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DTI-015 (BCNU in 100% ethanol) utilizes solventfacilitated perfusion for the intratumoral treatment of gliomas. The water-miscible organic solvent vehicle, ethanol, facilitates a rapid and thorough saturation of the tumor with the dissolved anticancer agent, BCNU. Rats bearing established intracranial T9 gliosarcoma tumors received no treatment (group 1), a single intratumoral injection of ethanol vehicle (group 2) or DTI-015 (5 mg/kg BCNU) (group 3), or a single intratumoral injection of DTI-015 followed by systemic BCNU (group 4). Ethanol alone (n=13) had no effect on survival; MST = 17 days compared to 18 days for untreated controls (n=35). DTI-015 (n=45) produced an I LS of 417% (MST = 93) and 472% (MST = 103) when combined with systemic BCNU (n=14). Overall, 24 of 59 rats receiving DTI-015 were judged to be cured, with 20 living a normal life span of 600 to 700 days, and 4 rats sacrificed healthy at 121, 135, 307, and 384 days post DTI-015 with no evidence of viable T9 tumor. Histology demonstrated that DTI-015 totally eradicated the T9 tumors in animals living a normal life span. The results demonstrate that a single injection of DTI-015 produces a 40% cure rate in rats bearing established intracranial T9 tumors.

Objective: This study examined the association of adolescent BMI trajectory with adult metabolic syndrome (MetSyn) and with intergenerational obesity., Methods: This study used data from the National Heart, Lung, and Blood Institute (NHLBI) Growth and Health Study (1987-1997). Data from the 20-year follow-up (2016-2019) study were included from the original participants (N = 624) and their children (N = 645). Adolescent BMI trajectories were identified using latent trajectory modeling. Mediation analysis using logistic regression models was performed to estimate confounder-adjusted odds ratios (OR) and 95% CI between adolescent BMI trajectory and adult MetSyn. Using similar methods, the association between BMI trajectory and offspring obesity was examined., Results: Latent trajectory modeling identified four patterns: "weight loss then gain" (N = 62); "persistently normal" (N = 374); "persistently high BMI" (N = 127); and "weight gain then loss" (N = 61). Women who had a persistently high BMI trajectory had twice the odds of having children who met the definition for obesity compared with the persistently normal group, adjusting for adult BMI (OR: 2.76; 95% CI: 1.39-5.46). None of the trajectory groups was associated with adult MetSyn compared with the persistently normal group., Conclusions: Intermittent adolescent obesity may not confer MetSyn risk during adulthood. However, maternal adolescent BMI trajectories that are persistently high may increase the odds of intergenerational obesity among offspring., (© 2023 The Obesity Society.)

