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PubMed1991

Early detection of damage following bilateral renal irradiation in the mouse.

The rate and early pattern of development of radiation-induced renal damage has been determined in the mouse by measuring reductions in both haematocrit and excretion of 51Cr-EDTA, and increases in both urination frequency and urine volume. Kidneys of CBA mice were irradiated bilaterally with 2 fractions of X-rays, one week apart. Renal function was determined immediately prior to irradiation and at 3-4 weekly intervals to 22 weeks post-irradiation. Onset of damage was detected as early as 3-6 weeks using the urination frequency assay. This was confirmed by estimating the volume of urine excreted. A significant fall in haematocrit was not detected until 6-9 weeks post-treatment and a fall in isotope clearance was not detected significantly until 12 weeks. This early detection of damage was consistent with reports using both mouse and other species. The time at which damage was detected first was independent of radiation dose for the frequency and haematocrit assays. For 51Cr-EDTA clearance, there was the suggestion of earlier functional loss for the higher doses. Following the onset of damage, a steady, dose-dependent decline in renal function was measured by all assays. The latency period is defined as the time required to reach a given level of functional damage. This time decreased with increasing radiation dose, to a minimum value set by the time of onset of damage, which varied from 3 to 12 weeks, depending on the assay used. The differences in response measured prior to 12 weeks post-irradiation represent the first occasion on which a dissociation between these 3 assays has been detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effect of sleep disruption on sleep, performance, and mood.

Eleven young adult subjects were briefly awakened after each minute of electroencephalographic-defined sleep for 2 consecutive nights after undisturbed laboratory adaptation and baseline nights. Two undisturbed recovery nights followed disruption nights. On disruption nights, subjects were awakened with an audiometer and signaled the awakening by subjective rating of sleep state or button push response. The disruption procedure resulted in severely fragmented sleep with only very small amounts of slow-wave and REM sleep. Total sleep time was reduced by approximately 1 h on each night. Arousal threshold increased 56 dB across the disruption nights. Following disruption, subjects performed more poorly and rated themselves sleepier than on baseline. The level of decline was similar to that seen after periods of total sleep loss of 40-64 h. Recovery sleep was also similar to that seen after total sleep loss. It was concluded that periodic disruption of sleep, perhaps by destroying sleep continuity, quickly results in impaired function. These data may help explain function loss in severe sleep apneics.

Achievement↗
PubMed1999

Seeing into old age: vision function beyond acuity.

PURPOSE: To provide a comprehensive description of vision function beyond acuity in older individuals. METHODS: A sample of 900 individuals between the ages of 58 and 102 years (mean age of 75.5) was binocularly tested wearing habitual correction on a battery of psychophysical tests including high and low contrast acuity, low contrast low luminance acuity, disability glare, contrast sensitivity, color vision, stereoacuity, recovery from glare, and attentional visual fields. RESULTS: High contrast acuity is reasonably well maintained on average, even into very old ages. Spatial vision measures under conditions of reduced contrast or luminance, or glare reveal significant impairment in a large portion of the aged. Many older individuals also have greatly reduced stereopsis, poor color discrimination, and severely restricted peripheral fields under conditions of divided attention. A single exponential function relating performance to age fits all spatial vision data sets. The function for individual spatial measures lies at different positions along the age scale. The derived aging function with a time constant of approximately 15 years also fits results from other recent aging studies of acuity and contrast sensitivity. CONCLUSIONS: Standard visual acuity underestimates the degree of vision function loss suffered by many older individuals under the nonoptimal viewing conditions encountered in daily life. All spatial vision functions show a similar rate of decline with age of the population, but the age at which decline begins varies among measures.

Aged↗
PubMed1992

Regeneration of free grafted respiratory epithelium on severely altered lamina propria.

The lamina propria of nasal mucosa has been thought to play a key role in function and metabolism of respiratory epithelia by allowing exchange of various substances and migratory cells from blood vessels into the epithelium. Here we show that the lamina propria of mucosa transplanted to rat rectus abdominis muscle looses its typical structure and becomes vascularized connective tissue. In the subepithelial space of free grafted respiratory epithelia nasal glands, ducts and nerves degenerate and are no more detectable 3 weeks after transplantation. By contrast the epithelial cell layer regenerates, resulting in a healthy appearing mucosa. Histological and functional controls revealed that regenerated respiratory epithelium lies on a layer of vascularized connective tissue and displays normal cellular differentiation and ciliary function. The present experiments demonstrate that the lamina propria can be replaced by vascularized connective tissue without functional loss of the overlaying epithelium. Thus the results argue against a key role of lamina propria in mucosal function.

