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1.
World J Orthop ; 15(4): 379-385, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38709896

RESUMO

BACKGROUND: De-Quervain's tenosynovitis is a disorder arising from the compression and irritation of the first dorsal extensor compartment of the wrist. Patients who fail conservative treatment modalities are candidates for surgical release. However, risks with surgery include damage to the superficial radial nerve and an incomplete release due to inadequate dissection. Currently, there is a paucity of literature demonstrating the exact anatomic location of the first dorsal extensor compartment in reference to surface anatomy. Thus, this cadaveric study was performed to determine the exact location of the first extensor compartment and to devise a reliable surgical incision to prevent complications. AIM: To describe the location of the first dorsal compartment in relation to bony surface landmarks to create replicable surgical incisions. METHODS: Six cadaveric forearms, including four left and two right forearm specimens were dissected. Dissections were performed by a single fellowship trained upper extremity orthopaedic surgeon. Distance of the first dorsal compartment from landmarks such as Lister's tubercle, the wrist crease, and the radial styloid were calculated. Other variables studied included the presence of the superficial radial nerve overlying the first dorsal compartment, additional compartment sub-sheaths, number of abductor pollicis longus (APL) tendon slips, and the presence of a pseudo-retinaculum. RESULTS: Distance from the radial most aspect of the wrist crease to the extensor retinaculum was 5.14 mm ± 0.80 mm. The distance from Lister's tubercle to the distal aspect of the extensor retinaculum was 13.37 mm ± 2.94 mm. Lister's tubercle to the start of the first dorsal compartment was 18.43 mm ± 2.01 mm. The radial styloid to the initial aspect of the extensor retinaculum measured 2.98 mm ± 0.99 mm. The retinaculum length longitudinally on average was 26.82 mm ± 3.34 mm. Four cadaveric forearms had separate extensor pollicis brevis compartments. The average number of APL tendon slips was three. A pseudo-retinaculum was present in four cadavers. Two cadavers had a superficial radial nerve that crossed over the first dorsal compartment and retinaculum proximally (7.03 mm and 13.36 mm). CONCLUSION: An incision that measures 3 mm proximal from the radial styloid, 2 cm radial from Lister's tubercle, and 5 mm proximal from the radial wrist crease will safely place surgeons at the first dorsal compartment.

2.
J Pain Res ; 17: 1461-1501, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38633823

RESUMO

Introduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

4.
Int J Mol Sci ; 24(18)2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37762379

RESUMO

Much of today's molecular science revolves around next-generation sequencing. Frequently, the first step in analyzing such data is aligning sequencing reads to a reference genome. This step is often taken for granted, but any analysis downstream of the alignment will be affected by the aligner's ability to correctly map sequences. In most cases, for research into chromatin structure and nucleosome positioning, ATAC-seq, ChIP-seq, and MNase-seq experiments use short read lengths. How well aligners manage these reads is critical. Most aligner programs will output mapped reads and unmapped reads. However, from a biological point of view, reads will fall into one of three categories: correctly mapped, incorrectly mapped, and unmapped. While increased sequencing depth can often compensate for unmapped reads, incorrectly and correctly mapped reads appear algorithmically identical but can produce biologically significant alterations in the results. For this reason, we are benchmarking various alignment programs to determine their propensity to incorrectly map short reads. As short-read alignment is an important step in ATAC-seq, ChIP-seq, and MNase-seq experiments, caution should be taken in mapping reads to ensure that the most accurate conclusions can be made from the data generated. Our analysis is intended to help investigators new to the field pick the alignment program best suited for their experimental conditions. In general, the aligners we tested performed well. BWA, Bowtie2, and Chromap were all exceptionally accurate, and we recommend using them. Furthermore, we show that longer read lengths do in fact lead to more accurate mappings.


Assuntos
Benchmarking , Cromatina , Cromatina/genética , Alinhamento de Sequência , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Software , Algoritmos
5.
Elife ; 122023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-37171075

RESUMO

Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.


