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1.
Thyroid ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33108969

RESUMO

Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease (n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.

3.
Mol Psychiatry ; 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753686

RESUMO

We previously reported that SNPs near TSPAN5 were associated with plasma serotonin (5-HT) concentrations which were themselves associated with selective serotonin reuptake inhibitor treatment outcomes in patients with major depressive disorder (MDD). TSPAN5 SNPs were also associated with alcohol consumption and alcohol use disorder (AUD) risk. The present study was designed to explore the biological function of TSPAN5 with a focus on 5-HT and kynurenine concentrations in the tryptophan pathway. Ethanol treatment resulted in decreased 5-HT concentrations in human induced pluripotent stem cell (iPSC)-derived neuron culture media, and the downregulation of gene expression of TSPAN5, DDC, MAOA, MAOB, TPH1, and TPH2 in those cells. Strikingly, similar observations were made when the cells were treated with acamprosate-an FDA approved drug for AUD therapy. These results were replicated in iPSC-derived astrocytes. Furthermore, TSPAN5 interacted physically with proteins related to clathrin and other vesicle-related proteins, raising the possibility that TSPAN5 might play a role in vesicular function in addition to regulating expression of genes associated with 5-HT biosynthesis and metabolism. Downregulation of TSPAN5 expression by ethanol or acamprosate treatment was also associated with decreased concentrations of kynurenine, a major metabolite of tryptophan that plays a role in neuroinflammation. Knockdown of TSPAN5 also influenced the expression of genes associated with interferon signaling pathways. Finally, we determined that TSPAN5 SNPs were associated with acamprosate treatment outcomes in AUD patients. In conclusion, TSPAN5 can modulate the concentrations of 5-HT and kynurenine. Our data also highlight a potentially novel pharmacogenomic mechanism related to response to acamprosate.

4.
AJR Am J Roentgenol ; 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32755210

RESUMO

BACKGROUND: Background parenchymal uptake (BPU) on molecular breast imaging (MBI) was identified as a breast cancer risk factor beyond mammographic density in a case-control study, but has not been confirmed in a cohort study. OBJECTIVE: To examine association of BPU with breast cancer, and to estimate absolute risk and discriminatory accuracy of BPU using a cohort study. METHODS: A retrospective cohort of women having MBI from 2004-2015, without prior breast cancer, was established. Radiologists, blinded to future breast cancer diagnoses, assessed BPU at baseline MBI as low (photopenic or minimal) or elevated (mild, moderate, or marked). Associations of BPU with breast cancer were estimated with multivariable Cox proportional hazards models of time to diagnosis. Five-year absolute risk was calculated for study subgroups. Discriminatory accuracy of BPU was assessed. RESULTS: Among 2992 women with mean age 56.3 years (sd 10.6) at MBI, breast cancer events occurred in 144 over 7.3 years median follow-up. Median time to diagnosis was 4.2 years (range 0.5-11.6 years) after MBI. Elevated BPU was associated with greater breast cancer risk (HR=2.39 [1.68, 3.41]; p=<0.001). This association remained in postmenopausal women (HR=3.50 [2.31, 5.31; p<0.001]) but was not significant in premenopausal women (HR=1.29 [0.72, 2.32]; p=0.39). Women with elevated BPU had five-year absolute risk of 4.3% (2.9, 5.7) vs. 2.5% (1.8, 3.1) for those with low BPU. Postmenopausal women with dense breasts and elevated BPU had five-year absolute risk of 8.1% (4.3, 11.8) vs. 2.8% (1.8, 3.8) for those with low BPU. Among postmenopausal women, discriminatory accuracy for invasive cancer was improved with addition of BPU over Gail risk score alone (C-statistic 65.1 vs. 59.1; p=0.04) and over BCSC risk score alone (66.4 vs. 60.4; p=0.04). CONCLUSION: BPU on MBI is an independent breast cancer risk factor, with the strongest association observed among postmenopausal women with dense breasts. In postmenopausal women, BPU provides incremental discrimination in breast cancer risk prediction when combined with the Gail model or BCSC model. CLINICAL IMPACT: Elevated BPU on MBI may identify a subset of women with dense breasts who would benefit most from supplemental screening or preventive options.

