Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
1.
BMC Psychiatry ; 24(1): 199, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38475800

ABSTRACT

BACKGROUND: Globally, individuals with mental illness get in contact with the law at a greater rate than the general population. The goal of this review was to identify and describe: (1) effectiveness of mental health interventions for individuals with serious mental illness (SMI) who have criminal legal involvement; (2) additional outcomes targeted by these interventions; (3) settings/contexts where interventions were delivered; and (4) barriers and facilitating factors for implementing these interventions. METHODS: A systematic review was conducted to summarize the mental health treatment literature for individuals with serious mental illness with criminal legal involvement (i.e., bipolar disorder, schizophrenia, major depressive disorder). Searches were conducted using PsychINFO, Embase, ProQuest, PubMed, and Web of Science. Articles were eligible if they were intervention studies among criminal legal involved populations with a mental health primary outcome and provided description of the intervention. RESULTS: A total of 13 eligible studies were identified. Tested interventions were categorized as cognitive/behavioral, community-based, interpersonal (IPT), psychoeducational, or court-based. Studies that used IPT-based interventions reported clinically significant improvements in mental health symptoms and were also feasible and acceptable. Other interventions demonstrated positive trends favoring the mental health outcomes but did not show statistically and clinically significant changes. All studies reported treatment outcomes, with only 8 studies reporting both treatment and implementation outcomes. CONCLUSION: Our findings highlight a need for more mental health research in this population. Studies with randomized design, larger sample size and studies that utilize non-clinicians are needed.


Subject(s)
Bipolar Disorder , Criminals , Depressive Disorder, Major , Mental Disorders , Humans , Mental Health , Mental Disorders/psychology
2.
Contemp Clin Trials ; 132: 107297, 2023 09.
Article in English | MEDLINE | ID: mdl-37473848

ABSTRACT

PURPOSE: To examine the effectiveness, cost-outcome, equity, scalability, and mechanisms of the Reach Out, Stay strong, Essentials for mothers of newborns (ROSE) postpartum depression prevention (PPD) program as universal versus selective or indicated prevention. BACKGROUND: The United States Preventive Services Task Force (USPSTF) currently recommends PPD prevention for pregnant people at risk of PPD (i.e., selective/indicated prevention). However, universal prevention may be more scalable, equitable, and cost-beneficial. DESIGN: Effectiveness of ROSE for preventing PPD among people at risk is known. To assess ROSE as universal prevention, we need to determine the effectiveness of ROSE among all pregnant people, including those screening negative for PPD risk. We will enroll 2320 pregnant people, assess them with commonly available PPD risk prediction tools, randomize everyone to ROSE or enhanced care as usual, and assess ROSE as universal, selective, and indicated prevention in terms of: (1) effectiveness (PPD prevention and functioning), (2) cost-benefit, (3) equity (PPD cases prevented by universal prevention that would not be prevented under selective/indicated for minority vs. non-Hispanic white people), (4) quantitative and qualitative measures of scalability (from 98 agencies previously implementing ROSE), (5) ROSE mechanisms across risk levels. We will integrate results to outline pros and cons of the three prevention approaches (i.e., universal, selective, indicated). CONCLUSION: This will be the first trial to assess universal vs. selective/indicated PPD prevention. Trial design illustrates a novel, efficient way to make these comparisons. This trial, the largest PPD prevention trial to date, will examine scalability, an understudied area of implementation science.


Subject(s)
Depression, Postpartum , Female , Humans , Infant, Newborn , Pregnancy , Cost-Benefit Analysis , Depression, Postpartum/diagnosis , Depression, Postpartum/prevention & control , Mothers , Preventive Health Services , Research Design , United States
3.
Adv Mater ; 35(14): e2211027, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36738161

ABSTRACT

Creating multifunctional concrete materials with advanced functionalities and mechanical tunability is a critical step toward reimagining the traditional civil infrastructure systems. Here, the concept of nanogenerator-integrated mechanical metamaterial concrete is presented to design lightweight and mechanically tunable concrete systems with energy harvesting and sensing functionalities. The proposed metamaterial concrete systems are created via integrating the mechanical metamaterial and nano-energy-harvesting paradigms. These advanced materials are composed of reinforcement auxetic polymer lattices with snap-through buckling behavior fully embedded inside a conductive cement matrix. We rationally design their composite structures to induce contact-electrification between the layers under mechanical excitations/triggering. The conductive cement enhanced with graphite powder serves as the electrode in the proposed systems, while providing the desired mechanical performance. Experimental studies are conducted to investigate the mechanical and electrical properties of the designed prototypes. The metamaterial concrete systems are tuned to achieve up to 15% compressibility under cycling loading. The power output of the nanogenerator-integrated metamaterial concrete prototypes reaches 330 µW. Furthermore, the self-powered sensing functionality of the nanogenerator concrete systems for distributed health monitoring of large-scale concrete structures is demonstrated. The metamaterial concrete paradigm can possibly enable the design of smart civil infrastructure systems with a broad range of advanced functionalities.