Assuntos
Apolipoproteína E4 , Mitocôndrias , Animais , Humanos , Camundongos , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Genótipo , Mitocôndrias/metabolismo , Mitocôndrias/patologia
6.
Front Neurosci ; 16: 851463, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35573305

RESUMO

Reason for Performing Study: So far, only transcranial motor evoked potentials (MEP) of the extensor carpi radialis and tibialis cranialis have been documented for diagnostic evaluation in horses. These allow for differentiating whether lesions are located in either the thoraco-lumbar region or in the cervical myelum and/or brain. Transcranial trapezius MEPs further enable to distinguish between spinal and supraspinal located lesions. No normative data are available. It is unclear whether transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) are interchangeable modalities. Objectives: To provide normative data for trapezius MEP parameters in horses for TES and TMS and to discern direct and indirect conduction routes by neurophysiological models that use anatomical geometric characteristics to relate latency times with peripheral (PCV) and central conduction velocities (CCV). Methods: Transcranial electrical stimulation-induced trapezius MEPs were obtained from twelve horses. TES and TMS-MEPs (subgroup 5 horses) were compared intra-individually. Trapezius MEPs were measured bilaterally twice at 5 intensity steps. Motoneurons were localized using nerve conduction models of the cervical and spinal accessory nerves (SAN). Predicted CCVs were verified by multifidus MEP data from two horses referred for neurophysiological assessment. Results: Mean MEP latencies revealed for TES: 13.5 (11.1-16.0)ms and TMS: 19.7 (12-29.5)ms, comprising ∼100% direct routes and for TMS mixed direct/indirect routes of L:23/50; R:14/50. Left/right latency decreases over 10 > 50 V for TES were: -1.4/-1.8 ms and over 10 > 50% for TMS: -1.7/-3.5 ms. Direct route TMS-TES latency differences were 1.88-4.30 ms. 95% MEP amplitudes ranges for TES were: L:0.26-22 mV; R:0.5-15 mV and TMS: L:0.9 - 9.1 mV; R:1.1-7.9 mV. Conclusion: This is the first study to report normative data characterizing TES and TMS induced- trapezius MEPs in horses. The complex trapezius innervation leaves TES as the only reliable stimulation modality. Differences in latency times along the SAN route permit for estimation of the location of active motoneurons, which is of importance for clinical diagnostic purpose. SAN route lengths and latency times are governed by anatomical locations of motoneurons across C2-C5 segments. TES intensity-dependent reductions of trapezius MEP latencies are similar to limb muscles while MEP amplitudes between sides and between TES and TMS are not different. CCVs may reach 180 m/s.

7.
Campbell Syst Rev ; 18(3): e1265, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36909888

RESUMO

This is the protocol for a Campbell systematic review. The objective of this systematic review is to assess the effectiveness of interventions with gender transformative approach (GTA) components in improving women's empowerment in low- and middle-income countries, and to curate evidence on the mechanisms through which GTA works to improve women's empowerment in agriculture.

8.
Front Neurosci ; 14: 570372, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33122992

RESUMO

INTRODUCTION: Transcranial electrical (TES) and magnetic stimulation (TMS) are both used for assessment of the motor function of the spinal cord in horses. Muscular motor evoked potentials (mMEP) were compared intra-individually for both techniques in five healthy horses. mMEPs were measured twice at increasing stimulation intensity steps over the extensor carpi radialis (ECR), tibialis cranialis (TC), and caninus muscles. Significance was set at p < 0.05. To support the hypothesis that both techniques induce extracranially elicited mMEPs, literature was also reviewed. RESULTS: Both techniques show the presence of late mMEPs below the transcranial threshold appearing as extracranially elicited startle responses. The occurrence of these late mMEPs is especially important for interpretation of TMS tracings when coil misalignment can have an additional influence. Mean transcranial motor latency times (MLT; synaptic delays included) and conduction velocities (CV) of the ECR and TC were significantly different between both techniques: respectively, 4.2 and 5.5 ms (MLT TMS --MLT TES ), and -7.7 and -9.9 m/s (CV TMS -CV TES ). TMS and TES show intensity-dependent latency decreases of, respectively, -2.6 (ECR) and -2.7 ms (TC)/30% magnetic intensity and -2.6 (ECR) and -3.2 (TC) ms/30V. When compared to TMS, TES shows the lowest coefficients of variation and highest reproducibility and accuracy for MLTs. This is ascribed to the fact that TES activates a lower number of cascaded interneurons, allows for multipulse stimulation, has an absence of coil repositioning errors, and has less sensitivity for varying degrees of background muscle tonus. Real axonal conduction times and conduction velocities are most closely approximated by TES. CONCLUSION: Both intracranial and extracranial mMEPs inevitably carry characteristics of brainstem reflexes. To avoid false interpretations, transcranial mMEPs can be identified by a stepwise latency shortening of 15-20 ms when exceeding the transcranial motor threshold at increasing stimulation intensities. A ring block around the vertex is advised to reduce interference by extracranial mMEPs. mMEPs reflect the functional integrity of the route along the brainstem nuclei, extrapyramidal motor tracts, propriospinal neurons, and motoneurons. The corticospinal tract appears subordinate in horses. TMS and TES are interchangeable for assessing the functional integrity of motor functions of the spinal cord. However, TES reveals significantly shorter MLTs, higher conduction velocities, and better reproducibility.

