Dietary Recommendations for Familial Hypercholesterolaemia: an Evidence-Free Zone.

We have evaluated dietary recommendations for people diagnosed with familial hypercholesterolaemia (FH), a genetic condition in which increased low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk for coronary heart disease (CHD). Recommendations for FH individuals have emphasised a low saturated fat, low cholesterol diet to reduce their LDL-C levels. The basis of this recommendation is the 'diet-heart hypothesis', which postulates that consumption of food rich in saturated fat increases serum cholesterol levels, which increases risk of CHD. We have challenged the rationale for FH dietary recommendations based on the absence of support for the diet-heart hypothesis, and the lack of evidence that a low saturated fat, low cholesterol diet reduces coronary events in FH individuals. As an alternative approach, we have summarised research which has shown that the subset of FH individuals that develop CHD exhibit risk factors associated with an insulin-resistant phenotype (elevated triglycerides, blood glucose, haemoglobin A1c (HbA1c), obesity, hyperinsulinaemia, high-sensitivity C reactive protein, hypertension) or increased susceptibility to develop coagulopathy. The insulin-resistant phenotype, also referred to as the metabolic syndrome, manifests as carbohydrate intolerance, which is most effectively managed by a low carbohydrate diet (LCD). Therefore, we propose that FH individuals with signs of insulin resistance should be made aware of the benefits of an LCD. Our assessment of the literature provides the rationale for clinical trials to be conducted to determine if an LCD would prove to be effective in reducing the incidence of coronary events in FH individuals which exhibit an insulin-resistant phenotype or hypercoagulation risk.

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements-alternatives to KDs-may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucose and R-beta-hydroxybutyrate (R-ßHB) levels in rodent models with and without pathology. The effect of KD, butanediol (BD), ketone-ester (KE), ketone-salt (KS), and their combination (KE + KS: KEKS) or mixtures with medium chain triglyceride (MCT) (KE + MCT: KEMCT; KS + MCT: KSMCT) was tested in Sprague-Dawley (SPD) and WAG/Rij (WR) rats and in GLUT-1 Deficiency Syndrome (G1D) mice. Motor performance was enhanced by KEMCT acutely, KE and KS subchronically in SPD rats, by KEKS and KEMCT groups in WR rats, and by KE chronically in G1D mice. We demonstrated that exogenous ketone supplementation improved motor performance to various degrees in rodent models, while effectively elevated R-ßHB and in some cases offsets postexercise blood glucose elevations. Our results suggest that improvement of motor performance varies depending on the strain of rodents, specific ketone formulation, age, and exposure frequency.

Exogenous Ketones Lower Blood Glucose Level in Rested and Exercised Rodent Models.

Diseases involving inflammation and oxidative stress can be exacerbated by high blood glucose levels. Due to tight metabolic regulation, safely reducing blood glucose can prove difficult. The ketogenic diet (KD) reduces absolute glucose and insulin, while increasing fatty acid oxidation, ketogenesis, and circulating levels of ß-hydroxybutyrate (ßHB), acetoacetate (AcAc), and acetone. Compliance to KD can be difficult, so alternative therapies that help reduce glucose levels are needed. Exogenous ketones provide an alternative method to elevate blood ketone levels without strict dietary requirements. In this study, we tested the changes in blood glucose and ketone (ßHB) levels in response to acute, sub-chronic, and chronic administration of various ketogenic compounds in either a post-exercise or rested state. WAG/Rij (WR) rats, a rodent model of human absence epilepsy, GLUT1 deficiency syndrome mice (GLUT1D), and wild type Sprague Dawley rats (SPD) were assessed. Non-pathological animals were also assessed across different age ranges. Experimental groups included KD, standard diet (SD) supplemented with water (Control, C) or with exogenous ketones: 1, 3-butanediol (BD), ßHB mineral salt (KS), KS with medium chain triglyceride/MCT (KSMCT), BD acetoacetate diester (KE), KE with MCT (KEMCT), and KE with KS (KEKS). In rested WR rats, the KE, KS, KSMCT groups had lower blood glucose level after 1 h of treatment, and in KE and KSMCT groups after 24 h. After exercise, the KE, KSMCT, KEKS, and KEMCT groups had lowered glucose levels after 1 h, and in the KEKS and KEMCT groups after 7 days, compared to control. In GLUT1D mice without exercise, only KE resulted in significantly lower glucose levels at week 2 and week 6 during a 10 weeks long chronic feeding study. In 4-month and 1-year-old SPD rats in the post-exercise trials, blood glucose was significantly lower in KD and KE, and in KEMCT groups, respectively. After seven days, the KSMCT group had the most significantly reduced blood glucose levels, compared to control. These results indicate that exogenous ketones were efficacious in reducing blood glucose levels within and outside the context of exercise in various rodent models of different ages, with and without pathology.