5.
Physiol Rep ; 8(16): e14535, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32857481

RESUMO

BACKGROUND: Estrogen may inhibit cell senescence that contributes to age-related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. METHODS: Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead-based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17ß-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. RESULTS: Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [-108 pg/mL (p = .008), -234 pg/mL (p = .0006), and -1374 pg/mL (p < .0001), respectively] than for tE2 [-76 pg/mL (p = .072), -105 pg/mL (p = .076), and -695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019). CONCLUSIONS: Circulating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

6.
Ultrasound Med Biol ; 46(9): 2236-2244, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32600671

RESUMO

Excursion of the median nerve and the surrounding subsynovial connective tissue (SSCT) is diminished in patients with carpal tunnel syndrome (CTS). This study sought to determine if SSCT excursion could be utilized to predict surgical outcome. Idiopathic CTS patients were reviewed with ultrasound and electrodiagnostic tests at baseline. A speckle tracking algorithm was used to determine SSCT relative to tendon motion (shear index). Analysis of variance tests were used to compare SSCT motion with disease severity at baseline. Adjusted linear regressions were used to test the association with patient-reported outcome. A total of 90 CTS patients were analyzed and found to have an average shear index of 79% (95% confidence interval: 76.3%-81.6%). SSCT motion was lower in CTS patients with increasing electrophysiological severity (p = 0.0475). There was no significant association of pre-operative SSCT motion with symptomatic improvement (p = 0.268). Overall, SSCT motion is decreased in CTS patients, but exhibits limited correlation with clinical severity.

7.
Pain Med ; 21(3): 570-575, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142149

RESUMO

OBJECTIVES: The S1 dorsal foramen is the route for 30% of lumbar transforaminal epidural injections; it is therefore important to identify structures impeding S1 foraminal access. The study objective was to characterize the imaging findings, prevalence, and anatomic origin of synovial cysts presenting within the S1 neural foramen. METHODS: A case series (N = 14) established imaging characteristics of S1 synovial cysts. Imaging studies of 400 patients undergoing epidural injections were reviewed for lesions compromising S1 foraminal access. Cadaveric dissections defined the relationship of the inferior recess of the L5-S1 facet to the S1 dorsal foramen. RESULTS: Elderly patients (mean age = 76) exhibited S1 synovial cysts. Synovial cysts were typically 1-2 cm in diameter, hyperintense on sagittal T2 weighted magnetic resonance images (MRIs), fluid-density on computed tomography, and dorsal to the S1 spinal nerve. Sixty percent of cysts exhibited complex MRI signal characteristics (thick wall, internal structure). Tarlov cysts, in contrast, were larger, lobular, and exhibited pure fluid intensity. Lesions impeded access to the S1 dorsal foramina in 5% of reviewed imaging studies (16 Tarlov cysts, three synovial cysts, one conjoint S1-S2 nerve root). The multifidus muscle was interposed between the L5-S1 facet inferior recess and the S1 dorsal foramen on dissection specimens; severe atrophy of the ipsilateral multifidus was noted on imaging in 17/18 synovial cysts. CONCLUSIONS: The S1 neural foramina should be inspected on sagittal MRI, when available, for confounding lesions before performing S1 epidural injections. Tarlov cysts are more common than synovial cysts; the latter are seen in elderly patients with severe multifidus atrophy.

8.
Nat Commun ; 11(1): 87, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911667

RESUMO

Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism.


