Frailty-Related Factors among Women Living with and without HIV Aged 40 Years and Older. The Women's Interagency HIV Study.

BACKGROUND: Frailty is a clinical, geriatric syndrome linked to disability and mortality; and may be associated with a variety of factors among underrepresented and underserved women living with HIV (WLWH) and without HIV (WLWOH) transitioning through the adult life course. OBJECTIVES: Determine whether a published set of factors associated cross-sectionally with frailty in WLWH and similar WLWOH at average age 39 years in 2005/2006 were associated with frailty in 2018/2019 among women who initiated frailty assessments at age ≥40 years, or whether a new set of factors were associated with frailty. DESIGN: Cross-sectional analyses within a longitudinal cohort study. SETTING: The multi-center Women's Interagency HIV Study (WIHS). PARTICIPANTS: 1285 participants (951 WLWH, 334 WLWOH), median age 53 years (interquartile range 47-58 years). MEASUREMENTS: The Fried Frailty Phenotype (FFP) in association with 23 factors representing HIV serostatus, other infections, sociodemographic factors, health behaviors, and chronic diseases. RESULTS: Frailty prevalence was 11.1% in 2018/2019 (12.6% among WLWOH, 9.6% among WLWH, p=0.121). The published 2005/2006 final multivariable stepwise regression model contained 9 predictors of frailty. When refit to women in 2018/2019, only age ≥50 years and annual income ≤$12,000 were independently positively associated with frailty; other significant 2005/2006 factors, HIV serostatus, CD4+ count <500 cells/mL among WLWH, smoking, drinking, FIB-4 and eGFR, were not. A newly-derived stepwise model considering all 23 predictors measured in 2018/2019, showed independent positive associations between frailty and age ≥50 years, annual income ≤$12,000, obesity (body mass index (BMI) ≥30kg/m2), and history of tuberculosis and cancer. CONCLUSION: Different chronic and infectious disease factors were associated with frailty among WLWH and WLWOH over the adult life course. Understanding factors associated with frailty by adult life stage, allows identification and implementation of novel, temporal interventions to alleviate frailty-associated outcomes and enhance quality of life among WLWH and WLWOH.

The formation of ubiquitin rich condensates triggers recruitment of the ATG9A lipid transfer complex to initiate basal autophagy.

Autophagy is an essential cellular recycling process that maintains protein and organelle homeostasis. ATG9A vesicle recruitment is a critical early step in autophagy to initiate autophagosome biogenesis. The mechanisms of ATG9A vesicle recruitment are best understood in the context of starvation-induced non-selective autophagy, whereas less is known about the signals driving ATG9A vesicle recruitment to autophagy initiation sites in the absence of nutrient stress. Here we demonstrate that loss of ATG9A or the lipid transfer protein ATG2 leads to the accumulation of phosphorylated p62 aggregates in the context of basal autophagy. Furthermore, we show that p62 degradation requires the lipid scramblase activity of ATG9A. Lastly, we present evidence that poly-ubiquitin is an essential signal that recruits ATG9A and mediates autophagy foci assembly in nutrient replete cells. Together, our data support a ubiquitin-driven model of ATG9A recruitment and autophagosome formation during basal autophagy.

Feasibility of Brain Atrophy Measurement in Clinical Routine without Prior Standardization of the MRI Protocol: Results from MS-MRIUS, a Longitudinal Observational, Multicenter Real-World Outcome Study in Patients with Relapsing-Remitting MS.