9.
Meat Sci ; 156: 131-138, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31154206

RESUMO

Eighteen Nellore steers were classified as either excitable (high index) or calm (low index) temperament, and high or low WB Shear Force (SF) in Longissimus lumborum at 16 days postmortem, with a subset assigned to four groups: HTHS-high temperament and SF (n = 5); HTLS-high temperament and low SF (n = 4); LTHS-low temperament and high SF (n = 4); LTLS-low temperament and SF (n = 5). Only the second calpastatin peak was detected at 48 h in the all samples, and the calpastatin activity only differed (P < .05) between shear force groups. High WBSF groups had greater expression of CAST gene (P < .05) in the high and low temperament. Western blots showed a calpastatin fragmentation pattern very particular to each group with high molecular weight bands present in the HTHS. Temperament was not a determinant factor in postmortem proteolysis variation. However, greater WBSF aged meat from high temperament animals had greater calpastatin activity and less calpastatin fragments formed during the postmortem period analyzed.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Bovinos/fisiologia , Carne Vermelha/análise , Resistência ao Cisalhamento , Temperamento , Animais , Proteínas de Ligação ao Cálcio/genética , Masculino , Músculo Esquelético/química , Proteólise
10.
J Am Soc Nephrol ; 30(1): 33-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530834

RESUMO

BACKGROUND: During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored. METHODS: We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis-mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet-as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects. RESULTS: Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-ß1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker α-smooth muscle actin and the proliferation of renal fibroblasts, corroborating our in vivo data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation. CONCLUSIONS: Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Piridonas/farmacologia , Pirimidinonas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Animais , Biópsia por Agulha , Células Cultivadas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Fibrose/patologia , Imuno-Histoquímica , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Terapia de Alvo Molecular/métodos , Distribuição Aleatória , Valores de Referência , Insuficiência Renal Crônica/genética , Transdução de Sinais/genética
11.
BMC Med Genomics ; 11(1): 125, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591067

RESUMO

BACKGROUND: There is a clear need for assays that can predict the risk of metastatic prostate cancer following curative procedures. Importantly these assays must be analytically robust in order to provide quality data for important clinical decisions. DNA microarray based gene expression assays measure several analytes simultaneously and can present specific challenges to analytical validation. This study describes the analytical validation of one such assay designed to predict metastatic recurrence in prostate cancer using primary formalin fixed paraffin embedded tumour material. METHODS: Accuracy was evaluated with a method comparison study between the assay development platform (Prostate Disease Specific Array) and an alternative platform (Xcel™ microarray) using 50 formalin-fixed, paraffin-embedded prostate cancer patient samples. An additional 70 samples were used to establish the assay reportable range. Determination of assay precision and sensitivity was performed on multiple technical replicates of three prostate cancer samples across multiple variables (operators, days, runs, reagent lots, and equipment) and RNA/cDNA inputs respectively using the appropriate linear mixed model. RESULTS: The overall agreement between the development and alternative platform was 94.7% (95% confidence interval, 86.9-98.5%). The reportable range was determined to be 0.150 to 1.107 for core needle biopsy samples and - 0.214 to 0.844 for radical prostatectomy samples. From the precision study, the standard deviations for assay repeatability and reproducibility were 0.032 and 0.040 respectively. The sensitivity study demonstrated that a total RNA input and cDNA input of 50 ng and 3.5 µg respectively was conservative. CONCLUSION: The Metastatic Assay was found to be highly reproducible and precise. In conclusion the studies demonstrated an acceptable analytical performance for the assay and support its potential use in the clinic.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/patologia , Perfilação da Expressão Gênica/normas , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/normas , Inclusão em Parafina , Prognóstico , Prostatectomia , Neoplasias da Próstata/genética , Controle de Qualidade , Reprodutibilidade dos Testes
12.
Adv Orthop ; 2018: 6085962, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30402292

