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PubMed2004

Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator.

Sensory experience physically rewires the brain in early postnatal life through unknown processes. Here, we identify a robust anatomical consequence of monocular deprivation (MD) in layer II/III of visual cortex that corresponds to the rapid, functional loss of responsiveness preceding any changes in axonal input. Protrusions on pyramidal cell apical dendrites increased steadily after eye opening, but were transiently lost through competitive mechanisms after brief MD only during the physiological critical period. Proteolysis by tissue-type plasminogen activator (tPA) conversely declined with age and increased with MD only in young mice. Targeted disruption of tPA release or its upstream regulation by glutamic acid decarboxylase (GAD65) prevented MD-induced spine loss that was pharmacologically rescued concomitant with critical period plasticity. An extracellular mechanism for structural remodeling that is limited to the binocular zone upon proper detection of competing inputs thus links early sensory experience to visual function.

Animals↗

PubMed1999

Surgery in patients with systemic sclerosis of the hand.

Systemic sclerosis of the hand is an uncommon form of arthritis that can cause significant functional loss in the hand. It poses serious problems for the surgeon because of the diminished circulation of the digits. The tightness of the skin and joint stiffness that are characteristic of this condition make restoration of function difficult. Calcinosis, which is common in patients with systemic sclerosis of the hand, can be treated by excision or curettage. Patients with severe deformities of the digits and thumb often require fusions to improve grasp. Joint replacements with implants are not as successful in patients with systemic sclerosis as they are in patients with rheumatoid or degenerative arthritis. There have been recent attempts to improve the circulation to the fingers by sympathectomy or by vein grafts. These techniques, however, provide only temporary improvement and do not prevent or correct the severe digital and thumb deformities associated with this disease.

Arthritis↗

PubMed2006

Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development.

The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.

Animals↗

PubMed1997

Reliability of nursing assistants' observations of functioning and clinical symptoms and signs.

Simple methods for the early detection of function loss and disease in the elderly were evaluated. Such methods might be used by non-professional personnel as case-finding tools for early intervention. The aim of this study was to assess the reliability of functional and clinical data collected by non-professional nursing assistants. The study group consisted of sixty elderly short-stay patients in a stable clinical situation, admitted for rehabilitation and aid in a nursing home. Barthel ADL index items and clinical symptoms and signs were scored by nursing assistants and nurses (the reference method). Agreement between scores was assessed by Cohen's kappa statistics and test of marginal homogeneity. All the Barthel items and the clinical symptoms and signs had fair or better agreement (weighted kappa > 0.40). For dressing, chair-to-bed transfer, ambulation, bathing, paresis and edema, the agreement was strong (weighted kappa > 0.75). The reliability of the Barthel sumscores was also acceptable. We concluded that observation of functioning and clinical symptoms and signs by non-professional nursing assistants is reliable.

Activities of Daily Living↗

PubMed1998

Three cases of isolated mucoceles and one case of an Aspergillus infection in the sphenoid sinus with orbital signs and symptoms.

Four patients with an isolated sphenoid lesion: three with a mucocele and one with an Aspergillus infection of the sphenoid sinus in whom the orbital impairment had a rhinogenic cause, are described. They all presented with one or more of the following features: visual loss, motility disturbances, visual field defects, and sensitivity loss of the infraorbital nerve. In one patient, optic disc edema was seen. Diagnostic imaging technologies such as computer tomography (CT) and magnetic resonance (MRI) make an early diagnosis possible but nevertheless, very large mucoceles with major functional loss were detected at a late stage of the disease. The Aspergillus infection was detected at an early stage without delay because of its specific appearance on CT and MRI. The signs and symptoms of these lesions are more striking in the orbital and neuro-ophthalmological field than in the ear-nose-throat (ENT) field, but nevertheless, primary treatment should be marsupialization by an ENT-surgeon.

Journal Article↗

PubMed2004

A statistical framework for genomic data fusion.

MOTIVATION: During the past decade, the new focus on genomics has highlighted a particular challenge: to integrate the different views of the genome that are provided by various types of experimental data. RESULTS: This paper describes a computational framework for integrating and drawing inferences from a collection of genome-wide measurements. Each dataset is represented via a kernel function, which defines generalized similarity relationships between pairs of entities, such as genes or proteins. The kernel representation is both flexible and efficient, and can be applied to many different types of data. Furthermore, kernel functions derived from different types of data can be combined in a straightforward fashion. Recent advances in the theory of kernel methods have provided efficient algorithms to perform such combinations in a way that minimizes a statistical loss function. These methods exploit semidefinite programming techniques to reduce the problem of finding optimizing kernel combinations to a convex optimization problem. Computational experiments performed using yeast genome-wide datasets, including amino acid sequences, hydropathy profiles, gene expression data and known protein-protein interactions, demonstrate the utility of this approach. A statistical learning algorithm trained from all of these data to recognize particular classes of proteins--membrane proteins and ribosomal proteins--performs significantly better than the same algorithm trained on any single type of data. AVAILABILITY: Supplementary data at http://noble.gs.washington.edu/proj/sdp-svm

Algorithms↗

PubMed2003

Guanosine promotes myelination and functional recovery in chronic spinal injury.