Abdominal Muscles↗
PubMed1989

Secobarbital-mediated inactivation of rat liver cytochrome P-450b: a mechanistic reappraisal.

Administration of the allylbarbiturate secobarbital (SB) to phenobarbital-pretreated rats is known to result in structural and functional loss of hepatic cytochrome P-450 and generation of N-alkylated prosthetic heme derivatives. Isozyme-selective functional markers have led us to confirm P-450b as the isozyme selectively inactivated by the drug. In contrast to its inactivation by allylisopropylacetamide, such SB-inactivated P-450b is not amenable to structural and functional repair by exogenous heme, for reasons that remain unclear. In an effort to gain some insight, we have explored various possible mechanisms. In the course of these studies with rat liver microsomes enriched in P-450b as well as isolated purified P-450b, we have found that, along with prosthetic heme alkylation, a significant fraction of the hemoprotein also undergoes drug-mediated alkylation of the apocytochrome, presumably at the active site. Accordingly, an equimolar ratio of irreversibly bound drug to functionally inactive residual P-450b chromophore is observed after incubation of the purified isozyme with SB and NADPH. Thus, P-450b-mediated oxidative metabolism of SB appears to partition not only between prosthetic heme alkylation and epoxidation but apoprotein alkylation as well.

Alkylation↗
PubMed1984

The rheumatoid thumb.

Although the thumb is frequently involved in rheumatoid arthritis, causing significant functional loss as well as pain and deformity, much can be done surgically to alleviate the condition and restore function to the patient. It is important to understand the factors leading to the various thumb deformities. With this understanding it is possible to formulate a rational treatment programme which will benefit the patient and satisfy the surgeon.

Arthritis, Rheumatoid↗
PubMed2005

Impaired response to amphetamine and neuronal degeneration in the nucleus accumbens of autoimmune MRL-lpr mice.

Spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by a constellation of behavioral deficits, including blunted responsiveness to sucrose. Although autoimmunity-induced damage of limbic areas is proposed to underlie this deficit, the systemic nature of the disease precludes inference of a causal relationship between CNS damage and functional loss. Based on the stimulatory effects of d-amphetamine sulfate (AMPH) on sucrose intake, the present study pharmacologically probes the functional status of central dopaminergic circuits involved in control of behavioral reward. The response rates were compared between diseased MRL-lpr mice and congenic MRL +/+ controls tested in the sucrose preference paradigm. Neuronal loss was assessed by Fluoro Jade B (FJB) staining of nucleus accumbens and the CA2/CA3 region. While control mice significantly increased intake of sucrose solutions 60 min after administration of AMPH (i.p., 0.5 mg/kg), the intake in drugged MRL-lpr mice was comparable to those given saline injection. Increased FJB staining was detected in the nucleus accumbens and hippocampus of diseased mice, and AMPH treatment neither altered this nor other measures of organ pathology. The results obtained are consistent with previously observed changes in the mesolimbic dopamine system of MRL-lpr mice and suggest that the lesion in the nucleus accumbens and deficits in dopamine release underlie impaired responsiveness to palatable stimulation during the progress of systemic autoimmune disease. As such, they point to a neurotransmitter-specific regional brain damage which may account for depressive behaviors in neuropsychiatric lupus erythematosus.

Amphetamine↗
PubMed2001

Upper bound of the expected training error of neural network regression for a Gaussian noise sequence.

In neural network regression problems, often referred to as additive noise models, NIC (Network Information Criterion) has been proposed as a general model selection criterion to determine the optimal network size with high generalization performance. Although NIC has been derived using asymptotic expansion, it has been pointed out that this technique cannot be applied under the assumption that a target function is in a family of assumed networks and the family is not minimal for representing the target true function, i.e. the overrealizable case, in which NIC reduces to the well-known AIC (Akaike Information Criterion) and others depending on a loss function. Because NIC is the unbiased estimator of generalization error based on training error, it is required to derive the expectations of errors for neural networks for such cases. This paper gives upper bounds of the expectations of training errors with respect to the distribution of training data, which we call the expected training error, for some types of networks under the squared error loss. In the overrealizable case, because the errors are determined by fitting properties of networks to noise components, including in data, the target set of data is taken to be a Gaussian noise sequence. For radial basis function networks and 3-layered neural networks with bell shaped activation function in the hidden layer, the expected training error is bounded above by sigma2* - 2nsigma2*logT/T, where sigma2* is the variance of noise, n is the number of basis functions or the number of hidden units and T is the number of data. Furthermore, for 3-layered neural networks with sigmoidal activation function in the hidden layer, we obtained the upper bound of sigma2* - O(log T/T) when n > 2. If the number of data is large enough, these bounds of the expected training error are smaller than sigma2* - N(n)sigma2*/T as evaluated in NIC, where N(n) is the number of all network parameters.