4.
Am J Dermatopathol ; 45(2): 123-126, 2023 Feb 01.
Article in English | MEDLINE | ID: mdl-36669077

ABSTRACT

ABSTRACT: Primary cutaneous mucinous carcinoma is a rare, indolent malignancy with a debated history regarding cell of origin. Recurrence is rare but has been documented in up to a third of cases. Recent literature reviews have recognized 2 possible subtypes-neuroendocrine and nonneuroendocrine- with different possible prognostic implications for patients. We describe a case of recurrent primary cutaneous mucinous carcinoma in a 50-year-old man with subtle neuroendocrine features not initially recognized on routine H&E staining but highlighted by immunohistochemical studies. We underscore the importance of immunohistochemical use in these rare cases and emphasize that awareness of these neuroendocrine and nonneuroendocrine subtypes is essential for a complete diagnosis.


Subject(s)
Adenocarcinoma, Mucinous , Carcinoma, Neuroendocrine , Skin Neoplasms , Male , Humans , Middle Aged , Scalp/surgery , Scalp/pathology , Adenocarcinoma, Mucinous/surgery , Adenocarcinoma, Mucinous/pathology , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Carcinoma, Neuroendocrine/pathology
5.
J Org Chem ; 87(24): 16517-16525, 2022 12 16.
Article in English | MEDLINE | ID: mdl-36455157

ABSTRACT

Alkyne carbopalladation reactions can rapidly generate multiple new C-C bonds; however, regioselectivity is challenging for intermolecular variants. Using ynol ethers, we observe complete regiocontrol of migratory insertion followed by a second migratory insertion with a pendant alkene to turn-over the catalytic cycle. The resulting products are oligosubstituted 1-indenol ethers with defined stereochemistry based on the initial alkene geometry. Blocking ß-hydride elimination allowed for C-H and C-C reductive elimination steps for catalyst turnover.


Subject(s)
Alkenes , Ethers , Ethers/chemistry , Alkenes/chemistry , Catalysis , Alkynes
6.
Article in English | MEDLINE | ID: mdl-36011633

ABSTRACT

Wu et al. found a strong positive association between cumulative daily county-level COVID-19 mortality and long-term average PM2.5 concentrations for data up until September 2020. We replicated the results of Wu et al. and extended the analysis up until May 2022. The association between PM2.5 concentration and cumulative COVID-19 mortality fell sharply after September 2020. Using the data available from Wu et al.'s "updated_data" branch up until May 2022, we found that the effect of a 1 µg/m3 increase in PM2.5 was associated with only a +0.603% mortality difference. The 95% CI of this difference was between -0.560% and +1.78%, narrow bounds that include zero, with the upper bound far below the Wu et al. estimate. Short-term trends in the initial spread of COVID-19, not a long-term epidemiologic association, caused an early correlation between air pollution and COVID-19 mortality.


Subject(s)
Air Pollutants , Air Pollution , COVID-19 , Air Pollutants/adverse effects , Air Pollutants/analysis , Air Pollution/adverse effects , Air Pollution/analysis , COVID-19/epidemiology , Environmental Exposure/analysis , Humans , Pandemics , Particulate Matter/analysis
7.
BMJ Open ; 12(4): e057747, 2022 04 19.
Article in English | MEDLINE | ID: mdl-35440458

