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At least 1,063 records · Page 59Linked to original sources

PubMed1996

Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells.

We have examined microsatellite instability and loss of p53 function in human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independent cisplatin-resistant sublines are RER(+), whereas the parental line shows no evidence of microsatellite instability. Microsatellite mutations in random, nonselected subclones of a cislatin-resistant line are observed in the absence of further drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather than being transiently induced by DNA damage. Furthermore, a cisplatin-resistant derivative shows reduction in a G:T mismatch recognition activity compared to the parental line. Independent lines selected by multiple exposure to cisplatin show resistance factors of up to a 5-fold by clonogenic assay and have reduced cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of loss of p53-dependent functions, as measured by a loss of radiation-induced G(1) arrest and reduced CIP1 mRNA. Induced loss of p53 function by transfection of mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that tolerance of DNA damage and expansion of cells with an RER(+) phenotype may select for reduced ability to engage apoptosis and loss of p53 function.

Antibiotics, Antineoplastic↗

PubMed2004

Novel nuclear defects in KLP61F-deficient mutants in Drosophila are partially suppressed by loss of Ncd function.

KLP61F in Drosophila and other BimC kinesins are essential for spindle bipolarity across species; loss of BimC function generates high frequencies of monopolar spindles. Concomitant loss of Kar3 kinesin function increases the frequency of bipolar spindles although the underlying mechanism is not known. Recent studies raise the question of whether BimC kinesins interact with a non-microtubule spindle matrix rather than spindle microtubules. Here we present cytological evidence that loss of KLP61F function generates novel defects during M-phase in the organization and integrity of the nuclear lamina, an integral component of the nuclear matrix. Larval neuroblasts and spermatocytes of klp61F mutants showed deep involutions in the nuclear lamina extending toward the centrally located centrosomes. Repositioning of centrosomes to form monopolar spindles probably does not cause invaginations as similar invaginations formed in spermatocytes lacking centrosomes entirely. Immunofluorescence microscopy indicated that non-claret disjunctional (Ncd) is a component of the nuclear matrix in somatic cells and spermatocytes. Loss of Ncd function increases the frequency of bipolar spindles in klp61F mutants. Nuclear defects were incompletely suppressed; micronuclei formed near telophase at the poles of bipolar spindle in klp61F ncd spermatocytes. Our results are consistent with a model in which KLP61F prevents Ncd-mediated collapse of a nonmicrotubule matrix derived from the interphase nucleus.

Animals↗

PubMed1994

Preoperative risk evaluation for lung cancer resection: predicted postoperative product as a predictor of surgical mortality.

We assessed the capacity to predict surgical mortality, complications, and functional loss by using the results of resting and exercise respiratory function. Measurements were made before and 4 mo after lung resection in 54 consecutive patients with bronchogenic carcinoma. Predicted postoperative (ppo) FEV1 and DLCO were derived using quantitative lung perfusion scans when baseline FEV1 was < 55% predicted, and by proportional loss of pulmonary segments (total = 19 segments) when FEV1 was > 55% predicted. The patients were aged 67 +/- 7 (mean +/- SD) yr, with an FEV1 of 76 +/- 23% predicted, FEV1/FVC of 55 +/- 13%. and DLCO of 85 +/- 22% predicted. Eleven of the patients had pneumonectomy, 29 had lobectomy, 12 had wedge resection, and two had no resection. Wilcoxon and stepwise logistic regression analyses were used to determine which indices best predicted outcome. Postoperative values were correlated (r = 0.87, p < 0.0001) with actual 4/12 postoperative values of FEV1% and of DLCO (r = 0.56, p < 0.0001). The best predictors (all p < 0.05) for each outcome, in order of usefulness, were as follows. For surgical mortality: (1) the predicted postoperative product (PPP) of ppo FEV1% x ppo DLCO%; (2) ppo DLCO%; (3) ppo FEV1%, and (4) RV, FRC, and SaO2 on the maximal step exercise test. For respiratory complications: body mass index (BMI) (for patients undergoing lobectomy or wedge resection only). For cardiac complications: (1) age; (2) SaO2 at baseline and on the maximal step exercise test; (3) PaO2; (4) PaCO2; and (5) minute ventilation at maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1998

Adenosine endogenously released during early reperfusion mitigates postischemic myocardial dysfunction by inhibiting platelet adhesion.

