Changes in elderly women's health-related quality of life following discontinuation of hormone replacement therapy

BACKGROUND: Many women have discontinued hormone replacement therapy (HRT) in view of recent findings. The goal of this study was to determine if HRT discontinuation is associated with changes in health-related quality of life (HRQOL) in elderly women. METHODS: We studied women enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PACE) program, linking prescription claims with data from a longitudinal mail survey. HRQOL measures included the number of days out of the last 30 that physical health was not good and analogous measures for mental health, pain, and interference with activities, as well as a composite "healthy days" measure developed by CDC. Longitudinal analyses focused on 2,357 women who completed surveys in both 2002 and 2003, and who used HRT at baseline (mean age = 75.5, range = 65–102). Propensity scores were used to match HRT continuers and discontinuers according to HRT type, demographics, and baseline HRQOL. Analysis of covariance was used to compare HRQOL change in continuers and discontinuers. RESULTS: Between 2002 and 2003, 43% of HRT users discontinued therapy. Analysis of covariance to examine HRQOL change revealed complex interactions with age. Discontinuers aged 65–74 reported greater increases in days in which mental health was not good (p < .05), fewer "healthy days" (p < .05), more days in which health interfered with activities (p < .01), and more days with pain (p < .01). Among women aged 75–84, HRT discontinuers reported more days in which physical health was not good (p < .01); no other significant effects were observed in this group. Relative to HRT continuers, discontinuers aged 85 and older experienced apparent HRQOL improvements following cessation, with fewer days in which physical health was not good (p < .01), fewer days of poor mental health (p < .05), and more "healthy days" (p < .01). CONCLUSIONS: These results suggest that there are substantial age differences in response to HRT discontinuation. While women aged 65–74 experienced apparent declines in HRQOL following HRT cessation, women aged 85 and older experienced relative improvements. The HRQOL declines observed among younger women underscore the importance of communication between clinicians and patients throughout the discontinuation process. These results also demonstrate the value of HRQOL surveillance as a component of health program administration

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients

A randomized control trial of cardiac rehabilitation

A randomized trial using controls tested whether psycho-social rehabilitation of acute myocardial infarction (MI) patients would improve significantly their return to work rate and assessed the importance of various psychological, social, occupational, socio-demographic, and medical factors in facilitating or impeding rapid return to work. Eighty-nine patients were assigned randomly to participate in an experimental cardiac rehabilitation program (rehab care), and 91 patients were controls who received conventional hospital rehabilitation (usual care). By the first follow-up interview at three months, patients assigned to experimental treatment were significantly less distressed psychologically and less dependent on family support than controls (P = 0.04 and P = 0.05, respectively). By the final follow-up interview at 13 months, there was a marginally significant difference in favor of the experimental group in the frequency of reported deterrents to work resumption (P = 0.07). However, the intervention did not result in a statistically significant difference in the return to work rate (P >; 0.10). In each group, 88% were back at work by approximately the first year after infarction. In addition, the two groups were similar in the amount of time patients remained out of the workforce (median days rehab CARE = 75, usual CARE = 81; P > 0.10). A multi-stage data analysis procedure utilizing the Cox regression technique indicated that while several independent variables had significant univariate associations with the length of time patients convalesced, outcome was most influenced by the patient's initial cardiological status and clinical course, by the patterns of family support, and by the several variables measuring the presence of obstacles to resuming work. Our findings suggest that rehabilitation programs intervening on multiple levels (psychological, social, occupational, and physical) may best meet the needs of chronically ill cardiac patients. Results indicate that implementing measures addressing the patient's general psycho-social adjustment to MI may improve existing programs.cardiac rehabilitation stress disability

Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats

Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO2). Adult male rats (n = 60) were implanted with radiotelemetry units to measure electroencephalogram (EEG). One week postsurgery, rats were administered a single oral dose of BD-AcAc2, 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn at room pressure from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, Po2, Pco2, β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc2 caused a rapid (30 min) and sustained (\u3e4 h) elevation of BHB (\u3e3 mM) and AcAc (\u3e3 mM), which exceeded values reported with a KD or starvation. BD-AcAc2 increased LS by 574 ± 116% compared with control (water) and was due to the effect of AcAc and acetone but not BHB. BD produced ketosis in rats by elevating BHB (\u3e5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc2 produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone. seizures from hyperbaric oxygen (HBO2), also known as central nervous system oxygen toxicity (CNS-OT), compromise the safety of undersea divers using rebreathers and patients undergoing HBO2 therapy (HBOT) (13). Breathing 100% O2 at barometeric pressure (Pb) \u3e 2.4 atmospheres absolute (ATA) increases the likelihood of seizures in patients, and current applications of HBOT routinely use up to 3 ATA HBO2 (48). The potential for CNS-OT is the primary limiting factor in HBOT. HBO2 provides a unique, reversible, and reproducible stimulus for generalized tonic-clonic seizures in animal models and is thus an effective model for assessing anti-seizure strategies. Previous studies in rats show that fasting delays the onset of CNS-OT (4), presumably by fundamentally shifting brain energy metabolism. Fasting (24–36 h) delays the latency to seizure from HBO2 by up to 300%, which is comparable to high doses of anti-epileptic drugs (AEDs) (3, 50) and experimental anticonvulsants that block excitatory glutamatergic neurotransmission (10). During periods of fasting or ketogenic diet (KD) use, the body utilizes energy obtained from free fatty acids (FFA) released from adipose tissue; however, the brain is unable to derive significant energy from FFA (8). Hepatic ketogenesis converts FFAs into the ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc), and a small percentage of AcAc spontaneously decarboxylates to acetone. During prolonged fasting or KD, large quantities of ketone bodies accumulate in the blood (\u3e5 mM) and are transported across the blood-brain barrier (BBB) by monocarboxylic acid transporters (MCT1–4) to fuel brain function, and this ketone transport is enhanced under oxidative stress or limited glucose availability (40). The brain derives \u3e60% of its energy from ketones when glucose availability is limited (8). The metabolic adaptations associated with fasting-induced ketosis improve mitochondrial function, decrease reactive oxygen species (ROS) production, reduce inflammation, and increase the activity of neurotrophic factors (34). KD mimics the metabolic state of fasting (i.e., therapeutic ketosis) and is efficacious in treating drug-resistant seizure disorders (22). This therapeutic method is well established in children and adults (30). The anticonvulsant effects of the KD correlate with an elevation of blood ketones, especially AcAc and acetone (6, 36). The KD requires extreme dietary carbohydrate restriction and only modestly increases blood ketones compared with levels associated with prolonged fasting (8). Elevating blood ketones with ketogenic medical foods or exogenous ketones is largely ineffective or problematic for a variety of reasons. Ketogenic fats, like medium chain triglyceride oil (MCT oil), are generally not well tolerated by the gastrointestinal system, and supplementation produces only low levels of ketones (\u3c0.5 mM) (27). Oral administration of BHB and AcAc in their free acid form is expensive and ineffective at producing sustained ketosis. One idea has been to buffer the free acid form of BHB with sodium salts, but this is largely ineffective at preventing seizures in animal models and causes a potentially harmful sodium overload at therapeutic levels of ketosis (6). However, esters of BHB or AcAc can effectively induce a rapid and sustained ketosis (7, 21) that mimics the sustained ketosis achieved with a strict KD or prolonged fasting without dietary restriction. Recent studies have demonstrated that orally administered esters of BHB are safe and well tolerated in rats (14) and humans (15). Producing esters of BHB or AcAc is expensive and technically challenging but offers great therapeutic potential (52). Orally administered ketone esters have the potential to induce ketosis and circumvent the problems associated with fasting-induced or diet-induced ketosis (15). The ketone ester that we synthesized and tested [R,S-1,3-butanediol acetoacetate diester (BD-AcAc2)] has been shown to induce therapeutic ketosis in dogs (12, 41) and pigs (21) and was proposed as a metabolic therapy for parenteral and enteral nutrition (7). We were interested in esters of AcAc because precursors to BHB do not prevent CNS-OT (9), and animal studies suggest that AcAc and acetone have the greatest anticonvulsant potential (6, 23, 33, 36). In this study, we explored the potential of ketone ester-induced therapeutic ketosis as a mitigation strategy against CNS-OT seizures. We hypothesized that oral administration of BD-AcAc2 mimics the anticonvulsant effect of fasting-induced ketosis and delays the onset of CNS-OT

IFN-β-Induced Alteration of VSV Protein Phosphorylation in Neuronal Cells

Vesicular stomatitis virus (VSV) replication is highly sensitive to interferon (IFN)-induced antiviral responses. VSV infection of well-known cell lines pretreated with IFN-β results in a 104-fold reduction in the release of infectious particles, with a concomitant abrogation in viral transcript and/or protein levels. However, in cell lines of neuronal lineage only a threefold reduction in viral transcript and protein levels was observed, despite the same 104-fold reduction in released infectious virions, suggesting an assembly defect. Examination of VSV matrix (M) protein ubiquitination yielded no differences between mock- and IFN-β-treated neuronal cells. Further analysis of potential post-translational modification events, by scintillation and two-dimensional electrophoretic methods, revealed IFN-β-induced alterations in M protein and phosphoprotein (P) phosphorylation. Hypophosphorylated P protein was demonstrated by reduced 32P counts, normalized by 35S-cysteine/methionine incorporation, and by a shift in isoelectric focusing. Hypophosphorylation of VSV P protein was found to occur in neuronal cell lysates, but not within budded virions from the same IFN-β-treated cells. In contrast, hyperphosphorylation of VSV M protein was observed in both cell lysates and viral particles from IFN-β-treated neuronal cells. Hyperphosphorylated M protein was demonstrated by increased 32P counts relative to 35S-cysteine/methionine normalization, and by altered isoelectric focusing in protein populations from cell and viral lysates. Hyperphosphorylated VSV M protein was found to inhibit its association with VSV nucleocapsid, suggesting a possible mechanism for type I IFN-mediated misassembly through disruption of the interactions between ribonucleoprotein cores, and hyperphosphorylated M protein bound to the plasma membrane inner leaflet