Analysis of Variance↗
PubMed2004

[What is the role of neuropsychological testing in the investigation and management of pharmacologically intractable partial epilepsy?].

Neuropsychological testing is an integral part of investigation and management of pharmacologically intractable epilepsy. Patients often complain of cognitive difficulties, in particular memory disturbances. A review of the literature demonstrates that correlations between subjective memory difficulties and objective memory deficits are often poor with mood correlating more consistently with subjective complaints. Nevertheless, objective memory difficulties are often found, especially in patients with temporal lobe epilepsy. Many factors can contribute to cognitive difficulties in patients with pharmacoresistant partial epilepsy. These include brain pathology that may be the cause or the consequence of chronic seizures (or both), physiological brain dysfunction due to epileptic activity and effects of antiepileptic medications. We review some of the abundant relevant literature. Neuropsychological evaluation is routinely used in pre-surgical evaluations of patients and cognitive dysfunction has some degree of correlation with lateralization and localization of epileptic activity, thus helping to determine a surgical strategy. The goal of seizure control is tempered with an assessment of the potential cognitive loss resulting from resective surgery. A number of studies have addressed postoperative neuropsychological findings and it is universally recognized that patients who have high levels of cognitive functioning in the areas targeted for resection (for instance verbal memory in dominant temporal lobe) show the greatest functional loss following surgery. More selective surgery probably results in some level of preservation of cognitive function.

Adult↗
PubMed2004

[Arthrolysis of the elbow joint].

A stiff elbow is usually defined as having less than 30 degrees in extension or flexion less than 130 degrees. Most activities of daily living are possible if the elbow has a range of motion of 100 degrees (30-130 degrees of flexion, Morrey's arc of motion). Loss of motion of the elbow is not uncommon after trauma, burns, or coma and severely impairs upper limb function. Loss of motion may be difficult to avoid and is challenging to treat. Detailed analysis of the etiology and diagnostic evaluation is of utmost importance for planning any surgical intervention for elbow stiffness. Current operative techniques, such as arthroscopic or open arthrolysis and closed distraction with external fixation (arthrodiatasis), are presented and evaluated. Elbow arthrolysis is a technically demanding procedure, but if indication and techniques are used correctly and surgeon, physiotherapist, and patient are familiar with the procedure, good long-term results may be achieved.

Ankylosis↗
PubMed2006

Effect of estrogen on calcium-handling proteins, beta-adrenergic receptors, and function in rat heart.

Regulation of cellular Ca(2+) cycling is central to myocardial contractile function. Loss of Ca(2+) regulation is associated with cardiac dysfunction and pathology. Estrogen has been shown to modify contractile function and to confer cardioprotection. Therefore, we investigated the effect of estrogen on expression of rat heart myocardial Ca(2+)-handling proteins and beta-adrenergic receptor (beta(1)-AR) and examined functional correlates. Female rats were sham-operated (SHAM) or ovariectomized. Two weeks after ovariectomy rats were injected (i.p.) daily with estradiol benozoate (OVX+EB) or sesame oil (OVX) for 2 weeks. Protein abundance was measured by immunoblotting and mRNA was quantified by real-time RT-PCR. OVX significantly decreased estrogen and progesterone levels and EB replacement returned both estrogen and progesterone to physiological levels. OVX induced a 75% reduction of uterine weight and a gain in body weight. Replacement restored weights to SHAM level. OVX increased and estrogen-replacement normalized abundance of beta(1)-AR and L-type Ca(2+) channel (Cav1.2) protein. OVX decreased sodium-Ca(2+) exchange protein (NCX) and estrogen restored protein abundance to SHAM levels. Sarcoplasmic reticular ATPase (SERCA), phospholamban (PLB), and ryanodine receptor (RyR) abundance was not altered by hormone status. Levels of mRNA encoding for beta(1)-AR, Cav1.2, and NCX were not influenced by OVX or estrogen replacement. OVX had no effect on SERCA and PLB mRNA level but estrogen replacement elicited a significant increase compared to OVX and SHAM. Estrogen-dependent changes in Ca(2+)-handling proteins and beta(1)-AR are theoretically consistent reduced myocellular Ca(2+) load. However, hormone-dependent alterations in protein were not associated with changes in contractile function.

