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1.
Cureus ; 12(10): e10774, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33033668

RESUMO

The cutaneous manifestations of secondary syphilis can vary significantly between patients, leading to a more difficult or delayed diagnosis. Here we present an instructive case of secondary syphilis in a 45-year-old, HIV-positive male patient. He presented with a solitary, crusted anterior neck nodule without concomitant systemic symptoms. Together, history and physical exam were concerning for non-melanoma skin cancer. Histopathologic evaluation of the lesion revealed an extensive infiltrate of plasma cells at the dermoepidermal junction, and immunohistochemical staining revealed numerous Treponema pallidum microorganisms. Physicians must keep syphilis in the differential diagnosis when evaluating atypical nodular lesions resembling non-melanoma skin cancer for the purpose of initiating appropriate antibiotic treatment and preventing future infectious complications.

2.
Pain Physician ; 23(2): E85-E131, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214287

RESUMO

BACKGROUND: The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES: The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS: The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS: Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS: Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.


Assuntos
Transplante de Medula Óssea/normas , Medicina Baseada em Evidências/normas , Doenças Musculoesqueléticas/terapia , Manejo da Dor/normas , Médicos/normas , Sociedades Médicas/normas , Medula Óssea/fisiologia , Transplante de Medula Óssea/métodos , Medicina Baseada em Evidências/métodos , Humanos , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/epidemiologia , Dor/diagnóstico , Dor/epidemiologia , Manejo da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration/normas
3.
Cell Rep ; 25(10): 2742-2754.e31, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30517862

RESUMO

The lack of disease-modifying treatments for neurodegenerative disease stems in part from our rudimentary understanding of disease mechanisms and the paucity of targets for therapeutic intervention. Here we used an integrated discovery paradigm to identify a new therapeutic target for diseases caused by α-synuclein (α-syn), a small lipid-binding protein that misfolds and aggregates in Parkinson's disease and other disorders. Using unbiased phenotypic screening, we identified a series of compounds that were cytoprotective against α-syn-mediated toxicity by inhibiting the highly conserved enzyme stearoyl-CoA desaturase (SCD). Critically, reducing the levels of unsaturated membrane lipids by inhibiting SCD reduced α-syn toxicity in human induced pluripotent stem cell (iPSC) neuronal models. Taken together, these findings suggest that inhibition of fatty acid desaturation has potential as a therapeutic approach for the treatment of Parkinson's disease and other synucleinopathies.


Assuntos
Estearoil-CoA Dessaturase/antagonistas & inibidores , alfa-Sinucleína/toxicidade , Animais , Citoproteção/efeitos dos fármacos , Ácidos Graxos/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxidiazóis/química , Oxidiazóis/farmacologia , Agregados Proteicos , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismo
4.
J Cutan Pathol ; 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29920738

RESUMO

With the rising popularity of tattoos, many physicians have seen complications of their application, usually transient and inflammatory in nature, although both benign and malignant neoplasms have been reported as well. We present an unusual case of a hemangioma arising after tattoo application.

5.
Langmuir ; 34(27): 8075-8080, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29897774

RESUMO

We demonstrate rapid [∼mm3/(h·L)] organic ligand-free self-assembly of three-dimensional, >50 µm single-domain microassemblies containing up to 107 individual aligned nanoparticles through a scalable aqueous process. Organization and alignment of aqueous solution-dispersed nanoparticles are induced by decreasing their pH-dependent surface charge without organic ligands, which could be temperature-sensitive or infrared light absorbing. This process is exhibited by transforming both dispersed iron oxide hydroxide nanorods and lithium yttrium fluoride nanoparticles into high packing density microassemblies. The approach is generalizable to nanomaterials with pH-dependent surface charge (e.g., oxides, fluorides, and sulfides) for applications requiring long-range alignment of nanostructures as well as high packing density.

6.
Oncol Nurs Forum ; 45(2): 141-142, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29466343

RESUMO

The Power Over Pain-Coaching (POP-C) intervention was developed to improve functional status and decrease pain and pain-related distress among ambulatory African American patients with cancer. By bypassing the effects of disparities, the POP-C intervention may help to decrease suffering among African American patients with cancer pain; consequently, it contributes to improving quality of life and addressing social and other determinants of health among members of this population. 
.


