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PubMed1986

Psychometric functions for frequency discrimination from listeners with sensorineural hearing loss.

Psychometric functions for pulsed pure-tone frequency discrimination were obtained from hearing-impaired listeners at frequencies with normal hearing and at frequencies with mild or moderate hearing losses. The general form of psychometric functions at hearing-impaired frequencies was found to be the same as at normal-hearing frequencies, i.e.,d' was linear with the frequency difference between tones, in Hz. For all but one psychometric function, the addition of an intercept term to the fitting equation did not account for significantly more variance than did the slope term alone. Therefore, it was concluded that psychometric functions for frequency discrimination can be adequately described with only one parameter: the slope of the psychometric function. Deficits in discrimination at hearing-loss frequencies were manifested by more gradual slopes of psychometric functions. Procedures for normalizing psychometric functions are presented, which facilitate comparisons of normal and impaired frequency discrimination data across studies and frequencies. Comparisons of dlf's (difference limen for frequency) obtained with adaptive and fixed procedures show a bias toward larger dlf's with adaptive procedures, but only at higher frequencies. A discussion of equal-interval and equal-ratio adaptive stepping rules indicates that an equal-ratio rule may be preferable.

Auditory Threshold↗

PubMed2004

Contrast-processing deficits in melanoma-associated retinopathy.

PURPOSE: To evaluate the hypothesis that patients with melanoma-associated retinopathy (MAR) have a selective functional loss within the magnocellular (MC) pathway of the cone system, with sparing of parvocellular (PC) pathway function. METHODS: Two patients with MAR, ages 57 and 61 years, with normal Snellen visual acuity, participated in the study. Contrast sensitivity was measured at spatial frequencies ranging from 0.25 to 8 cycles per degree (cpd), using two paradigms (steady pedestal and pulsed pedestal) designed to assess the functional integrity of the MC and PC pathways, respectively. Results in patients with MAR were compared with those in 10 visually normal observers, aged 23 to 57 years. RESULTS: Both patients with MAR showed a loss of contrast sensitivity compared to normal observers, but the pattern of loss differed for the two testing paradigms. For the steady-pedestal paradigm (presumed MC-pathway mediation), the patients' sensitivity loss was greatest at the lowest spatial frequency (0.25 cpd) and the sensitivity loss decreased systematically with increasing spatial frequency. For the pulsed-pedestal paradigm (presumed PC-pathway mediation), the sensitivity loss was greatest at an intermediate spatial frequency of 1 cpd. For both paradigms, the patients' sensitivities were within the normal range at the highest spatial frequency (8 cpd), consistent with their normal visual acuity. CONCLUSIONS: The contrast sensitivity deficits of patients with MAR under photopic conditions are not specific to the MC pathway, as proposed previously, but instead are related to the spatial frequency of the test target. The overall pattern of contrast sensitivity loss shown by the patients with MAR is consistent with the dysfunction at the level of the retinal bipolar cells that is presumed to underlie the MAR syndrome.

Adult↗

PubMed2005

How patients experience progressive loss of visual function: a model of adjustment using qualitative methods.

BACKGROUND: People with retinitis pigmentosa (RP) experience functional and psychological challenges as they adjust to progressive loss of visual function. The authors aimed to understand better the process of adjusting to RP in light of the emotional suffering associated with this process. METHODS: Adults with RP were recruited from the Foundation Fighting Blindness and the Wilmer Eye Institute in Baltimore. Focus groups and semistructured interviews addressed the process of adjusting to RP and were audiotaped and transcribed. The transcripts were analysed qualitatively in order to generate a model of adjustment. RESULTS: A total of 43 individuals participated. It was found that, on diagnosis, people with RP seek to understand its meaning in their lives. Mastering the progressive functional implications associated with RP is contingent upon shifting personal identity from a sighted to a visually impaired person. In this sample, six participants self identified as sighted, 10 self identified as in transition, and 27 self identified as visually impaired. This adjustment process can be understood in terms of a five stage model of behaviour change. CONCLUSIONS: The proposed model presents one way to understand the process of adjusting to RP and could assist ophthalmologists in meeting their moral obligation to lessen patients' suffering, which arises in the course of their adjustment to progressive loss of visual function.

Adaptation, Psychological↗

PubMed1999

Self-rated function, self-rated health, and postmortem evidence of brain infarcts: findings from the Nun Study.