BACKGROUND AND PURPOSE: Feasibility of brain atrophy measurement in patients with MS in clinical routine, without prior standardization of the MRI protocol, is unknown. Our aim was to investigate the feasibility of brain atrophy measurement in patients with MS in clinical routine. MATERIALS AND METHODS: Multiple Sclerosis and Clinical Outcome and MR Imaging in the United States (MS-MRIUS) is a multicenter (33 sites), retrospective study that included patients with relapsing-remitting MS who began treatment with fingolimod. Brain MR imaging examinations previously acquired at the baseline and follow-up periods on 1.5T or 3T scanners with no prior standardization were used, to resemble a real-world situation. Brain atrophy outcomes included the percentage brain volume change measured by structural image evaluation with normalization of atrophy on 2D-T1-weighted imaging and 3D-T1WI and the percentage lateral ventricle volume change, measured by VIENA on 2D-T1WI and 3D-T1WI and NeuroSTREAM on T2-fluid-attenuated inversion recovery examinations. RESULTS: A total of 590 patients, followed for 16 months, were included. There were 585 (99.2%) T2-FLAIR, 425 (72%) 2D-T1WI, and 166 (28.2%) 3D-T1WI longitudinal pairs of examinations available. Excluding MR imaging examinations with scanner changes, the analyses were available on 388 (65.8%) patients on T2-FLAIR for the percentage lateral ventricle volume change, 259 and 257 (43.9% and 43.6%, respectively) on 2D-T1WI for the percentage brain volume change and the percentage lateral ventricle volume change, and 110 (18.6%) on 3D-T1WI for the percentage brain volume change and percentage lateral ventricle volume change. The median annualized percentage brain volume change was -0.31% on 2D-T1WI and -0.38% on 3D-T1WI. The median annualized percentage lateral ventricle volume change was 0.95% on 2D-T1WI, 1.47% on 3D-T1WI, and 0.90% on T2-FLAIR. CONCLUSIONS: Brain atrophy was more readily assessed by estimating the percentage lateral ventricle volume change on T2-FLAIR compared with the percentage brain volume change or percentage lateral ventricle volume change using 2D- or 3D-T1WI in this observational retrospective study. Although measurement of the percentage brain volume change on 3D-T1WI remains the criterion standard and should be encouraged in future prospective studies, T2-FLAIR-derived percentage lateral ventricle volume change may be a more feasible surrogate when historical or other practical constraints limit the availability of percentage brain volume change on 3D-T1WI.

Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities.

The amyloid imaging agent, Pittsburgh Compound-B, binds with high affinity to ß-amyloid (Aß) in the brain, and it is well established that PiB also shows non-specific retention in white matter (WM). However, little is known about retention of PiB in areas of white matter hyperintensities (WMH), abnormalities commonly seen in older adults. Further, it is hypothesized that WMH are related to both cognitive dysfunction and Aß deposition. The goal of the present study was to explore PiB retention in both normal-appearing WM (NAWM) and WMH in a group of elderly, cognitively normal individuals. In a group of cognitively normal elderly (n = 64; 86.5 ± 2.6 years) two analyses were applied: (1) ROIs were placed over periventricular areas in which WMH caps are commonly seen on all subjects, regardless of WMH burden or size. (2) Subject-specific maps of NAWM and WMH were co-registered with the PiB-PET images and mean SUVR values were calculated in these NAWM and WMH maps. PiB retention was significantly reduced in the ROIs of subjects with high WMH compared to subjects with low WMH. Additionally, in subjects with high WMH, there was significantly lower PiB retention in subject-specific maps of WMH compared to NAWM, which was not observed in subjects with low WMH, likely because of the small size of WMH maps in this group. These data suggest that WM in areas of WMH binds PiB less effectively than does normal WM. Further exploration of this phenomenon may lead to insights about the molecular basis of the non-specific retention of amyloid tracers in white matter.

Relationships between biomarkers in aging and dementia.

BACKGROUND: PET imaging using [(18)F]fluorodeoxyglucose (FDG) and [(11)C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. METHODS: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts. RESULTS: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42). CONCLUSIONS: PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. [(18)F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Evaluation of a commercial radiochromatography module as an arterial blood activity monitor.

