Genetic Dissection of Antibiotic Adjuvant Activity.

Small molecule adjuvants that enhance the activity of established antibiotics represent promising agents in the battle against antibiotic resistance. Adjuvants generally act by inhibiting antibiotic resistance processes, and specifying the process acted on is a critical step in defining an adjuvant's mechanism of action. This step is typically carried out biochemically by identifying molecules that bind adjuvants and then inferring their roles in resistance. Here, we present a complementary genetic strategy based on identifying mutations that both sensitize cells to antibiotic and make them "adjuvant blind." We tested the approach in Acinetobacter baumannii AB5075 using two adjuvants: a well-characterized ß-lactamase inhibitor (avibactam) and a compound enhancing outer membrane permeability (aryl 2-aminoimidazole AI-1). The avibactam studies showed that the adjuvant potentiated one ß-lactam (ceftazidime) through action on a single ß-lactamase (GES-14) and a second (meropenem) by targeting two different enzymes (GES-14 and OXA-23). Mutations impairing disulfide bond formation (DsbAB) also reduced potentiation, possibly by impairing ß-lactamase folding. Mutations reducing AI-1 potentiation of canonical Gram-positive antibiotics (vancomycin and clarithromycin) blocked lipooligosaccharide (LOS/LPS) synthesis or its acyl modification. The results indicate that LOS-mediated outer membrane impermeability is targeted by the adjuvant and show the importance of acylation in the resistance. As part of the study, we employed Acinetobacter baylyi as a model to verify the generality of the A. baumannii results and identified the principal resistance genes for ceftazidime, meropenem, vancomycin, and clarithromycin in A. baumannii AB5075. Overall, the work provides a foundation for analyzing adjuvant action using a comprehensive genetic approach. IMPORTANCE One strategy to confront the antibiotic resistance crisis is through the development of adjuvant compounds that increase the efficacy of established drugs. A key step in the development of a natural product adjuvant as a drug is identifying the resistance process it undermines to enhance antibiotic activity. Previous procedures designed to accomplish this have relied on biochemical identification of cell components that bind adjuvant. Here, we present a complementary strategy based on identifying mutations that eliminate adjuvant activity.

Effect of age, ethnicity, sex, cognitive status and APOE genotype on amyloid load and the threshold for amyloid positivity.

The threshold for amyloid positivity by visual assessment on PET has been validated by comparison to amyloid load measured histopathologically and biochemically at post mortem. As such, it is now feasible to use qualitative visual assessment of amyloid positivity as an in-vivo gold standard to determine those factors which can modify the quantitative threshold for amyloid positivity. We calculated quantitative amyloid load, measured as Standardized Uptake Value Ratios (SUVRs) using [18-F]florbetaben PET scans, for 159 Hispanic and non-Hispanic participants, who had been classified clinically as Cognitively Normal (CN), Mild Cognitive Impairment (MCI) or Dementia (DEM). PET scans were visually rated as amyloid positive (A+) or negative (A-), and these judgments were used as the gold standard with which to determine (using ROC analyses) the SUVR threshold for amyloid positivity considering factors such as age, ethnicity (Hispanic versus non-Hispanic), gender, cognitive status, and apolipoprotein E ε4 carrier status. Visually rated scans were A+ for 11% of CN, 39.0% of MCI and 70% of DEM participants. The optimal SUVR threshold for A+ among all participants was 1.42 (sensitivity = 94%; specificity = 92.5%), but this quantitative threshold was higher among E4 carriers (SUVR = 1.52) than non-carriers (SUVR = 1.31). While mean SUVRs did not differ between Hispanic and non-Hispanic participants;, a statistically significant interaction term indicated that the effect of E4 carrier status on amyloid load was greater among non-Hispanics than Hispanics. Visual assessment, as the gold standard for A+, facilitates determination of the effects of various factors on quantitative thresholds for amyloid positivity. A continuous relationship was found between amyloid load and global cognitive scores, suggesting that any calculated threshold for the whole group, or a subgroup, is artefactual and that the lowest calculated threshold may be optimal for the purposes of early diagnosis and intervention.

Slab fractures of the third tarsal bone: Minimally invasive repair using a single 3.5 mm cortex screw placed in lag fashion in 17 Thoroughbred racehorses.