The purpose of this study was to investigate platelet effects on postischemic heart function in conjunction with adenosine effects on intracoronary platelet adhesion. Homologous platelets were infused into the coronaries of isolated guinea pig hearts, either during low-flow ischemia or during reperfusion, and external heart work (EHW) and intracoronary platelet adhesion were determined. In most experiments, thrombin was added to the perfusate. The influence of endogenous adenosine was studied by use of the uptake blocker dipyridamole and the unspecific adenosine-receptor blocker theophylline, the A1-receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and the A2-receptor blocker 3,7-dimethyl-1-propargylxanthine (DMPX). The importance of nitric oxide and prostaglandin I2 (PGI2) was tested by using nitro-L-arginine (NOLAG) and indomethacin, respectively. When platelets were applied with thrombin during low-flow ischemia, EHW recovered to only 63 +/- 4% of the preischemic value, as compared with 89 +/- 3% without platelets (p < 0.05). Despite thrombin, platelets incurred no significant functional loss when applied in the first minute of reperfusion (but again in the fifth minute); however, when theophylline was also present, recovery of EHW amounted to only 42 +/- 12%. Intracoronary adhesion of platelets was negligible without thrombin, and highest during low-flow ischemia with thrombin (35 +/- 3% of the applied number). No adhesion occurred during the first minute of reperfusion, whereas in the fifth minute, adhesion was again 20.8 +/- 4%. Dipyridamole increased adenosine release and attenuated adhesion at this time. Theophylline increased adhesion in the first minute of reperfusion (33 +/- 6.4%), whereas NOLAG and indomethacin proved to be ineffective. DPCPX and DMPX each increased platelet retention during the first minute of reperfusion, their effects being additive. Intracoronary adhesion of platelets induced by thrombin in isolated hearts can reduce postischemic recovery of heart function. During reperfusion, but not during low-flow, endogenous adenosine can prevent platelet adhesion and loss of myocardial function, an action mediated both by A1- and A2-receptor-dependent mechanisms.

Adenosine↗

PubMed2003

Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis.

During apoptosis, the permeabilization of the mitochondrial outer membrane allows the release of cytochrome c, which induces caspase activation to orchestrate the death of the cell. Mitochondria rapidly lose their transmembrane potential (Delta Psi m) and generate reactive oxygen species (ROS), both of which are likely to contribute to the dismantling of the cell. Here we show that both the rapid loss of Delta Psi m and the generation of ROS are due to the effects of activated caspases on mitochondrial electron transport complexes I and II. Caspase-3 disrupts oxygen consumption induced by complex I and II substrates but not that induced by electron transfer to complex IV. Similarly, Delta Psi m generated in the presence of complex I or II substrates is disrupted by caspase-3, and ROS are produced. Complex III activity measured by cytochrome c reduction remains intact after caspase-3 treatment. In apoptotic cells, electron transport and oxygen consumption that depends on complex I or II was disrupted in a caspase-dependent manner. Our results indicate that after cytochrome c release the activation of caspases feeds back on the permeabilized mitochondria to damage mitochondrial function (loss of Delta Psi m) and generate ROS through effects of caspases on complex I and II in the electron transport chain.

Amino Acid Chloromethyl Ketones↗

PubMed2004

Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice.

Lung tissue elastic recoil and the dimension and number of pulmonary gas-exchange units (alveoli) are major determinants of gas-exchange function. Loss of gas-exchange function accelerates after menopause in the healthy aged and is progressively lost in individuals with chronic obstructive pulmonary disease (COPD). The latter, a disease of midlife and later, though more common in men than in women, is a disease to which women smokers and never smokers may be more susceptible than men; it is characterized by diminished lung tissue elastic recoil and presently irremediable alveolar loss. Ovariectomy in sexually immature rats diminishes the formation of alveoli, and estrogen prevents the diminution. In the present work, we found that estrogen receptor-alpha and estrogen receptor-beta, the only recognized mammalian estrogen receptors, are required for the formation of a full complement of alveoli in female mice. However, only the absence of estrogen receptor-beta diminishes lung elastic tissue recoil. Furthermore, ovariectomy in adult mice results, within 3 wk, in loss of alveoli and of alveolar surface area without a change of lung volume. Estrogen replacement, after alveolar loss, induces alveolar regeneration, reversing the architectural effects of ovariectomy. These studies 1) reveal estrogen receptors regulate alveolar size and number in a nonredundant manner, 2) show estrogen is required for maintenance of already formed alveoli and induces alveolar regeneration after their loss in adult ovariectomized mice, and 3) offer the possibility estrogen can slow alveolar loss and induce alveolar regeneration in women with COPD.