Assuntos
Afro-Americanos/psicologia , Terapia Comportamental/métodos , Dor do Câncer/psicologia , Dor do Câncer/terapia , Manejo da Dor/métodos , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Disparidades em Assistência à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Racismo , Estados Unidos
7.
Adv Mater ; 30(9)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29322634

RESUMO

At the microscopic scale, carbon nanotubes (CNTs) combine impressive tensile strength and electrical conductivity; however, their macroscopic counterparts have not met expectations. The reasons are variously attributed to inherent CNT sample properties (diameter and helicity polydispersity, high defect density, insufficient length) and manufacturing shortcomings (inadequate ordering and packing), which can lead to poor transmission of stress and current. To efficiently investigate the disparity between microscopic and macroscopic properties, a new method is introduced for processing microgram quantities of CNTs into highly oriented and well-packed fibers. CNTs are dissolved into chlorosulfonic acid and processed into aligned films; each film can be peeled and twisted into multiple discrete fibers. Fibers fabricated by this method and solution-spinning are directly compared to determine the impact of alignment, twist, packing density, and length. Surprisingly, these discrete fibers can be twice as strong as their solution-spun counterparts despite a lower degree of alignment. Strength appears to be more sensitive to internal twist and packing density, while fiber conductivity is essentially equivalent among the two sets of samples. Importantly, this rapid fiber manufacturing method uses three orders of magnitude less material than solution spinning, expanding the experimental parameter space and enabling the exploration of unique CNT sources.

8.
Science ; 357(6353): 773-778, 2017 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-28839068

RESUMO

Mechanical energy harvesters are needed for diverse applications, including self-powered wireless sensors, structural and human health monitoring systems, and the extraction of energy from ocean waves. We report carbon nanotube yarn harvesters that electrochemically convert tensile or torsional mechanical energy into electrical energy without requiring an external bias voltage. Stretching coiled yarns generated 250 watts per kilogram of peak electrical power when cycled up to 30 hertz, as well as up to 41.2 joules per kilogram of electrical energy per mechanical cycle, when normalized to harvester yarn weight. These energy harvesters were used in the ocean to harvest wave energy, combined with thermally driven artificial muscles to convert temperature fluctuations to electrical energy, sewn into textiles for use as self-powered respiration sensors, and used to power a light-emitting diode and to charge a storage capacitor.

9.
J Urban Health ; 93(4): 732-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27270912

RESUMO

It is well known that health disparities exist and that a significant majority of patients who suffer disproportionately from them are lower income, non-white residents of dense, and diverse urban neighborhoods. It is our belief that factors hindering the reduction of health disparities in these neighborhoods are a lack of a framework and preparation needed to engage these communities in identifying specific health care needs. This paper describes one curricular intervention, a graduate level community engagement course, developed within an academic medical center located in an urban setting, that demonstrates promise in effecting change in the extent to which clinicians are able to engage communities and practice "neighborhood-engaged care" with the central goal of mitigating disparities.


Assuntos
Redes Comunitárias , Participação da Comunidade , Pessoal de Saúde/educação , Disparidades nos Níveis de Saúde , População Urbana , Centros Médicos Acadêmicos , Currículo , Grupos Focais , Humanos , Avaliação de Programas e Projetos de Saúde
10.
Support Care Cancer ; 24(5): 2147-2154, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26556212

RESUMO

PURPOSE: Children diagnosed with brain tumors increasingly survive to adulthood, although they do so with needs often requiring continued parental caregiving. We sought to describe the nature of caregivers' expectations about survivors' function and how expectations connect to ongoing management and decision-making. METHODS: Forty-five qualitative interviews with mother-caregivers were conducted and coded for themes related to expectations for their adolescent/young adult children living post-childhood brain tumors. RESULTS: Five main themes emerged as integral to mother-caregiver expectations: realizing a difference in the survivor, noticing limitations to independence in the survivor, memories of learning about clinical prognoses as understood from consent meetings and education, managing these realizations, and acknowledging unresolved challenges. CONCLUSIONS: Caregiver expectations are influenced by both initial clinical interactions and contemporary family dynamics and require individual- and family-specific survivorship planning. As caregiver expectations can influence management behaviors that impact outcomes and possibly independence, implications for clinician-caregiver shared decision-making are substantial.