Input functions required for positron emission tomography (PET) tracer kinetic modeling are often obtained from arterial blood. In some situations, using short-lived radiotracers, e.g. [(15)O]water, rapid sample handling is required. A method used at several facilities is to pump blood through a detector system at a constant rate. We investigate the suitability of a commercial radiochromatography module (IN/US Posi-RAM) for this new use. The Posi-RAM consists of two 2.5 cm (length) x 2.5 cm (diameter) cylindrical bismuth germanate (BGO) detectors that can operate in coincidence mode. Arterial blood is transported through the system via a length of tubing with flow rate controlled by a peristalsis pump. A custom-counting loop and support frame were designed for the Posi-RAM for PET studies. System sensitivity was determined to be 1.1 x 10(4) cps/(MBq ml(-1)). Dead time as a function of count-rate was found to be less than 1% for concentrations below 3.5 MBq ml(-1), a range encompassing all human-study values. In a human study, the performance of the device was found to be similar to that of the facility's current blood monitor (Siemens Fluid Monitor). We conclude that the Posi-RAM has the necessary sensitivity and count-rate capabilities to be used as a real-time blood activity monitor.

Registration-based method for determining relative PET/MR left-right image orientation.

A quality control method is described for verifying that the coordinate systems of a PET and MR image from the same subject have the same relative left-right orientation. Such ambiguities can arise, for example, at the coordinating center receiving data from many institutions in large multisite studies. In this study, image registration was performed on the PET/MR image pair. The MR image was then reflected (left/right reversed) and the image registration was performed again. A comparison of the values of the cost function describing the accuracy of the registration was used to identify the correct relative orientation. In 122 studies using data with known orientations, 100% accuracy of the method was observed.

Imaging beta-amyloid burden in aging and dementia.

OBJECTIVE: To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. METHODS: Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio. RESULTS: Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. CONCLUSIONS: Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity.

We examined the contribution of 5-HT1A autoreceptors (with [11C]WAY100635 positron emission tomography) to amygdala reactivity (with blood oxygenation level-dependent functional magnetic resonance imaging) in 20 healthy adult volunteers. We found a significant inverse relationship wherein 5-HT1A autoreceptor density predicted a notable 30-44% of the variability in amygdala reactivity. Our data suggest a potential molecular mechanism by which a reduced capacity for negative feedback regulation of 5-HT release is associated with increased amygdala reactivity.

Preparation and in vitro evaluation of propylthiouracil microspheres made of Eudragit RL 100 and cellulose acetate butyrate polymers using the emulsion-solvent evaporation method.

The objectives of this investigation are to evaluate the encapsulation efficiency of the anti-thyroid agent 6-n-propyl-2-thiouracil using two polymers of different characteristics (cellulose acetate butyrate polymer, (CAB-551-0.01) and ammonio methacrylate copolymer (Eudragit RL 100) and to study the effect of this encapsulation on the drug release properties. Polymers were used separately and in combination to prepare different microspheres. Also, the effect of polymer solution phase viscosity was studied for each of the polymers and for their combinations. An Ostwald viscometer was used to evaluate the relative viscosities of polymer solution phases and their combinations. Microspheres with 25% theoretical drug loading of 6-n-propyl-2-thiouracil core material were prepared by the emulsion solvent evaporation method. Microspheres prepared from CAB-551-0.01, which has higher relative polymer phase viscosity than Eudragit RL 100, showed significantly lower drug release rates and a noticeable lag time. Polymer combinations of CAB-551-0.01 and Eudragit RL 100 (1:1) showed an interesting synergistic increase in relative polymer solution viscosities at all concentrations. Unlike microspheres prepared from the two polymers separately which follow Higuchi spherical matrix release kinetics, microspheres prepared using a combination (1:1) of the two polymers showed near zero order with faster rates compared to those prepared using CAB-551-0.01 equivalent polymer concentrations. The results of this study suggest that 6-n-propyl-2-thiouracil was successfully and efficiently encapsulated and release rates of matrix microspheres are related to polymer solution phase viscosity, but when polymer combinations were used other factors such as structural effects must be considered.

Controlled-release matrix tablets of ibuprofen using cellulose ethers and carrageenans: effect of formulation factors on dissolution rates.