REASONS FOR PERFORMING THE STUDY: A technique for minimally invasive repair of slab fractures of the third tarsal bone has not previously been reported. Results of third tarsal bone slab fracture repair in Thoroughbred racehorses are lacking. OBJECTIVES: To report the outcomes of repair of uniplanar frontal slab factures of the third tarsal bone using a single 3.5 mm cortex screw in lag fashion. STUDY DESIGN: Retrospective case series. METHODS: Case records of horses that had undergone this procedure were reviewed. RESULTS: Seventeen horses underwent surgery. Eighteen percent of cases had wedge shaped third tarsal bones. A point midway between the long and lateral digital extensor tendons and centrodistal and tarsometatarsal joints created a suitable entry site for implants. The fracture location, configuration and curvature of the third tarsal bone and associated joints requires a dorsolateral proximal-plantaromedial distal trajectory for the screw, which was determined by preplaced needles. There were no complications and fractures healed in all cases at 4-6 months post surgery. Seventy-nine percent of horses returned to racing and, at the time of reporting, 3 are in post operative rehabilitation programmes. CONCLUSION: The technique reported provides a safe, appropriate and repeatable means of repairing slab fractures of the third tarsal bone. Surgical repair is a viable alternative to conservative management.

Dorsal laminectomy for treatment of cervical vertebral stenotic myelopathy in an alpaca.

CASE DESCRIPTION: An 11-year-old male breeding alpaca was evaluated for a 2-day history of lowered head carriage and lethargy. CLINICAL FINDINGS: On initial examination, the alpaca had signs of lethargy and lowered carriage of the head and neck, but no specific neurologic deficits. Medical management improved the clinical signs, but 8 months later, the alpaca developed acute, progressive general proprioceptive ataxia affecting all 4 limbs and was referred for further evaluation and treatment. Magnetic resonance imaging and CT identified disruption of the normal osseous architecture of C7 and T1. Medical management was attempted, but because of a lack of improvement, the patient underwent surgery 14 months after initial examination. TREATMENT AND OUTCOME: A dorsal laminectomy of C7 and T1 via a dorsal midline approach was performed, and the spinous processes of both vertebrae were removed prior to removal of the overlying lamina. Free dorsal expansion of the spinal cord was ensured by resection of the ligamentum flavum. Six months after surgery, the alpaca had returned to successful breeding with 7 hembra bred in the first year after surgery, producing 6 crias, and 4 crias in the second year. The patient was eventually euthanized 28 months after surgery because of neurologic deterioration but was still ambulatory at that time. CONCLUSIONS AND CLINICAL RELEVANCE: A good outcome with adequate alleviation of clinical signs and breeding soundness for > 2 years following dorsal laminectomy was achieved in this camelid patient. The surgical approach was similar to that in other species and was associated with mild postoperative morbidity. Veterinarians treating camelids should be aware of the initial clinical signs and treatment options for cervical vertebral stenotic myelopathy. In acute cases, the signs of reduced cervical mobility and pain on manipulation should prompt investigation including appropriate diagnostic imaging. Timely surgical intervention should be considered in patients that respond poorly to medical treatment to avoid irreversible spinal cord injury and optimize outcome.

Morphologic and morphometric features of the calcaneal insertions of the superficial digital flexor tendon in the horse.

INTRODUCTION: Accurate description of the calcaneal insertions of the superficial digital flexor tendon (SDFT) is lacking and inconsistent. The aim of this study was to undertake morphologic and morphometic evaluations of these structures to assist in elucidating their functional and pathogenic roles in displacement of the SDFT from the calcaneal tuber. METHOD: Dissections were performed on 10 normal cadaveric hindlimbs. The anatomy was photographed to allow measurements at repeatable locations and differences in SDFT dimensions at the various locations were compared using a paired student t-test. RESULTS: This study demonstrated that the calcaneal insertions of the SDFT are independent from the overlying tarsal insertions of the biceps femoris and semitendinosus, which blend into the plantar surface of the fibrocartilaginous cap (FCC) of the SDFT before inserting dorsal to the insertion of the SDFT on the calcaneal tuber. The lateral insertion of the SDFT is larger in cross-sectional area (median: 219 mm²) at its origin from the FCC than its medial counterpart (median: 159 mm², p = 0.004) and has a more complex fibre alignment. The lateral site of attachment of the SDFT on the calcaneal tuber is dorsolateral to the insertion of the gastrocnemius tendon and is larger (median: 525 mm²) than the medial insertion (median: 428 mm², p = 0.036), which inserts distal to the insertion of the gastrocnemius tendon. CONCLUSION: The features identified in this study suggest that the calcaneal insertions of the SDFT are complex and their morphological and morphometric differences are likely to contribute to clinical lesions identified at this site.

Rater agreement on gait assessment during neurologic examination of horses.