Assuntos
Osso e Ossos/metabolismo , Metabolismo Energético , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Remodelação Óssea , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Denosumab/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Estudos Prospectivos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
9.
World J Biol Psychiatry ; 21(3): 230-237, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31749403

RESUMO

Objectives: To investigate the effect of sample handling on inflammatory cytokines in serum and highlight challenges with using samples pre-collected from biobanks for biomarker research.Methods: Cytokine concentrations (IL-1ß, IL-2, IL-6, IL-8, IL-10, TNFα, and IFNγ) were measured in serum samples of 205 patients with bipoldar disorder (BD) from the Mayo Clinic Bipolar Disorder Biobank and 205 non-psychiatric controls from the Mayo Clinic Biobank. As cytokine concentrations varied by recruitment site, post-hoc models were used to test the effect of clinical variables and pre-processing time on cytokines. To evaluate the effect of pre-processing time experimentally, cytokines were assayed in serum and plasma from 6 healthy volunteers processed at different time points.Results: Cytokine levels were significantly higher in the BD group. However, both cytokine levels and pre-processing times differed by recruitment site, and post-hoc analyses revealed that pre-processing time was significantly associated with several cytokines. An experiment using samples from healthy volunteers confirmed that concentrations for most cytokines increased with longer pre-processing times.Conclusions: Delays in processing influence cytokine concentrations in blood samples. Given the increasing use of biobanks in research, this study highlights the need to carefully evaluate sample collection and handling methods when designing biomarker studies.

10.
Psychol Serv ; 17(1): 25-32, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30010360

RESUMO

Few children with mental health problems receive evidence-based psychotherapy, partly because of unsuccessful dissemination of evidence-based treatments (EBTs). Previous research suggests that the length and structure of EBT protocols for anxiety disorders may impede their adoption in community practice. To examine the potential discrepancy between EBT protocols and clinical practice across disorders, we examined patient diagnoses and average length of treatment for childhood psychiatric disorders in a regional medical center where child and adolescent patients from the community have access to mental health care. The findings suggest that although a large portion of youth seeking mental health care presented with symptoms consistent with those addressed by common evidence-based psychotherapy protocols, less than half of these patients ever met with a therapist and less than 10% of those attended a sufficient number of sessions to complete a full treatment protocol. These results underscore the need to develop brief and flexible EBT protocols, such as modular treatments, that introduce essential elements early in the course of treatment. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

11.
Mol Psychiatry ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745236

RESUMO

Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.

12.
Ultrasound Med Biol ; 45(11): 2887-2897, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31488311

RESUMO

Nerve movement is decreased in patients with carpal tunnel syndrome and can be assessed with ultrasound. In addition to morphologic features, this study describes a novel approach in which nerve movement and the association with short-term patient-reported outcome are assessed. Ultrasound images at the carpal tunnel inlet were acquired during finger and wrist flexion. Linear regression models were used with the Boston Carpal Tunnel Questionnaire as main outcome. Eighty-five patients were included; 93% completed the 3-mo follow-up. Pre-surgical mean nerve area was 14.5 ± 4.2 mm2 and decreased to 13.3 ± 3.8 mm2 (p < 0.001). Displacement in dorsal direction with wrist flexion increased from 1.9 ± 1.3 to 2.4 ± 1.3 mm (p < 0.01). A pre-surgical larger nerve area was associated with more functional improvement (ß = -0.024, p = 0.02), but baseline mobility was not. Change in excursion with finger flexion was associated with symptomatic improvement, but with a small effect (ß = -0.05, p = 0.01). This indicates that there is limited prognostic potential for dynamic transverse ultrasound in carpal tunnel syndrome.