Assuntos
Neoplasias Encefálicas , Cuidadores/psicologia , Mães/psicologia , Sobreviventes , Adolescente , Adulto , Idade de Início , Idoso , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/psicologia , Neoplasias Encefálicas/reabilitação , Criança , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Adulto Jovem
11.
Cancer Nurs ; 39(2): 134-43, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25950583

RESUMO

BACKGROUND: To date, there are few studies that examine the perspectives of older survivors of childhood brain tumors who are living with their families in terms of their sense of self and their role in their families. OBJECTIVE: The aim of this study was to describe how adolescent and young adult survivors of childhood brain tumors describe their health-related quality of life, that is, their physical, emotional, and social functioning. METHODS: This qualitative descriptive study included a purposive sample of 41 adolescent and young adult survivors of a childhood brain tumor who live with their families. Home interviews were conducted using a semistructured interview guide. Directed content analytic techniques were used to analyze data using health-related quality of life as a framework. RESULTS: This group of brain tumor survivors described their everyday lives in terms of their physical health, neurocognitive functioning, emotional health, social functioning, and self-care abilities. Overall, survivors struggle for normalcy in the face of changed functioning due to their cancer and the (late) effects of their treatment. CONCLUSIONS: Neurocognitive issues seemed most compelling in the narratives. The importance of families went beyond the resources, structure, and support for functioning. Their families provided the recognition that they were important beings and their existence mattered to someone. IMPLICATIONS FOR PRACTICE: The value and complexity of care coordination were highlighted by the multifaceted needs of the survivors. Advocacy for appropriate and timely educational, vocational, and social support is critical as part of comprehensive cancer survivorship care.


Assuntos
Neoplasias Encefálicas/psicologia , Qualidade de Vida/psicologia , Sobreviventes/psicologia , Adolescente , Adulto , Neoplasias Encefálicas/enfermagem , Neoplasias Encefálicas/terapia , Relações Familiares/psicologia , Feminino , Humanos , Masculino , Pesquisa Qualitativa , Apoio Social , Sobreviventes/estatística & dados numéricos , Adulto Jovem
12.
World J Gastrointest Pathophysiol ; 6(4): 131-9, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26600971

RESUMO

Tumors and cancers of the gastrointestinal tract and pancreas are commonly derived from precursor lesions so that understanding the physiological, cellular, and molecular mechanisms underlying the pathogenesis of precursor lesions is critical for the prevention and treatment of those neoplasms. Pancreatic neuroendocrine tumors (PNETs) can also be derived from precursor lesions. Pancreatic α cell hyperplasia (ACH), a specific and overwhelming increase in the number of α cells, is a precursor lesion leading to PNET pathogenesis. One of the 3 subtypes of ACH, reactive ACH is caused by glucagon signaling disruption and invariably evolves into PNETs. In this article, the existing work on the mechanisms underlying reactive ACH pathogenesis is reviewed. It is clear that the liver secretes a humoral factor regulating α cell numbers but the identity of the liver factor remains elusive. Potential approaches to identify the liver factor are discussed.

13.
J Pediatr Hematol Oncol ; 37(8): 577-83, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26492583

RESUMO

The transition from pediatric to adult health care is often challenging for adolescents and young adults with sickle cell disease (SCD). Our study aimed to identify (1) measures of success for the transition to adult health care; and (2) barriers and facilitators to this process. We interviewed 13 SCD experts and asked them about their experiences caring for adolescents and young adults with SCD. Our interview guide was developed based on Social-Ecological Model of Adolescent and Young Adult Readiness to Transition framework, and interviews were coded using the constant comparative method. Our results showed that transition success was measured by health care utilization, quality of life, and continuation on a stable disease trajectory. We also found that barriers to transition include negative experiences in the emergency department, sociodemographic factors, and adolescent skills. Facilitators include a positive relationship with the provider, family support, and developmental maturity. Success in SCD transition is primarily determined by the patients' quality of relationships with their parents and providers and their developmental maturity and skills. Understanding these concepts will aid in the development of future evidence-based transition care models.


