Evidence Of Progressive Change Research Articles

Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review.

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target. Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis, there is considerable heterogeneity, including clinical presentation, progression, and the underlying triggers for disease initiation. Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations, it has become apparent that overt disease is preceded by a prodromal phase, possibly in years, where compensatory mechanisms delay symptom onset. Since 85-90% of amyotrophic lateral sclerosis is sporadic, there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration. Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease. Skeletal muscle, including the neuromuscular junction, manifests abnormalities at the earliest stages of the disease, before motor neuron loss, making it a promising source for identifying biomarkers of the prodromal phase. The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time. The advent of "omics" technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle, ranging from coding and non-coding RNAs to proteins and metabolites. This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms. A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease. There are two major goals of this review. The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity, evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages, and evidence of progressive change during disease progression. The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression, and as such, their potential as therapeutic targets in amyotrophic lateral sclerosis.

Early cutaneous inflammatory response at different degree of burn and its significance for clinical diagnosis and management

A complete characterization of the burn wound based on cutaneous architectural changes and inflammatory response is extremely important to provide evidence for progressive changes in the burn wound. Burn wounds are highly susceptible to conversion into deeper wounds, which need special care and attention; thereby, the complete characterization of burn wound type and their subsequent inflammatory status in the cutaneous system at the earliest is of paramount importance. Inflammatory markers at different degrees will help clinicians devise better and more specific treatment strategies for each burn type.The present study is carried out to profile pro-inflammatory gene expression along with immune cell quantification, vascular perfusion, and histopathological assessment in the cutaneous system of murine models. The study revealed that burn injury caused an immediate increase in vascular perfusion in superficial and partial-thickness burns, whereas there was a decrease in vascular perfusion in full-thickness burns. An influx of lymphocytes at the edges of burn wounds in each type of burn injury was well-orchestrated with the event of vascular perfusion. Further, pro-inflammatory gene expression profiling revealed significant upregulation vis-à-vis upregulation of TNF-α and MCP-1 genes, with an increase in the number of neutrophils following 72 h of injury that evidently cemented the conversion of superficial burn into partial-thickness burn. The molecular findings were profoundly supported by the histopathological changes.Thus, our foundational studies show distinct characteristic cutaneous changes correlated with the expression of key pro-inflammatory genes in three different types of burn injuries. Characterization of these cutaneous inflammatory responses provides a promising future for medical interventions involved with different degrees of burn injury, and it will also help in the pre-clinical testing of therapies for burn injury.

Northern Raglai voicing and its relation to Southern Raglai register: evidence for early stages of registrogenesis.

Northern and Southern Raglai are two closely related Austronesian dialects (Chamic branch) spoken in south-central Vietnam. Although they are mutually intelligible, Northern Raglai is described as having a voicing contrast in onset stops, while Southern Raglai is assumed to have replaced the Chamic voicing contrast with a register contrast realized on the whole syllable (but primarily on its vowel). A production study of the two dialects confirms that Northern Raglai preserves a voicing contrast, even if most women exhibit partial devoicing of their voiced stops, and that Southern Raglai has developed a register contrast based on F1 and phonation cues at the beginning of vowels. The weights of the acoustic properties of voicing and register are similar across ages and genders, suggesting that the two laryngeal contrasts are phonetically stable. Even if there is little evidence of change in progress, a close inspection of the Northern Raglai voicing contrast reveals voicing-conditioned modulations of F1 and perturbations of phonation after partially devoiced stops that could be precursors of a register system similar to that of Southern Raglai. We argue that this is a pathway to registrogenesis and speculate about the articulatory laryngeal mechanisms that could trigger registrogenetic changes. Our data also show that the Northern Raglai voicing contrast is unstable in aspirated stops and that voiced aspirated stops typically have a partially voiceless and partially voiced aspiration.