Delaying latency to hyperbaric oxygen-induced CNS oxygen toxicity seizures by combinations of exogenous ketone supplements.

Central nervous system oxygen toxicity (CNS-OT) manifests as tonic-clonic seizures and is a limitation of hyperbaric oxygen therapy (HBOT), as well as of recreational and technical diving associated with elevated partial pressure of oxygen. A previous study showed that ketone ester (1,3-butanediol acetoacetate diester, KE) administration delayed latency to seizures (LS) in 3-month-old Sprague-Dawley (SD) rats. This study explores the effect of exogenous ketone supplements in additional dosages and formulations on CNS-OT seizures in 18 months old SD rats, an age group correlating to human middle age. Ketogenic agents were given orally 60 min prior to exposure to hyperbaric oxygen and included control (water), KE (10 g/kg), KE/2 (KE 5 g/kg + water 5 g/kg), KE + medium-chain triglycerides (KE 5 g/kg + MCT 5 g/kg), and ketone salt (Na+ /K+ ßHB, KS) + MCT (KS 5 g/kg + MCT 5 g/kg). Rats were exposed to 100% oxygen at 5 atmospheres absolute (ATA). Upon seizure presentation (tonic-clonic movements) experiments were immediately terminated and blood was tested for glucose and D-beta-hydroxybutyrate (D-ßHB) levels. While blood D-ßHB levels were significantly elevated post-dive in all treatment groups, LS was significantly delayed only in KE (P = 0.0003), KE/2 (P = 0.023), and KE + MCT (P = 0.028) groups. In these groups, the severity of seizures appeared to be reduced, although these changes were significant only in KE-treated animals (P = 0.015). Acetoacetate (AcAc) levels were also significantly elevated in KE-treated animals. The LS in 18-month-old rats was delayed by 179% in KE, 219% in KE + MCT, and 55% in KE/2 groups, while only by 29% in KS + MCT. In conclusion, KE supplementation given alone and in combination with MCT elevated both ßHB and AcAc, and delayed CNS-OT seizures.