OBJECTIVES: Self-rated function is a new global measure. Previous findings suggest that self-rated function predicts future functional decline and is strongly associated with all-cause mortality. We hypothesized that the strength of the relationship of self-rated function to all-cause mortality was in part due to functional decline, such as would occur with brain infarcts. METHODS: Self-ratings of function and health (on a 5-point scale, ranging from excellent to poor) were assessed annually on 630 participants in the Nun Study. Mortality surveillance extended from October 31, 1991 to March 1, 1998, and, among those who died, neuropathological examination determined postmortem evidence of brain infarcts. Cox regression modeling with self-rated function and health as time-dependent covariates and stratification by assessment period were used in these analyses. RESULTS: Self-rated function and health ratings of good, fair, and poor were significantly associated with doubling of the risk of mortality, compared with ratings of very good and excellent. Self-rated function ratings of fair or poor were associated with a threefold increase in the risk of mortality with brain infarcts, but self-rated function and health ratings of fair and poor were comparable in their association with all-cause mortality and mortality without brain infarcts. DISCUSSION: Self-rated function was significantly associated with mortality with brain infarcts, suggesting that brain infarcts may be experienced as functional loss but not recognized or labeled as disease. Our results suggest that self-rated function and health should be explored simultaneously in future research.

Activities of Daily Living↗

PubMed2004

Loss of nuclear factor-kappaB is tumor promoting but does not substitute for loss of p53.

Inactivation of apoptotic pathways is a common event in cancer. Two transcription factors that regulate apoptosis during tumorigenesis are p53 and nuclear factor (NF)-kappaB. Although NF-kappaB is generally considered a suppressor of cell death, we showed previously that NF-kappaB can contribute to p53-induced death. Here, we show that loss of p65, a critical subunit of NF-kappaB, can cause resistance to different agents that signal death through p53. Loss of p65 also enhances tumorigenesis induced by E1a and Ras. Unlike loss of p53, however, loss of p65 does not cause anchorage-independent growth or enable tumor development following expression of a single oncogene. These findings reaffirm the role of NF-kappaB in p53-induced death but show that its loss does not substitute for loss of p53 in tumor development. Moreover, this indicates that, although perhaps central to p53 function, loss of the ability to induce programmed cell death does not completely inactivate p53's tumor-suppressive effects.

Adenovirus E1A Proteins↗

PubMed2002

Generation of large homozygous chromosomal segments by mitotic recombination during lymphomagenesis in F1 hybrid mice.

The loss of heterozygosity (LOH) has been reported in numerous neoplasms in both human and animals, and has often been observed in chromosomal regions, which contain tumor-suppressor genes. We previously found frequent LOH on chromosomes 4, 12 and 19 in radiation-induced lymphomas from (BALB/cHeA x STS/A)F1 hybrid mice by allelotype analysis at polymorphic microsatellite loci. In this study, to elucidate the nature of allelic losses, we refined the loss regions on chromosomes 4, 12 and 19 of the tumors from the F1 mice and then analyzed them cytogenetically. The results represent evidence of a wide range of allelic losses owing to mitotic recombination on chromosomes 4 and 19 in the tumors, possibly reflecting functional losses of putative tumor-suppressor genes. It is suggested that the generation of these large homozygous chromosomal segments probably containing the affected genes is one of the genetic alterations responsible for tumorigenesis.

Animals↗

PubMed1999

The MutT motif family of nucleotide phosphohydrolases in man and human pathogens (review).

Human cells express at least eight members of the MutT motif protein (or nudix hydrolase) family. These enzymes are believed to eliminate toxic nucleotide derivatives from the cell and regulate the levels of important signalling nucleotides and their metabolites. Six have been fully or partially characterized: i) hMTH1 is a nucleoside triphosphatase which restricts AT-->CG transversions by specifically degrading the oxidized nucleotide 8-oxo-dGTP; ii) hAPAH1 preferentially degrades the signalling dinucleotide Ap4A; iii) DIPP is unusual in hydrolysing two seemingly unrelated signalling substrate groups - the dinucleotides Ap6A and Ap5A, and the diphosphoinositol polyphosphates; iv) DIPP2 is closely related to DIPP; v) hYSAH1 is an NDP-sugar hydrolase which prefers ADP-ribose, and vi) hGFG is a protein of unknown function encoded by the antisense transcript of the basic fibroblast growth factor gene. Although not yet associated with known hereditary or acquired disorders, the functional loss of any one of these hydrolases would be expected to be detrimental to cellular function. Furthermore, the ialA invasion gene of Bartonella bacilliformis and other invasive pathogens encodes a MutT motif Ap4A hydrolase while poxviruses express two MutT motif proteins, at least one of which is essential for infectivity. This protein family, therefore, occupies a position of some importance in controlling human health and disease.