BACKGROUND: Reproducible and accurate recognition of presence and severity of ataxia in horses with neurologic disease is important when establishing a diagnosis, assessing response to treatment, and making recommendations that might influence rider safety or a decision for euthanasia. OBJECTIVES: To determine the reproducibility and validity of the gait assessment component in the neurologic examination of horses. ANIMALS: Twenty-five horses referred to the Royal Veterinary College Equine Referral Hospital for neurological assessment (n = 15), purchased (without a history of gait abnormalities) for an unrelated study (n = 5), or donated because of perceived ataxia (n = 5). METHODS: Utilizing a prospective study design; a group of board-certified medicine (n = 2) and surgery (n = 2) clinicians and residents (n = 2) assessed components of the equine neurologic examination (live and video recorded) and assigned individual and overall neurologic gait deficit grades (0-4). Inter-rater agreement and assessment-reassessment reliability were quantified using intraclass correlation coefficients (ICC). RESULTS: The ICCs of the selected components of the neurologic examination ranged from 0 to 0.69. "Backing up" and "recognition of mistakes over obstacle" were the only components with an ICC > 0.6. Assessment-reassessment agreement was poor to fair. The agreement on gait grading was good overall (ICC = 0.74), but poor for grades ≤ 1 (ICC = 0.08) and fair for ataxia grades ≥ 2 (ICC = 0.43). Clinicians with prior knowledge of a possible gait abnormality were more likely to assign a grade higher than the median grade. CONCLUSION AND CLINICAL IMPORTANCE: Clinicians should be aware of poor agreement even between skilled observers of equine gait abnormalities, especially when the clinical signs are subtle.

Comparative reliability analysis of publicly available software packages for automatic intracranial volume estimation.

Intracranial volume is an important measure in brain research often used as a correction factor in inter subject studies. The current study investigates the resulting outcome in terms of the type of software used for automatically estimating ICV measure. Five groups of 70 subjects are considered, including adult controls (AC) (n=11), adult with dementia (AD) (n=11), pediatric controls (PC) (n=18) and two groups of pediatric epilepsy subjects (PE1.5 and PE3) (n=30) using 1.5 T and 3T scanners, respectively. Reference measurements were calculated for each subject by manually tracing intracranial cavity without sub-sampling. Four publicly available software packages (AFNI, Freesurfer, FSL, and SPM) were examined in their ability to automatically estimate ICV across the five groups. Linear regression analyses suggest that reference measurement discrepancy could be explained best by SPM [R(2)= 0.67;p <; 0.01] for the AC group, Freesurfer [R(2) = 0.46; p = 0.02] for the AD group, AFNI [R(2)=0.97;p<; 0.01] for the PC group and FSL [R(2) = 0.6; p = 0.1] for the PE1.5 and [R(2) = 0.6; p <; 0.01] for PE3 groups. The study demonstrates that the choice of the automated software for ICV estimation is dependent on the population under consideration and whether the software used is atlas-based or not.

The use of intrathecal analgesia and contrast radiography as preoperative diagnostic methods for digital flexor tendon sheath pathology.

REASONS FOR PERFORMING STUDY: The sensitivity of ultrasonography for the diagnosis of manica flexoria (MF) tears within the digital flexor tendon sheath (DFTS) is lower than for diagnosis of marginal tears of the deep digital flexor tendon (DDFT). Additional diagnostic tools would assist in appropriate decision making for either conservative or surgical management. OBJECTIVES: To evaluate the improvement in lameness of horses with MF or DDFT tears following intrathecal analgesia and to assess the sensitivity and specificity of contrast radiography for the diagnosis of these tears. METHODS: The case records of horses presented to a referral clinic over a 7-year period that underwent intrathecal diagnostic analgesia, or intrathecal analgesia and contrast radiography, of the DFTS with subsequent tenoscopy were examined. RESULTS: Fifty-three limbs had intrathecal diagnostic analgesia performed and 23 contrast tenograms were assessed in horses undergoing DFTS tenoscopy. Horses with DDFT tears were significantly more likely to respond positively to intrathecal diagnostic analgesia than those with MF tears (P = 0.02). Using contrast radiography, tears of the MF were predicted with an overall sensitivity of 96% and specificity of 80%; marginal tears of the DDFT were predicted with an overall sensitivity of 57% and specificity of 84%. CONCLUSIONS: The results of intrathecal analgesia of the DFTS in combination with contrast radiography have a high sensitivity for predicting MF tears. The sensitivity of contrast radiography for predicting tears of the DDFT is lower but the specificity remains high. POTENTIAL RELEVANCE: Contrast radiography performed at the same time as intrathecal analgesia provides useful information regarding the presence of MF tears and DDFT tears, which can assist in the decision of whether to manage the lameness conservatively or with tenoscopic evaluation.