Animals↗
PubMed2002

Sex- and age-related elevation of cochlear nerve envelope response (CNER) and auditory brainstem response (ABR) thresholds in C57BL/6 mice.

The C57BL/6 mouse has long been considered, in scores of published studies, as a model of early adult-onset, progressive sensorineural hearing loss (presbycusis). The auditory brainstem response (ABR) has most often been used in these studies as a measure of functional loss. Whereas the ABR measures the response to a rapid acoustic onset, the cochlear nerve envelope response (CNER) measures the ability of cochlear nerve axons to respond to the low frequency modulations of the entire acoustic waveform, acoustic changes that are utilized in vocalizations and music. The present study compared the ability of these two measures to assess presbycusis in male and female C57BL/6 mice, at ages ranging from 50 to 400 days. Thresholds to the CNER were almost invariably more sensitive than the ABR, in response to stimulus frequencies ranging from 8 to 56 kHz. By 100 days of age, mice showed elevation of thresholds in response to high frequency stimuli, and this loss was greater in females than in males. These trends persisted for both measures over the next 300 days, involving successively lower frequencies.

Aging↗
PubMed1990

Neuro-axonal recruitment: a result of selective compression.

Many acoustic neurinomas and CPA tumours present an audiometric picture of positive-recruitment hearing impairment although often the CMs are not significantly impaired (according to ECochG) and because, even in the case of a small acoustic neuroma, the interpeak latency between wave I and V (ERA) is increased in the majority of cases. Recruitment cannot be explained, in these cases, as an expression of an accompanying vascular inner ear lesion. Therefore, we attempt to interpret the differential audiometric picture to the various patterns of damage of the auditory nerve. The finding of tone decay is seen as an expression of myelin damage corresponding to the hearing loss in multiple sclerosis. The absence of any degree of tone decay excludes an isolated damage of the myelin sheaths; hearing loss then results from a disturbance also of the associated axons. At such a stage, where there is a functional loss to part of the neural fibres but with intact myelinated residual fibres, the result could be the phenomenon of recruitment for suprathreshold stimulation. This theory of selective compression is compared to an isolated efferent lesion theory as the cause for recruitment in AN and CPA tumours.

Audiometry↗
PubMed2000

Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent's disease.

BACKGROUND: Dent's disease is an X-linked renal tubular disorder that is characterized by low molecular weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. The disease is caused by inactivation of a renal chloride channel gene, CLCN5, that encodes a 746-amino acid protein with 12 to 13 transmembrane domains. The Japanese variant of Dent's disease has been observed to be less severe, and we have investigated two unrelated Japanese families for CLCN5 mutations. METHODS: Six patients from two unrelated families were studied. Leukocyte DNA from probands was used with CLCN5-specific primers for polymerase chain reaction (PCR) amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products were determined to identify abnormalities in the gene. RNA extracted from the kidney, leukocytes, or urine sediments was used to characterize further the effects of the identified mutations. RESULTS: beta2-microglobulinuria was detected in five patients, hypercalciuria in two patients, nephrolithiasis in three patients (2 of whom were females), and one 51-year-old man had renal failure. Two novel CLCN5 mutations consisting of an a to g transition at the invariant ag acceptor splice site of intron 5 and an intragenic deletion that encompassed the region between intron 3 and intron 6 were identified. The acceptor splice site mutation led to the utilization of two alternative cryptic splice sites in exon 6 that resulted in a frameshift or skipping of the exon 6. The deletional mutation, which resulted in a loss of exons 4, 5, and 6, is predicted to lead to a loss of domains 1 through 4. Both mutations predict truncated chloride channels that are likely to result in a functional loss. CONCLUSIONS: The observations of renal failure in one male and nephrolithiasis in two females represent important new findings in this Japanese variant of Dent's disease that is associated with CLCN5 mutations. In addition, our study is the first to demonstrate the use of urinary sediment cells and renal tissue for the detection of CLCN5 transcript abnormalities. These results help to expand the spectrum of CLCN5 mutations associated with Dent's disease.