Amino Acid Sequence↗

PubMed1991

Whole disease care planning: fitting the program to the client with Alzheimer's disease.

Care of the person with a chronic dementing illness is best approached from a conceptual perspective. As the "whole disease care planning" model demonstrates, care is logically derived from knowledge of the client's premorbid characteristics, and intervention strategies develop from following the individual's daily routine and simplifying it as the disease progresses. Although it is impossible to discuss the entire scope of care planning for demented adults in a brief article, this information can help nurses determine which intervention strategies to pursue based on the sociocultural background of clients and their level of functional loss. The desired outcomes at all levels of care include maximizing the potential for safe function by controlling for excess disability and providing appropriate levels of assistance; participation in activities as desired by the client; and minimizing discomfort and maximizing expressions of comfort.

Activities of Daily Living↗

PubMed2003

Multiple-electron excitation in X-ray absorption: a screened model of the core-hole-photoelectron potential.

The probability of secondary electron shake-off in X-ray absorption is calculated using a model form for the time- and energy-dependent core-hole-photoelectron potential, screened by the single plasmon pole dielectric function of the surrounding material. The resultant excitation probabilities are related to the energy-dependent intrinsic loss function in EXAFS data analysis and compared with experiment. Reasonable agreement is obtained close to the absorption edge although the calculation is less accurate at higher photon energies. The theory described allows the losses to be calculated with little computational effort, making the method suitable for routine EXAFS data analysis.

Journal Article↗

PubMed2004

Conditions of aging as manifestations of sympathetic bias unmasked by loss of parasympathetic function.

We propose a unifying hypothesis that many clinical consequences of aging are pleiotropic manifestations of the loss of parasympathetic function that occurs during post-reproductive senescence. The loss of parasympathetic function unmasks the baseline sympathetic bias inherent in the end-organs, resulting in the familiar signs of aging including tachycardia, constipation, insomnia, erectile dysfunction, fluid retention, and systemic inflammation. These consequences in turn may contribute to many of the common diseases associated with aging including type-2 diabetes, Alzheimer's, atherosclerosis, and cancer. Maintenance and restoration of parasympathetic function may enable upstream control over the deleterious aspects of inherent end-organ adrenergic bias.

Aging↗

PubMed1999

Loss of HNF1alpha function in human renal cell carcinoma: frequent mutations in the VHL gene but not the HNF1alpha gene.

Human renal cell carcinoma (RCC) is a common malignant disease of the kidney characterized by dedifferentiation of renal epithelial cells. Our previous experiments showed that most RCCs have a loss of function of the tissue-specific transcription factor hepatocyte nuclear factor (HNF) 1alpha. Detailed analyses of the 10 exons encoding HNF1alpha in 32 human RCCs by single-strand conformation polymorphism analysis and direct DNA sequencing revealed no tumor-associated mutation, whereas with the same probes we frequently found mutations in the von Hippel-Lindau tumor suppressor gene. No mutation leading to loss of HNF1alpha function was detected by analyzing the integrity of the HNF1alpha transcripts in the RNA derived from RCCs by the protein truncation test. Investigating human RCC cell lines by western blotting and gel retardation assays showed a dramatic loss in the expression of the tissue-specific transcription factor HNF1alpha in eight of 10 cell lines. As the HNF1alpha-related transcription factor HNF1beta was expressed in all these tumor cell lines, the loss of HNF1alpha expression was a specific event and was maintained in RCC cell lines. The loss of HNF1alpha expression in RCC cell lines on the RNA level was confirmed by reverse transcription polymerase chain reaction. We propose that tumor-associated mutations in the HNF1alpha gene do not occur in human RCC and that the loss of function is partially due to a transcriptional inactivation of the HNF1alpha gene.

Adenocarcinoma, Clear Cell↗

PubMed1991

Limb function following conservation treatment of adult soft tissue sarcoma.