Pathology and temporal onset of visual hallucinations, misperceptions and family misidentification distinguishes dementia with Lewy bodies from Alzheimer's disease.

OBJECTIVE: To determine whether the temporal onset of visual phenomena distinguishes Lewy body disease (LBD) from Alzheimer's disease (AD), and to characterize the extent Lewy bodies and neurofibrillary tangles are associated with these clinical features. METHODS: Consecutive cases of autopsy-confirmed LBD (n = 41), AD (n = 70), and AD with amygdala-predominant Lewy bodies (AD-ALB) (n = 14) with a documented clinical history of dementia were included. We mailed questionnaires to next-of-kin asking about symptoms during life. Lewy pathology and neurofibrillary tangle pathology were assessed. RESULTS: The occurrence of visual hallucinations, misperceptions and family misidentification did not distinguish LBD from AD or AD-ALB, but the onset was earlier in LBD compared to AD and AD-ALB. When visual hallucinations developed within the first 5 years of dementia, the odds were 4-5 times greater for autopsy-confirmed LBD (or intermediate/high likelihood dementia with Lewy bodies) and not AD or AD-ALB. In LBD, limbic but not cortical Lewy body pathology was related to an earlier onset of visual hallucinations, while limbic and cortical Lewy body pathology were associated with visual misperceptions and misidentification. Cortical neurofibrillary tangle burden was associated with an earlier onset of misidentification and misperceptions in LBD and AD, but only with earlier visual hallucinations in AD/AD-ALB. CONCLUSION: When visual hallucinations occur within the first 5 years of the dementia, a diagnosis of LBD was more likely than AD. Visual hallucinations in LBD were associated with limbic Lewy body pathology. Visual misperceptions and misidentification delusions were related to cortical Lewy body and neurofibrillary tangle burden in LBD and AD/AD-ALB.

Soft tissue injuries of the tarsocrural joint: a retrospective analysis of 30 cases evaluated arthroscopically.

REASONS FOR PERFORMING THE STUDY: Intra-articular soft tissue injuries of the equine tarsocrural joint have been poorly defined. METHODS: All horses that underwent arthroscopic surgery of a tarsocrural joint over a 10 year period were identified. Those with primary intra-articular soft tissue injuries were selected for inclusion and the cases evaluated retrospectively. RESULTS: Two hundred and eighty-one horses underwent tarsocrural joint arthroscopy during the study period, 30 of which met the inclusion criteria (30 joints). A combination of soft tissue lesions was more common than injury to a single structure. Injuries involved the joint capsule (n = 25), collateral ligaments (n = 20), dorsal plica (n = 8) and open communication between the tarsocrural joint and extensor bundle (n = 7). Following arthroscopic surgery and rehabilitation, 81% of horses were able to return to their previous function. CONCLUSION: Intra-articular soft tissue injuries of the tarsocrural joint may be associated with localising clinical signs of inflammation. This series represented 11% of the total number of arthroscopic procedures undertaken on that joint in a single referral hospital. Arthroscopic surgery allows accurate definition of the injuries and facilitates lesion management. Case outcome following arthroscopic debridement and a subsequent period of rehabilitation is favourable. POTENTIAL RELEVANCE: In lame horses with clinical signs localised to the tarsocrural joint, disrupted intra-articular soft tissues should be considered in the list of differential diagnoses. Attending clinicians should consider arthroscopic evaluation in cases where primary intra-articular soft tissue injuries are suspected to be causative.

Case-control study of orf in preweaned lambs and an assessment of the financial impact of the disease.

Orf, a viral disease which causes proliferative skin lesions around the mouths of lambs and on the teats of ewes, has long been assumed to have production-limiting consequences. This case-control study involved the collection of data from naturally occurring outbreaks of orf in young lambs on eight commercial farms in north-east England. Measurements of weight were taken and orf lesions were scored on a numerical scale for 44 orf-affected lambs, matched to unaffected controls within the same group. Data from corresponding ewes were available from five farms. Paired t tests showed that affected lambs weighed approximately 10 per cent less than their unaffected controls for a period of at least five weeks following the start of the outbreak. The effects were highly significant whether the orf lesions affected the mouth or were found elsewhere on the body. If a lamb had orf, then there was a 82 per cent chance that its mother also had orf on its udder or teats. The financial consequences of orf in young lambs were estimated using average UK figures and conservative assumptions based on the results of this study.