The study was conducted to investigate the effects of carrageenans, and cellulose ethers on the drug release rates of ibuprofen controlled-release tablet matrices prepared by direct compression. Polymer blends containing carrageenans or cellulose ethers were used for the formulation and the effect of varying the polymer concentration on the release of the drug was studied. Other factors such as changes in surface topography of the matrices due to hydration were observed using a cryogenic scanning electron microscopy technique. Multiple regression analysis was used to predict the time for 50% release (t50) as a function of the concentration of the polymers used. Most of the formulations showed linear release profiles (r(2)>or=0.96-0.99) and sustained the release of ibuprofen over 12-16 h. The highest t50 (9.3 h) was for the formulation that contained a blend of 1:2 ratio of Viscarin and HPMC, while the lowest (3 h) was for the matrices that contained a 2:1 ratio of methylcellulose and Gelcarin. The majority of the matrix tablets that contained 10% polymer disintegrated prematurely. Of all the polymer blends that were investigated, the combination of Viscarin and HPMC gave almost linear release profiles over the entire range of concentration that was studied. The least effective combination was methylcellulose in combination with HPMC. Most of the formulations released ibuprofen by an anomalous (non-Fickian) transport mechanism, except those matrices that contained methylcellulose and Gelcarin (in a 1:1 and 1:2 ratio), which showed zero-order release.

Reduced cerebral blood flow response and compensation among patients with untreated hypertension.

OBJECTIVE: To determine whether memory performance in hypertensive subjects induces diminished parietal and prefrontal blood flow activation relative to normotensive subjects but compensatory amygdala/hippocampal activation. METHODS: Thirty-seven untreated hypertensive subjects and 59 normotensive control subjects performed in two memory and one sensorimotor task while global and regional cerebral blood flow (rCBF) was assessed with [15O]water and PET. Neuropsychological, carotid artery ultrasound, and MRI assessments were obtained. RESULTS: When they were engaged in memory tasks, increases of CBF in hypertensive subjects were less than in normotensive subjects in the posterior parietal area, as expected; blunted responses were also shown within the middle posterior arterial watershed and thalamus. Relative to all other participants, hypertensive subjects that performed relatively well on verbal memory showed an enhanced rCBF response in the right amygdala/hippocampus. Furthermore, hypertensive, but not normotensive, subjects showed task-induced rCBF in the amygdala/hippocampal area that was significantly correlated with task-induced prefrontal rCBF. No confounding influences were identified from carotid artery or MRI measures. CONCLUSIONS: Memory performance in hypertensive individuals is related to a blunted regional cerebral blood flow (rCBF) response, particularly in parietal cortex. Potentially compensatory rCBF responses appear to occur in midbrain and correlate with prefrontal rCBF.

Evaluation of enteric matrix microspheres prepared by emulsion-solvent evaporation using scanning electron microscopy.

Theophylline microspheres were prepared by the emulsion-solvent evaporation method using cellulose acetate butyrate (CAB381-20) and mixtures of CAB381-20(R) and cellulose acetate phthalate. The physical state of the drug, polymers and microspheres surfaces were determined using scanning electron microscopy. For those microspheres prepared using mixtures of CAB381-20 and cellulose acetate phthalate, scanning electron micrographs were taken before dissolution and also at different stages of dissolution (in SGF, pH 1.2 and in simulated intestinal fluid, pH 7.5). Micrographs were taken of the outside surfaces of the microspheres and of the cleaved microspheres showing their interiors (core). Drug crystals were observed on or near the surface of microspheres prepared from the polymer mixtures, while no drug particles or crystals were seen on the surfaces of microspheres prepared solely from CAB381-20. An acid wash for less than 2 min was capable of extracting all drug on the surface of the microspheres prepared from a mixture of CAB381-20 and cellulose acetate phthalate. The absence of drug crystals on the surface of CAB381-20 microspheres is believed to prevent initial drug release and create a lag time in release profiles. Results suggest that in both microsphere formulations, a layer of drug-free polymer is formed outside the core matrix and is believed to be responsible for the near zero-order release profiles.

Viscosity of polymer solution phase and other factors controlling the dissolution of theophylline microspheres prepared by the emulsion solvent evaporation method.