ABSTRACT

INTRODUCTION: This protocol describes a study testing the efficacy of interpersonal psychotherapy (IPT) for major depressive disorder following perinatal loss (early and late fetal death and early neonatal death). Perinatal loss is associated with elevated risk of major depressive disorder and post-traumatic stress disorder (PTSD). Perinatal loss conveys specific treatment needs. The trial will be the first fully powered randomised trial of treatment for any psychiatric disorder following perinatal loss. METHODS AND ANALYSIS: A sample of 274 women in Flint and Detroit areas in Michigan who experience a major depressive episode following a perinatal loss will be randomised to group IPT for perinatal loss or to group coping with depression. We anticipate that 50% of the sample will have co-occurring PTSD. Assessments occur at baseline, mid-treatment (8 weeks), post-treatment (16 weeks) and follow-up (28 weeks). Clinical outcomes include time to recovery from major depressive episode (primary), depressive symptoms, PTSD symptoms and time to recovery from PTSD. Additional outcomes include social support, social role functioning (including parental functioning for those with living children), well-being, grief (including complicated grief and fault beliefs) and fear of subsequent pregnancies. Social support and grief are hypothesised mediators of IPT effects on time to recovery from major depressive episode. ETHICS AND DISSEMINATION: The trial was approved by Michigan State University's Biomedical Institutional Review Board. It has a data and safety monitoring board and has been submitted to the community-based organisation partners community ethics review board. Written operating procedures outline methods for protecting confidentiality, monitoring and recording adverse events, and safeguarding participants. We will share study results with research and clinical communities, community organisations through which we recruited, and will offer results to study participants. Deidentified datasets will be available through the National Institute of Mental Health Data Archive and to qualified investigators on request. TRIAL REGISTRATION NUMBER: NCT04629599.


Subject(s)
Depressive Disorder, Major , Interpersonal Psychotherapy , Stress Disorders, Post-Traumatic , Child , Depression , Depressive Disorder, Major/psychology , Depressive Disorder, Major/therapy , Female , Humans , Infant, Newborn , Male , Parturition , Pregnancy , Psychotherapy/methods , Randomized Controlled Trials as Topic , Stress Disorders, Post-Traumatic/therapy , Treatment Outcome
8.
Oncology ; 100(6): 337-343, 2022.
Article in English | MEDLINE | ID: mdl-35344965

ABSTRACT

BACKGROUND: In patients with hormone receptor-positive metastatic breast cancer, palbociclib has been shown to improve overall survival and progression-free survival (PFS) when combined with endocrine therapy. Dose modification of palbociclib is effective in the management of adverse events. Despite variable clinical response, no predictive biomarkers of efficacy to palbociclib have been identified in metastatic breast cancer. In our study, we aimed to assess the PFS of metastatic breast cancer patients who received dose-reduced palbociclib and compare the results in the non-dose-reduced group. We also evaluated the clinical significance of progesterone receptor (PR) and Ki67 as predictive biomarkers of palbociclib. METHODS: Seventy-six palbociclib-treated metastatic breast cancer patients were included in our study. PFS was compared between dose-reduced and non-dose-reduced groups. PR expression and Ki67 status were assessed by immunohistochemistry. Kaplan-Meier method and log-rank test were used to analyze PFS. RESULTS: Of the 76 patients, 40 (52.6%) experienced dose reduction (DR). Statistical analysis of the results revealed that there were no statistically significant differences observed between dose-reduced (16.5 months) versus non-dose-reduced (17.7 months) patients in PFS (p = 0.5493). For patients with Ki67 ≥14%, PFS was 15.2 months (95% CI: 10.2-22.2 months; p = 0.3024). In patients with PR ≥20%, median PFS was 25.0 months (lower 95% CI: 16.8 months; p = 0.0069). CONCLUSION: Our study indicated that DR of palbociclib is frequently required but does not appear to affect PFS. PR expression was suggested to be a significant predictive factor for palbociclib responsiveness.


Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Female , Humans , Ki-67 Antigen , Piperazines , Progression-Free Survival , Pyridines , Receptor, ErbB-2/metabolism
9.
Commun Biol ; 4(1): 1085, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34526658

ABSTRACT

We present two high-throughput compatible methods to detect the interaction of ectopically expressed (RT-Bind) or endogenously tagged (EndoBind) proteins of interest. Both approaches provide temporal evaluation of dimer formation over an extended duration. Using examples of the Nrf2-KEAP1 and the CRAF-KRAS-G12V interaction, we demonstrate that our method allows for the detection of signal for more than 2 days after substrate addition, allowing for continuous monitoring of endogenous protein-protein interactions in real time.