Adult↗
PubMed2004

Correlation of quantitative digital image analysis with the glomerular filtration rate in chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is characterized by progressive renal functional loss and histologic abnormalities of one or more tissue compartments. In this study, correlations between histologic abnormalities and graft function [glomerular filtration rate (GFR, measured by iothalamate clearance), serum creatinine (SCr) and urinary protein (UPr)] were investigated using biopsies from 49 patients with newly diagnosed CAN. Extent of tubulointerstitial fibrosis (%TIF), as assessed by a semi-quantitative score, correlated significantly with GFR, SCr and UPr. The close correlation between %TIF and GFR suggested that quantitative measurement of %TIF may predict functional consequences of CAN. Calculation of %TIF by computerized digital analysis was performed using four strategies: (a) quantitation of blue material in Masson's trichrome (MT)-stained sections, (b) quantitation of red material in Sirius Red-stained sections (SR-nonpolarized), (c) quantitation of birefringent material in Sirius Red stained-sections examined under polarized light (SR-polarized) and (d) quantification of brown material in sections stained by immunoperoxidase for alpha-smooth muscle actin. Only the SR-nonpolarized score correlated significantly with GFR at the time of biopsy-diagnosis of CAN. We conclude that digital analysis strategies demonstrate variable accuracy in quantifying %TIF. Validation of the SR-nonpolarized strategy against histologic scoring and GFR supports the application of this technique to longitudinal studies of CAN.

Biopsy↗
PubMed2002

Metformin improves cardiac functional recovery after ischemia in rats.

The biguanide, metformin, is widely used for the treatment of type 2 diabetes mellitus. In the recently published United Kingdom Prospective Diabetes Study (UKPDS), it was shown that the use of metformin was associated with a reduction of macrovascular complications compared to other blood glucose-lowering strategies. The present study was aimed at determining whether metformin has direct beneficial effects on the heart. We tested the effects of metformin on cardiac functional recovery after a mild ischemic incident (stunning) in our isolated, erythrocyte perfused, rat working-heart model. Three groups were tested: vehicle, 50 and 500 micromol/l metformin (total n = 6). In diabetic rats, a concentration of 50 microM has been shown to reduce the blood glucose concentration. Slight metformin-induced increases in coronary blood flow during normoxia (pre-ischemically) and during reperfusion (post-ischemically) were observed and compared to vehicle (p < 0.05). Both metformin concentrations significantly reduced cardiac functional loss induced by the 12-min global ischemic incident compared with vehicle (3.4 +/- 1.0 % and 3.5 +/- 0.6 % loss during metformin versus 10.7 +/- 0.8 % during vehicle, p < 0.001). This study clearly shows that metformin acutely improves cardiac function after a mild ischemic incident (stunning) in rats.

Animals↗
PubMed2005

Methylation of the gamma-catenin gene is associated with poor prognosis of renal cell carcinoma.

PURPOSE: Gamma-catenin is a cell adhesion protein, and its functional loss is associated with tumor invasion and metastasis. We hypothesize that (1) promoter CpG methylation regulates the expression and function of the gamma-catenin gene in renal cell carcinoma (RCC) and (2) methylation of the gamma-catenin gene is associated with poor prognosis of RCC. To test these hypotheses, we analyzed the CpG methylation status of the gamma-catenin gene and its correlation with clinical outcome in RCC. EXPERIMENTAL DESIGN: Genomic DNA and total RNA were extracted from three renal cancer cell lines (A498, Caki-1, and Caki-2) and 54 RCC tissue samples with their corresponding normal kidney tissue samples. Expression of gamma-catenin gene was analyzed by reverse transcription-PCR and immunostaining. Promoter methylation was analyzed by two different methylation-specific PCR (MSP-A and MSP-B), and the results were verified by DNA sequencing. RESULTS: The demethylating agent (5-aza-2'-deoxycytidine) increased levels of mRNA transcript of the gamma-catenin gene in three renal cancer cell lines. Gamma-catenin mRNA and protein expression were significantly reduced in RCC samples compared with normal kidney samples, respectively (P < 0.05). MSP-A and MSP-B bands were detected in 45 of 54 (83.3%) and 49 of 54 (90.7%) RCC samples, respectively. In normal kidney, weak products of MSP-A and MSP-B were detected in 5 of 54 (9.3%) and 6 of 54 (11.1%) samples, respectively. Likewise, both MSP-A and MSP-B ratios were significantly higher in RCC samples compared with normal kidney samples, respectively (P < 0.01). Multivariate analysis revealed that the MSP-B ratio was a powerful and independent predictor superior to nuclear grade and Robson stage with respect to survival and disease progression (P = 0.029 and 0.0071, respectively). No mutations in the NH(2)-terminal region of gamma-catenin were found in this study. CONCLUSION: Expression of gamma-catenin is regulated by promoter CpG methylation, and the balance between methylated and unmethylated RCC cell populations could determine its functional role. Because the conventional nuclear grade and/or staging system have some limitations to predict precise clinical outcome, this is the first report demonstrating that promoter CpG methylation of gamma-catenin can be an independent and superior predictor for survival and disease progression.

Adult↗