-based, case-control epidemiologic study in Iowa from 1993 to 1997. Subjects were female Iowa residents who had occupied their current home for at least 20 years. A total of 413 lung cancer cases and 614 age-frequency-matched controls were included in the final analysis. Excess odds were calculated per 11 working-level months for exposures that occurred 5-19 years (WLM(5-19)) prior to diagnosis for cases or prior to time of interview for controls. Eleven WLM(5-19) is approximately equal to an average residential radon exposure of 4 pCl/liter (148 Bq/m3) during this period. After adjustment for age, smoking, and education, the authors found excess odds of 0.50 (95% confidence interval: 0.004, 1.81) and 0.83 (95% percent confidence interval: 0.11, 3.34) using categorical radon exposure estimates for all cases and for live cases, respectively. Slightly lower excess odds of 0.24 (95 percent confidence interval: -0.05, 0.92) and 0.49 (95 percent confidence interval: 0.03, 1.84) per 11 WLM(5-19) were noted for continuous radon exposure estimates for all subjects and live subjects only. The observed risk estimates suggest that cumulative ambient radon exposure presents an important environmental health hazard.

We investigated pulmonary endothelial function in vivo in 12- to 18-mo-old male Watanabe heritable hyperlipidemic (WHHL; n = 7) and age- and sex-matched New Zealand White (n = 8) rabbits. The animals were anesthetized and artificially ventilated, and the chest was opened and put in total heart bypass. The single-pass transpulmonary utilizations of the angiotensin-converting enzyme (ACE) substrate [(3)H]benzoyl-Phe-Ala-Pro (BPAP) and the 5'-nucleotidase (NCT) substrate [(14)C]AMP were estimated, and the first-order reaction parameter A(max)/K(m), where A(max) is the product of enzyme mass and the catalytic rate constant and K(m) is the Michaelis-Menten constant, was calculated. BPAP transpulmonary utilization and A(max)/K(m) were reduced in WHHL (1.69 +/- 0.16 vs. 2.9 +/- 0.44 and 599 +/- 69 vs. 987 +/- 153 ml/min in WHHL and control rabbits, respectively; P < 0.05 for both). No differences were observed in the AMP parameters. BPAP K(m) and A(max) values were estimated separately under mixed-order reaction conditions. No differences in K(m) values were found (9.79 +/- 1 vs. 9.9 +/- 1.31microM), whereas WHHL rabbit A(max) was significantly decreased (5.29 +/- 0.88 vs. 7. 93 +/- 0.8 micromol/min in WHHL and control rabbits, respectively; P < 0.05). We conclude that the observed pulmonary endothelial ACE activity reduction in WHHL rabbits appears related to a decrease in enzyme mass rather than to alterations in enzyme affinity.

A point-of-use waterborne radon-222 (222Rn) survey of a small Iowa town was performed to determine the cause of unnaturally high waterborne 222Rn concentrations in the municipality. The source of the elevated 222Rn concentrations was a newly discovered reservoir of waterborne 222Rn originating from distribution-system radium-226 (226Ra) adsorbed internal pipe scale deposits. Because the proposed national drinking water regulations for 222Rn require sampling at the origin of the distribution system rather than at the point of use, the proposed scheme for collection of water samples may not represent actual consumer waterborne 222Rn exposure in all cases.

Limited epidemiological data on acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) infection have been assembled by voluntarily reported AIDS figures, blood donor serum prevalence and high-risk sentinel population and random background population sero-prevalence studies. The HIV epidemic in South Africa can thus be shown to consist of four separate epidemics of which the heterosexual epidemic will undoubtedly constitute the major growth in this country. Intervention must be directed to shrinking the promiscuous core which sustains this epidemic by directing attention at female prostitution and limiting the reproductive rate of the epidemic by energetic and professionally directed education at an early stage of a child's school career. Sexually transmitted diseases will play a major role in the determination of the extent of the heterosexual epidemic.