Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 + or - 12.46) and without FXTAS (n = 17, age: 44.94 + or - 11.23), in genetically normal female controls (n = 8, age: 50.63 + or - 11.43), male carriers with FXTAS (n = 34, age: 66.44 + or - 6.77) and without FXTAS (n = 21, age: 52.38 + or - 12.11), and genetically normal male controls (n = 30, age: 57.20 + or - 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Verbal learning and memory among heterozygous fragile X females.

In this paper we report the results of a brief examination of verbal learning and memory in 20 heterozygous fragile X [fra(X)] positive females and in 2 control groups of 20 subjects each. One control group was composed of fra(X)-negative mothers (obligate carriers) and sisters of male probands with fra(X) syndrome, while the other consisted of 14 head injured and 6 learning disabled females. Intellectual functioning was assessed by means of the Wechsler scales, and learning was assessed by several different clinical memory tests. Significant differences were found between groups on measures of short-term memory and learning efficiency. Groups did not differ on measures of cued recall or delayed recall. The findings are consistent with other data and suggest the possibility that central information processing and/or specific encoding processes are defective in persons with fra(X).

Neuropsychological dysfunction among affected heterozygous fragile X females.

Fragile X (or Martin-Bell) syndrome is an X-linked disorder that often produces mental retardation in males, but usually affects heterozygous females to a lesser degree. Here we report the results of a brief neuropsychological examination of 20 heterozygous fra(x) girls and women and two control groups of 20 individuals each. One control group was composed of fra(x)-negative mothers (obligate carriers) and sisters of male probands with fra(x) syndrome, whereas the other was composed of 14 head-injured and six learning disabled women and girls. In addition to general intellectual impairment, several specific cognitive deficits were consistently found in individuals with the Martin-Bell syndrome, suggesting focal neuropsychological dysfunction. Significant differences were noted between fra(x) individuals and controls on most cognitive and neuropsychological measures studied. Over one-third of the fra(x) individuals demonstrated neuropsychological symptoms characteristic of the full developmental Gerstmann syndrome, whereas another third had three or four of the five signs of possible parietal lobe dysfunction. In our sample, there was an association between improved performance and increasing age. Differences among heterozygous individuals in number of focal symptoms may reflect some variability in the penetrance of the fra(x) gene, as well as in the functional organization of the brain.

Prediction of independent functioning and behavior problems in geriatric patients.

Folstein's Mini Mental State Exam, a test assessing the capacity to perform novel and/or repetitive motor tasks (Behavioral Dyscontrol Scale) and a brief measure of working memory were used in a sample of 50 male Veterans Affairs geriatric clinic patients who ranged in age from 63 to 105 (mean, 80.1). The purpose of this study was to attempt to predict the patients' capacity to regulate their behavior independently. We hypothesized that frontal lobe disorders often impair a patient's ability to function autonomously and that the Behavioral Dyscontrol Scale, a measure of frontal lobe impairment, would best predict the capacity for independent regulation of purposeful behavior. Therefore, we examined the relationship of the Behavioral Dyscontrol Scale with spouses' and caregivers' ratings of patients' independent living skills, and with behaviors that interfere with independent functioning. The results of hierarchial regression analyses indicated that the Behavioral Dyscontrol Scale was the only predictor of functional autonomy and was the best predictor of both impulsivity and apathy among geriatric patients. The Behavioral Dyscontrol Scale appears to assess a different functional domain than do the MMSE and similar measures, which rely heavily on the evaluation of orientation and gross cognitive status.

Executive cognitive abilities and functional status among community-dwelling older persons in the San Luis Valley Health and Aging Study.