Tract integrity in amyotrophic lateral sclerosis: 6\u2013month evaluation using MR diffusion tensor imaging

BackgroundThis study was performed to assess changes in diffusion tensor imaging (DTI) over time in patients with amyotrophic lateral sclerosis (ALS).MethodsWe performed DTI in 23 ALS patients who had two magnetic resonance imaging (MRI) scans at 6 month intervals and to correlate results with clinical features. The revised ALS functional rating scale (ALSFRS–R) was administered at each clinical visit. Data analysis included voxel–based white matter tract–based spatial statistics (TBSS) and atlas–based region–of–interest (ROI) analysis of fractional anisotropy (FA) and mean diffusivity (MD).ResultsWith TBSS, there were no significant changes between the two scans. The average change in FA and MD in the ROIs over 6 months was small and not significant after allowing for multiple comparisons. After allowing for multiple comparisons, there was no significant correlation of FA or MD with ALSFRS–R.ConclusionThis study shows that there is little evidence of progressive changes in DTI over time in ALS. This could be because white matter is already substantially damaged by the time of onset of symptoms of ALS.

A Longitudinal Assessment of Structural and Chemical Alterations in Mixed Martial Arts Fighters

Growing evidence suggests that temporally proximal acute concussions and repetitive subconcussive head injuries may lead to long-term neurological deficits. However, the underlying mechanisms of injury and their relative time-scales are not well documented in human injury models. The current study therefore investigated whether biomarkers of brain chemistry (magnetic resonance [MR] spectroscopy: N-acetylaspartate [NAA], combined glutamate and glutamine [Glx], total creatine [Cre], choline compounds [Cho], and myo-inositol [mI]) and structure (cortical thickness, white matter [WM]/subcortical volume) differed between mixed martial artists (MMA; n = 13) and matched healthy controls (HC) without a history of contact sport participation (HC; n = 14). A subset of participants (MMA = 9; HC = 10) returned for follow-up visits, with MMA (n = 3) with clinician-documented acute concussions also scanned serially. As expected, MMA self-reported a higher incidence of previous concussions and significantly more cognitive symptoms during prior concussion recovery. Fighters also exhibited reduced memory and processing speed relative to controls on neuropsychological testing coupled with cortical thinning in the left posterior cingulate gyrus and right occipital cortex at baseline assessment. Over a 1-year follow-up period, MMA experienced a significant decrease in both WM volume and NAA concentration, as well as relative thinning in the left middle and superior frontal gyri. These longitudinal changes did not correlate with self-reported metrics of injury (i.e., fight diary). In contrast, HC did not exhibit significant longitudinal changes over a 4-month follow-up period (p > 0.05). Collectively, current results provide preliminary evidence of progressive changes in brain chemistry and structure over a relatively short time period in individuals with high exposure to repetitive head hits. These findings require replication in independent samples.

Fair Housing Enforcement in the South and Non‐South*

ObjectiveWe compare outcomes in racial discrimination fair housing complaints processed by southern state and local civil rights agencies to those handled by state and local agencies outside the South and the federal agency, HUD (Department of Housing and Urban Development).MethodsBased on data obtained directly from HUD, we rely on a fixed effects logistic regression model with cluster‐correlated standard errors.ResultsFirst, southern local agencies are significantly more likely to provide outcomes favorable to complainants in racial discrimination fair housing cases than are local agencies outside the South. Second, state and local agencies in the Deep South provide favorable outcomes to the same extent as their nonsouthern counterparts. Third, southern local agencies are more likely to provide favorable outcomes than is HUD, whereas southern state agencies provide favorable outcomes at roughly the same rate as HUD. Variations within the South partially explain these findings.ConclusionWe find evidence of progressive changes in southern fair housing enforcement, although those changes occur in an uneven fashion depending on the state or locality.

