259 resultados para Chronic intermittent hypoxia


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Working on the serotonin (5-hydroxytryptamine, 5-HT) 5-HT2B receptor since several years, we have read with high interest the review by Hertz et al. (2015). Previous studies from our group demonstrated that a direct injection in mouse raphe nucleus of the 5-HT2B agonist BW723C86 has the ability to increase extracellular levels of serotonin, which can be blocked by the selective 5-HT2B receptor antagonist RS127445 (Doly et al., 2008, 2009). We also reported that an acute injection of paroxetine 2 mg/kg in mice knocked out for the 5-HT2B receptor gene or in wild type mice injected with RS127445 (0.5 mg/kg) triggers a strong reduction in extracellular accumulation of 5-HT in hippocampus (Diaz et al., 2012). Following these observations, we showed that acute and chronic BW723C86 injection (3 mg/kg) can mimic the fluoxetine (3 mg/kg) and paroxetine (1 mg/kg) behavioral and biochemical antidepressant effects in mice (Diaz and Maroteaux, 2011; Diaz et al., 2012)...

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Future time perspective - the way individuals perceive their remaining time in life - importantly influences socio-emotional goals and motivational outcomes. Recently, researchers have called for studies that investigate relationships between personality and future time perspective. Using a cross-lagged panel design, this study investigated effects of chronic regulatory focus dimensions (promotion and prevention orientation) on future time perspective dimensions (focus on opportunities and limitations). Survey data were collected two times, separated by a 3. month time lag, from 85 participants. Results of structural equation modeling showed that promotion orientation had a positive lagged effect on focus on opportunities, and prevention orientation had a positive lagged effect on focus on limitations.

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Dietary nitrate (NO3−) supplementation with beetroot juice (BR) over 4–6 days has been shown to reduce the O2 cost of submaximal exercise and to improve exercise tolerance. However, it is not known whether shorter (or longer) periods of supplementation have similar (or greater) effects. We therefore investigated the effects of acute and chronic NO3− supplementation on resting blood pressure (BP) and the physiological responses to moderate-intensity exercise and ramp incremental cycle exercise in eight healthy subjects. Following baseline tests, the subjects were assigned in a balanced crossover design to receive BR (0.5 l/day; 5.2 mmol of NO3−/day) and placebo (PL; 0.5 l/day low-calorie juice cordial) treatments. The exercise protocol (two moderate-intensity step tests followed by a ramp test) was repeated 2.5 h following first ingestion (0.5 liter) and after 5 and 15 days of BR and PL. Plasma nitrite concentration (baseline: 454 ± 81 nM) was significantly elevated (+39% at 2.5 h postingestion; +25% at 5 days; +46% at 15 days; P < 0.05) and systolic and diastolic BP (baseline: 127 ± 6 and 72 ± 5 mmHg, respectively) were reduced by ∼4% throughout the BR supplementation period (P < 0.05). Compared with PL, the steady-state V̇o2 during moderate exercise was reduced by ∼4% after 2.5 h and remained similarly reduced after 5 and 15 days of BR (P < 0.05). The ramp test peak power and the work rate at the gas exchange threshold (baseline: 322 ± 67 W and 89 ± 15 W, respectively) were elevated after 15 days of BR (331 ± 68 W and 105 ± 28 W; P < 0.05) but not PL (323 ± 68 W and 84 ± 18 W). These results indicate that dietary NO3− supplementation acutely reduces BP and the O2 cost of submaximal exercise and that these effects are maintained for at least 15 days if supplementation is continued.