With expanding legalization and cultural acceptance of cannabis, consumption among older adults in institutional care settings is increasing. State-by-state regulations vary widely and are evolving rapidly, adding layers of complexity to institutional policy and transitions of care. Owing to its current federal legal status, physicians cannot prescribe or dispense medical cannabis-they may only issue a recommendation for medical cannabis consumption. Furthermore, owing to the federally illicit status of cannabis, institutions accredited through the Centers for Medicare and Medicaid Services (CMS) may risk their CMS contracts if they accept cannabis in their facilities. Institutions should clarify their policy around the specific cannabis formulations approved for on-site storage and administration, including safe handling and appropriate storage. Inhalation dosage forms of cannabis require additional considerations in institutional settings, such as secondhand exposure prevention and adequate ventilation. As with other controlled substances, institutional policies to prevent diversion are essential, such as secure storage, staff procedures, and inventory documentation. Cannabis consumption should be included in patient medical histories, medication reconciliation, medication therapy management, and other evidence-based methods to reduce the risk of potential medication-cannabis interactions during transitions of care., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Although reinfections with SARS-CoV-2 have occurred in the United States with increasing frequency, U.S. epidemiologic trends in reinfections and associated severe outcomes have not been characterized. Weekly counts of SARS-CoV-2 reinfections, total infections, and associated hospitalizations and deaths reported by 18 U.S. jurisdictions during September 5, 2021-December 31, 2022, were analyzed overall, by age group, and by five periods of SARS-CoV-2 variant predominance (Delta and Omicron [BA.1, BA.2, BA.4/BA.5, and BQ.1/BQ.1.1]). Among reported reinfections, weekly trends in the median intervals between infections and frequencies of predominant variants during previous infections were calculated. As a percentage of all infections, reinfections increased substantially from the Delta (2.7%) to the Omicron BQ.1/BQ.1.1 (28.8%) periods; during the same periods, increases in the percentages of reinfections among COVID-19-associated hospitalizations (from 1.9% [Delta] to 17.0% [Omicron BQ.1/BQ.1.1]) and deaths (from 1.2% [Delta] to 12.3% [Omicron BQ.1/BQ.1.1]) were also substantial. Percentages of all COVID-19 cases, hospitalizations, and deaths that were reinfections were consistently higher across variant periods among adults aged 18-49 years compared with those among adults aged ≥50 years. The median interval between infections ranged from 269 to 411 days by week, with a steep decline at the start of the BA.4/BA.5 period, when >50% of reinfections occurred among persons previously infected during the Alpha variant period or later. To prevent severe COVID-19 outcomes, including those following reinfection, CDC recommends staying up to date with COVID-19 vaccination and receiving timely antiviral treatments, when eligible., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Germline mutations in tubulin beta class I (TUBB), which encodes one of the β-tubulin isoforms, were previously associated with neurological and cutaneous abnormalities. Here, we describe the first case of inherited bone marrow (BM) failure, including marked thrombocytopenia, morphological abnormalities, and cortical dysplasia, associated with a de novo p.D249V variant in TUBB. Mutant TUBB had abnormal cellular localisation in transfected cells. Following interferon/ribavirin therapy administered for transfusion-acquired hepatitis C, severe pancytopenia and BM aplasia ensued, which was unresponsive to immunosuppression. Acquired chromosome arm 6p loss of heterozygosity was identified, leading to somatic loss of the mutant TUBB allele., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Environmental health research produces scientific knowledge about environmental hazards crucial for public health and environmental justice movements that seek to prevent or reduce exposure to these hazards. The environment in environmental health research is conceptualized as the range of possible social, biological, chemical, and/or physical hazards or risks to human health, some of which merit study due to factors such as their probability and severity, the feasibility of their remediation, and injustice in their distribution. This paper explores the ethics of identifying the relevant environment for environmental health research, as judgments involved in defining an environmental hazard or risk, judgments of that hazard or risk's probability, severity, and/or injustice, as well as the feasibility of its remediation, all ought to appeal to non-epistemic as well as epistemic values. I illustrate by discussing the case of environmental lead, a housing-related hazard that remains unjustly distributed by race and class and is particularly dangerous to children. Examining a controversy in environmental health research ethics where researchers tested multiple levels of lead abatement in lead-contaminated households, I argue that the broader perspective on the ethics of environmental health research provided in the first part of this paper may have helped prevent this controversy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Collision tumors of the spine are extremely uncommon. Prior reports have detailed intracranial collision tumors comprising meningiomas and astrocytomas, as well as metastases to meningiomas. Spinal collision tumors are even rarer, with only 5 cases in the literature, none involving the osseous spine. In this report, we highlight the salient features of a case of lymphoma metastasis to a preexisting benign osseous hemangioma, resulting in cord compression., Case Description: An 81-year-old woman with a known typical T8 vertebral body hemangioma stable for over 6 years was evaluated for increasing back pain, new gait instability, and urinary retention. Magnetic resonance imaging showed a change in the appearance of the T8 hemangioma, with marrow replacement and new associated epidural soft tissue causing cord compression. A biopsy was performed, which showed diffuse large B-cell lymphoma within blood elements, consistent with lymphoma metastasis to a vertebral body hemangioma. The patient was treated with intravenous steroids and radiation therapy., Conclusions: Collision tumors of the spine are extremely rare. New or increasingly aggressive appearance of a previously benign spinal osseous lesion should prompt consideration for a collision tumor or malignant transformation of the benign tumor. Biopsy of the lesion should be strongly pursued whenever feasible, as the treatment strategy may vary depending on the histology of the tumor., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/aims: To report a case of Rosai-Dorfman disease (RDD) presenting as a solitary, choroidal mass, initially suspicious for uveal melanoma, in a 72-year-old woman., Methods: Retrospective case report of a single patient., Results: A 72-year-old woman presented with sudden vision loss in the right eye. A month prior, visual acuity was 20/40, but she was noted to have a choroidal mass confirmed with B-scan ultrasonography. Patient's vision deteriorated significantly a month later and a shallow retinal detachment was newly noted. Magnetic resonance imaging was obtained, demonstrating a hyperintense intraocular tumor on TI imaging. Patient underwent enucleation of the right eye for suspicion of a uveal melanoma. Pathology revealed a mixed cellular infiltrate with histiocytes, some exhibiting emperipolesis. Macrophage immunohistochemical stains were positive, while melanocytic markers were negative. A diagnosis of RDD was made. Subsequently, the patient had a negative workup for systemic involvement. A final diagnosis of intraocular RDD without extraocular and systemic involvement was determined., Conclusion: We describe a rare presentation of RDD as a solitary choroidal mass in an elderly patient with overlapping features of uveal melanoma. Definitive diagnosis could only be made on histology. RDD should be considered in the differential diagnosis of a choroidal lesion in the elderly., Competing Interests: F.F., T.R., A.J.A., D.M.F., A.R., A.W., V.L.: The authors have no conflicts of interest to disclose., (Copyright © 2019 by S. Karger AG, Basel.)