A longitudinal study investigating sub-threshold symptoms and white matter changes in individuals with an ‘at risk mental state’ (ARMS)

BackgroundEvidence supports disruption in white matter (WM) connectivity in established schizophrenia, however, it is unclear when these abnormalities occur during the course of illness and if they are progressive. Here we investigated whether WM abnormalities predate illness onset by examining a group of individuals with an ‘at risk mental state’ (ARMS) and assess whether there is evidence of progressive change. We hypothesized that WM abnormalities are associated with symptom change. MethodsSixteen healthy controls and 41 ARMS subjects at baseline underwent Diffusion Tensor Imaging (DTI). Sub-threshold positive symptoms were measured using the Scale of Prodromal Symptoms (SOPS). Imaging and symptoms were re-administered in the ARMS group after one year (52weeks). Fractional anisotropy (FA) value differences between ARMS and control groups at baseline were localized using the method of Tract-Based Spatial Statistics (TBSS). ResultsAt baseline, FA was significantly reduced in a sub-region of the corpus callosum (CC) in the ARMS group as a whole compared to controls. This reduction was also found in the 34 individuals who did not transition (ARMS-N) during the one-year follow-up. However, the ARMS-N group showed a significant improvement in sub-threshold positive symptoms at follow-up, which was correlated with an increase in FA in the same CC region (r=−0.664, p<0.001). DiscussionThere was a significant FA reduction in the CC in individuals at high risk for psychosis regardless of transition status at one year. This suggests that WM abnormalities in the CC may represent a biological vulnerability to psychosis. Improvement in sub-threshold positive symptoms was associated with improvement in measures of WM integrity in the CC. This may suggest that neurobiological ‘resilience’ is associated with improved outcomes, although this notion requires future study.

Protease Inhibitors and Renal Function in Patients with HIV Infection: a Systematic Review.

IntroductionDespite antiretroviral (ARV) therapy reducing renal disease in human immunodeficiency virus overall, there is concern that certain ARVs, particularly tenofovir disoproxil fumarate (TDF) with or without a boosted protease inhibitor (PI), may reduce renal function over time. It is not known whether effects seen with PI-based regimens are independent, result from interactions with TDF coadministration, or are artefactual owing to inhibition of renal tubular creatinine transport by ritonavir or cobicistat pharmacoenhancement. The aim of this review was to conduct a systematic review of studies, weighted toward high-quality evidence, examining changes in renal function over time with PI-based regimens.MethodsPubMed, Embase, and Medline databases and conference abstracts were searched using pre-defined terms for English language articles, published up to and including August 12, 2013, describing changes in renal function over time with PI-based regimens. All available randomized controlled trials (RCTs) were selected; however, to reduce bias, only observational studies recruiting from more than one center and analyzing data from more than 1,000 patients were included. Evidence was qualitatively evaluated according to levels established by the Oxford Centre for Evidence-Based Medicine (OCEBM).ResultsA total of 2,322 articles were retrieved by the initial search. Of these, 37 were selected for full review, comprising 24 RCTs (OCEBM Level 1 evidence: 4 reports of fully double-blinded or blinded with respect to the PI component). The remaining 20 RCTs and 13 observational studies qualified as OCEBM Level 2 evidence. Level 1 evidence showed initial but non-progressive increases in serum creatinine and corresponding decreases in estimated glomerular filtration rate (eGFR), suggesting an effect on renal tubular transport of creatinine. Level 2 evidence suggested that atazanavir and lopinavir especially in combination with TDF were associated with non-progressive reductions in eGFR over time, with a decreased risk for the development of chronic kidney disease (CKD) on cessation and without the development of advanced CKD or end-stage renal disease (ESRD); whether these reductions were independent or associated with interactions with coadministered TDF could not be established with certainty. Data on darunavir were insufficient to draw any conclusions. The principal limitation of the reviewed studies was the lack of standardization of creatinine measurements in virtually all studies and the lack of corroborative data on changes in proteinuria or other indices of renal function.DiscussionIn this review, there was little evidence for progressive changes in eGFR, or the development of advanced CKD, or ESRD with lopinavir or atazanavir. Further long-term studies, employing a wide range of validated renal function assessments, are required to fully evaluate potential association of PIs with CKD.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0056-4) contains supplementary material, which is available to authorized users.