RESUMO

OBJECTIVE: Blunt spinal trauma classification systems are well established and provide reliable treatment algorithms. To date, stability of the spine after civilian gunshot wounds (CGSWS) is poorly understood. Herein, we investigate the validity of trauma classification systems including the Thoracolumbar Injury Classification and Severity Score (TLICS), Subaxial Cervical Spine Injury Classification and Severity Score (SLIC), and Denis' three-column model when applied to spinal penetrating trauma from gunshots, while secondarily evaluating stability of these injuries. METHODS: Gunshot injuries to the spine were identified from an institutional database from ICD-nine codes. Trauma scorings systems were applied using traditional criteria. Neurologic compromise and spinal stability were evaluated using follow-up clinic notes and radiographs. RESULTS: Thirty-one patients with CSGSW were evaluated. There was an equal distribution of injuries amongst the spinal levels and spinal columns. Twenty patients had neurological deficits at presentation. Eight patient had a TLICS score >4. Three patients had a SLIC score >4. One patient had surgical treatment. Nonoperative treatment did not lead to spinal instability or adverse outcomes in any cases. The posterior column had a high correlation with neurologic compromise, though not statistically significant (p=.118). CONCLUSIONS: The TLICS, SLIC, and three-column classification systems cannot be applied to CSGSW to quantify injury severity, predict outcomes, or guide treatment decision-making. Despite significant neurologic injuries and disruption of multiple spinal columns, CSGSW do not appear to result in unstable injuries requiring operative intervention. Further research is needed to identify the rare spinal gunshot injury that would benefit from immediate surgical intervention.

13.
PLoS One ; 13(10): e0204060, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30278042

RESUMO

Human amniotic membrane (AM) has a long history of clinical use for wound treatment. AM serves as a wound protective barrier maintaining proper moisture. AM is anti-inflammatory, anti-microbial and antifibrotic, and supports angiogenesis, granulation tissue formation and wound re-epithelialization. These properties of AM are attributed to its native extracellular matrix, growth factors, and endogenous cells including mesenchymal stem cells. Advances in tissue preservation have helped to overcome the short shelf life of fresh AM and led to the development of AM products for clinical use. Viable cryopreserved amnion (VCAM), which retains all native components of fresh AM, has shown positive outcomes in clinical trials for wound management. However, cryopreservation requires ultra-low temperature storage and shipment that limits widespread use of VCAM. We have developed a lyopreservation technique to allow for ambient storage of living tissues. Here, we compared the structural, molecular, and functional properties of a viable lyopreserved human amniotic membrane (VLAM) with properties of VCAM using in vitro and in vivo wound models. We found that the structure, growth factors, and cell viability of VLAM is similar to that of VCAM and fresh AM. Both, VCAM and VLAM inhibited TNF-α secretion and upregulated VEGF expression in vitro under conditions designed to mimic inflammation and hypoxia in a wound microenvironment, and resulted in wound closure in a diabetic mouse chronic wound model. Taken together, these data demonstrate that VLAM structural and functional properties are equivalent to VCAM but without the constraints of ultra-low temperature storage.