Subject(s)
High-Throughput Screening Assays/methods , Kelch-Like ECH-Associated Protein 1/chemistry , NF-E2-Related Factor 2/chemistry , Proto-Oncogene Proteins p21(ras)/chemistry , HEK293 Cells , Humans , Protein Binding
10.
ChemMedChem ; 15(16): 1562-1570, 2020 08 19.
Article in English | MEDLINE | ID: mdl-32613743

ABSTRACT

Loss of ß-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase ß-cell mass are less developed. Promoting ß-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring ß-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3ß (GSK3ß) was previously reported to induce primary human ß-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring ß-cell proliferation.


Subject(s)
Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Insulin-Secreting Cells/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Rats , Structure-Activity Relationship , Dyrk Kinases
11.
PLoS One ; 15(3): e0224344, 2020.
Article in English | MEDLINE | ID: mdl-32176701

ABSTRACT

A key event in the development of both major forms of diabetes is the loss of functional pancreatic islet ß-cell mass. Strategies aimed at enhancing ß-cell regeneration have long been pursued, but methods for reliably inducing human ß-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor NKX6.1 stimulates ß-cell proliferation, while also enhancing GSIS and providing protection against ß-cell cytotoxicity through induction of the VGF prohormone. We developed an NKX6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation, but not expression of NKX6.1 or VGF, suggesting an alternative mechanism of action. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human ß-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. GNF-9228 stimulates proliferation via a mechanism distinct from recently emergent DYRK1A inhibitors, as it is unaffected by DYRK1A overexpression and does not activate NFAT translocation. In conclusion, we have identified a small molecule with pleiotropic positive effects on islet biology, including stimulation of human ß-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.


Subject(s)
Cell Proliferation/drug effects , Insulin Secretion/drug effects , Insulin-Secreting Cells/metabolism , Insulinoma/metabolism , Protein Kinase Inhibitors/pharmacology , Animals , Cell Line, Tumor , Glucagon-Secreting Cells/metabolism , Glucagon-Secreting Cells/pathology , Glucose/pharmacology , Homeodomain Proteins/metabolism , Humans , Insulin-Secreting Cells/pathology , Insulinoma/pathology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Rats , Dyrk Kinases
12.
Cell Rep ; 25(10): 2904-2918.e8, 2018 12 04.
Article in English | MEDLINE | ID: mdl-30517875

ABSTRACT

Pancreatic ß cell physiology changes substantially throughout life, yet the mechanisms that drive these changes are poorly understood. Here, we performed comprehensive in vivo quantitative proteomic profiling of pancreatic islets from juvenile and 1-year-old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism. We show that these changes in protein abundance are associated with higher activities of glucose metabolic enzymes involved in coupling factor generation as well as increased activity of the coupling factor-dependent amplifying pathway of insulin secretion. Nutrient tracing and targeted metabolomics demonstrated accelerated accumulation of glucose-derived metabolites and coupling factors in islets from 1-year-old mice, indicating that age-related changes in glucose metabolism contribute to improved glucose-stimulated insulin secretion with age. Together, our study provides an in-depth characterization of age-related changes in the islet proteome and establishes metabolic rewiring as an important mechanism for age-associated changes in ß cell function.


Subject(s)
Cellular Senescence , Insulin-Secreting Cells/metabolism , Metabolomics/methods , Proteomics/methods , Aging , Animals , Carbon/metabolism , Cell Respiration/drug effects , Citric Acid Cycle/drug effects , Female , Gene Expression Regulation , Glucose/metabolism , Glucose/pharmacology , Insulin Secretion , Male , Mice, Inbred C57BL , Proteome/metabolism
13.
Org Biomol Chem ; 16(44): 8639-8646, 2018 11 14.
Article in English | MEDLINE | ID: mdl-30383066

ABSTRACT

The rhodium-catalyzed C-H activation and annulation with ynol ethers to directly provide 4-oxy substituted isoquinolinones is reported. The polarized nature of ynol ethers provides an electronic bias for controlling the regioselectivity of the migratory insertion process. While the highly reactive nature of ynol ethers presents a challenge, mild conditions were found to provide product in moderate to good yield. Utility was demonstrated by application in the synthesis of a prolyl-4-hydroxylase inhibitor framework.

14.
Orthop Clin North Am ; 48(3): 359-369, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28577785

ABSTRACT

In the surgical treatment of foot and ankle abnormality, many problems require bone grafting for successful osseous union. Nonunion, reconstruction, and arthrodesis procedures pose specific challenges due to bony defects secondary to trauma, malunions, or previous surgery. Nonunion in foot and ankle arthrodesis is a significant risk and is well documented in recent literature. This article is a review of the recent literature regarding the use of bone graft and orthobiologics in foot and ankle surgery.