Association of white matter hyperintensity measurements on brain MR imaging with cognitive status, medial temporal atrophy, and cardiovascular risk factors.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are frequently characterized as markers of cerebrovascular disease, whereas medial temporal atrophy (MTA) is a recognized marker of Alzheimer disease (AD). Our purpose was to test the reliability of a visual rating system (VRS) in evaluating WMHs and MTA and in distinguishing healthy from cognitively impaired subjects. MATERIALS AND METHODS: Subjects (n = 192) enrolled in the Florida Alzheimer's Disease Research Center were diagnosed with no cognitive impairment, nonamnestic mild cognitive impairment (na-MCI), amnestic MCI (a-MCI), or probable AD. The severity of WMHs was assessed on T2-weighted fluid-attenuated inversion recovery axial MR images, and the severity of MTA was evaluated on 1.5-mm-thick coronal MR images by using a computer-based visual rating system. Cardiovascular risk factor scores were calculated as the sum of 10 independent cardiovascular risk factors. RESULTS: WMH and MTA scores were greater in subjects with probable AD, relative to those with no cognitive impairment and na-MCI. MTA scores differentiated subjects with a-MCI from those with no cognitive impairment and na-MCI. The total WMH score was significantly related to MTA (r = 0.39; P < .001) but not to cardiovascular risk factor scores (r = 0.07; P = not significant). The overall correct classification rate of probable AD versus no cognitive impairment by using MTA scores was 81.8%, improving to 86.5% when combined with WMH scores. CONCLUSIONS: Both MTA and WMH scores distinguished subjects with no cognitive impairment and probable AD. Combining MTA and WMH scores improved the correct classification rate, whereas WMH scores were significantly related to MTA scores, but not to cardiovascular risk factor scores. This finding suggests that among subjects with a-MCI and probable AD, WMHs on MR images are primarily associated with neurodegenerative disease.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease.

BACKGROUND: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. METHODS: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. RESULTS: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. CONCLUSION: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.

A study of the use of Ephedra in the manufacture of methamphetamine.

The Ephedra plant has been identified as an excellent source of ephedrine and pseudoephedrine, both of which can be chemically reduced to form the widely abused illicit drug methamphetamine. Ephedra contains several additional alkaloids that undergo analogous reductions to form amphetamine and N,N-dimethylamphetamine (also drugs of abuse). The main alkaloids obtained from the Ephedra plant have been reduced using four common methods used by the clandestine operator. The intermediates and byproducts of these reductions have been identified and/or tentatively assigned and the mechanism of formation discussed.

Family history of dementia is a risk factor for Lewy body disease.

Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.

White matter lesions in Fabry disease occur in 'prior' selectively hypometabolic and hyperperfused brain regions.

Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency.

Mild cognitive impairment: directions for future research.

Mild cognitive impairment (MCI), an intermediate state between normal aging and dementia, is characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. Studies conducted on MCI have introduced new concepts regarding the possible distinctions between normal and pathologic aging of the brain. Neuroimaging and genetic testing have aided in the identification of individuals at increased risk for dementia. The measurement of change in cognitive and functional status in MCI remains challenging, because it requires instruments that are more sensitive and specific than those considered adequate for research in dementia. The authors provide an overview of the many methods that have been used to study MCI and directions that may help achieve greater uniformity in methodology. Considerable heterogeneity exists in research methodology used to study the epidemiology, thresholds for cognitive and functional impairment, rate of progression, risk factors, and defining subtypes of MCI. This article emphasizes the need for uniformity in the use of 1) appropriate and sensitive neuropsychological and functional measures to diagnose MCI, 2) reliable methods to determine progression or improvement of cognitive impairment, and 3) instruments in epidemiologic studies to establish population estimates for diverse ethnic and cultural groups. Greater consensus is needed to standardize definitions and research methodology for MCI, so as to make future studies more comparable and more useful for designing effective treatment strategies.

Factor structure of the Cornell Scale for Depression in Dementia for Anglo and Hispanic patients with dementia.

The authors assessed the equivalence of the factor structure of the Cornell Scale for Depression in Dementia (CSDD) in samples of Anglo and Hispanic patients with Alzheimer's disease (AD). Comparing the factor structure of the CSDD in these groups helps establish its validity and aids in its clinical interpretation with Hispanic patients. CSDD ratings were first subjected to preliminary exploratory factor analyses; then the factor structure of the CSDD across groups of English- and Spanish-speaking patients was tested using structural equation modeling. Analyses showed overall similarity in the CSDD factor structure for the two groups but also revealed differences in factor content for several items. The authors discuss the relevance of these differences for those using the CSDD with Hispanic AD patients.

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease.

We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.