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- Objective This study examined chronic disease risks and the use of a smartphone activity tracking application during an intervention in Australian truck drivers (April-October 2014). - Methods Forty-four men (mean age=47.5 [SD 9.8] years) completed baseline health measures, and were subsequently offered access to a free wrist-worn activity tracker and smartphone application (Jawbone UP) to monitor step counts and dietary choices during a 20-week intervention. Chronic disease risks were evaluated against guidelines; weekly step count and dietary logs registered by drivers in the application were analysed to evaluate use of the Jawbone UP. - Results Chronic disease risks were high (e.g. 97% high waist circumference [≥94 cm]). Eighteen drivers (41%) did not start the intervention; smartphone technical barriers were the main reason for drop out. Across 20-weeks, drivers who used the Jawbone UP logged step counts for an average of 6 [SD 1] days/week; mean step counts remained consistent across the intervention (weeks 1–4=8,743[SD 2,867] steps/day; weeks 17–20=8,994[SD 3,478] steps/day). The median number of dietary logs significantly decreased from start (17 [IQR 38] logs/weeks) to end of the intervention (0 [IQR 23] logs/week; p<0.01); the median proportion of healthy diet choices relative to total diet choices logged increased across the intervention (weeks 1–4=38[IQR 21]%; weeks 17–20=58[IQR 18]%). - Conclusions Step counts were more successfully monitored than dietary choices in those drivers who used the Jawbone UP. - Implications Smartphone technology facilitated active living and healthy dietary choices, but also prohibited intervention engagement in a number of these high-risk Australian truck drivers.

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- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

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Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

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- BACKGROUND Chronic diseases are increasing worldwide and have become a significant burden to those affected by those diseases. Disease-specific education programs have demonstrated improved outcomes, although people do forget information quickly or memorize it incorrectly. The teach-back method was introduced in an attempt to reinforce education to patients. To date, the evidence regarding the effectiveness of health education employing the teach-back method in improved care has not yet been reviewed systematically. - OBJECTIVES This systematic review examined the evidence on using the teach-back method in health education programs for improving adherence and self-management of people with chronic disease. - INCLUSION CRITERIA Types of participants: Adults aged 18 years and over with one or more than one chronic disease. Types of intervention: All types of interventions which included the teach-back method in an education program for people with chronic diseases. The comparator was chronic disease education programs that did not involve the teach-back method. Types of studies: Randomized and non-randomized controlled trials, cohort studies, before-after studies and case-control studies. Types of outcomes: The outcomes of interest were adherence, self-management, disease-specific knowledge, readmission, knowledge retention, self-efficacy and quality of life. - SEARCH STRATEGY Searches were conducted in CINAHL, MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, ProQuest Nursing and Allied Health Source, and Google Scholar databases. Search terms were combined by AND or OR in search strings. Reference lists of included articles were also searched for further potential references. - METHODOLOGICAL QUALITY Two reviewers conducted quality appraisal of papers using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument. - DATA EXTRACTION Data were extracted using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument data extraction instruments. - DATA SYNTHESIS There was significant heterogeneity in selected studies, hence a meta-analysis was not possible and the results were presented in narrative form. - RESULTS Of the 21 articles retrieved in full, 12 on the use of the teach-back method met the inclusion criteria and were selected for analysis. Four studies confirmed improved disease-specific knowledge in intervention participants. One study showed a statistically significant improvement in adherence to medication and diet among type 2 diabetics patients in the intervention group compared to the control group (p < 0.001). Two studies found statistically significant improvements in self-efficacy (p = 0.0026 and p < 0.001) in the intervention groups. One study examined quality of life in heart failure patients but the results did not improve from the intervention (p = 0.59). Five studies found a reduction in readmission rates and hospitalization but these were not always statistically significant. Two studies showed improvement in daily weighing among heart failure participants, and in adherence to diet, exercise and foot care among those with type 2 diabetes. - CONCLUSION Overall, the teach-back method showed positive effects in a wide range of health care outcomes although these were not always statistically significant. Studies in this systematic review revealed improved outcomes in disease-specific knowledge, adherence, self-efficacy and the inhaler technique. There was a positive but inconsistent trend also seen in improved self-care and reduction of hospital readmission rates. There was limited evidence on improvement in quality of life or disease related knowledge retention.

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High concentrations of nitrate-nitrogen degrade the quality of aquatic environments. The primary mechanism by which nitrate-nitrogen is removed (denitrification) requires anoxic conditions and electron donors. While removal of total and ammonium-nitrogen is often high in stormwater biofilters, poor removal or even the release of nitrate-nitrogen in the outflow has often been observed. Five Perspex biofilter columns (94 mm internal diameter) were fabricated with a filter layer that contained 8% organic material. Columns were operated at 875  mm/h 875  mm/h and fed with simulated stormwater with different antecedent dry days (ADDs) and concentrations of nitrate-nitrogen. Samples were collected from the outflow at different time intervals between 2 and 150 min and were tested for nitrate-nitrogen. The removal of nitrate-nitrogen varied during an event from a high removal percentage (60–90%) in the initial outflow that gradually decreased in the first 30 min and settled at 0–15% removal thereafter. This remained consistent during all simulated events independent of the number of ADDs or inflow concentrations. ADDs and previous event feed concentrations affected the outflow nitrate-nitrogen concentration in the first 30 min of the current event. Therefore, from this study it is concluded that denitrification within stormwater biofilters occurs mainly during drying periods rather than wetting periods.