Subject(s)
Ankle Injuries , Biological Therapy/methods , Bone Transplantation/methods , Foot Injuries , Ankle Injuries/complications , Ankle Injuries/physiopathology , Ankle Injuries/therapy , Foot Deformities, Acquired/etiology , Foot Deformities, Acquired/physiopathology , Foot Deformities, Acquired/therapy , Foot Injuries/complications , Foot Injuries/physiopathology , Foot Injuries/therapy , Fracture Healing/physiology , Humans
15.
J Clin Invest ; 127(1): 215-229, 2017 01 03.
Article in English | MEDLINE | ID: mdl-27941246

ABSTRACT

The recognition of ß cell dedifferentiation in type 2 diabetes raises the translational relevance of mechanisms that direct and maintain ß cell identity. LIM domain-binding protein 1 (LDB1) nucleates multimeric transcriptional complexes and establishes promoter-enhancer looping, thereby directing fate assignment and maturation of progenitor populations. Many terminally differentiated endocrine cell types, however, remain enriched for LDB1, but its role is unknown. Here, we have demonstrated a requirement for LDB1 in maintaining the terminally differentiated status of pancreatic ß cells. Inducible ablation of LDB1 in mature ß cells impaired insulin secretion and glucose homeostasis. Transcriptomic analysis of LDB1-depleted ß cells revealed the collapse of the terminally differentiated gene program, indicated by a loss of ß cell identity genes and induction of the endocrine progenitor factor neurogenin 3 (NEUROG3). Lineage tracing confirmed that LDB1-depleted, insulin-negative ß cells express NEUROG3 but do not adopt alternate endocrine cell fates. In primary mouse islets, LDB1 and its LIM homeodomain-binding partner islet 1 (ISL1) were coenriched at chromatin sites occupied by pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), forkhead box A2 (FOXA2), and NK2 homeobox 2 (NKX2.2) - factors that co-occupy active enhancers in 3D chromatin domains in human islets. Indeed, LDB1 was enriched at active enhancers in human islets. Thus, LDB1 maintains the terminally differentiated state of ß cells and is a component of active enhancers in both murine and human islets.


Subject(s)
Cell Differentiation , DNA-Binding Proteins/metabolism , Insulin-Secreting Cells/metabolism , LIM Domain Proteins/metabolism , Transcription Factors/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , DNA-Binding Proteins/genetics , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Hepatocyte Nuclear Factor 3-beta/genetics , Hepatocyte Nuclear Factor 3-beta/metabolism , Homeobox Protein Nkx-2.2 , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Insulin-Secreting Cells/pathology , LIM Domain Proteins/genetics , LIM-Homeodomain Proteins/genetics , LIM-Homeodomain Proteins/metabolism , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/genetics , Zebrafish Proteins
16.
J Pediatr Orthop B ; 26(4): 350-357, 2017 Jul.
Article in English | MEDLINE | ID: mdl-27509482

ABSTRACT

Femoral neck and pelvic fractures are rarely encountered in the pediatric population secondary to the resilient nature of the immature skeleton. Both fracture types usually result from high-energy blunt trauma including motor vehicle collisions, motor vehicle-pedestrian accidents, and falls from height. Considerable studies have been published on the natural history, management, and complications of pediatric pelvis and femoral neck fractures. However, few case reports have documented both fracture types in the same patient. Management of concomitant injuries presents unique challenges both for operative stabilization and for clinical postoperative care. After appropriate consent was obtained, a thorough review was performed of the patient's hospital records and imaging history. The senior author of the report also provided insight into the management of the patient's initial injuries and subsequent complications. Our case involves a 4-year-old female who was overrun by an all-terrain vehicle. Her orthopedic injuries included a nondisplaced Delbet type 3 fracture of the right femoral neck, a completely displaced Delbet type 3 fracture of the left femoral neck, bilateral sacroiliac fracture-dislocations, severe comminution of her left pubic rami, and a free-floating right pubic rami segment spanning from the triradiate cartilage to the pubic symphysis with severe rotational deformity. Her postoperative recovery was complicated by refracture of her left femoral neck (Delbet type 1), left hip osteomyelitis, and left femoral head avascular necrosis. The salient features of her operative management, subsequent complications, and functional recovery are described in this report. Cases of bilateral femoral neck fractures and multiple pelvic fractures in pediatric patients are sparsely documented in the literature because of their infrequent occurrence. Pediatric pelvic fractures typically do well with conservative treatment secondary to the incredible remodeling ability of the immature pelvis. Femoral neck fractures, in contrast, are highly associated with complications including coxa vara, nonunion, infection, physeal closure, and avascular necrosis. This case report documents two rare fracture types in the same patient and describes the challenges encountered throughout the duration of her recovery. LEVEL OF EVIDENCE: Level V, Case report.