Synthetic urine (SU), which was primarily utilized by drug testing laboratories as a matrix for quality control preparations, is now commercially sold and can be used to "fool" a positive drug test. To determine if SU can pass as authentic urine, we challenged Army urine drug testing specimen accessioning and testing procedures using eight different commercial SU products. Adulteration (Sciteck AdultaCheck ® 6) and Onsite SU (Synthetic UrineCheck™) test strips were also evaluated. Five of the eight SU were identified by physical observation. All SU products screened negative in the drug immunoassay and additionally passed the specimen validity testing (SVT) as authentic urine. Furthermore, SU was not detected as adulterated with the adulteration test strips (Sciteck AdultaCheck ® 6) but was successfully detected as SU with the On-site synthetic urine (Synthetic UrineCheck™). To deter SU use, direct observation, as utilized by the military, may be recommended during the collection process., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Candida albicans is a common human fungal pathogen capable of causing serious systemic infections that can progress to become lethal. Current therapeutic approaches have limited effectiveness, especially once a systemic infection is established, in part due to the lack of an effective immune response. Boosting the immune response to C. albicans has been the goal of immunotherapy, but it has to be done selectively to prevent deleterious hyperinflammation (sepsis). Although an efficient inflammatory response is necessary to fight infection, the typical response to C. albicans results in collateral damage to tissues thereby exacerbating the pathological effects of infection. For this reason, identifying specific ways of modulating the immune system holds promise for development of new improved therapeutic approaches. This review will focus on recent studies that provide insight using mutant strains of mice that are more resistant to bloodstream infection by C. albicans . These mice are deficient in signal transduction proteins including the Jnk1 MAP kinase, the Cbl-b E3 ubiquitin ligase, or the Sts phosphatases. Interestingly, the mutant mice display a different response to C. albicans that results in faster clearance of infection without hyper-inflammation and collateral damage. A common underlying theme between the resistant mouse strains is loss of negative regulatory proteins that are known to restrain activation of cell surface receptor-initiated signaling cascades. Understanding the cellular and molecular mechanisms that promote resistance to C. albicans in mice will help to identify new approaches for improving antifungal therapy.

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD., (© 2016 Wiley Periodicals, Inc.)

The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. The authors present an exceptional case of erythroderma secondary to pre-B-cell lymphoblastic leukemia cutis, with diagnostic findings on biopsy.

Most studies regarding the neuroanatomy and neurophysiology of molluscan ctenidia have focused on isolated ctenidial tissue preparations. This study investigated how bivalve molluscs modulate their feeding rates by examining the effects of a variety of neurotransmitters, including serotonin, dopamine, and the dopamine agonist apomorphine on both isolated ctenidial tissue and in intact members of two commercially important bivalve species: the blue mussel, Mytilus edulis; and the bay scallop Argopecten irradians. In particular, we examined the effect of changes in: 1) beat of the lateral cilia (in vitro), 2) distance between ctenidial filaments and/or plicae (in vivo), and 3) diameter of the siphonal openings (in vivo) on alteration of bulk water flow through the mantle cavity. Important differences were found between isolated tissue and whole animals, and between species. Drugs that stimulated ciliary beat in vitro did not increase water processing rate in vivo. None of the treatments increased water flow through the mantle cavity of intact animals. Results suggest that A. irradians was primarily modulating lateral ciliary activity, while M. edulis appeared to have a number of ways to control water processing activity, signifying that the two species may have different compensatory and regulatory mechanisms controlling feeding activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20-25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric-onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging-immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets.

A primary cause of morbidity and mortality following cervical spinal cord injury (SCI) is respiratory compromise, regardless of the level of trauma. In particular, SCI at mid-cervical regions targets degeneration of both descending bulbospinal respiratory axons and cell bodies of phrenic motor neurons, resulting in deficits in the function of the diaphragm, the primary muscle of inspiration. Contusion-type trauma to the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. We have generated a mouse model of cervical contusion SCI that unilaterally targets both C4 and C5 levels, the location of the phrenic motor neuron pool, and have examined histological and functional outcomes for up to 6 weeks post-injury. We report that phrenic motor neuron loss in cervical spinal cord, phrenic nerve axonal degeneration, and denervation at diaphragm neuromuscular junctions (NMJ) resulted in compromised ipsilateral diaphragm function, as demonstrated by persistent reduction in diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation and abnormalities in spontaneous diaphragm electromyography (EMG) recordings. This injury paradigm is reproducible, does not require ventilatory assistance, and provides proof-of-principle that generation of unilateral cervical contusion is a feasible strategy for modeling diaphragmatic/respiratory deficits in mice. This study and its accompanying analyses pave the way for using transgenic mouse technology to explore the function of specific genes in the pathophysiology of phrenic motor neuron degeneration and respiratory dysfunction following cervical SCI.