Assuntos
Anemia Falciforme/terapia , Atitude do Pessoal de Saúde , Pessoal de Saúde/psicologia , Transição para Assistência do Adulto , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/psicologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Modelos Psicológicos , Motivação , Relações Pais-Filho , Aceitação pelo Paciente de Cuidados de Saúde , Relações Profissional-Família , Relações Profissional-Paciente , Psicologia do Adolescente , Pesquisa Qualitativa , Qualidade de Vida , Fatores Socioeconômicos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/psicologia , Adulto Jovem
14.
Oncol Nurs Forum ; 42(5): E319-29, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26302289

RESUMO

PURPOSE/OBJECTIVES: To describe the development and feasibility of a protocol for nonpsychiatric subspecialty research staff members to screen research participants who endorse suicidal ideations or behaviors during data collection
. DESIGN: Descriptive protocol development.
. SETTING: The Children's Hospital of Philadelphia and the University of Pennsylvania.
. SAMPLE: 186 mother caregivers and 134 adolescent or young adult survivors of childhood brain tumors, with the protocol implemented for 5 caregivers and 11 survivors. METHODS: During telephone- and home-based interviews, the interviewer assessed the participant using the Columbia-Suicide Severity Rating Scale (C-SSRS). MAIN RESEARCH VARIABLES: Expressed suicidal ideation or behavior
. FINDINGS: Implementation of the C-SSRS by nonpsychiatric subspecialty staff members was feasible and valid. Interviewers' conclusions based on this instrument matched those of the mental health professional who followed up with participants. Process notes contained themes about the participants, including anger and sadness in survivors and the physical and emotional demands of the survivor in caregivers. Progress notes for the interviewer included a reiteration of events, whether the assessment was successful, and whether the recommendation of the interviewer was in agreement with that of the mental health professional
. CONCLUSIONS: The protocol based on the C-SSRS was useful and feasible for nonpsychiatric subspecialty staff members to use in the collection of data from survivors of childhood brain tumors and their caregivers. IMPLICATIONS FOR NURSING: Survivors of childhood brain tumors and their caregivers may experience psychosocial distress. Nurses, as research assistants or in other roles, can use tools such as the C-SSRS to assist in front-line assessments. 
.


Assuntos
Comportamento , Neoplasias Encefálicas/psicologia , Mães/psicologia , Ideação Suicida , Sobreviventes/psicologia , Adolescente , Adulto , Idoso , Pesquisa Biomédica , Cuidadores , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Narrat Inq Bioeth ; 4(3): 233-51, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25482002

RESUMO

Survivors of childhood brain tumors face many obstacles to living independently as adults. Causes for lack of independence are multifactorial and generally are investigated in terms of physical, cognitive, and psychosocial treatment-related sequelae. Little is known, however, about the role of expectation for survivors' function. From a mixed-methods study including qualitative interviews and quantitative measures from 40 caregiver-survivor dyads, we compared the data within and across dyads, identifying four distinct narrative profiles: (A) convergent expectations about an optimistic future, (B) convergent expectations about a less optimistic future, (C) non-convergent expectations about a less optimistic future, and (D) non-convergent expectations about an unclear future. Dyads both do well and/or struggle in systematically different manners in each profile. These profiles may inform the design of interventions to be tested in future research and help clinicians to assist families in defining, (re-)negotiating, and reaching their expectations of function and independence.


Assuntos
Atividades Cotidianas , Neoplasias Encefálicas/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Esperança , Vida Independente , Mães , Sobreviventes , Cuidadores , Criança , Humanos , Qualidade de Vida
16.
Future Med Chem ; 6(16): 1811-27, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25407369

RESUMO

Following on the heels of the US FDA approval of tofacitinib (Xeljanz, Pfizer, USA), an inhibitor of the JAK family members, and ibrutinib (Imbruvica, Janssen, Belgium), an inhibitor of BTK, for the treatment of rheumatoid arthritis and chronic lymphocytic leukemia, respectively, there is now renewed interest in the biopharmaceutical industry in the development of orally active small-molecule agents targeting key protein kinases implicated in immune regulation. One such 'immunokinase' target is SYK, a non-receptor tyrosine protein kinase critical for transducing intracellular signaling cascades for various immune recognition receptors, such as the B-cell receptor and the Fc receptor. Here, we review and discuss the progress and challenges in the development of small-molecule inhibitors of SYK and their potential as a new class of disease-modifying immunosuppressive agents for certain inflammatory and autoimmune disorders.


Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Baço/efeitos dos fármacos , Baço/enzimologia , Humanos , Doenças do Sistema Imunitário/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/química
17.
Inflamm Bowel Dis ; 20(11): 2083-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25137417

RESUMO

BACKGROUND: For adolescents and young adults (AYA) with inflammatory bowel disease (IBD), the transition from pediatric to adult care is often challenging and associated with gaps in care. Our study objectives were to (1) identify outcomes for evaluating transition success and (2) elicit the major barriers and facilitators of successful transition. METHODS: We interviewed pediatric and adult IBD providers from across the United States with experience caring for AYAs with IBD until thematic saturation was reached after 12 interviews. We elicited the participants' backgrounds, examples of successful and unsuccessful transition of AYAs for whom they cared, and recommendations for improving transition using the Social-Ecological Model of Adolescent and Young Adult Readiness to Transition framework. We coded interview transcripts using the constant comparative method and identified major themes. RESULTS: Participants reported evaluating transition success and failure using health care utilization outcomes (e.g., maintaining continuity with adult providers), health outcomes (e.g., stable symptoms), and quality of life outcomes (e.g., attending school). The patients' level of developmental maturity (i.e., ownership of care) was the most prominent determinant of transition outcomes. The style of parental involvement (i.e., helicopter parent versus optimally involved parent) and the degree of support by providers (e.g., care coordination) also influenced outcomes. CONCLUSIONS: IBD transition success is influenced by a complex interplay of patient developmental maturity, parenting style, and provider support. Multidisciplinary IBD care teams should aim to optimize these factors for each patient to increase the likelihood of a smooth transfer to adult care.


Assuntos
Serviços de Saúde do Adolescente , Continuidade da Assistência ao Paciente/tendências , Assistência à Saúde/tendências , Doenças Inflamatórias Intestinais/terapia , Planejamento de Assistência ao Paciente , Qualidade de Vida , Transição para Assistência do Adulto/tendências , Adolescente , Desenvolvimento do Adolescente , Adulto , Criança , Continuidade da Assistência ao Paciente/organização & administração , Assistência à Saúde/organização & administração , Feminino , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pediatria , Prognóstico , Indicadores de Qualidade em Assistência à Saúde , Transição para Assistência do Adulto/organização & administração
18.
J Med Chem ; 57(6): 2683-91, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24520947

RESUMO

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridazinas/síntese química , Piridazinas/farmacologia , Baço/enzimologia , Amidas/síntese química , Amidas/farmacologia , Animais , Biologia Computacional , Simulação por Computador , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/farmacocinética , Ratos , Baço/efeitos dos fármacos , Relação Estrutura-Atividade , Difração de Raios X
19.
Int Sch Res Notices ; 2014: 742387, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27433523

RESUMO

This study evaluated the natural prey preferences and spatial variability of predation pressure (PP = proportion of colonies with snails and/or clear predation signs) by the gastropod Cyphoma gibbosum on octocoral communities off the La Parguera Natural Reserve, Puerto Rico. All octocoral colonies were checked for presence of C. gibbosum and/or clear predation signs in four permanent band-transects (2 × 10 m), along three depth intervals (0-5, 7-12, >15 m deep) in each of six reefs along an inshore offshore gradient. Results indicate that C. gibbosum preys on at least 16 species, six of which (Briareum asbestinum, Gorgonia ventalina, Pseudoterogorgia americana, P. acerosa, Plexaura flexuosa, and Pseudoplexaura porosa) consistently showed significantly higher (K-W, P < 0.05) (17-37%) PP compared to all other species. Plexaura flexuosa, P. americana, and P. porosa had significantly higher PP (11-38%) among inner and mid-shelf reefs, and G. ventalina had higher PP in shelf-edge reefs (16-20%). A combination of differential spatial distributions and octocoral species abundances seems to explain the observed patterns of predation by C. gibbosum. Prey preference and higher abundances of 3-dimensional octocorals providing increased refuge or microhabitats utilized for mating or egg-deposition could be driving the spatial distribution of C. gibbosum and the observed differential predation pressure.

20.
Arthritis Res Ther ; 15(5): R146, 2013 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-24286216

RESUMO

INTRODUCTION: Spleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy. METHODS: A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA). RESULTS: A novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation. CONCLUSIONS: Inhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/prevenção & controle , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Piridazinas/química , Piridazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Quinase Syk
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