Assuntos
Âmnio/fisiologia , Membrana Celular/química , Criopreservação/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Âmnio/citologia , Animais , Sobrevivência Celular , Liofilização , Humanos , Camundongos , Temperatura , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular , Cicatrização
14.
J Med Internet Res ; 20(9): e11652, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217793

RESUMO

BACKGROUND: This is a case study from an HIV prevention project among young black men who have sex with men. Individual-level prevention interventions have had limited success among young black men who have sex with men, a population that is disproportionately affected by HIV; peer network-based interventions are a promising alternative. Facebook is an attractive digital platform because it enables broad characterization of social networks. There are, however, several challenges in using Facebook data for peer interventions, including the large size of Facebook networks, difficulty in assessing appropriate methods to identify candidate peer change agents, boundary specification issues, and partial observation of social network data. OBJECTIVE: This study aimed to explore methodological challenges in using social Facebook networks to design peer network-based interventions for HIV prevention and present techniques to overcome these challenges. METHODS: Our sample included 298 uConnect study respondents who answered a bio-behavioral survey in person and whose Facebook friend lists were downloaded (2013-2014). The study participants had over 180,000 total Facebook friends who were not involved in the study (nonrespondents). We did not observe friendships between these nonrespondents. Given the large number of nonrespondents whose networks were partially observed, a relational boundary was specified to select nonrespondents who were well connected to the study respondents and who may be more likely to influence the health behaviors of young black men who have sex with men. A stochastic model-based imputation technique, derived from the exponential random graph models, was applied to simulate 100 networks where unobserved friendships between nonrespondents were imputed. To identify peer change agents, the eigenvector centrality and keyplayer positive algorithms were used; both algorithms are suitable for identifying individuals in key network positions for information diffusion. For both algorithms, we assessed the sensitivity of identified peer change agents to the imputation model, the stability of identified peer change agents across the imputed networks, and the effect of the boundary specification on the identification of peer change agents. RESULTS: All respondents and 78.9% (183/232) of nonrespondents selected as peer change agents by eigenvector on the imputed networks were also selected as peer change agents on the observed networks. For keyplayer, the agreement was much lower; 42.7% (47/110) and 35.3% (110/312) of respondent and nonrespondent peer change agents, respectively, selected on the imputed networks were also selected on the observed network. Eigenvector also produced a stable set of peer change agents across the 100 imputed networks and was much less sensitive to the specified relational boundary. CONCLUSIONS: Although we do not have a gold standard indicating which algorithm produces the most optimal set of peer change agents, the lower sensitivity of eigenvector centrality to key assumptions leads us to conclude that it may be preferable. The methods we employed to address the challenges in using Facebook networks may prove timely, given the rapidly increasing interest in using online social networks to improve population health.


Assuntos
Infecções por HIV/prevenção & controle , Mídias Sociais/normas , Rede Social , Feminino , Humanos , Masculino , Grupo Associado
15.
J Biol Chem ; 293(17): 6544-6555, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29507094

RESUMO

Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor critical for the regulation of many cellular functions in both normal and neoplastic cells. Here, using human glioblastoma cells, we investigated KLF4's effects on cancer cell metabolism. We found that forced KLF4 expression promotes mitochondrial fusion and induces dramatic changes in mitochondrial morphology. To determine the impact of these changes on the cellular functions following, we analyzed how KLF4 alters glioblastoma cell metabolism, including glucose uptake, glycolysis, pentose phosphate pathway, and oxidative phosphorylation. We did not identify significant differences in baseline cellular metabolism between control and KLF4-expressing cells. However, when mitochondrial function was impaired, KLF4 significantly increased spare respiratory capacity and levels of reactive oxygen species in the cells. To identify the biological effects of these changes, we analyzed proliferation and survival of control and KLF4-expressing cells under stress conditions, including serum and nutrition deprivation. We found that following serum starvation, KLF4 altered cell cycle progression by arresting the cells at the G2/M phase and that KLF4 protected cells from nutrition deprivation-induced death. Finally, we demonstrated that methylation-dependent KLF4-binding activity mediates mitochondrial fusion. Specifically, the downstream targets of KLF4-mCpG binding, guanine nucleotide exchange factors, serve as the effector of KLF4-induced mitochondrial fusion, cell cycle arrest, and cell protection. Our experimental system provides a robust model for studying the interactions between mitochondrial morphology and function, mitochondrial dynamics and metabolism, and mitochondrial fusion and cell death during tumor initiation and progression.