OBJECTIVES: The purpose of this study was to evaluate the contribution of the executive cognitive functions to self-reported and observed performance of activities of daily living and instrumental activities of daily living. DESIGN: These data were collected as part of a cross-sectional survey of community-dwelling older persons, using statistical sampling, in a two-county area of southern Colorado. SETTING: Participants were interviewed and administered measures of general cognition, depression, executive functioning, and performance of self-care and instrumental activities, either in their homes or at the study clinic. PARTICIPANTS: A total of 1158 community-dwelling persons between the ages of 60 and 99 participated. Of these, 657 were female, 501 were male, 637 were Hispanic, and 521 were non-Hispanic whites. MEASUREMENTS: Subjects were administered the Mini-Mental State Exam (MMSE), a measure of executive functioning (the Behavioral Dyscontrol Scale), the Center for Epidemiologic Studies Depression scale (CES-D), and the Structured Assessment of Independent Living Skills (SAILS, a measure of observed performance of daily tasks). They also were interviewed regarding their reported ADL and IADL status using measures from the Longitudinal Study on Aging. RESULTS: Both general mental status and executive functioning demonstrated statistically significant univariate associations with all seven functional status measures (both self-report and observed performance). In a series of ordinary least squares regression models, executive functioning was a predictor for self-reported ADLs and observed performance of complex IADL tasks such as managing money and medications. Mental status did not predict self-reported functioning but was a predictor of observed performance. Depression was a significant variable for self-report measures but not for observed performance. Executive functioning and general mental status demonstrated some degree of independence from one another. CONCLUSION: Executive functioning is an important determinant of functional status for both self-reported and observed ADLs and IADLs and should be assessed routinely when evaluating the mental status and functional abilities of older people. These results replicate and extend previous research on executive functioning among older persons by examining these factors in a large bi-ethnic community sample.

Outcome and utilization differences for older persons with stroke in HMO and fee-for-service systems.

OBJECTIVES: To compare treatment and outcomes for older persons with stroke in Medicare health maintenance organizations (HMOs) and fee-for-service (FFS) systems. DESIGN: Inception cohort stratified by payer and followed for 1 year. SETTING: Six HMOs and five FFS systems with large Medicare populations in the West, Midwest, and Eastern United States. PARTICIPANTS: A total of 429 randomly selected stroke patients receiving rehabilitation in nursing homes or rehabilitation hospitals (RHs) from June 1993 to June 1995. MEASUREMENTS: Improvement in activities of daily living (ADLs) during rehabilitation, and ADL recovery, community residence, and utilization until 12 months after stroke. Outcomes were adjusted for premorbid function, marital status, comorbid illness, posthospital function, cognition, psychological problems, and stroke deficits. RESULTS: At baseline, HMO patients were more likely to be married, and less likely to be blind or have psychiatric diagnoses. HMO patients had shorter hospitalizations (P < .001), were less likely to be admitted to RHs (13% vs 85%, P < .001), and received fewer therapy and physician specialist visits (P < .001) but more home health visits (P < .001). During rehabilitation, FFS patients made greater improvement in ADLs (difference, 0.73 ADLs; 95% CI, .37-1.09). At 1 year, there was no difference in ADL recovery (difference, -0.24 ADL; 95% CI, -0.64-0.16), but FFS patients were more likely to reside in the community (adjusted OR, 1.8; 95% CI, 1.1-3.1), and HMO patients were more likely to reside in nursing homes (adjusted OR, 2.4; 95% CI, 1.1-5.5). CONCLUSION: Study findings suggest that short-term functional outcomes and eventual community residence rates are poorer for Medicare HMO patients with stroke than for stroke patients receiving FFS care, consistent with the lower intensity of rehabilitation (in nursing homes vs RHs) and less specialty physician care.

High prevalence of cobalamin deficiency in elderly outpatients.