Subject(s)
Femoral Neck Fractures/surgery , Ileum/injuries , Pubic Bone/injuries , Sacroiliac Joint/injuries , Anti-Bacterial Agents/therapeutic use , Bone Screws , Child, Preschool , Closed Fracture Reduction , Female , Femoral Neck Fractures/complications , Femoral Neck Fractures/diagnostic imaging , Humans , Ileum/diagnostic imaging , Ileum/surgery , Off-Road Motor Vehicles , Pubic Bone/diagnostic imaging , Pubic Bone/surgery , Radiography , Sacroiliac Joint/diagnostic imaging , Sacroiliac Joint/surgery , Surgical Wound Infection/diagnosis , Surgical Wound Infection/drug therapy , Tomography, X-Ray Computed
17.
Laryngoscope ; 126(8): 1854-8, 2016 08.
Article in English | MEDLINE | ID: mdl-27426940

ABSTRACT

OBJECTIVES/HYPOTHESIS: Determine swallowing mechanics associated with the first and second epiglottic movements, that is, movement to horizontal and full inversion, respectively, to provide a clinical interpretation of impaired epiglottic function. STUDY DESIGN: Retrospective cohort study. METHODS: A heterogeneous cohort of patients with swallowing difficulties was identified (n = 92). Two speech-language pathologists reviewed 5-mL thin and 5-mL pudding videofluoroscopic swallow studies per subject, and assigned epiglottic component scores of 0 = complete inversion, 1 = partial inversion, and 2 = no inversion, forming three groups of videos for comparison. Coordinates mapping minimum and maximum excursion of the hyoid, pharynx, larynx, and tongue base during pharyngeal swallowing were recorded using ImageJ software. A canonical variate analysis with post hoc discriminant function analysis of coordinates was performed using MorphoJ software to evaluate mechanical differences between groups. Eigenvectors characterizing swallowing mechanics underlying impaired epiglottic movements were visualized. RESULTS: Nineteen of 184 video swallows were rejected for poor quality (n = 165). A Goodman-Kruskal index of predictive association showed no correlation between epiglottic component scores and etiologies of dysphagia (λ = .04). A two-way analysis of variance by epiglottic component scores showed no significant interaction effects between sex and age (f = 1.4, P = .25). Discriminant function analysis demonstrated statistically significant mechanical differences between epiglottic component scores: 1 and 2, representing the first epiglottic movement (Mahalanobis distance = 1.13, P = .0007); and 0 and 1, representing the second epiglottic movement (Mahalanobis distance = 0.83, P = .003). Eigenvectors indicate that laryngeal elevation and tongue base retraction underlie both epiglottic movements. CONCLUSIONS: Results suggest that reduced tongue base retraction and laryngeal elevation underlie impaired first and second epiglottic movements. The styloglossus, hyoglossus, and long pharyngeal muscles are implicated as targets for rehabilitation in dysphagic patients with impaired epiglottic inversion. LEVEL OF EVIDENCE: 2b Laryngoscope, 126:1854-1858, 2016.


Subject(s)
Deglutition Disorders/physiopathology , Deglutition/physiology , Epiglottis/physiopathology , Cohort Studies , Female , Humans , Male , Middle Aged , Retrospective Studies
18.
Nat Commun ; 6: 8372, 2015 Oct 26.
Article in English | MEDLINE | ID: mdl-26496802

ABSTRACT

Insufficient pancreatic ß-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from ß-cells in diabetic patients, no pharmacological agents have been described that increase ß-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust ß-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces ß-cell proliferation, increases ß-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore ß-cell mass, and highlights a tractable pathway for future drug discovery efforts.