Respiratory dysfunction is the leading cause of morbidity and mortality following traumatic spinal cord injury (SCI). Injuries targeting mid-cervical spinal cord regions affect the phrenic motor neuron pool that innervates the diaphragm, the primary respiratory muscle of inspiration. Contusion-type injury in the cervical spinal cord is one of the most common forms of human SCI; however, few studies have evaluated mid-cervical contusion in animal models or characterized consequent histopathological and functional effects of degeneration of phrenic motor neuron-diaphragm circuitry. In an attempt to target the phrenic motor neuron pool, two unilateral contusion injury paradigms were tested, a single injury at level C4 and a double injury both at levels C3 and C4, and animals were followed for up to 6 weeks post-injury. Both unilateral cervical injury paradigms are reproducible with no mortality or need for breathing assistance, and are accompanied by phrenic motor neuron loss, phrenic nerve axon degeneration, diaphragm atrophy, denervation and subsequent partial reinnervation at the diaphragm neuromuscular junction, changes in spontaneous diaphragm EMG recordings, and reduction in phrenic nerve compound muscle action potential amplitude. These findings demonstrate significant and chronically persistent respiratory compromise following mid-cervical SCI due to phrenic motor neuron degeneration. These injury paradigms and accompanying analyses provide important tools both for understanding mechanisms of phrenic motor neuron and diaphragm pathology following SCI and for evaluating therapeutic strategies in clinically relevant cervical SCI models., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Major advances in myeloproliferative neoplasms in the last decade have cast light on their complexity. The identification of JAK2 (V617F) briefly promised a unifying mechanism of pathogenesis with a single pathway that could be efficiently targeted. Instead, there have been major advances in understanding acquired and background genetic and epigenetic contributors to this group of disorders, with refined risk prediction models and experimental therapeutics that have provided a more nuanced model of disease. In aggregate these observations likely explain the heterogeneity of these disorders and their generally unpredictable response to therapy. Molecular studies, beginning with the identification of JAK2 (V617F), have led to a concept of MPN subtypes existing on a continuum, and additional discoveries such as TET2 and EZH2 mutations have provided the molecular underpinnings to begin to explain overlapping phenotypes in myeloid malignancies more generally. In many ways the pace of molecular discovery is outstripping our ability to integrate these observations into clinical care, both in terms of molecular diagnostics and medical decision making. This review will attempt to summarize, within a clinical context, our evolving understanding of myeloproliferative neoplasms. It focuses on biology, histopathology, prognostic scoring systems, stem cell transplantation as well as selected clinical/preclinical therapeutic observations.

Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4(+) and CD8(+) T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4(+) T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4(+) T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.

Background: Chagas disease, caused by Trypanosoma cruzi, remains a serious public health concern in many areas of Latin America, including México. It is also endemic in Texas with an autochthonous canine cycle, abundant vectors (Triatoma species) in many counties, and established domestic and peridomestic cycles which make competent reservoirs available throughout the state. Yet, Chagas disease is not reportable in Texas, blood donor screening is not mandatory, and the serological profiles of human and canine populations remain unknown. The purpose of this analysis was to provide a formal risk assessment, including risk maps, which recommends the removal of these lacunae., Methods and Findings: The spatial relative risk of the establishment of autochthonous Chagas disease cycles in Texas was assessed using a five-stage analysis. 1. Ecological risk for Chagas disease was established at a fine spatial resolution using a maximum entropy algorithm that takes as input occurrence points of vectors and environmental layers. The analysis was restricted to triatomine vector species for which new data were generated through field collection and through collation of post-1960 museum records in both México and the United States with sufficiently low georeferenced error to be admissible given the spatial resolution of the analysis (1 arc-minute). The new data extended the distribution of vector species to 10 new Texas counties. The models predicted that Triatoma gerstaeckeri has a large region of contiguous suitable habitat in the southern United States and México, T. lecticularia has a diffuse suitable habitat distribution along both coasts of the same region, and T. sanguisuga has a disjoint suitable habitat distribution along the coasts of the United States. The ecological risk is highest in south Texas. 2. Incidence-based relative risk was computed at the county level using the Bayesian Besag-York-Mollié model and post-1960 T. cruzi incidence data. This risk is concentrated in south Texas. 3. The ecological and incidence-based risks were analyzed together in a multi-criteria dominance analysis of all counties and those counties in which there were as yet no reports of parasite incidence. Both analyses picked out counties in south Texas as those at highest risk. 4. As an alternative to the multi-criteria analysis, the ecological and incidence-based risks were compounded in a multiplicative composite risk model. Counties in south Texas emerged as those with the highest risk. 5. Risk as the relative expected exposure rate was computed using a multiplicative model for the composite risk and a scaled population county map for Texas. Counties with highest risk were those in south Texas and a few counties with high human populations in north, east, and central Texas showing that, though Chagas disease risk is concentrated in south Texas, it is not restricted to it., Conclusions: For all of Texas, Chagas disease should be designated as reportable, as it is in Arizona and Massachusetts. At least for south Texas, lower than N, blood donor screening should be mandatory, and the serological profiles of human and canine populations should be established. It is also recommended that a joint initiative be undertaken by the United States and México to combat Chagas disease in the trans-border region. The methodology developed for this analysis can be easily exported to other geographical and disease contexts in which risk assessment is of potential value.