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Objective The objective of this study was to investigate the risk of chronic kidney disease (CKD) stage 4-5 and dialysis treatment on incidence of foot ulceration and major lower extremity amputation in comparison to CKD stage 3. Methods In this retrospective study, all individuals who visited our hospital between 2006 and 2012 because of CKD stages 3 to 5 or dialysis treatment were included. Medical records were reviewed for incidence of foot ulceration and major amputation. The time from CKD 3, CKD 4-5, and dialysis treatment until first foot ulceration and first major lower extremity amputation was calculated and analyzed by Kaplan-Meier curves and multivariate Cox proportional hazards model. Diabetes mellitus, peripheral arterial disease, peripheral neuropathy, and foot deformities were included for potential confounding. Results A total of 669 individuals were included: 539 in CKD 3, 540 in CKD 4-5, and 259 in dialysis treatment (individuals could progress from one group to the next). Unadjusted foot ulcer incidence rates per 1000 patients per year were 12 for CKD 3, 47 for CKD 4-5, and 104 for dialysis (P < .001). In multivariate analyses, the hazard ratio for incidence of foot ulceration was 4.0 (95% confidence interval [CI], 2.6-6.3) in CKD 4-5 and 7.6 (95% CI, 4.8-12.1) in dialysis treatment compared with CKD 3. Hazard ratios for incidence of major amputation were 9.5 (95% CI, 2.1-43.0) and 15 (95% CI, 3.3-71.0), respectively. Conclusions CKD 4-5 and dialysis treatment are independent risk factors for foot ulceration and major amputation compared with CKD 3. Maximum effort is needed in daily clinical practice to prevent foot ulcers and their devastating consequences in all individuals with CKD 4-5 or dialysis treatment.

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Background Around the world, guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) vary greatly. To prevent occlusion, most institutions recommend the use of heparin when the CVC is not in use. However, there is debate regarding the need for heparin and evidence to suggest normal saline may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased costs. Objectives To assess the clinical effects (benefits and harms) of heparin versus normal saline to prevent occlusion in long-term central venous catheters in infants, children and adolescents. Design A Cochrane systematic review of randomised controlled trials was undertaken. - Data sources: The Cochrane Vascular Group Specialised Register (including MEDLINE, CINAHL, EMBASE and AMED) and the Cochrane Register of Studies were searched. Hand searching of relevant journals and reference lists of retrieved articles was also undertaken. - Review Methods: Data were extracted and appraisal undertaken. We included studies that compared the efficacy of normal saline with heparin to prevent occlusion. We excluded temporary CVCs and peripherally inserted central catheters. Rate ratios per 1000 catheter days were calculated for two outcomes, occlusion of the CVC, and CVC-associated blood stream infection. Results Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin. However, between studies, all used different protocols with various concentrations of heparin and frequency of flushes. The quality of the evidence ranged from low to very low. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). Conclusions It remains unclear whether heparin is necessary for CVC maintenance. More well-designed studies are required to understand this relatively simple, but clinically important question. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.

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Background Chronic kidney disease (CKD) leads to a range of symptoms, which are often under-recognised and little is known about the multidimensional symptom experience in advanced CKD. Objectives To examine (1) symptom burden at CKD stages 4 and 5, and dialysis modalities, and (2) demographic and renal history correlates of symptom burden. Methods Using a cross-sectional design, a convenience sample of 436 people with CKD was recruited from three hospitals. The CKD Symptom Burden Index (CKD-SBI) was used to measure the prevalence, severity, distress and frequency of 32 symptoms. Demographic and renal history data were also collected. Results Of the sample, 75.5 % were receiving dialysis (haemodialysis, n = 287; peritoneal dialysis, n = 42) and 24.5 % were not undergoing dialysis (stage 4, n = 69; stage 5, n = 38). Participants reported an average of 13.01 ± 7.67 symptoms. Fatigue and pain were common and burdensome across all symptom dimensions. While approximately one-third experienced sexual symptoms, when reported these symptoms were frequent, severe and distressing. Haemodialysis, older age and being female were independently associated with greater symptom burden. Conclusions In CKD, symptom burden is better understood when capturing the multidimensional aspects of a range of physical and psychological symptoms. Fatigue, pain and sexual dysfunction are key contributors to symptom burden, and these symptoms are often under-recognised and warrant routine assessment. The CKD-SBI offers a valuable tool for renal clinicians to assess symptom burden, leading to the commencement of timely and appropriate interventions.