Subject(s)
Cell Proliferation , Glycogen Synthase Kinase 3/genetics , Insulin-Secreting Cells/cytology , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , Animals , Cell Division/drug effects , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Down-Regulation/drug effects , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/enzymology , Male , Mice , Mice, Transgenic , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Pyridazines/pharmacology , Dyrk Kinases
19.
Diabetes ; 64(3): 897-903, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25277396

ABSTRACT

All forms of diabetes are characterized by a loss of functional ß-cell mass, and strategies for expanding ß-cell mass could have significant therapeutic benefit. We have recently identified the transcription factor Nkx6.1 as an essential maintenance factor of the functional ß-cell state. In addition, Nkx6.1 has been proposed to control ß-cell proliferation, but a role for Nkx6.1 in regulating ß-cell mass has not been demonstrated. Here, we show that Nkx6.1 is required for postnatal ß-cell mass expansion. Genetic inactivation of Nkx6.1 in newly formed ß-cells caused a drastic decrease in early postnatal ß-cell proliferation, leading to reduced ß-cell mass and glucose intolerance. Interestingly, Nkx6.1 was dispensable for prenatal ß-cell proliferation. We found that Nkx6.1 regulates the expression of several ß-cell maturation markers as well as expression of the nutrient sensors Glut2 and Glp1r. Manifestation of the ß-cell mass defect at the transition to postnatal feeding suggests that Nkx6.1 could regulate ß-cell growth by enabling ß-cells to respond to nutrient-dependent proliferation signals, such as glucose and Glp1. Identification of ß-cell-intrinsic regulators that connect nutrient-sensing and proliferation suggests new therapeutic targets for expanding functional ß-cell mass.


Subject(s)
Homeodomain Proteins/metabolism , Insulin-Secreting Cells/metabolism , Animals , Cell Proliferation/genetics , Cell Proliferation/physiology , Homeodomain Proteins/genetics , Hyperglycemia/genetics , Hyperglycemia/metabolism , Mice , Mice, Knockout
20.
J Vis Exp ; (87)2014 May 06.
Article in English | MEDLINE | ID: mdl-24836901

ABSTRACT

Characterizing hyolaryngeal movement is important to dysphagia research. Prior methods require multiple measurements to obtain one kinematic measurement whereas coordinate mapping of hyolaryngeal mechanics using Modified Barium Swallow (MBS) uses one set of coordinates to calculate multiple variables of interest. For demonstration purposes, ten kinematic measurements were generated from one set of coordinates to determine differences in swallowing two different bolus types. Calculations of hyoid excursion against the vertebrae and mandible are correlated to determine the importance of axes of reference. To demonstrate coordinate mapping methodology, 40 MBS studies were randomly selected from a dataset of healthy normal subjects with no known swallowing impairment. A 5 ml thin-liquid bolus and a 5 ml pudding swallows were measured from each subject. Nine coordinates, mapping the cranial base, mandible, vertebrae and elements of the hyolaryngeal complex, were recorded at the frames of minimum and maximum hyolaryngeal excursion. Coordinates were mathematically converted into ten variables of hyolaryngeal mechanics. Inter-rater reliability was evaluated by Intraclass correlation coefficients (ICC). Two-tailed t-tests were used to evaluate differences in kinematics by bolus viscosity. Hyoid excursion measurements against different axes of reference were correlated. Inter-rater reliability among six raters for the 18 coordinates ranged from ICC = 0.90 - 0.97. A slate of ten kinematic measurements was compared by subject between the six raters. One outlier was rejected, and the mean of the remaining reliability scores was ICC = 0.91, 0.84 - 0.96, 95% CI. Two-tailed t-tests with Bonferroni corrections comparing ten kinematic variables (5 ml thin-liquid vs. 5 ml pudding swallows) showed statistically significant differences in hyoid excursion, superior laryngeal movement, and pharyngeal shortening (p < 0.005). Pearson correlations of hyoid excursion measurements from two different axes of reference were: r = 0.62, r2 = 0.38, (thin-liquid); r = 0.52, r2 = 0.27, (pudding). Obtaining landmark coordinates is a reliable method to generate multiple kinematic variables from video fluoroscopic images useful in dysphagia research.


Subject(s)
Deglutition/physiology , Hyoid Bone/anatomy & histology , Hyoid Bone/physiology , Larynx/anatomy & histology , Larynx/physiology , Biomechanical Phenomena , Humans , Image Processing, Computer-Assisted , Reference Values , Software
SELECTION OF CITATIONS
SEARCH DETAIL
...