Functional loss after spinal cord injury (SCI) is caused, in part, by demyelination of axons surviving the trauma. Administration of guanosine (8 mg/kg/day, i.p.) for 7 consecutive days, starting 5 weeks after moderate SCI in rats, improved locomotor function and spinal cord remyelination. Myelinogenesis was associated with an increase in the number of mature oligodendrocytes detected in guanosine-treated spinal cord sections in comparison with controls. These data indicate that guanosine-induced remyelination resulted, at least in part, from activation of endogenous oligodendrocyte lineage cells. These findings may have significant implications for chronic demyelinating diseases.

Animals↗

PubMed2006

Measures of visual function and their association with driving modification in older adults.

PURPOSE: Older drivers may place restrictions on their driving by reducing their mileage and avoiding high-risk driving situations in an effort to improve safety. This project identifies what types of visual function loss are associated with subsequent driving modifications. METHODS: Data were used from the baseline and 2-year follow-up rounds of the Salisbury Eye Evaluation project, a cohort study of 2520 older adults. Measures of visual function tested were visual acuity, contrast sensitivity, visual fields, and glare sensitivity. Driving information was self-reported. Among drivers at baseline who continued to drive at follow-up, multiple logistic regression was used to estimate the odds of incident driving modification by visual function status. RESULTS: Worse baseline scores in acuity, contrast sensitivity, and central and lower peripheral visual fields were individually associated with an increased odds of reduced mileage 2 years later (linear trend P < 0.05). Worse baseline scores in contrast sensitivity and central and lower peripheral visual fields were individually associated with a greater odds of cessation of night driving 2 years later, whereas worse baseline acuity scores were associated with an increased odds of cessation of driving in an unfamiliar areas 2 years later (linear trend P < 0.05). CONCLUSIONS: Older drivers with worse visual function were more likely to modify their driving by reducing mileage and avoiding high-risk driving situations. Furthermore, these modifications to driving differed depending on what type of visual function was affected.

Aged↗

PubMed2002

[Clinical aspects of osteoporosis].

The main clinical presentation of osteoporosis is fracture and its consequences. However a number of diseases and factors can induce bone loss and increase the risk of fracture. Therefore the clinical approach should be initially directed to exclude secondary osteoporosis. Vertebral fractures are the most common osteoporotic fractures; they are characterized by back pain, typical physical changes such as kyphosis and height loss, functional impairment and social decline. On the other hand, hip fracture is the most severe consequence of osteoporosis, because of its higher morbility and mortality. The main pathogenetic determinants of hip fracture are represented by both bone loss and several factors contributing to fall in the elderly. Moreover, a number of conditions are responsible for the high mortality rate following hip fracture. Colles' fracture is rarely hospitalized; however, most patients complain a complex algodystrophic syndrome which impairs the quality of life.

Activities of Daily Living↗

PubMed1980

Transferring the flexor superficialis tendon: technical considerations in the prevention of proximal interphalangeal joint disability.

Transfer of the flexor digitorum superficialis tendon to restore functional loss may result in a flexion contracture or hyperextension deformity of the proximal interphalangeal joint of the donor finger. Removal of the flexor tendon through the membranous interval in the fibro-osseous sheath between the annular pulley (A2) and the proximal collar (A1) avoids scarring of the structures volar to the proximal interphalangeal joint. Sixteen flexor superficialis tendons were removed at this membranous interval for transfer. No functional impairment from flexion contracture or hyperextension deformity developed after operation in the donor fingers, although an average 8 degrees of loss of extension was noted at the proximal interphalangeal joint in 50% of the donor fingers.

Adolescent↗

PubMed2003

Correlation between glomerular size and long-term renal function in patients with substantial loss of renal mass.

