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.

FMR1 CGG repeat length predicts motor dysfunction in premutation carriers.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged >or=50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS).

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. METHODS: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 +/- 10.3 years), 20 unaffected female carriers (43.3 +/- 11.2 years), 11 genetically normal female controls (51.0 +/- 10.3 years), 36 affected male carriers (65.0 +/- 5.6 years), 25 unaffected male carriers (53.5 +/- 12.5 years), and 39 male controls (58.0 +/- 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. RESULTS: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. CONCLUSIONS: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.

OBJECTIVES: To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes. METHODS: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education. RESULTS: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity. CONCLUSIONS: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X-associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.

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).

Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

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.

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.

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.

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.

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.

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.

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.

Results of a meta-analysis of cost-benefit research: is this a question worth asking?

We attempted a meta-analysis of telemedicine research studies of the costs associated with telemedicine. First, we performed a search of six well known databases with a variety of relevant keywords. After discarding non-English publications, books and duplicate publications resulting from the same study, we were left with 551 articles for analysis. Our second step was to separate the articles into two groups: those with and those without quantitative cost data. Only 38 articles contained any type of real data. Because many of these 38 studies proved to be inadequately designed or conducted, we were unable to perform a traditional meta-analysis. Furthermore, there were a number of disturbing features common to these studies, including the omission of the number of consultations or patients, almost non-existent longitudinal data collection and lack of uniformity in cost analyses. We conclude that it is premature for any statements to be made, either positive or negative, regarding the cost-effectiveness of telemedicine in general.

The value of trauma scores: predicting discharge after traumatic brain injury.

OBJECTIVE: To determine the association of acute variables with disposition after acute hospitalization. DESIGN: Revised Trauma Score (RTS), Injury Severity Score (ISS), and the Combined Trauma Score Injury Severity Score (TRISS(RTS)) were compared with discharge disposition after acute hospitalization of 378 consecutive patients who sustained a traumatic brain injury (TBI) and were treated at a level 1 trauma center between September 1997 and May 1998. RESULTS: Logistic regression modeling found TRISS(RTS) to predict discharge to home with or without home health assistance or inpatient rehabilitation vs. nursing home placement or death. Subsequent modeling, excluding patients who died or went to nursing homes, identified RTS and ISS as predictors of discharge to home with or without home health vs. inpatient rehabilitation. A sensitivity of 97.78% and 93.91% were achieved with these two models when tested on a population of 4,625 patients with TBI treated during the last 10 yr at the same facility. CONCLUSIONS: The results suggest that RTS, ISS, and TRISS(RTS) are predictors of discharge disposition after acute hospitalization with TBI and may be useful measures of rehabilitation services resource planning early in the course of TBI management.

Sexual dysfunction following vulvectomy.

OBJECTIVE: This is a pilot study to evaluate sexual dysfunction in women after vulvectomy. METHODS: An 88-question survey was used to assess body image and the DSM IV criteria for sexual dysfunction on women who had undergone vulvectomy. RESULTS: Forty-seven women agreed to participate in the study and 41 women (87%) returned the survey. There was a significant alteration of body image in these women after vulvectomy (P = 0.004). Sexual frequency significantly decreased after surgery (P = 0.001) and there was significant sexual dysfunction in the categories of sexual aversion disorder (P = 0.01), arousal disorder (P = 0.02), and hypoactive sexual disorder (P = 0. 001). The extent of surgery did not correlate with degree of sexual dysfunction in any category. Women who were depressed at the time of survey (as determined by the PRIME-MD scale) were more likely to suffer sexual aversion disorder (P = 0.05) and tended to have more body image disturbance (P = 0.1) and global sexual dysfunction (P = 0.06). CONCLUSIONS: Women experience significant sexual dysfunction after vulvectomy and the extent of surgery or type of vulvectomy did not correlate with degree of sexual dysfunction. There is a significant need to address sexual problems with all women after any vulvectomy. Age, depression, worsening GOG performance status, and preoperative hypoactive sexual dysfunction were risk factors for sexual dysfunction after vulvar surgery. Appropriate counseling and treatment of depression may be of benefit to this patient population.

Osteoblast numbers after calcitonin therapy: a retrospective study of paired biopsies obtained during long-term calcitonin therapy in postmenopausal osteoporosis.

The present study is a retrospective examination of osteoblast indices in human iliac crest bone biopsies from a study on the long-term efficacy of calcitonin. Paired baseline and 2-year biopsies were examined from eight control subjects and 10 treated subjects; treated subjects received 100 MRC units synthetic salmon calcitonin (Calcimar, Armour Pharmaceutical Co, Scottsdale, AZ) injected i.m. sub Q at bedtime. Control patients did not receive a placebo injection. All subjects received 400 units vitamin D(2) p.o. q.d. and 1200 mg CaCO(3) p.o. q.d. When the differences in baseline and 2-year values were analyzed, subjects receiving calcitonin showed no decrease compared with control subjects for the fraction of osteoid surface lined by osteoblasts (ObS/OS) (but were in fact significantly greater, P = 0.04). There was no difference from control subjects in the number of osteoblasts/mm bone surface (NOb/BPm), or mean mineral apposition rate (MAR). Since calcitonin is receiving renewed interest for osteoporosis therapy, these data (derived from paired human biopsies) are valuable since they show that no decrease in osteoblast cell number resulted from long-term calcitonin therapy. Results point to the need for renewed investigation concerning the effect of calcitonin on osteoblast-osteoclast interactions.

Adequate dietary calcium mitigates osteopenia induced by chronic lead exposure in adult rats.

The purpose of the present study was to investigate bone changes in the adult rat exposed to low lead levels during intake of normal dietary calcium and to contrast these findings with data from our earlier studies performed with animals receiving low dietary calcium concurrent with lead exposure. The present study exposed adult rats to 100 ppm lead via drinking water for 12 weeks and assessed bone histology, 1,25-dihydroxyvitamin D, 25(OH)vitamin D and parathyroid hormone levels. No osteopenia was evident by quantitative bone histology, and circulating levels of 1,25-dihydroxyvitamin D, 25(OH) vitamin D and parathyroid hormone were normal. Bone ash findings documented incorporation of significant amounts of lead into bone mineral. These findings document absence of interference with vitamin D metabolism, absence of secondary hyperparathyroidism and absence of osteopenia following 12 weeks of low lead exposure in the adult rat maintained on normal calcium intake. Results stress the importance of adequate calcium intake in our elderly population who may be exposed to cumulative, low-level lead exposure.