Quality of life and limb function were studied in 54 patients who were disease-free 2 or more years after limb-conserving treatment for soft tissue sarcoma of the leg or pelvic girdle. Tumours of the thigh predominated (25 patients) and the mean tumour size was 9.9 cm. 41 patients had been treated with a combination of surgery and radiotherapy (29 with conventional and 12 with high dose), 12 with surgery alone and one with irradiation and intra-arterial doxorubicin. Only 15 patients had a normal range of movement in all lower limb joints and only 12 had normal power in all muscle groups; tumours of the lower leg were particularly unfavourable in this respect. Gait was normal in 42 patients but 8 required a walking aid and 4 a joint support. 16 had detectable lymphoedema but only 2 needed to wear compression hosiery. 35 patients still experienced pain at some time but only 6 required analgesia. However, when assessed by questionnaire for locomotion, grooming and home/leisure/vocational activities, 37 patients (68%) reported excellent function, and only 2 had moderate impairment. Function loss was most marked in leisure (25 patients) and vocational (8) activities, but was mild in 66% of cases. Multivariate analysis was carried out to determine the prognostic factors for poor limb function. The results suggested that overall functional score was predominantly determined by gait (P less than 0.001), muscle power or range of movement (P less than 0.001), with increasing age, female sex and the use of radiotherapy poor prognostic factors. Reduced muscle power or range of movement were the major factors determining gait (P less than 0.02) with the use of radiotherapy the significant prognostic factor for both in the conventionally treated group. Doses in excess of 60 Gy resulted in increased fibrosis and a worse functional outcome. Extent of surgery was not an independent prognostic factor for limb function, although univariate analysis suggested an association with range of movement in the conventionally treated group (P less than 0.025). Despite significant objective loss of range of movement and muscle power patients retain excellent limb function and quality of life following limb conserving treatment. For optimal function, radiotherapy should be given with small fractions to a dose not exceeding 60 Gy.

Adult↗

PubMed1992

Prolonged in vitro exposure of rat brain slices to adenosine analogues: selective desensitization of adenosine A1 but not A2 receptors.

Agonist-induced desensitization of adenosine A1 and A2 receptors was studied in rat striatum slices maintained in carbo-oxygenated Krebs buffer. Slices were exposed to adenosine analogues (either cyclo-pentyl-adenosine or N-ethyl-carboxamido-adenosine) for selected time periods (15-60 min) and repeatedly washed at the end of agonist exposure. Agonist-induced changes of adenosine receptors were then evaluated in P2 fractions prepared from slices by measuring A1 and A2 receptor-regulated adenylate cyclase. A1 receptors were rapidly desensitized by agonist exposure, as shown by a gradual loss of A1 receptor-mediated inhibition of basal cyclase activity and cAMP formation, which was evident within 15-30 min after addition of the adenosine analogue. Agonist-induced desensitization of A1 receptors was dose- and time-dependent, and seemed quicker in onset with cyclo-pentyl-adenosine, according to the higher A1 selectivity of this receptor agonist, with respect to N-ethyl-carboxamido-adenosine. Binding of the A1-selective agonist [3H]cyclo-hexyl-adenosine was unaffected by the desensitization procedure at any of the exposure periods utilized, suggesting that an uncoupling of A1 receptors from their transduction system is indeed responsible for the loss of functional activity. Loss of A1 receptor function was accompanied by a time-dependent amplification of A2 receptor-mediated stimulation of adenylate cyclase activity, likely due to an 'unmasking' of A2 stimulatory receptor function as a consequence of the desensitization of A1 inhibitory receptors. All these effects could be completely counteracted by the concomitant exposure to an adenosine receptor antagonist, and specifically involved the coupling mechanisms of adenosine receptors with their effector system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed2005

Dynamics and pathology of dendritic spines.

Dendritic spines are key players in information processing in the brain. Changes in spine shape and wholesale spine turnover provide mechanisms for modifying existing synaptic connections and altering neuronal connectivity. Although neuronal cell death in acute and chronic neurodegenerative diseases is clearly an important factor in decline of cognitive or motor function, loss of dendritic spines, in the absence of cell death, may also contribute to impaired brain function in these diseases, as well as in psychiatric disorders and aging. Because spines can function in neuroprotection in vitro, advances toward a molecular understanding of spine maintenance might one day aid in the design of therapies to minimize neurological damage following excitotoxic injury. In addition, progress in defining the biochemical basis of spine development and stabilization may yield insights into mental retardation and psychiatric disorders.

Animals↗

PubMed1995

Relation between functional deficit and intraneural local anesthetic during peripheral nerve block. A study in the rat sciatic nerve.