Realization of Thai tone change in the Northern Thai dialect of Chiang Mai

Recent studies have found evidence of tone change in progress among Thai speakers. In particular, changes in the high tone, traditionally considered a level tone, have caused some to suggest it should instead be considered a contour tone (Zsiga, 2008; Teeranon and Rungrojsuwan, 2009). However, the previous research has focused primarily on the Central Thai dialect found in Bangkok, the standard dialect of Thai. This study examines the current state of tones in the Northern Thai dialect of Chiang Mai, which has six contrastive tones, rather than the five found in Central Thai. This data allows for a comparison to both the Central Thai literature as well as previous studies of Northern Thai, to examine whether Northern Thai is undergoing tone change as well and whether it exhibits similar changes to those reported for Central Thai. Significant exposure to Central Thai via mass media as well as the education system, and widespread bi-dialectalism, may carry the influences of Central Thai tone changes into Northern Thai as well. This study aims to provide further insight into the ongoing changes in the Thai tonal space, in order to clarify the nature of Thai tones today.

Progression of Foot Deformity in Charcot Neuropathic Osteoarthropathy

Charcot neuropathic osteoarthropathy associated foot deformity can result in joint instability, ulceration, and even amputation. The purpose of the present study was to follow patients with and without active Charcot osteoarthropathy for as long as two years to examine the magnitude and timing of foot alignment changes. We studied fifteen subjects with Charcot osteoarthropathy and nineteen subjects with diabetes mellitus and peripheral neuropathy without Charcot osteoarthropathy for one year; eight of the subjects with osteoarthropathy and five of the subjects with diabetes and peripheral neuropathy were followed for two years. Bilateral weight-bearing radiographs of the foot were made at baseline for all subjects, with repeat radiographs being made at six months for the osteoarthropathy group and at one and two years for both groups. Radiographic measurements included the Meary angle, cuboid height, calcaneal pitch, and hindfoot-forefoot angle. The Meary angle, cuboid height, and calcaneal pitch worsened in feet with Charcot osteoarthropathy over one year as compared with the contralateral, uninvolved feet and feet in patients with diabetes and peripheral neuropathy. Cuboid height continued to worsen over the two-year follow-up in the feet with Charcot osteoarthropathy. These feet also had a greater change in the hindfoot-forefoot angle at one year as compared with the feet in patients with diabetes and peripheral neuropathy and at two years as compared with the contralateral, uninvolved feet. In patients with Charcot neuropathic osteoarthropathy, radiographic alignment measurements demonstrate the presence of foot deformity at the time of the initial clinical presentation and evidence of progressive changes over the first and second years. The six-month data suggest worsening of medial column alignment prior to lateral column worsening. This radiographic evidence of worsening foot alignment over time supports the need for aggressive intervention (conservative bracing or surgical fixation) to attempt to prevent limb-threatening complications.

Onshore evidence for progressive changes in rifting directions during continental break-up in the NE Atlantic

Abstract: Current models for the Palaeogene-aged continental break-up in the North Atlantic invoke a NW–SE extension vector throughout the rift-to-drift process, accommodated by margin-parallel normal faults, and margin-oblique (strike-slip) transfer zones. However, Palaeogene and younger faults in the Faroe Islands provide evidence for a progressive anticlockwise rotation in extension vectors immediately prior to and following North Atlantic break-up. Six deformation stages are recognized: (1) east–west to NE–SW extension, accommodated by dip-slip north–south- and NW–SE-trending faults; (2) continued NE–SW extension accommodated by NW–SE- and NNE–SSW-oriented dykes; (3) north–south extension accommodated by ENE–WSW and ESE–WNW conjugate dykes; (4) crustal extrusion involving both east–west shortening and further north–south extension along ENE–WSW (dextral) and ESE–WNW (sinistral) conjugate strike-slip faults; (5) during the final stages of rifting, the regional extension vector became NW–SE and was accommodated predominantly by slip along NE–SW dextral oblique-slip faults; (6) pre-existing structures were locally reactivated as tensional and extensional–shear features, characterized by the entrainment of clastic material along fault planes. The present study reveals a distinct period of margin-parallel extension immediately prior to break-up that is not accounted for by existing models, illustrating the importance of conducting field-based studies to validate otherwise widely accepted margin-scale models worldwide.