OBJECTIVE: To measure the prevalence of cobalamin (vitamin B12) deficiency in geriatric outpatients as documented by both low serum cobalamin levels and elevations of serum methylmalonic acid and homocysteine and to determine the response to cobalamin treatment. DESIGN: Prospective study screening elderly subjects for cobalamin deficiency using radiodilution cobalamin assays as well as stable isotope dilution gas chromatography-mass spectrometry methylmalonic acid and homocysteine assays. In patients with serum cobalamin levels < or = 300 pg/mL, the response to cobalamin treatment in the group with levels of methylmalonic acid and/or homocysteine > 3 standard deviations (SD) above the mean for normals was compared with that of those without such elevations. SETTING: Outpatient geriatric clinics at the VA Medical Center and University Health Sciences Center, Denver, CO. PATIENTS: One-hundred and fifty-two consecutive outpatients, ages 65 to 99, were screened. Twenty-nine subjects with serum cobalamin levels < or = 300 pg/mL were prospectively evaluated and treated with cobalamin. MAIN OUTCOME MEASURES: Cobalamin, methylmalonic acid, homocysteine, complete blood counts, neurologic examination, and neuropsychological testing. RESULTS: The prevalence of cobalamin deficiency as defined by a serum cobalamin level < or = 300 pg/mL and levels of serum methylmalonic acid and/or homocysteine elevated to > 3 SD was 14.5% of the screened outpatients. A similar proportion of patients with low normal serum cobalamin levels (between 201 and 300 pg/mL) demonstrated elevated metabolites > 3 SD (56%) compared with patients with low serum cobalamin levels (< or = 200 pg/mL) (62%). Cobalamin therapy caused a marked fall or complete correction of the elevated methylmalonic acid and homocysteine levels in each patient who was treated prospectively. Results for complete blood count, lactate dehydrogenase, bilirubin, baseline neurologic score, and baseline neuropsychologic scores did not differ in the group of patients with elevated metabolites compared with those with normal metabolites. The mean red cell volume fell significantly in the patients with elevated metabolites after 6 months of cobalamin treatment. One patient with elevated metabolites had marked improvement in his neurologic abnormalities after 6 months of cobalamin treatment. CONCLUSION: There was a high (14.5%) prevalence of cobalamin deficiency as demonstrated by elevations in serum methylmalonic acid and homocysteine in addition to low or low normal serum cobalamin levels in elderly outpatients. The serum cobalamin level was insensitive for screening since similar numbers of patients with low normal serum cobalamin levels of 201-300 pg/mL compared with patients with low cobalamin levels (< or = 200 pg/mL) had markedly elevated metabolites which fell with cobalamin treatment. Additional studies will be required to define the full clinical benefit from treatment with Cbl in elderly subjects.

Rural telemedicine data/image transfer methods and purposes of interactive video sessions.

A national survey conducted for the Office of Rural Health Policy in 1995 identified 558 participants in rural telemedicine; 499 (89%) responded to a detailed follow-up survey to describe type of use. While 84% of respondents reported using interactive video, only 25% reported access to e-mail for exchange of data. The challenge to medical informatics is to connect dispersed providers, not just with videoconferencing, but also with other information-sharing methods.

Working memory impairment among persons with chronic progressive multiple sclerosis.

We examined short-term memory (STM) among a group of 23 definite, chronic progressive multiple sclerosis (MS) patients, all of whom had experienced recent significant disease activity, and a control group matched closely on age and education. MS patients were impaired, relative to controls, on the majority of the measures used. Although there were no significant differences between groups on the Mini Mental State Examination, patients performed more poorly on digits forward and backward, the Brown-Peterson test, and the logical memory scale of the Revised Wechsler Memory Scale (both immediate and delayed). Performance on tests sensitive to central processing capacity was significantly correlated with measures of STM. Working memory was significantly impaired in this sample of chronic progressive MS patients. In conjunction with previous research showing deficient information processing and prefrontal dysfunction among this population, the findings suggest that an impairment of central information processing may be a fundamental aspect of the mnestic and cognitive decline observed in many chronic progressive MS patients.

Effect of secondary structure on the potential of mean force for poly-L-lysine in the alpha-helix and beta-sheet conformations.