BACKGROUND: During peripheral nerve block, local anesthetic (LA) penetrates within and along the nerve to produce the observed functional deficits. Although much is known about the kinetics and steady-state relation for LA inhibition of impulse activity in vitro in isolated nerve, little is known about the relation between functional loss and intraneural LA content in vivo. This study was undertaken to investigate the relation of functional change to intraneural LA. METHODS: A sciatic nerve block was performed in rats with 0.1 ml 1% lidocaine radiolabeled with 14C. The total intraneural uptake of LA was determined at different times after injection, and the distribution of lidocaine along the nerve was assayed at different stages of functional block. Drug content was also compared with equilibrium lidocaine uptake in the isolated rat sciatic nerve. RESULTS: Total intraneural lidocaine in vivo increased to near steady-state in about 3 min, stabilizing at approximately 14.3 nmol/mg wet tissue for about 12 min before decreasing to zero at 70 min after injection. Although intraneural lidocaine was 1.6% of the injected dose during full block, only 0.3% was left when deep pain sensation returned and 0.065% was still detected when functions fully recovered. Despite these large differences in total lidocaine content, the longitudinal distribution remained constant. Intraneural lidocaine concentrations obtained at full block and partial recovery could be achieved in vitro by equilibration in 0.7-0.9 and 0.2-0.3 mM lidocaine, respectively. CONCLUSIONS: During peripheral nerve block only a small amount of injected LA penetrates into the nerve. The intraneural content of LA correlates with the depth of functional block.

Animals↗

PubMed1997

Aesthetic fingertip reconstruction with a free vascularized nail graft: a review of 60 flaps involving partial toe transfers.

Microsurgical toe transfer is an established procedure for functional reconstruction of fingers. However, even if the functional loss is minimal, the fingertip defect is often a large problem for patients for not only functional reasons but also aesthetic reasons. In these patients, although the normal appearance of the fingertip is very important, total toe transfer is not acceptable because of resection of an entire toe. With this background, partial toe transfer techniques have greatly progressed. On the other hand, various types of innervated finger flaps also have been developed in hand surgery. Based on this progress, we developed the combined technique of innervated finger flaps in the hand and osteo-onychocutaneous flaps from the toe. This technique provides better aesthetic results in fingertip reconstruction, thus broadening the indications for vascularized nail grafts. We have now experienced 60 flaps in partial toe transfer. In this report, a review of 60 consecutive flaps is presented, and the indications, technique, and postoperative treatment are discussed.

Adult↗

PubMed2002

Role for radA/sms in recombination intermediate processing in Escherichia coli.

RadA/Sms is a highly conserved eubacterial protein that shares sequence similarity with both RecA strand transferase and Lon protease. We examined mutations in the radA/sms gene of Escherichia coli for effects on conjugational recombination and sensitivity to DNA-damaging agents, including UV irradiation, methyl methanesulfonate (MMS), mitomycin C, phleomycin, hydrogen peroxide, and hydroxyurea (HU). Null mutants of radA were modestly sensitive to the DNA-methylating agent MMS and to the DNA strand breakage agent phleomycin, with conjugational recombination decreased two- to threefold. We combined a radA mutation with other mutations in recombination genes, including recA, recB, recG, recJ, recQ, ruvA, and ruvC. A radA mutation was strongly synergistic with the recG Holliday junction helicase mutation, producing profound sensitivity to all DNA-damaging agents tested. Lesser synergy was noted between a mutation in radA and recJ, recQ, ruvA, ruvC, and recA for sensitivity to various genotoxins. For survival after peroxide and HU exposure, a radA mutation surprisingly suppressed the sensitivity of recA and recB mutants, suggesting that RadA may convert some forms of damage into lethal intermediates in the absence of these functions. Loss of radA enhanced the conjugational recombination deficiency conferred by mutations in Holliday junction-processing function genes, recG, ruvA, and ruvC. A radA recG ruv triple mutant had severe recombinational defects, to the low level exhibited by recA mutants. These results establish a role for RadA/Sms in recombination and recombinational repair, most likely involving the stabilization or processing of branched DNA molecules or blocked replication forks because of its genetic redundancy with RecG and RuvABC.

ATP-Dependent Proteases↗

PubMed2004

Learning eigenfunctions links spectral embedding and kernel PCA.

In this letter, we show a direct relation between spectral embedding methods and kernel principal components analysis and how both are special cases of a more general learning problem: learning the principal eigenfunctions of an operator defined from a kernel and the unknown data-generating density. Whereas spectral embedding methods provided only coordinates for the training points, the analysis justifies a simple extension to out-of-sample examples (the Nyström formula) for multidimensional scaling (MDS), spectral clustering, Laplacian eigenmaps, locally linear embedding (LLE), and Isomap. The analysis provides, for all such spectral embedding methods, the definition of a loss function, whose empirical average is minimized by the traditional algorithms. The asymptotic expected value of that loss defines a generalization performance and clarifies what these algorithms are trying to learn. Experiments with LLE, Isomap, spectral clustering, and MDS show that this out-of-sample embedding formula generalizes well, with a level of error comparable to the effect of small perturbations of the training set on the embedding.

Algorithms↗