Automatic Sensory Discrimination Deficits in the Prodrome and First-Episode of Psychosis

Event Abstract Back to Event Automatic Sensory Discrimination Deficits in the Prodrome and First-Episode of Psychosis Kristin S. Cadenhead1*, C. Jahchan1, D. L. Braff1 and G. Light1 1 Department of Psychiatry, University of California, United States BACKGROUND Schizophrenia is a neurodevelopmental disorder with evidence of progressive changes in the early phase of illness. Earlier identification and a better understanding of the mechanism by which psychosis evolves can lead to preventive, more personalized treatment. Deficits in automatic sensory discrimination as indexed by mismatch negativity (MMN) are well documented in chronic schizophrenia patients. The majority of previous studies in the early stages of illness, however, failed to detect MMN impairments to either pitch or duration deviants. METHODS 12 individuals at-risk for psychosis (AR), 23 patients with first-episode psychosis (FE), and 40 normal comparison subjects (NC) underwent duration-deviant MMN testing (1000 Hz tones, standards: 50 msec, P=0.90; deviants: 100 msec, P=0.10). RESULTS Group differences were present in the amplitude of the MMN at fronto-central electrodes (Fz p=.008, F3 p=.007, F4 p=.013, Cz p=.012, C3 p=.027, C4 p=.118). The AR group's MMN amplitudes were intermediate between those of the NC group and the FE group, but those differences did not reach statistical significance (effect sizes .21-.35). CONCLUSIONS Robust duration-deviant MMN deficits were observed in first-episode psychosis patients. Individuals at risk for developing schizophrenia had small reductions relative to normal subjects that likely reflect the fact that less than ½ will go on to develop a psychotic illness. MMN may represent an important disease marker that can help to predict who is at greatest risk of psychotic illness. Conference: MMN 09 Fifth Conference on Mismatch Negativity (MMN) and its Clinical and Scientific Applications, Budapest, Hungary, 4 Apr - 7 Apr, 2009. Presentation Type: Oral Presentation Topic: Symposium 1: MMN as a potential endophenotype in schizophrenia Citation: Cadenhead KS, Jahchan C, Braff DL and Light G (2009). Automatic Sensory Discrimination Deficits in the Prodrome and First-Episode of Psychosis. Conference Abstract: MMN 09 Fifth Conference on Mismatch Negativity (MMN) and its Clinical and Scientific Applications. doi: 10.3389/conf.neuro.09.2009.05.033 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 20 Mar 2009; Published Online: 20 Mar 2009. * Correspondence: Kristin S Cadenhead, Department of Psychiatry, University of California, San Diego, United States, kcadenhead@ucsd.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Kristin S Cadenhead C. Jahchan D. L Braff G. Light Google Kristin S Cadenhead C. Jahchan D. L Braff G. Light Google Scholar Kristin S Cadenhead C. Jahchan D. L Braff G. Light PubMed Kristin S Cadenhead C. Jahchan D. L Braff G. Light Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Abstract 3356: Does Severe Obesity Cause Progressive Impairment of Left Ventricular Systolic Function?