Because poly-L-lysine (PLL) can exist in the alpha-helix or beta-sheet conformation depending on solution preparation and solution conditions, PLL is a suitable candidate to probe the dependence of protein interactions on secondary structure. The osmotic second virial coefficient and weight-average molecular weight are reported from low-angle laser-light scattering measurements for PLL as a function of NaCl concentration, pH, and alpha-helix or beta-sheet content. Interactions between PLL molecules become more attractive as salt concentration increases due to screening of PLL charge by salt ions and at low salt concentration become more attractive as pH increases due to decreased net charge on PLL. The experimental results show that interactions are stronger for the beta-sheet conformation than for the alpha-helix conformation. A spherically-symmetric model for the potential of mean force is used to account for specific interactions not described by DLVO theory and to show how differences in secondary structure affect PLL interactions.

Cloud-point temperatures for lysozyme in electrolyte solutions: effect of salt type, salt concentration and pH.

Liquid-liquid phase-separation data were obtained for aqueous saline solutions of hen egg-white lysozyme at a fixed protein concentration (87 g/l). The cloud-point temperature (CPT) was measured as a function of salt type and salt concentration to 3 M, at pH 4.0 and 7.0. Salts used included those from mono and divalent cations and anions. For the monovalent cations studied, as salt concentration increases, the CPT increases. For divalent cations, as salt concentration rises, a maximum in the CPT is observed and attributed to ion binding to the protein surface and subsequent water structuring. Trends for sulfate salts were dramatically different from those for other salts because sulfate ion is strongly hydrated and excluded from the lysozyme surface. For anions at fixed salt concentration, the CPT decreases with rising anion kosmotropic character. Comparison of CPTs for pH 4.0 and 7.0 revealed two trends. At low ionic strength for a given salt, differences in CPT can be explained in terms of repulsive electrostatic interactions between protein molecules, while at higher ionic strength, differences can be attributed to hydration forces. A model is proposed for the correlation and prediction of the CPT as a function of salt type and salt concentration. NaCl was chosen as a reference salt, and CPT deviations from that of NaCl were attributed to hydration forces. The Random Phase Approximation, in conjunction with a square-well potential, was used to calculate the strength of protein-protein interactions as a function of solution conditions for all salts studied.

Effects and effectiveness of telemedicine.

The use of telemedicine has recently undergone rapid growth and proliferation. Although the feasibility of many applications has been tested for nearly 30 years, data concerning the costs, effects, and effectiveness of telemedicine are limited. Consequently, the development of a strategy for coverage, payment, and utilization policy has been hindered. Telemedicine continues to expand, and pressure for policy development increases in the context of Federal budget cuts and major changes in health service financing. This article reviews the literature on the effects and medical effectiveness of telemedicine. It concludes with several recommendations for research, followed by a discussion of several specific questions, the answers to which might have a bearing on policy development.

Panel discussion: impact of guidelines on third-party payors and HMOs.

Utilization management (preauthorization) has given way to disease management, i.e., the management, by providers in cooperation with third-party payors, of patients and their disease states from beginning to end. Managed-care organizations are seeking guidelines-based cancer disease management programs that result in: lower, more predictable costs; authoritative quality assurance; measured outcomes; reduced preauthorization disputes; and improved management of cases in clinical trials. Guidelines also need to provide some consistency and consensus regarding the management of common clinical problems. Good guidelines help assist managed-care companies gather data, build a more solid utilization management foundation and support a clinically sound disease management program. Aetna's Institutes of Excellence (IOE) program seeks to address the issue of coverage for high-dose chemotherapy and bone marrow transplantation, but can serve as a useful model for the development of comprehensive cancer networks.

Paths for future population aging.

Developed countries with low fertility and mortality rates are already experiencing population aging and will continue to do so. Some developing countries undergoing demographic transitions are beginning to acknowledge the issues of population aging. The projected declines in fertility in other developing countries will mean substantial population aging in the future. Alternative measures for population aging can clarify issues that arise with this process. Because population aging is inevitable, all countries need to incorporate aging policies with population policies.

Aging and heterogeneity: genetics, social structure, and personality.