13.
Spine (Phila Pa 1976) ; 44(19): E1161-E1168, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31261283

RESUMO

STUDY DESIGN: Retrospective matched cohort study. OBJECTIVE: To determine if low-pressure lumbar provocation discography (PD) results in long-term accelerated disc degeneration, internal disc disruption, or disc herniation in patients with symptomatic low back pain (LBP). SUMMARY OF BACKGROUND DATA: Study of subjects without clinically-significant LBP suggests that high-pressure PD may accelerate disc degeneration. METHODS: Consecutive patients with symptomatic LBP who underwent magnetic resonance imaging (MRI), PD, and repeat MRI more than 7 years later, but did not undergo subsequent spinal fusion surgery, were included. Punctured discs were matched (1:2 to 1:4) to corresponding discs in a control cohort by age, BMI, Pfirrmann score (±2), and presence of disc herniation; control cohort inclusion required MRIs for symptomatic LBP, separated by more than 7 years. The primary outcome of the study was a progression in Pfirrmann score category (I-II, III-IV, V). MRI disc-to-CSF T2 signal-intensity ratio, disc height, disc herniations, high intensity zones (HIZs), and Modic changes were assessed. RESULTS: Baseline and follow-up MRIs were available for 77 discs exposed to PD, and for 260 discs in the matched control cohort. There was no difference in the proportion of punctured discs that advanced in Pfirrmann score category in the PD group (17%, 95% CI 9-27%) compared with corresponding discs in the Control group (21%, 95% CI 17-27%), P = 0.3578, or in non-punctured discs in the PD group (35%, 95% CI 21-51%) compared with corresponding discs in the Control group (34%, 95% CI 27-42%), P = 0.1169. There were no differences in disc-to-CSF T2 signal-intensity ratio, presence of disc herniations, HIZs, or Modic changes following puncture in the PD versus matched cohort discs or in the non-punctured PD cohort discs versus corresponding control cohort discs (P > 0.05). CONCLUSION: Patients with symptomatic LBP who underwent low-pressure PD, but who did not undergo a subsequent spinal fusion surgery, developed disc degeneration and new disc herniations at a similar rate to corresponding discs in matched control patients. LEVEL OF EVIDENCE: 3.


Assuntos
Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Disco Intervertebral , Mielografia , Progressão da Doença , Humanos , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/fisiopatologia , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/fisiopatologia , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/fisiopatologia , Imagem por Ressonância Magnética , Mielografia/efeitos adversos , Mielografia/métodos , Mielografia/estatística & dados numéricos , Estudos Retrospectivos
14.
Transl Psychiatry ; 9(1): 149, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123248

RESUMO

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy (1H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3' untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate-glutamine cycling, and its contribution to subphenotypes of mood disorders.


Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Transportador 2 de Aminoácido Excitatório/genética , Ácido Glutâmico/metabolismo , Giro do Cíngulo/metabolismo , Adulto , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espectroscopia de Prótons por Ressonância Magnética
15.
J Neurosurg Sci ; 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30942050

RESUMO

BACKGROUND: Identification of the central sulcus can require inspection of subtle differences or require certain pulse sequences. This study identifies the central sulcus by signal intensity on Double Inversion Recovery (DIR) images in multiple anatomic locations and imaging planes. METHODS: 49 patients (98 hemispheres) were retrospectively reviewed by three neuroradiologists and one radiology resident. The central sulcus was compared to the surrounding sulci for differences in signal intensity at axial hand knob, axial operculum, and lateral convexity sagittal images (294 locations) on DIR images. The use of the 'disappearing central sulcus sign' where the window level is increased at constant width and black/white inversion were also assessed. RESULTS: In 49 patients (22 female, 27 male; median age 36 years), the central sulcus cortex signal intensity was lower than adjacent sulci with a frequency of 90/98 (91.8%) at the axial hand knob level, 68/98 (69.4%) at the axial operculum level, and 76/98 (77.5%) at the sagittal level. With black and white inversion, the frequencies were of 96/98 (98%), 92/98 (94%), and 87/98 (89%). The central sulcus was the first to disappear at all three levels with high degrees of inter-reader agreement (86%-99%). Traditional anatomic landmarks were absent or conflicting in seven hemispheres (5 patients). The central sulcus was identified by DIR signal intensity in all seven hemispheres. CONCLUSIONS: The central sulcus can be identified by differences in signal intensity of the peri-rolandic cortex on DIR. Use of black/white inversion and the disappearing central sulcus sign may further facilitate identification.

16.
Front Pharmacol ; 10: 83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837869

RESUMO

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance. Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003-2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.