Assuntos
Divisão Celular , Fase G2 , Glioblastoma/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Dinâmica Mitocondrial , Proteínas de Neoplasias/metabolismo , Consumo de Oxigênio , Linhagem Celular Tumoral , Sobrevivência Celular , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Proteínas de Neoplasias/genética
16.
JMIR Res Protoc ; 6(6): e113, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28615158

RESUMO

BACKGROUND: Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feeding and developmental outcomes. Pulsed pneumatic orocutaneous stimulation has been shown to improve nonnutritive sucking (NNS) skills in preterm infants who exhibit delayed or disordered nipple feeding behaviors. Separately, the study of the salivary transcriptome in neonates has helped identify biomarkers directly linked to successful neonatal oral feeding behavior. The combination of noninvasive treatment strategies and transcriptomic analysis represents an integrative approach to oral feeding in which rapid technological advances and personalized transcriptomics can safely and noninvasively be brought to the bedside to inform medical care decisions and improve care and outcomes. OBJECTIVE: The study aimed to conduct a multicenter randomized control trial (RCT) to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of PULSED somatosensory stimulation on salivary gene expression in the context of the acquisition of oral feeding habits in high-risk human neonates. The aims of this study represent the first attempt to combine noninvasive treatment strategies and transcriptomic assessments of high-risk extremely preterm infants (EPI) to (1) improve oral feeding behavior and skills, (2) further our understanding of the gene ontology of biologically diverse pathways related to oral feeding, (3) use gene expression data to personalize neonatal care and individualize treatment strategies and timing interventions, and (4) improve long-term developmental outcomes. METHODS: A total of 180 extremely preterm infants from three neonatal intensive care units (NICUs) will be randomized to receive either PULSED or SHAM (non-pulsing) orocutaneous intervention simultaneous with tube feedings 3 times per day for 4 weeks, beginning at 30 weeks postconceptional age. Infants will also be assessed 3 times per week for NNS performance, and multiple saliva samples will be obtained each week for transcriptomic analysis, until infants have achieved full oral feeding status. At 18 months corrected age (CA), infants will undergo neurodevelopmental follow-up testing, the results of which will be correlated with feeding outcomes in the neo-and post-natal period and with gene expression data and intervention status. RESULTS: The ongoing National Institutes of Health funded randomized controlled trial R01HD086088 is actively recruiting participants. The expected completion date of the study is 2021. CONCLUSIONS: Differential salivary gene expression profiles in response to orosensory entrainment intervention are expected to lead to the development of individualized interventions for the diagnosis and management of oral feeding in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02696343; https://clinicaltrials.gov/ct2/show/NCT02696343 (Archived by WebCite at http://www.webcitation.org/6r5NbJ9Ym).

18.
FEMS Microbiol Ecol ; 92(12)2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27612495

RESUMO

Impacts of long-term CO2 exposure on environmental processes and microbial populations of near-surface soils are poorly understood. This near-surface long-term CO2 injection study demonstrated that soil microbiology and geochemistry is influenced more by seasonal parameters than elevated CO2 Soil samples were taken during a 3-year field experiment including sampling campaigns before, during and after 24 months of continuous CO2 injection. CO2 concentrations within CO2-injected plots increased up to 23% during the injection period. No CO2 impacts on geochemistry were detected over time. In addition, CO2-exposed samples did not show significant changes in microbial CO2 and CH4 turnover rates compared to reference samples. Likewise, no significant CO2-induced variations were detected for the abundance of Bacteria, Archaea (16S rDNA) and gene copy numbers of the mcrA gene, Crenarchaeota and amoA gene. The majority (75%-95%) of the bacterial sequences were assigned to five phyla: Firmicutes, Proteobacteria, Actinobacteria, Acidobacteria and Bacteroidetes The majority of the archaeal sequences (85%-100%) were assigned to the thaumarchaeotal cluster I.1b (soil group). Univariate and multivariate statistical as well as principal component analyses showed no significant CO2-induced variation. Instead, seasonal impacts especially temperature and precipitation were detected.