Life-course studies of human development suggest that birth cohorts become more internally differentiated with respect to personality characteristics as their members age. This article examines possible explanations for this macro-level phenomenon in terms of three micro-level research traditions: (1) individual differentiation, (2) social structure/allocation, and (3) behavioral genetics. We conclude that each tradition can marshal credible empirical support, and that, therefore, all three are needed for a full understanding of older-age heterogeneity processes. A model is developed, synthesizing all three approaches. Study designs in any one of these traditions that fail to take account of the others are likely to draw misleading or erroneous conclusions concerning sources of variation and covariation. Several types of study designs are suggested which would avoid such problems.

Effects of very high antibiotic concentrations on human intervertebral disc cell proliferation, viability, and metabolism in vitro.

STUDY DESIGN: Four antibiotics commonly used during spinal surgery (cefazolin, gentamycin, cefamandole, and vancomycin) were tested for their effects on cultured human disc cells from the anulus. OBJECTIVE: To determine the viability, proliferation, and metabolism of cells cultured from the human anulus after they were exposed to four antibiotics. SUMMARY OF BACKGROUND DATA: Previous studies concerning the effect of antibiotics on the disc have used animal models or explanted discs, but little is understood about the effect of antibiotics on the proliferation, viability, and metabolism of cells from the anulus. METHODS: In this study, 3H-thymidine incorporation, trypan blue exclusion, and cell metabolism were determined using cells from the human anulus grown in monolayer culture. The latter measurement used a cytosensor microphysiometer to monitor the rate at which cells acidified their microenvironment, an event that is proportional to cellular metabolism because it reflects the excretion over time of acidic products such as lactic acid from glycolysis and CO2 from cellular respiration. RESULTS: After 48 hours of antibiotic exposure, cell viability was significantly lower as a result of all four antibiotics at the highest concentration tested. Cell proliferation was lower after exposure to cefazolin and cefamandole. During a 6-hour antibiotic exposure, anulus cells in the highest concentration of cefamandole or vancomycin displayed a significantly decreased rate of cell metabolism. CONCLUSIONS: These findings show that high doses of antibiotics can have direct, deleterious effects on cultured disc cell survival, cell proliferation, and metabolic rates. Discitis is a serious primary or postoperative complication that often requires prolonged antibiotic treatment. Studies such as the current investigation with cultured cells from the anulus show the importance of a greater understanding concerning antibiotic effects on disc cell proliferation and metabolism.

Aging in individuals with the FMR1 mutation.

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.

Attitudes of orthopaedic trauma surgeons regarding current controversies in the management of pelvic and acetabular fractures.

A closed-ended questionnaire was mailed to all 363 active members of the Orthopaedic Trauma Association. It directed, toward practicing pelvic and acetabular surgeons, questions pertaining to practice demographics and preferred methods for detection and prevention of deep venous thrombosis (DVT), nerve injury, and heterotopic ossification (HO). Questionnaires were received from 226 surgeons (62 percent). Of the surgeons who responded, 181 (80 percent) perform pelvic-fracture and acetabular-fracture surgery; only questionnaires from this group were analyzed. Standard statistical methods were used to perform both univariate and multivariate analyses. Preoperative DVT screening was performed by 48 percent of the surgeons; ultrasound was the most commonly used modality (82 percent). Preoperative DVT prophylaxis was administered by 88 percent of those surveyed; the majority (78 percent) used sequential compression devices. Postoperative prophylaxis was used by 99 percent; the most commonly used modality was sequential compression devices. Analysis suggests that fellowship-trained surgeons and surgeons in practice for fewer than twenty years are more likely to use preoperative DVT prophylaxis. HO prophylaxis was administered by 88 percent; the most commonly used modality was indomethacin. Intraoperative nerve monitoring was performed by only 15 percent of the respondents. Most surgeons employed prophylactic measures to prevent DVT and HO. The wide variation in type of prophylaxis and reasons for use suggests that controversy will continue, and a standard of care for these conditions has yet to be defined. Very few surgeons use intraoperative nerve monitoring routinely.