Background: Decision analysis and game theory have proved useful tools in various biodiversity conservation planning and modeling contexts. This paper shows how game theory may be used to inform group decisions in biodiversity conservation scenarios by modeling conflicts between stakeholders to identify Pareto-inefficient Nash equilibria. These are cases in which each agent pursuing individual self-interest leads to a worse outcome for all, relative to other feasible outcomes. Three case studies from biodiversity conservation contexts showing this feature are modeled to demonstrate how game-theoretical representation can inform group decision-making., Methodology and Principal Findings: The mathematical theory of games is used to model three biodiversity conservation scenarios with Pareto-inefficient Nash equilibria: (i) a two-agent case involving wild dogs in South Africa; (ii) a three-agent raptor and grouse conservation scenario from the United Kingdom; and (iii) an n-agent fish and coral conservation scenario from the Philippines. In each case there is reason to believe that traditional mechanism-design solutions that appeal to material incentives may be inadequate, and the game-theoretical analysis recommends a resumption of further deliberation between agents and the initiation of trust--and confidence--building measures., Conclusions and Significance: Game theory can and should be used as a normative tool in biodiversity conservation contexts: identifying scenarios with Pareto-inefficient Nash equilibria enables constructive action in order to achieve (closer to) optimal conservation outcomes, whether by policy solutions based on mechanism design or otherwise. However, there is mounting evidence that formal mechanism-design solutions may backfire in certain cases. Such scenarios demand a return to group deliberation and the creation of reciprocal relationships of trust.

Castleman disease is an uncommon lymphoproliferative disorder that usually presents asymptomatically at a single site, most commonly the mediastinum; it is rare in the head and neck. Although Castleman disease may be mistaken for a malignant process such as lymphoma, it is a benign condition that is curable with complete surgical resection. We report the case of a 43-year-old man with the hyaline vascular type of unicentric Castleman disease who presented with an isolated neck mass.

Burkitt lymphoma (BL) is an aggressive form of non-Hodgkin B-cell lymphoma with 3 variants: endemic, sporadic, and immunodeficiency-associated types. The sporadic form, most commonly involving the abdomen and ileocecal region, presents as an abdominal mass, rarely presenting in the orofacial region. A 36-year-old Indian female presented to the Hospital of the University of Pennsylvania for evaluation of a persistent intraoral swelling ulceration of the lower right mandibular alveolar ridge with minimal bony invasion. Progressive systemic symptoms of fatigue, weakness, and fever developed without resolution following treatment for a presumed odontogenic infection in the 4 weeks before presentation. An incisional biopsy revealed a diffuse proliferation of intermediate- to large-sized lymphocytes with multiple small peripheral nucleoli, scant cytoplasm, and nuclear pleomorphism. Nearly all cells displayed Ki67 expression. A final diagnosis of BL was rendered following confirmation of a cMYC translocation by fluorescence in situ hybridization. This article presents a case of the sporadic form of BL with atypical presentation clinically and morphologically, primarily involving the oral soft tissue.

Clinical experience and animal models have shown that donor T cell depletion (TCD) adversely affects engraftment of hematopoietic stem cells (HSCs). Although it is known that donor T cells are acting to overcome residual host immune barriers, they may also exert effects independent of host resistance via direct or indirect interactions with donor stem cells, their microenvironment, or key differentiation events. To more precisely define the effect of T cells on engraftment, we have performed human umbilical cord blood (UCB) transplantation into immunodeficient mice under limiting dilution conditions. UCB mononuclear cells (MNC) or TCD UCB were transplanted into NOD/LtSz-scid/scid B2m(null) (NOD/SCID-beta(2)m(-/-)) mice. Cohorts of mice received UCB MNC or TCD UCB at 5 dose levels between 5 x 10(4) and 5 x 10(6) cells. At dose levels at or above 10(5) cells, engraftment was higher in the MNC recipients (n = 32) than the TCD recipients (n = 31) in a dose-dependent manner. Despite this difference, limiting dilution analysis to determine functional stem cell frequency revealed that SCID repopulating cells in TCD UCB was not significantly less than in CB MNCs, suggesting that T cells may facilitate engraftment at stages beyond the stem cell. Add-back of CD3/CD28 costimulated T cells restored and appeared to enhance engraftment, both in NOD/SCID-beta(2)m(-/-) as well as NOD/LtSz-scid IL2Rgamma(null) (NOG) recipients. These results, in a model where there are minimal host immune barriers to overcome, suggest T cells possess additional graft-facilitating properties. CD3/CD28 costimulation of UCB T cells represents a potential strategy for enhancing the engraftment of UCB.