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Chronic kidney disease (CKD) is increasing globally and in Saudi Arabia it affects approximately 8% annual increment of dialysis population. It is associated with a high symptom burden. Previous studies have largely reported on the prevalence of symptoms only in the haemodialysis population. This study examined symptom burden across disease stages and treatment groups in advanced CKD, and their correlation with demographic and clinical factors. Using a cross-sectional design, a convenience sample of 436 patients with CKD was recruited from three hospitals in Saudi Arabia. The CKD Symptom Burden Index (CKD-SBI) was used to measure 32 CKD symptoms. Demographic and clinical data were also collected. Of the sample 75.5% were receiving dialysis (haemodialysis, n = 287; peritoneal dialysis, n = 42) and 24.5% were non-dialysis (CKD stage 4, n = 69; CKD stage 5, n = 38). Average symptom reported was 13.01 ± 7.67. Fatigue and pain were common and burdensome across all symptom dimensions.Approximately one-third of participants experienced sexual symptoms. Dialysis patients reported greater symptom burden, especially patients on haemodialysis. Haemodialysis treatment, older age and being female were independently associated with greater total symptom burden. In conclusion, symptom burden is high among advanced stages of CKD, particularly among those receiving dialysis. Although fatigue, pain and sexual dysfunction are key contributors to symptom burden in CKD, these symptoms are often under-recognised and warrant routine assessment. The CKD-SBI offers a valuable tool to assess symptom burden, leading to the commencement of timely and appropriate interventions.

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We have developed a totally new class of nonporphyrin photodynamic therapeutic agents with a specific focus on two lead candidates azadipyrromethene (ADPM)01 and ADPM06. Confocal laser scanning microscopy imaging showed that these compounds are exclusively localised to the cytosolic compartment, with specific accumulation in the endoplasmic reticulum and to a lesser extent in the mitochondria. Light-induced toxicity assays, carried out over a broad range of human tumour cell lines, displayed EC50 values in the micro-molar range for ADPM01 and nano-molar range for ADPM06, with no discernable activity bias for a specific cell type. Strikingly, the more active agent, ADPM06, even retained significant activity under hypoxic conditions. Both photosensitisers showed low to nondeterminable dark toxicity. Flow cytometric analysis revealed that ADPM01 and ADPM06 were highly effective at inducing apoptosis as a mode of cell death. The photophysical and biological characteristics of these PDT agents suggest that they have potential for the development of new anticancer therapeutics. © 2005 Cancer Research UK.

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BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

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The modern diet has become highly sweetened, resulting in unprecedented levels of sugar consumption, particularly among adolescents. While chronic long-term sugar intake is known to contribute to the development of metabolic disorders including obesity and type II diabetes, little is known regarding the direct consequences of long-term, binge-like sugar consumption on the brain. Because sugar can cause the release of dopamine in the nucleus accumbens (NAc) similarly to drugs of abuse, we investigated changes in the morphology of neurons in this brain region following short- (4 weeks) and long-term (12 weeks) binge-like sucrose consumption using an intermittent two-bottle choice paradigm. We used Golgi-Cox staining to impregnate medium spiny neurons (MSNs) from the NAc core and shell of short- and long-term sucrose consuming rats and compared these to age-matched water controls. We show that prolonged binge-like sucrose consumption significantly decreased the total dendritic length of NAc shell MSNs compared to age-matched control rats. We also found that the restructuring of these neurons resulted primarily from reduced distal dendritic complexity. Conversely, we observed increased spine densities at the distal branch orders of NAc shell MSNs from long-term sucrose consuming rats. Combined, these results highlight the neuronal effects of prolonged binge-like intake of sucrose on NAc shell MSN morphology.