17.
Drug Alcohol Depend ; 197: 183-190, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840924

RESUMO

BACKGROUND: Sex-related differences in the susceptibility, progression, and treatment response in alcohol-dependent subjects have been repeatedly reported. In this study, we aimed to investigate the associations of the sex-related hormone/protein levels with alcohol dependence (AD) and alcohol craving in male and female subjects. METHODS: Plasma sex-related hormones (estradiol, estrone, total testosterone, progesterone, follicle stimulated hormone [FSH], luteinizing hormone), and sex hormone binding globulin were measured by mass spectrometry or automated immunoassays from 44 recently-abstained subjects (29 males and 15 females; mean age = 45.9 ± 15.6) meeting DSM-IV-TR criteria for AD and 44 age-, sex- and race-matched non-AD controls. Conditional logistic regression was conducted to examine the association of sex-related hormone and protein levels with AD risk, accounting for matching variables. Their associations with alcohol craving scales (Penn Alcohol Craving Scale and Inventory of Drug-Taking Situations) were assessed in AD subjects. RESULTS: Plasma FSH level was significantly higher in AD males (10.3 ± 9.8 IU/L) than control males (8.0 ± 15.9 IU/L; p = 0.005, pcorrected = 0.035). We also found a significant inverse correlation of FSH level with propensity to drink in negative emotional situations (Spearman's rho=-.540; p = 0.021) and positive correlations between progesterone level and craving intensity (Spearman's rho=.464; p = 0.020) and between total testosterone level and propensity to drink under temptations (adjusted for no-drinking days; ß=6.496; p = 0.041) in AD males. CONCLUSIONS: These results suggest that FSH, progesterone, and testosterone levels may be associated with AD and alcohol craving in AD males. Future research is needed to replicate these findings and investigate the underlying biological mechanisms.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/sangue , Alcoolismo/psicologia , Fissura/fisiologia , Hormônios Esteroides Gonadais/sangue , Adulto , Alcoolismo/epidemiologia , Biomarcadores/sangue , Emoções/fisiologia , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Progesterona/sangue , Autorrelato , Testosterona/sangue
18.
Breast Cancer Res ; 21(1): 38, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850011

RESUMO

BACKGROUND: High background parenchymal uptake (BPU) on molecular breast imaging (MBI) has been identified as a breast cancer risk factor. We explored the feasibility of offering a short-term intervention of low-dose oral tamoxifen to women with high BPU and examined whether this intervention would reduce BPU. METHODS: Women with a history of high BPU and no breast cancer history were invited to the study. Participants had an MBI exam, followed by 30 days of low-dose oral tamoxifen at either 5 mg or 10 mg/day, and a post-tamoxifen MBI exam. BPU on pre- and post-tamoxifen MBI exams was quantitatively assessed as the ratio of average counts in breast fibroglandular tissue vs. average counts in subcutaneous fat. Pre-tamoxifen and post-tamoxifen BPU were compared with paired t tests. RESULTS: Of 47 women invited, 22 enrolled and 21 completed the study (10 taking 5 mg tamoxifen, 11 taking 10 mg tamoxifen). Mean age was 47.7 years (range 41-56 years). After 30 days low-dose tamoxifen, 8 of 21 women (38%) showed a decline in BPU, defined as a decrease from the pre-tamoxifen MBI of at least 15%; 11 of 21 (52%) had no change in BPU (within ± 15%); 2 of 21 (10%) had an increase in BPU of greater than 15%. Overall, the average post-tamoxifen BPU was not significantly different from pre-tamoxifen BPU (1.34 post vs. 1.43 pre, p = 0.11). However, among women taking 10 mg tamoxifen, 5 of 11 (45%) showed a decline in BPU; average BPU was 1.19 post-tamoxifen vs. 1.34 pre-tamoxifen (p = 0.005). In women taking 5 mg tamoxifen, 2 of 10 (20%) showed a decline in BPU; average BPU was 1.51 post-tamoxifen vs.1.53 pre-tamoxifen (p = 0.99). CONCLUSIONS: Short-term intervention with low-dose tamoxifen may reduce high BPU on MBI for some patients. Our preliminary findings suggest that 10 mg tamoxifen per day may be more effective than 5 mg for inducing declines in BPU within 30 days. Given the variability in BPU response to tamoxifen observed among study participants, future study is warranted to determine if BPU response could predict the effectiveness of tamoxifen for breast cancer risk reduction within an individual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979301 . Registered 01 December 2016.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Mamografia/métodos , Imagem Molecular/métodos , Tamoxifeno/administração & dosagem , Administração Oral , Adulto , Mama/patologia , Densidade da Mama/efeitos dos fármacos , Neoplasias da Mama/patologia , Estudos de Viabilidade , Feminino , Câmaras gama , Humanos , Mamografia/instrumentação , Pessoa de Meia-Idade , Imagem Molecular/instrumentação , Projetos Piloto , Estudos Prospectivos , Cintilografia/instrumentação , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Tecnécio Tc 99m Sestamibi/administração & dosagem , Fatores de Tempo
19.
Alcohol Alcohol ; 54(2): 167-172, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796778