Background: Obesity is associated with an increased risk of developing heart failure. Based on cross sectional studies, it has been hypothesized that the duration of obesity is the key factor leading to impaired cardiac function. However, longitudinal data to confirm this hypothesis are not available. Methods: We prospectively studied 62 severely obese patients at baseline, 2 and 5 years after randomization to nonsurgical therapy (NonSurg, n = 25) or Rouxen-Y gastric bypass surgery (GBS, n = 37). Echocardiography was used to measure left ventricular (LV) size and ejection fraction (EF). Results: At enrollment, the mean BMI was 46±9 and the mean age was 47±11 years (range 25– 66). GBS subjects lost 96± 26 vs. 6±18 lbs at 2 years and 78±42 vs. 17±42 lbs at 5 years compared to NonSurg (p&lt;0.0001 for both). At baseline LVEF was not different between GBS and nonsurg (67±9 vs. 64±8%) and it did not change at 2 years (64±9 vs. 63±9%) or 5 years (63±9 vs. 63±10%). LV diastolic dimension did not change over time in control (4.3±1.0 vs. 4.2±0.6 vs. 4.5±0.3) or GBS patients (4.4±0.6 vs. 4.3±0.7 vs. 4.4±0.4). Stratifying the entire group by quartiles of age or duration of obesity (quartile 1 avg duration = 16 years, quartile 4 average duration = 56 years), we found no evidence of time-dependent changes in LV size or function. Conclusion: In this, prospective study of severely obese patients we found no evidence of progressive changes in LV size or EF over a period of 5 years. Moreover, we find no relationship between age or duration of obesity and LV size or LVEF. These data argue strongly that other factors such as the development of coronary disease are the most likely causes of heart failure in obese patients.

Evidence for progressive changes in clinical presentation of myoclonus‐dystonia

Evidence for progressive changes in clinical presentation of myoclonus‐dystonia

Federal Subsidies and Evidence of Progressive Change

This research reviews the history of police change, documents law enforcement's sustained effort to maintain legitimacy through change, and serves as a backdrop for an empirical assessment of recent efforts by law enforcement to adopt meaningful change. This research quantitatively assesses the effects of federal funding on two outcomes: the percentage change in police employment between 1993 and 1999 and an index of progressive policing practices that reflect the community-oriented policing (COP) philosophy. The authors use regression with robust standard errors and a sample of 177 municipal police agencies staffed with 100 or more full-time officers to assess competing explanations for variation in these outcomes. Findings support claims that federal assistance grants contributed to progressive changes for the recipient agencies. Organizations receiving manpower grants increased hiring to a noteworthy extent, and innovation grants were closely associated with reforms in street-level practices. Targeted federal assistance helped municipal police agencies make progressive changes consistent with the COP model.

Standardization, functional shift and language change in Basque

This paper presents a quantitative variationist analysis of data collected in sociolinguistic interviews in the Basque town of Oiartzun in an effort to gauge the influence of a generation of language planning eff o rts on the local Basque ve rn a c u l a r. In part i c u l a r, this paper makes the following three claims about these processes. First, the data provide strong apparent-time evidence of change in progress toward standard features. For two morphological variables and one lexical variable, young speakers show significantly lower frequencies of nonstandard forms than middle-aged and older speakers. Second, the changing functional distribution of Basque vs. Spanish in Oiartzun also appears to have had an important impact on younger speakers’ speech. In particular, younger speakers show significantly lower frequencies than older speakers for two informal phonological features. This difference plausibly reflects the fact that younger speakers, unlike their elders, have grown up using Basque in high-register domains –especially schools and the media–where these phonological processes are least common. Third and finally, quantitative variation data together with speake r s ’ metalinguistic comments in sociolinguistic and ethnographic interviews suggests support for Echeverria’s (2000) proposal that masculinity is iconically linked to informal/low-prestige forms through their association with ‘traditional’ rural Basque spheres.