PURPOSE: Focal segmental glomerulosclerosis and progressive renal failure have been reported in reduced renal mass models. However, these findings are not consistent across all species. Increased intracapillary pressure and chronic glomerular hyperfiltration have been shown to contribute to this progression. Studies also have shown that a strong correlation exists between higher glomerular size and the degree of glomerular sclerosis that develops following loss of functioning nephrons. MATERIALS AND METHODS: To evaluate the relationship between glomerular size and long-term renal function following massive renal mass removal we describe 9 patients with less than 50% renal mass. All patients had undergone initial nephrectomy followed by partial second nephrectomy, with 30% to 50% of the second kidney excised for localized tumor. RESULTS: In 3 patients moderate to severe renal failure developed. Mean planar glomerular area (MPA) was 29.45 +/- 2.2 mm3 for all patients. Multivariate linear regression analysis demonstrated a significant association between MPA 30 mm3 or greater and increased serum creatinine. For patients with MPA 30 mm3 or greater the predicted delta creatinine was 2.43 mg/dl higher than that in patients with MPA less than 30 mm3 (p = 0.0028). Age was the only other covariate significantly associated with outcome in multivariate analysis. CONCLUSIONS: Our data indicate an individual susceptibility toward developing renal failure after significant renal mass reduction. We suggest that patients with less than 50% renal mass and higher MPA are at greater risk for progressive renal failure. MPA may be used as a marker in high risk patients with substantial loss of renal mass to predict long-term renal function.

Aged↗

PubMed1996

Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells.

CDKN2/p16 inhibits the cyclin D/cyclin-dependent kinase complexes that phosphorylate pRb, thus blocking cell cycle progression. We previously reported that p16 levels are low to undetectable in normal human uroepithelial cells (HUCs) and in immortalized uroepithelial cells with functional pRb, whereas p16 levels are markedly elevated in immortal HUCs with altered pRb (T. Yeager et al., Cancer Res., 55: 493-497, 1995). We now report that elevation of p16 levels occurs at senescence in HUCs, including HUCs transformed by human papillomavirus 16 E7 or E6, whose oncoprotein products lead to functional loss of pRb and p53, respectively. We also report that six of six independently immortalized E7 HUCs show high levels of p16 similar to those observed at HUC senescence, whereas p16 is undetectable in five of five immortal E6 HUCs. Four of the five independent E6 HUCs that lost p16 at immortalization showed hemizygous deletion of the 9p21 region. However, no homozygous CDKN2 deletions were detected, and only one CDKN2 mutation was identified. For the first time, these data associate elevated p16 with senescence in human epithelial cells. These data also suggest that a component of immortalization may be abrogation, either by pRb inactivation (as in the E7-transformed HUCs) or by p16 inactivation (as in the E6-transformed HUCs), of a p16-mediated senescence cell cycle block.

Carrier Proteins↗

PubMed2003

Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2.

Initially recognized for their importance in control of appetite, orexins (also called hypocretins) are neuropeptides that are also involved in regulating sleep, arousal, and cardiovascular function. Loss of orexin appears to be the primary cause of narcolepsy. Cells expressing the orexins are restricted to a discrete region of the hypothalamus, but their terminal projections are widely distributed throughout the brain. With the diversity of function and broad distribution of orexin terminals, it is not known whether the orexin cells constitute a homogeneous population. Because orexins produce neuroexcitatory effects, we hypothesized that orexin-containing neurons are glutamatergic. In the present study we used digoxigenin-labeled cRNA probes for the vesicular glutamate transporters, VGLUT1 and VGLUT2, for in situ hybridization studies in combination with immunohistochemical detection of orexin cell bodies in the hypothalamus. In general, cells in the hypothalamus expressed low levels of the vesicular glutamate transporters relative to other areas of the forebrain, such as the cortex and thalamus. Light labeling for VGLUT2 mRNA was detected in about 50% of the orexin-immunoreactive neurons, and a much smaller percentage (approximately 13%) of orexin-immunoreactive cells was found to express VGLUT1. Despite the fact that intense labeling for GAD67 mRNA was found in a large number of cells throughout the hypothalamus, none of the orexin-immunoreactive cells was found to be GABAergic. These findings, showing that many of the orexin neurons are glutamatergic, are consistent with the neuroexcitatory effects of orexin but suggest that another neurochemical phenotype may define the remaining subset of orexin neurons.

Animals↗

PubMed2005

Plasminogen activation/plasmin in rheumatoid arthritis: matrix degradation and more.

Rheumatoid arthritis (RA) is one of the most common and most debilitating joint diseases, producing high personal, social, and economic costs.(1,2) Patients with RA suffer pain and functional losses, often followed by disability and premature death. Although the etiology of RA is unknown, substantial efforts have been directed toward studying the transition of the joint from normal to diseased. The maintenance of normal joint architecture and function requires equilibrium between the synthesis and degradation of the specialized extracellular matrices that make up bone, cartilage, and tendons. In RA, the balance of tissue remodeling is disturbed,(3) and excessive proteolytic degradation of the joint matrices leads to joint destruction.(4,5) The early phase of RA is characterized by the infiltration of immune and inflammatory cells into the synovium and by hyperplasia of the fibroblasts in the synovial lining. This leads to pannus formation, cartilage breakdown, and eventual bone destruction.(1,2) Through the use of an experimental mouse model of RA, Li and colleagues(6) have implicated plasmin as an essential component of the early phase of RA, as reported in this issue of The American Journal of Pathology.