Clinical, Empirical, and Theoretical Rationale for Selection of Accelerated Resolution Therapy for Treatment of Post-traumatic Stress Disorder in VA and DoD Facilities.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a chronic, disabling psychiatric disorder prevalent among U.S. service members and veterans. First-line treatments for PTSD endorsed in the 2017 Veterans Affairs (VA)/Department of Defense (DoD) Clinical Practice Guideline for PTSD emphasize individual, manualized trauma-focused psychotherapies that have a primary component of exposure and/or cognitive restructuring. These include prolonged exposure (PE) therapy, cognitive processing therapy (CPT), eye movement desensitization and reprocessing (EMDR), and others. Accelerated resolution therapy (ART) is an emerging trauma-focused therapy not specifically referenced in the guideline, but one that is consistent with the recommendations and is derived directly from EMDR. One randomized clinical trial and multiple observational studies have suggested that ART can be delivered in an average of just four treatment sessions. This commentary reviews the clinical, empirical, and theoretical rationale for use of ART as a potential first-line PTSD treatment modality in VA and DoD facilities. MATERIALS AND METHODS: The clinical protocol of ART is summarized into discrete procedural steps. The theoretical rationale as to how ART may help clients process traumatic memories and resolve symptoms of PTSD is also discussed, including how repeated sets of smooth pursuit horizontal eye movements may facilitate a relaxation response and assist with processing emotionally intrusive memories. Herein, we review primary treatment results from four published studies of ART, including mean symptom score reductions on the 17-item PCL (PTSD checklist) after treatment with ART, along with effect sizes and percentage of treatment responders. Finally, the ART protocol is compared directly against specific recommended elements of trauma-focused therapy described in the VA/DoD Clinical Practice Guideline. RESULTS: The four published studies of ART reviewed (n = 291) included adult civilians and service members/veterans; the mean age was 42.3 ± 12.3 yr and 28.9% were female. Among 237 treatment completers (81.4% of the combined cohort), the mean number of ART sessions received was 3.9 ± 1.1. Across the four studies, mean treatment-related reductions in PCL scores ranged from 15.6 ± 13.2 to 25.6 ± 11.3, with a pooled mean reduction on the PCL of 20.6 ± 15.0. Effect sizes were large and ranged from 1.18 to 2.26 (p< 0.0005) across studies, with a pooled effect size of 1.38 (95% confidence interval: 1.20-1.56, p < 0.0001). Using the clinical cutpoint of >10-point reduction on the PCL instrument, clinically significant change (response) ranged from 63.8% to 100.0% across the four studies, with a pooled treatment response rate of 74.7%. Results were nominally attenuated when conservatively assuming no treatment response for non-completers. CONCLUSION: The ART protocol contains the core therapeutic elements and aligns closely with the current VA/DoD Clinical Practice Guideline. It has a plausible theoretical rationale and an evolving empirical research base that includes four studies with peer-reviewed publications, one of which was a randomized controlled trial. These features, along with the brevity of the treatment protocol, no requirement for narration, and high provider satisfaction rates, provide a rationale for the potential use of ART as a first-line PTSD treatment modality for active duty and veteran military personnel.

Case report and theoretical description of accelerated resolution therapy (ART) for military-related post-traumatic stress disorder.

OBJECTIVES: This article describes a new, brief exposure-based psychotherapy known as Accelerated Resolution Therapy (ART) that is currently being evaluated as a treatment for combat-related post-traumatic stress disorder (PTSD). METHODS: We describe a case report of an Army veteran with combat-related PTSD who was treated with 2 sessions of ART and experienced significant clinical improvement. We then discuss the theoretical basis and major components of the ART protocol, including use of lateral left-right eye movements, and differentiate ART with evidence-based psychotherapies currently endorsed by the Department of Defense and Veterans Administration. RESULTS: The number of military personnel who have served in the wars in Iraq and Afghanistan and are afflicted with PTSD is likely in the hundreds of thousands. The ART protocol, which is delivered in 2 to 5 sessions and without homework, uses the psychotherapeutic practices of imaginal exposure and imagery rescripting (IR) facilitated through sets of eye movements. In addition to its brevity, a novel component of ART is use of IR to "replace" negative imagery (and other sensations) with positive imagery. CONCLUSIONS: This theoretical description of ART and single case report provide a rationale for future formal evaluation of ART for treatment of military-related PTSD.

Randomized controlled trial of accelerated resolution therapy (ART) for symptoms of combat-related post-traumatic stress disorder (PTSD).

OBJECTIVES: Therapies for post-traumatic stress disorder (PTSD) endorsed by the Department of Defense and Veterans Administration are relatively lengthy, costly, and yield variable success. We evaluated Accelerated Resolution Therapy (ART) for the treatment of combat-related psychological trauma. METHODS: A randomized controlled trial of ART versus an Attention Control (AC) regimen was conducted among 57 U.S. service members/veterans. After random assignment, those assigned to AC were offered crossover to ART, with 3-month follow-up on all participants. Self-report symptoms of PTSD and comorbidities were analyzed among study completers and by the intention-to-treat principle. RESULTS: Mean age was 41 ± 13 years with 19% female, 54% Army, and 68% with prior PTSD treatment. The ART was delivered in 3.7 ± 1.1 sessions with a 94% completion rate. Mean reductions in symptoms of PTSD, depression, anxiety, and trauma-related guilt were significantly greater (p < 0.001) with ART compared to AC. Favorable results for those treated with ART persisted at 3 months, including reduction in aggression (p < 0.0001). Adverse treatment-related events were rare and not serious. CONCLUSIONS: ART appears to be a safe and effective treatment for symptoms of combat-related PTSD, including refractory PTSD, and is delivered in significantly less time than therapies endorsed by the Department of Defense and Veterans Administration.