Diffuse large B-cell lymphomas (DLBCLs) are a clinically and biologically heterogeneous group of hematologic malignancies. Specific genetic aberrations underlie some of this heterogeneity. These genetic events include distinct and separate translocations resulting in the dysregulated expression of either BCL6 protein with the t(3;14)(q27;q32) or c-MYC protein with the t(8;14)(q24;q32), as a consequence of the juxtaposition of these oncogenes with heterologous promoters or enhancers, such as those of the immunoglobulin heavy chain gene. Here, we report the case of a patient with DLBCL with a unique t(3;8)(q27;q24.1) that involves the BCL6 and MYC genes. We know of no previous report of this translocation in DLBCL, which simultaneously affects two key genes implicated in lymphomagenesis and may reflect a novel genetic mechanism in neoplastic transformation.

Background and Purpose: Efforts to make physical therapy more evidence based have increased demand for human participants, raising concerns for their safety and welfare. This study examined how often research articles in physical therapy journals report basic ethical protections., Methods: We carried out a retrospective audit of research articles in 6 physical therapy journals between 1996 and 2001., Results: Of 806 articles reviewed, 48% documented both research ethics committee approval and informed consent. Articles reporting clinical interventions had the highest reported rate (64%) of both protections. Articles reporting qualitative methods, chart reviews, and case reports had the lowest rates of documentation of both requirements: 30%, 17%, and 11%, respectively. Reported rates of both requirements in vulnerable populations were 55% for children, 48% for students, and 33% for employees. Twenty-six percent of articles included confidentiality assurances. Case reports were most likely and chart reviews were least likely to mention confidentiality: 88% and 8%, respectively., Discussion and Conclusion: There is no uniform editorial policy among physical therapy journals for reporting basic ethical requirements. Physical therapy journals should standardize ethical protections and make documentation of compliance a prerequisite of publication.

Team Child is designed to provide civil legal representation for very troubled delinquent youth to improve their access to needed education programs, mental health services, and family services. Better provision of these services is intended to reduce delinquency and potentially avoid the long-term incarceration of these youth. This article uses an incidental truncation model to evaluate two Team Child programs in Florida. The authors find the programs not to be effective in reducing recidivism among the youth but to be effective in reducing the arrest rate of the recidivating juveniles. The results indicate a reduction of 11% to 23% of arrests after treatment for the Team Child group.

Whether conceptualized as comorbid ADD with psychosis or as a distinct diagnostic entity--ADD psychosis--patients with features of both ADD and psychosis benefit from treatment with psychostimulants. It is hypothesized that psychostimulants have their therapeutic effect via amelioration of frontal lobe dysfunction.

The Hamilton Anxiety Rating Scale, a widely used clinical interview assessment tool, lacks instructions for administration and clear anchor points for the assignment of severity ratings. We developed a Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and report on a study comparing this version to the traditional form of this scale. Experienced interviewers from three Anxiety Disorders research sites conducted videotaped interviews using both traditional and structured instruments in 89 participants. A subset of the tapes was co-rated by all raters. Participants completed self-report symptom questionnaires. We observed high inter-rater and test-retest reliability using both formats. The structured format produced similar but consistently higher (+ 4.2) scores. Correlation with a self-report measure of overall anxiety was also high and virtually identical for the two versions. We conclude that in settings where extensive training is not practical, the structured scale is an acceptable alternative to the traditional Hamilton Anxiety instrument., (Copyright 2001 Wiley-Liss, Inc.)