Animals↗

PubMed2002

Molecular characterization of angiogenic properties of human oral squamous cell carcinoma cells.

Little is known about the specificity of angiogenic properties of oral cancer cells and the possible mechanisms. Stimulatory effects on proliferation and migration of human umbilical vein endothelial cells (HUVEC) characterized the angiogenic properties of oral cancer cells but not normal oral keratinocytes (NOK). ELISA found the presence of vascular endothelial growth factors (VEGF) both in the tested oral cancer cells and NOK. Attenuation of the proangiogenic effects by neutralizing VEGF antibodies suggests VEGF play a key role in the acquisition of the angiogenic phenotype in oral cancer cells. Western blotting of p53 and murine double mutant 2 (Mdm2) together with p53 DNA sequencing analysis indicate that p53 function loss by mutation or overexpression of Mdm2 occurred in all tested oral cancer cells regardless of their etiology. In summary, the angiogenic property of oral cancer cells is mediated by many factors in addition to VEGF and the functional status of p53.

Carcinoma, Squamous Cell↗

PubMed2006

Distortion product otoacoustic emission (DPOAE) in tinnitus patients.

The aim of this study was to determine the effect of tinnitus (experiment I) and the combined effect of tinnitus and sensorineural hearing loss (experiment II) on the distortion product otoacoustic emission (DPOAE) for two age groups of tinnitus patients. Tinnitus patients with normal earing, along with normal-hearing control subjects, participated in experiment I. They were divided into two age groups, below 50 and above 50 years. Experiment I showed that the DPOAE levels in the tinnitus patients were lower than those in the normal-hearing (nontinnitus) subjects. The differences depended on the frequency and the age of the patients, suggesting the confounding influence of presbyacusis. The second group of tinnitus patients with increasing and notch-like hearing loss participated in experiment II. They were also divided into two age groups, below 50 and above 50 years. The data from experiment II showed that DPOAE activity well reflects the increasing and notch-like hearing loss functions up to about 40 dB HL. The effect of age on the DPOAE level was clearly noted only for the tinnitus patients with clinically normal-hearing thresholds and was ambiguous for the tinnitus patients with hearing loss.

Adolescent↗

PubMed1997

The effect of botulinum toxin on hand function after incomplete spinal cord injury at the level of C5/6: a case report.

OBJECTIVE: To investigate the benefits of the focal use of botulinum toxin in spasticity in the forearm seen after incomplete spinal cord injury. DESIGN: A single case study with standardized assessment before and at three-week intervals after injection. INTERVENTION: EMG-guided selective injection of botulinum toxin. SUBJECT: A 23-year-old man, 18 months post injury. MEASURES: Rivermead Motor Assessment; grip strength; Jebsen hand tests; visual analogue scale; Ashworth spasticity scale. RESULTS: Weakness was seen as expected with some functional losses, but the patient made gains in the areas of concern: shaking hands, typing, using the hand to drink. These gains were sustained at 12 weeks. CONCLUSION: Selective use of botulinum toxin to weaken muscles can lead to functional benefit.

Adult↗

PubMed1992

Functional assessment measures in CNS trauma.

How effectively the survivor of CNS trauma can function in society is the ultimate clinical outcome. Many victims of spinal cord injury (SCI) and traumatic brain injury (TBI) are frequently left with permanent impairment. Measurements of impairment, and the direct relationship to the functional loss and resultant disability, should be the gold standard for determining the effectiveness of interventions. The primary impairments in SCI are motor and sensory loss while those in TBI are neurobehavioral disorders. Classifications for impairment are reasonably well defined in SCI and several approaches are gaining wide acceptance. We hope that internationally agreed upon standards will be forthcoming within the year. The functional independence measure (FIM), which was developed in the past 6-7 years, will be added to the standards. It shows good reliability for SCI as an overall assessment and some of the specific categories of self-care and mobility. An extension of the FIM is needed for more precise measurement of function in quadriplegic subjects. Classification of impairment in TBI has been more difficult. While the Glasgow Outcome Scale has gained international acceptance for almost 10 years, it has limitations in gradations from the moderate disability to the good recovery groups. The Disability Rating Scale (DRS) has shown good reliability, better precision than the Glasgow Outcome Scale, and greater reliability than other measures. An extension of the FIM, called the functional assessment measure (FAM), and the DRS are currently being tested by regional TBI centers in the United States. Functional assessment measures should be available within the next several years.

Brain Injuries↗