Location Variation in American Sign Language

This article, part of a larger project that studied sociolinguistic variation in American Sign Language, examines that variation in a class of American Sign Language signs exemplified by the verb know, which vary in their location. Usually these signs are produced at the forehead, but frequently they are produced at a lower level. Analysis of approximately twenty-nine hundred tokens of signs of this class from more than two hundred signers in seven U.S. sites shows that the lowering of signs such as know is constrained by both linguistic and social factors that parallel variation in spoken languages. Results from signers of three different age groups also provide evidence of change in progress. Despite similarities to variation in spoken languages, results for several social factors are best explained by reference to Deaf history and to the structure of the Deaf community.

Progressive Changes in Schizophrenia: Do They Exist and What Do They Mean?

Schizophrenia is a disorder characterized by multiple symptoms, with a varied course and outcome. The etiology is yet unknown, but multiple pathological processes or, equally likely, a unique pathophysiological process, may be involved. Here, we review evidence for progressive changes in schizophrenia in order to understand further the pathophysiology of this disorder. We first present evidence for clinical and psycho-social changes over time, followed by evidence from structural brain studies that suggests that schizophrenia is a brain disorder. We then review findings from the small number of longitudinal studies that have evaluated structural brain changes in schizophrenia, followed by a review of the evidence for neurophysiological changes, both cross-sectional and longitudinal. This is followed by a discussion of possible cellular mechanisms, including NMDA receptor abnormalities, that might account for structural and functional brain changes (temporal and frontal), and we discuss how these abnormalities might be related to not only the specific signs and symptoms of schizophrenia but also to the onset and course of the illness. Finally, we discuss neurodevelopment (static and perhaps non-static alterations) and neurodegenerative theories of schizophrenia. We propose that the two are not mutually exclusive, but instead likely reflect a "two-hit" model for some subtypes of schizophrenia.

Arthroscopic Synovectomy of the Knee in Hemophilia

Nine knees in 8 patients with severe hemophilia A and 1 patient with hemophilia B underwent arthroscopic synovectomy during the period of 1980 to 1985. This group of patients has been observed prospectively for the past 10 to 15 years. One complication occurred immediately postoperatively in an 8-year-old boy in whom a severe hemarthrosis developed that required arthroscopic evacuation. His postoperative recovery was compromised leading to significant loss of motion. Recurrent hemarthroses developed in only 1 patient after an injury to the knee. A second arthroscopic synovectomy was performed 45 months after the initial procedure. Other than the patient who lost motion after the postoperative complication, all patients initially regained or improved their range of motion. The latest followup, however, showed several patients losing motion which correlated with clinical and radiographic evidence of progressive changes of the hemophilic arthropathy. The 1 patient with Factor IX deficiency required a total knee replacement 8 years after synovectomy. Arthroscopic synovectomy was effective in reducing recurrent hemarthrosis and maintaining range of motion; however, joint deterioration continued to occur although probably at a slower rate.

Molecular preservation and crystallographic alterations in a weathering sequence of wildebeest bones

The changes that occur in bone after the death of an animal are important because they control whether the bone becomes a fossil and what information is retained concerning the original biology of the animal. Taphonomic study of two 10-year longitudinal samples of wildebeest bones subjected to natural weathering in Amboseli Park, Kenya, provides evidence for progressive change in both the organic and inorganic components of mammalian bone. These changes correspond to weathering stages described on macroscopic structural features. The bone samples were subjected to well-established techniques of protein extraction from mineralized tissue, protein identification by gel electrophoresis and reactivity to antibodies of noncollagenous proteins, as well as X-ray defractometry of the mineral component. Both adult and juvenile bones show progressive increase in hydroxyapatite crystal size and increased protein degradation over the 10-year period. Noncollagenous proteins persist at their original molecular weight in diminished amounts relative to modern controls. In the study area, 10 years or less of natural surface weathering altered the extractability of collagen, indicating peptide and crosslinking cleavage in this protein. Increased hydroxyapatite crystal size may reflect a tendency of crystals to enlarge in situ once the organic matrix begins to breakdown, without the addition of external minerals.