Background: Atrial fibrillation (AF) after coronary bypass graft surgery may result in hypotension, heart failure symptoms, embolic complications, and prolongation in length of hospital stay (LOHS). The purpose of this study was to determine whether intravenous diltiazem is more effective than digoxin for ventricular rate control in AF after coronary artery bypass graft surgery. A secondary end point was to determine whether ventricular rate control with diltiazem reduces postoperative LOHS compared with digoxin., Methods and Results: Patients with AF and ventricular rate > 100 beats/min within 7 days after coronary artery bypass graft surgery were randomly assigned to receive intravenous therapy with diltiazem (n = 20) or digoxin (n = 20). Efficacy was measured with ambulatory electrocardiography (Holter monitoring). Safety was assessed by clinical monitoring and electrocardiographic recording. LOHS was measured from the day of surgery. Data were analyzed with the intention-to-treat principle in all randomly assigned patients. In addition, a separate intention-to-treat analysis was performed excluding patients who spontaneously converted to sinus rhythm. In the analysis of all randomly assigned patients, those who received diltiazem achieved ventricular rate control (> or = 20% decrease in pretreatment ventricular rate) in a mean of 10 +/- 20 (median 2) minutes compared with 352 +/- 312 (median 228) minutes for patients who received digoxin (p < 0.0001). At 2 hours, the proportion of patients who achieved rate control was significantly higher in patients treated with diltiazem (75% vs 35%, p = 0.03). Similarly, at 6 hours, the response rate associated with diltiazem was higher than that in the digoxin group (85% vs 45%, p = 0.02). However, response rates associated with diltiazem and digoxin at 12 and 24 hours were not significantly different. At 24 hours, conversion to sinus rhythm had occurred in 11 of 20 (55%) patients receiving diltiazem and 13 of 20 (65%) patients receiving digoxin (p = 0.75). Results of the analysis of only those patients who remained in AF were similar to those presented above. There was no difference between the diltiazem-treated and digoxin-treated groups in postoperative LOHS (8.6 +/- 2.2 vs 7.7 +/- 2.0 days, respectively, p = 0.43)., Conclusions: Ventricular rate control occurs more rapidly with intravenous diltiazem than digoxin in AF after coronary artery bypass graft surgery. However, 12- and 24-hour response rates and duration of postoperative hospital stay associated with the two drugs are similar.

This review summarizes recent findings concerning the role of CD40-ligand and CD40 interactions in B-cell differentiation. CD40-ligand on helper CD4+ T lymphocytes interacts with CD40 on B cells and directs the selection and differentiation of clones of B lymphocytes to generate specific antibody-dependent immune responses. CD40-ligand is necessary for normal B-cell differentiation and plays several distinctive roles in this multistage process. The CD40 signaling pathway that normally regulates B-cell death appears to be usurped by the Epstein-Barr virus to mediate B-cell transformation.

We examined 11 children with infective endocarditis initially and serially by two-dimensional echocardiography. Nine (82%) of the 11 patients had echocardiographic findings at initial examination compatible with infective endocarditis. These results provided strong evidence in support of the diagnosis before bacteriologic confirmation was available. Congestive heart failure, major emboli, and/or the need for surgical intervention occurred in seven of the nine patients with positive two-dimensional echocardiograms. Echocardiographic evidence of vegetations persisted during antibiotic therapy and resolved slowly during many months. Serial echocardiograms were useful in cases in which obvious valve destruction or marked increase in vegetation size imaged echocardiographically could be combined with clinical evidence of progressive heart failure to support a decision for early surgical intervention. Two-dimensional echocardiography can make important contributions to the diagnosis and management of children with infective endocarditis.

Peak acceleration of blood in the ascending aorta, an index of global systolic left ventricular (LV) function, can be measured noninvasively using a continuous wave Doppler velocimeter applied suprasternally. The feasibility of this approach as a tool for detecting improvement of LV function was studied in 16 patients with congestive heart failure (CHF). Measurements were made daily for 6 consecutive days. The daily variability of peak acceleration examined in 11 normal subjects was +/- 2 m/s/s. In 11 of 16 patients with CHF, peak acceleration increased more than 2 m/s/s by day 6 compared with day 1 (group 1). In 5 of 16 patients, peak acceleration remained unchanged (group 2). In group 1, peak acceleration was 11 +/- 1 m/s/s on day 1 and increased to 16 +/- 1 m/s/s on day 6 (p less than 0.001). In this group, CHF resolved by day 6 in 9 of 11 patients. In group 2, peak acceleration was 9 +/- 1 m/s/s on day 1 and remained unchanged through day 6. In these 5 patients, the signs and symptoms of CHF persisted through day 6. The results suggest that peak acceleration measured noninvasively with continuous wave Doppler can detect improvement of LV function in patients with CHF. The approach provides a simple and reliable bedside means for serial evaluation of LV systolic function.