Assuntos
Bactérias/classificação , Dióxido de Carbono/química , Dióxido de Carbono/farmacologia , Crenarchaeota/classificação , Microbiologia do Solo , Solo/química , Bactérias/efeitos dos fármacos , Bactérias/genética , Crenarchaeota/efeitos dos fármacos , Crenarchaeota/genética , DNA Ribossômico/genética , Efeito Estufa , Filogenia , RNA Ribossômico 16S/genética , Reino Unido
19.
Am J Manag Care ; 22(4): e147-52, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27143351

RESUMO

OBJECTIVES: To provide a review of the outcomes and costs in patients seen by Clinical Pharmacy Specialist (CPS) Certified Diabetes Educators in ambulatory care for diabetes management. STUDY DESIGN: A retrospective chart review. METHODS: All patients discharged by a CPS for diabetes management between January 1, 2010, and December 31, 2013, were included. RESULTS: A total of 915 patients were discharged from CPS services. The majority of patients had type 2 diabetes (98.7%) and were female (63.1%), Hispanic (53.3%), and on average, were aged 56 years. The patients were seen by the CPS for approximately 5.3 face-to-face visits, and by their provider for 1.9 face-to-face visits. The average difference from baseline for glycated hemoglobin was -2.6%, while the average systolic and diastolic blood pressures improved by -8 mm Hg and -3 mm Hg, respectively. The major lipid parameters also reported improvement, averaging -23 mg/dL for total cholesterol, -54 mg/dL for triglycerides, -15 mg/dL for low-density lipoprotein cholesterol, -23 mg/dL for non-high-density lipoprotein cholesterol (non-HDL-C), and +0.8 mg/dL for HDL-C. Overall, the average difference from baseline to final visit for the numbers and costs of medications and diabetes supplies per patient increased slightly. Medication adherence also improved each year in patients with diabetes. CONCLUSIONS: The CPSs directly impact patient care through improvements in clinical outcomes. They help patients achieve disease-state goals for diabetes, hypertension, and dyslipidemia through a variety of clinical interventions and by promoting medication adherence. These data demonstrate the significant positive impact to the institution that clinical pharmacy services have in diabetes management.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/economia , Hipoglicemiantes/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Serviço de Farmácia Hospitalar/organização & administração , Cuidados de Saúde não Remunerados/economia , Adulto , Idoso , Assistência Ambulatorial/organização & administração , Análise Custo-Benefício , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Seguimentos , Humanos , Hipoglicemiantes/economia , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Alta do Paciente/estatística & dados numéricos , Melhoria de Qualidade , Estudos Retrospectivos , Resultado do Tratamento , Cuidados de Saúde não Remunerados/estatística & dados numéricos , Estados Unidos
20.
Guang Pu Xue Yu Guang Pu Fen Xi ; 35(10): 2781-6, 2015 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-26904818

RESUMO

With the global warming, people now pay more attention to the problem of the emission of greenhouse gas (CO2). Carbon capture and storage (CCS) technology is an effective measures to reduce CO2 emission. But there is a possible risk that the CO2 might leak from underground. However, there need to research and develop a technique to quickly monitor CO2 leaking spots above sequestration fields. The field experiment was performed in the Sutton Bonington campus of University of Nottingham (52. 8N, 1. 2W) from May to September in 2008. The experiment totally laid out 16 plots, grass (cv Long Ley) and beans (Vicia faba cv Clipper) were planted in eight plots, respectively. However, only four grass and bean plots were stressed by the CO2 leakage, and CO2 was always injected into the soil at a rate of 1 L x min(-1). The canopy spectra were measured using ASD instrument, and the grass was totally collected 6 times data and bean was totally collected 3 times data. This paper study the canopy spectral characteristics of grass and beans under the stress of CO2 microseepages through the field simulated experiment, and build the model to detect CO2 microseepage spots by using hyperspectral remote sensing. The results showed that the canopy spectral reflectance of grass and beans under the CO2 leakage stress increased in 580-680 nm with the stressed severity elevating, moreover, the spectral features of grass and beans had same rule during the whole experimental period. According to the canopy spectral features of two plants, a new index AREA(5800680 nm) was designed to detect the stressed vegetations. The index was tested through J-M distance, and the result suggested that the index was able to identify the center area and the core area grass under CO2 leakage stress, however, the index had a poor capability to discriminate the edge area grass from control. Then, the index had reliable and steady ability to identify beans under CO2 leakage stress. This result could provide theoretical basis and methods for detecting CO2 leakage spots using hyperspectral remote sensing in the future.

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