Animal models in translational studies of PTSD.

Understanding the neurobiological mechanisms of post-traumatic stress disorder (PTSD) is of vital importance for developing biomarkers and more effective pharmacotherapy for this disorder. The design of bidirectional translational studies addressing all facets of PTSD is needed. Animal models of PTSD are needed not only to capture the complexity of PTSD behavioral characteristics, but also to address experimentally the influence of variety of factors which might determine an individual's vulnerability or resilience to trauma, e.g., genetic predisposition, early-life experience and social support. The current review covers recent translational approaches to bridge the gap between human and animal PTSD research and to create a framework for discovery of biomarkers and novel therapeutics.

Brief Treatment of Symptoms of Post-Traumatic Stress Disorder (PTSD) by Use of Accelerated Resolution Therapy (ART(®)).

Post-Traumatic Stress Disorder (PTSD) is a prevalent, disabling anxiety disorder. This prospective cohort study reports on a new exposure-based therapy known as Accelerated Resolution Therapy (ART(®)) that incorporates the use of eye movements administered in a brief treatment period (1-5 one-hour sessions within three weeks). Eighty adults aged 21-60 years with symptoms of PTSD were recruited from the Tampa Bay area. The ART-based psychotherapy was designed to minimize anxiety and body sensations associated with recall of traumatic memories and to replace distressing images with favorable ones. Participants' mean age was 40 years, 77% were female, and 29% were Hispanic. Participants underwent a median of three ART sessions, 66 of 80 (82.5%) completed treatment, and 54 of 66 (81.8%) provided 2-month follow-up data. Mean scores pre- and post-ART and at 2-month follow-up were: PTSD Checklist: 54.5 ± 12.2 vs. 31.2 ± 11.4 vs. 30.0 ± 12.4; Brief Symptom Inventory: 30.8 ± 14.6 vs. 10.1 ± 10.8 vs. 10.1 ± 12.1; Center for Epidemiologic Studies Depression Scale: 29.5 ± 10.9 vs. 11.8 ± 11.1 vs. 13.5 ± 12.1; Trauma Related Growth Inventory-Distress scale: 18.9 ± 4.1 vs. 7.4 ± 5.9 vs. 8.2 ± 5.9 (p < 0.0001 for all pre-ART vs. post-ART and 2-month comparisons). No serious adverse events were reported. ART appears to be a brief, safe, and effective treatment for symptoms of PTSD.

Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones.

Heat-shock proteins (Hsp) play an important role in stress physiology. Exposure to a variety of stressors will induce intracellular Hsp72, and this induction is believed to be beneficial for cell survival. In contrast, Hsp72 released during stress (extracellular Hsp72; eHsp72) activates pro-inflammatory responses. Clearly, physical stressors such as heat, cold, H(2)O(2), intense exercise and tail shock will induce both intra- and extracellular Hsp72. The current study tested whether a psychological stressor, cat exposure, would also trigger this response. In addition, the potential role of adrenal hormones in the Hsp72 response was examined. Adult, male Sprague Dawley rats were either adrenalectomized (ADX) or sham operated. Ten days post-recovery, rats were exposed to either a cat with no physical contact or control procedures (n = 5-6/group) for 2 h. Levels of intracellular Hsp72 were measured in the brain (frontal cortex, hippocampus, hypothalamus, dorsal vagal complex) and pituitary (ELISA). Levels of eHsp72 (ELISA) and corticosterone (RIA) were measured from serum obtained at the end of the 2-h stress period. Rats that were exposed to a cat had elevated intracellular Hsp72 in hypothalamus and dorsal vagal complex, and elevated eHsp72 and corticosterone in serum. Both the intra- and extracellular Hsp72 responses were blocked or attenuated by ADX. This study demonstrates that cat exposure can stimulate the Hsp72 response and that adrenal hormones contribute to this response.

Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS).

Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people.