Glycine is the principal inhibitory neurotransmitter in posterior regions of the brain. In addition, glycine serves as an allosteric regulator of excitatory neurotransmission mediated by the N-methyl-D-aspartate (NMDA) acidic amino acid receptor subtype. The studies presented here characterize [3H]glycine binding to washed membranes prepared from rat spinal cord and cortex, areas enriched in glycine inhibitory and NMDA receptors, respectively, in an attempt to define the glycine recognition sites on the two classes of receptors. Specific binding for [3H]glycine was seen in both cortex and spinal cord. Saturation analyses in cortex were best fitted by a two-site model with respective equilibrium dissociation constants (KD values) of 0.24 and 5.6 microM and respective maximal binding constants (Bmax values) of 3.4 and 26.7 pmol/mg of protein. Similar analyses in spinal cord were best fitted by a one-site model with a KD of 5.8 microM and Bmax of 20.2 pmol/mg of protein. Na+ had no effect on [3H]glycine binding to cortical membranes but increased the binding to spinal cord membranes by greater than 15-fold. This Na+-dependent binding may reflect glycine binding to the recognition site of the high-affinity, Na+-dependent glycine uptake system. Several short-chain, neutral amino acids displaced [3H]glycine binding from both cortical and spinal cord membranes. The most potent displacers of [3H]glycine binding to cortical membranes were D-serine and D-alanine, followed by the L-isomers of serine and alanine and beta-alanine. In contrast, D-serine and D-alanine were similar in potency to L-serine in spinal cord membranes. Compounds active at receptors for the acidic amino acids had disparate effects on the binding of [3H]glycine. At 10 microM, NMDA resulted in a 25% increase, whereas D- and L-2-amino-5-phosphonovaleric acid at 100 microM resulted in a 30% decrease, in [3H]glycine binding to cortical membranes. Kynurenic acid was the most potent of the acidic amino acid-related compounds at displacing [3H]glycine binding. In cortical membranes, kynurenic acid displacement was resolved into a high- and a low-affinity component; the high-affinity component displaced the high-affinity component of [3H]glycine binding.(ABSTRACT TRUNCATED AT 400 WORDS)

The ability of paraquat, MPP+, and analogs to be reduced by chemical reductants and by NADPH, as catalyzed by liver microsomes or purified NADPH cytochrome P-450 reductase, is reported. The analogs span a range of electrochemical potential, including values in-between that of paraquat and MPP+. Analogs with an Eo below -.55 V (vs. NHE) are not reduced by either the NADPH-microsomes or NADPH-reductase systems. The inability of MPP+ to be bio-reduced or to stimulate the production of superoxide during aerobic reduction is evidence against a redox-cycling (oxidant stress) role of MPP+ in MPTP neurotoxicity.

The potential role of the cytochromes P-450 in methylcholanthrene (MC)-mediated suppression of cutaneous delayed hypersensitivity (CDH) in C57BL/6J (B6) mice was evaluated indirectly by treating mice with agents known to induce or inhibit hepatic cytochromes P-450 prior to contact sensitization. Subsequent alterations in aryl hydrocarbon hydroxylase (AHH) activity and CDH, as measured by suppression of 2,4-dinitrofluorobenzene (DNFB)-induced ear swelling, were measured. MC administration resulted in a dose-dependent suppression of ear swelling and a concomitant dose-dependent induction of hepatic AHH activity. Treatment of B6 mice with phenobarbital (PB), 80 mg/kg daily X 3, a broad spectrum inducer of P-450, resulted in a 2.5-fold increase in benzo[a]pyrene (B[a]P) hydroxylase activity without affecting CDH. Animals treated with the same PB protocol prior to an ED20 dose of MC showed no difference in suppression of CDH compared to animals treated with MC alone. In contrast, successive treatment with the selective P1-450 inducer, 5,6-benzoflavone (beta NF), prior to and following an ED20 dose of MC significantly increased suppression of CDH (p less than 0.001) usually seen at this MC dose. Treatment with a known inhibitor of cytochrome P1-450 activity, 7,8-benzoflavone (alpha NF), did not prevent AHH induction when administered prior to and following MC (ED100) nor did it suppress CDH when administered alone. However, this alpha NF treatment completely prevented suppression of CDH usually seen at this MC dose. These data provide evidence suggesting that metabolic activation by cytochrome P1-450 is required for the expression of the immunosuppressive activity of MC.

To determine the rate and extent of recovery of left ventricular (LV) performance following acute myocardial infarction (MI), peak aortic blood acceleration was measured serially in 26 patients and in 11 normal volunteers with a continuous wave Doppler placed suprasternally. In patients, Doppler measurements were made 20 +/- 2 hours after the acute onset of chest discomfort and were repeated daily for 6 consecutive days. Infarction patients were divided into two groups. Group I consisted of 15 patients who did not have a previous MI and whose present course was not complicated by congestive heart failure (CHF). Group II consisted of 11 patients who had either a previous MI or developed CHF during the present admission. Peak acceleration in the normal volunteers showed minimal daily variations over a period of 6 days. Peak acceleration in the entire group of 26 MI patients increased from 13 +/- 3 m/sec/sec on the day of admission (day 1) to 18 +/- 6 m/sec/sec on day 6 (p less than 0.001). In group I, peak acceleration increased from 13 +/- 4 to 20 +/- 6 m/sec/sec between day 1 and day 6 (p less than 0.001). In group II, however, peak acceleration was 12 +/- 2 m/sec/sec on day 1 and increased to only 15 +/- 4 m/sec/sec on day 6 (NS). These results indicate that LV performance, based upon peak acceleration of blood in the ascending aorta, improves markedly within 6 days in patients suffering their first MI uncomplicated by CHF.(ABSTRACT TRUNCATED AT 250 WORDS)