RESUMO

AIMS: Replicate the previously reported association of elevated alcohol craving, measured by Penn Alcohol Craving Scale (PACS) during residential treatment, with post-treatment relapse and explore whether elevated craving scores 3 months post-treatment are also associated with subsequent relapse. METHODS: Alcohol craving was assessed with the PACS on admission and at several time points post-treatment in 190 subjects with DSM-IV diagnosis of alcohol dependence admitted to residential treatment. Data about relapse to any drinking (primary outcome measure) was collected at 3, 6, 9 and 12 months after treatment. Cox regression models were used to determine whether PACS scores were associated with relapse. Statistical models were adjusted for meaningful demographic and clinical covariates. RESULTS: Follow-up data was available for 149/190 (78%) of subjects. Elevated PACS scores at discharge were associated with increased relapse risk within the first 3 and 12 months after discharge (P = 0.032 and P = 0.045, respectively). Elevated PACS scores at 3 months were associated with increased risk of subsequent relapse within 12 months after treatment in contacted subjects (P = 0.034) and in the intent-to-treat analysis (P = 0.0001). CONCLUSIONS: Our findings indicate strong association of post-treatment relapse with elevated alcohol craving measured at treatment completion and at 3 months after treatment and justify the use of this measure to guide relapse-prevention efforts.


Assuntos
Alcoolismo/psicologia , Fissura , Valor Preditivo dos Testes , Tratamento Domiciliar , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Tempo
20.
JCO Clin Cancer Inform ; 3: 1-11, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30807208

RESUMO

PURPOSE: Background parenchymal uptake (BPU), which describes the level of radiotracer uptake in normal fibroglandular tissue on molecular breast imaging (MBI), has been identified as a breast cancer risk factor. Our objective was to develop and validate a deep learning model using image convolution to automatically categorize BPU on MBI. METHODS: MBI examinations obtained for clinical and research purposes from 2004 to 2015 were reviewed to classify the BPU pattern using a standardized five-category scale. Two expert radiologists provided interpretations that were used as the reference standard for modeling. The modeling consisted of training and validating a convolutional neural network to predict BPU. Model performance was summarized in data reserved to test the performance of the algorithm at the per-image and per-breast levels. RESULTS: Training was performed on 24,639 images from 3,133 unique patients. The model performance on the withheld testing data (6,172 images; 786 patients) was evaluated. Using direct matching on the predicted classification resulted in an accuracy of 69.4% (95% CI, 67.4% to 71.3%), and if prediction within one category was considered, accuracy increased to 96.0% (95% CI, 95.2% to 96.7%). When considering the breast-level prediction of BPU, the accuracy remained strong, with 70.3% (95% CI, 68.0% to 72.6%) and 96.2% (95% CI, 95.3% to 97.2%) for the direct match and allowance for one category, respectively. CONCLUSION: BPU provided a robust target for training a convolutional neural network. A validated computer algorithm will allow for objective, reproducible encoding of BPU to foster its integration into risk-stratification algorithms.

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