The objectives of this investigation are to evaluate the effect of the viscosity of polymer solution phase on microsphere properties, especially the drug release characteristics since no studies on this formulation variable have been reported. Also, since it is known that polymer molecular weight affects both the viscosity of the polymer solution and the release properties of microspheres, the interaction of these factors was studied. Microspheres with 33% theoretical drug loading of anhydrous theophylline core material were prepared by the emulsion solvent evaporation method. Two cellulose acetate butyrate polymers, (CAB381-2, CAB381-20), chemically similar but having different molecular weights, were used to prepare different polymer solutions having different apparent viscosities in acetone. A Brookfield viscometer was used to evaluate the viscosities of polymer solutions. Dissolution rates of microspheres prepared from the polymer solutions were inversely related to the initial polymer solution viscosities for both CAB381-2 and CAB381-20. The times for the release of 30 and 50% of the drug from the microspheres have a linear relationship with initial polymer solution viscosity. Initial release was significantly decreased with increasing polymer solution viscosity. Unlike CAB381-2 microspheres which follow Higuchi spherical matrix release kinetics, microspheres prepared from the higher molecular weight polymer (CAB381-20) showed extended release dissolution profiles with near zero order kinetics. It is evident that both the polymer solution viscosity and the molecular weight have an effect on the drug release from microspheres. These results suggest that release rates of matrix microspheres could be predictably optimized by adjusting the viscosity of polymer solutions.

Solvent, emulsifier and drug concentration factors in poly(D,L-lactic acid) microspheres containing hexamethylmelamine.

Biodegradable poly(D,L-lactic acid) (PLA) microspheres containing hexamethylmelamine (HMM) were developed for potential use in chemoembolization and intraperitoneal implantation. The emulsion-solvent-evaporation/extraction method was used to prepare 15 formulations with different drug/polymer ratios, solvent compositions and emulsifer concentrations in the continuous aqueous phase. A central composite experimental design was used, with five levels of the three different factors. All formulations resulted in the formation of discrete matrix microspheres containing crystalline drug. The mean particle sizes of the microsphere formulations ranged from 62-348 microm and the effect of the independent variables on microsphere size was satisfactorily predicted using response surface methodology. For theoretical drug loads of 5-40%, efficiency of entrapment ranged from 75-107% and porosities of the microspheres were between 0-6.5%. The rate of drug release from the microspheres depended on drug loading and particle size. Microspheres with 22.5% or greater theoretical drug content released drug rapidly, with almost complete release occurring in 70 h or less. Formulations with drug loading of 5% and 9.57%, however, released drug very slowly, with less than 50% released in 40 days. Release kinetics of narrow sieve cuts of microspheres with high drug load (35.4%) followed square root of time profiles.

Plasma fatty acids, adiposity, and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus.

Skeletal muscle insulin resistance (IR) is typically severe in type 2 diabetes mellitus (DM). However, the factors that account for interindividual differences in the severity of IR are not well understood. The current study was undertaken to examine the respective roles of plasma FFA, regional adiposity, and other metabolic factors as determinants of the severity of skeletal muscle IR in type 2 DM. Twenty-three subjects (12 women and 11 men) with type 2 DM underwent positron emission tomography imaging using [18F]2-fluoro-2-deoxyglucose during euglycemic insulin infusions (120 mU/min x m2) to measure skeletal muscle IR, using Patlak analysis of the tissue activity curves. Body composition analysis included body mass index, fat mass, and fat-free mass by dual energy x-ray tomography, and computed tomography determinations of visceral adiposity, thigh adipose tissue distribution, and muscle composition. Body mass index, fat mass, subfascial adiposity in the thigh, and visceral adipose tissue (VAT) were all significantly related to skeletal muscle IR (r = -0.48 to -0.63; P < 0.01). However, the strongest simple correlate of IR in skeletal muscle was insulin-suppressed plasma FFA (r = -0.81; P < 0.001). VAT was the sole component of adiposity that significantly correlated with insulin-suppressed plasma FFA concentration (r = 0.64; P < 0.001). These findings indicate that the severity of skeletal muscle IR in type 2 DM is closely related to the IR of suppressing lipolysis and that plasma fatty acids and VAT are key elements mediating the link between obesity and skeletal muscle IR in type 2 DM.

Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance: a dose-response assessment using positron emission tomography.

It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport and phosphorylation has also been proposed. The current study examined whether the respective contributions of transport and phosphorylation to insulin resistance are modulated across a dose range of insulin stimulation. Rate constants for transport and phosphorylation in skeletal muscle were estimated using dynamic positron emission tomography (PET) imaging of 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) during insulin infusions at three rates (0, 40, and 120 mU/m2 per min) in lean glucose-tolerant, obese glucose-tolerant, and obese type 2 diabetic subjects. Parallel studies of arteriovenous fractional extraction across the leg of [18F]FDG and [2-3H] glucose were performed to measure the "lumped constant" (LC) (i.e., the analog effect) for [18F]FDG to determine whether this value is affected by insulin dose or insulin resistance. The value of the LC was similar across insulin doses and groups. Leg glucose uptake (LGU) also provided a measure of skeletal muscle glucose metabolism independent of PET. [18F]FDG uptake determined by PET imaging strongly correlated with LGU across groups and across insulin doses (r = 0.81, P < 0.001). Likewise, LGU correlated with PET parameters of glucose transport (r = 0.67, P < 0.001) and glucose phosphorylation (r = 0.86, P < 0.001). Glucose transport increased in response to insulin in the lean and obese groups (P < 0.05), but did not increase significantly in the type 2 diabetic group. A dose-responsive pattern of stimulation of glucose phosphorylation was observed in all groups of subjects (P < 0.05); however, glucose phosphorylation was lower in both the obese and type 2 diabetic groups compared with the lean group at the moderate insulin dose (P < 0.05). These findings indicate an important interaction between transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.

Altered serotonin 2A receptor activity in women who have recovered from bulimia nervosa.

OBJECTIVE: The authors' goal was to confirm that brain serotonin (5-HT) alterations are present in patients who have recovered from bulimia nervosa. Positron emission tomography imaging with [(18)F]altanserin was used to characterize binding of the 5-HT(2A) receptor, which might contribute to altered feeding, mood, or impulse control. METHOD: Nine women who had recovered from bulimia nervosa (they had no episodes of binge eating or purging, were at normal weight, and had regular menstrual cycles for more than 1 year) were compared with 12 female volunteers who had never had bulimia. RESULTS: The healthy volunteers, but not the women who had recovered from bulimia nervosa, had an age-related decline in 5-HT(2A) binding. Women who had recovered from bulimia nervosa had a reduction of medial orbital frontal cortex 5-HT(2A) binding. CONCLUSIONS: The lack of age-related changes in 5-HT activity is further evidence of 5-HT alterations in subjects who have recovered from bulimia nervosa. In addition, vulnerabilities for eating disorders, impulse dyscontrol, and mood disturbances may involve 5-HT and frontal lobe activity.

Controlled-release tablets from carrageenans: effect of formulation, storage and dissolution factors.

The purpose of this study was to investigate the potential of two carrageenans, iota-carrageenan and lambda-carrageenan for the preparation of controlled-release tablets. Tablets were compressed on a Carver press and the effect of formulation factors, moisture, and storage on the release of theophylline was studied. The effect of sodium chloride in the tablet formulation and a change in the ionic strength of the dissolution media was studied on the release of three model drugs. The release rate increased both with an increase in tablet diameter and increase in drug to carrageenan ratio in the tablets. The two lubricants studied had a negligible effect on the rate of drug release at their commonly used concentrations. Moisture content of carrageenans, storage of tablets at 37 degrees C/75% RH for 3 months, and incorporation of 10% sodium chloride in the tablets did not have any significant effect on the release rate. The change in ionic strength of simulated gastric fluid altered the release rate whereas the ionic strength of simulated intestinal fluid did not have a significant effect on the release rate. Carrageenan tablets were relatively insensitive to small changes in formulation parameters and dissolution conditions.