Animals↗

PubMed2002

Anisotropy and interplane interactions in the dielectric response of graphite.

We determined the anisotropic dielectric response of graphite by means of time-dependent density-functional theory and high-resolution valence electron energy-loss spectroscopy. The calculated loss function was in very good agreement with the experiment for a wide range of momentum-transfer orientations with respect to the graphitic basal planes, provided that local-field effects were included in the response. The calculations also showed strong effects of the interlayer Coulomb interaction on the total pi+sigma plasmon. This finding must be taken into account for the explanation of recent loss spectra of carbon nanotube materials.

Journal Article↗

PubMed2002

Use of the Cobb procedure in the treatment of posterior tibial tendon dysfunction.

Numerous surgical procedures have been described for the treatment of the adult acquired flatfoot deformity. The surgeon should review in detail all the clinical, radiographic and imaging tests and propose the best surgical procedure for the patient. Although flexor tendon transfer has shown excellent results, the split anterior tibial tendon transfer is a second option. If used properly, the Cobb procedure results in less functional loss, since only half of the anterior tibial tendon is transferred. Furthermore, the flexor tendon is not disrupted and continues its primary function in the foot and ankle. Ultimately, the goals of the surgical procedure are to alleviate the patient's symptoms and pain, restore a normal foot alignment, and limit the loss of foot and ankle function without causing any complications.

Foot Diseases↗

PubMed2005

Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function.

A major function of the limb bud apical ectodermal ridge (AER) is to produce fibroblast growth factors (FGFs) that signal to the underlying mesenchyme. Previous studies have suggested that of the four FGF genes specifically expressed in the mouse AER, Fgf8 is unique not only in its expression pattern, but also because it is the only such FGF gene that causes limb skeletal abnormalities when individually inactivated. However, when both Fgf8 and Fgf4 are simultaneously inactivated in the AER, the limb does not develop. One possible explanation for these observations is that although both of these FGF family members contribute to limb development, Fgf8 has functions that Fgf4 cannot perform. To test this hypothesis, we used a novel method to substitute Fgf4 for Fgf8 expression in the developing limb bud by concomitantly activating a conditional Fgf4 gain-of-function allele and inactivating an Fgf8 loss-of-function allele in the same cells via Cre-mediated recombination. Our data show that when Fgf4 is expressed in place of Fgf8, all of the skeletal defects caused by inactivation of Fgf8 are rescued, conclusively demonstrating that FGF4 can functionally replace FGF8 in limb skeletal development. We also show that the increase in FGF signaling that occurs when the Fgf4 gain-of-function allele is activated in a wild-type limb bud causes formation of a supernumerary posterior digit (postaxial polydactyly), as well as cutaneous syndactyly between all the digits. These data underscore the importance of controlling the level of FGF gene expression for normal limb development.

Animals↗

PubMed2004

Protein catabolism in pregnant snakes (Epicrates cenchria maurus Boidae) compromises musculature and performance after reproduction.

In many species the high energetic demands of reproduction induce a negative energy balance, and thus females must rely on tissue catabolism to complete the reproductive process. Previous works have shown that both fat and protein are energy resources during prolonged fasting in vertebrates. While many ecological studies on energy costs of reproduction have focused on variations in fat stores, the impact of protein investment on the female has not been thoroughly investigated. Notably, as there is no specialized storage form for proteins, intense catabolism is likely to entail structural (musculature) loss that may compromise maternal physical performance after reproduction. Measurements on captive rainbow boas ( Epicrates cenchria maurus) confirm that reproducing females undergo significant protein catabolism (as indicated by elevated plasma uric acid levels) and show considerable musculature loss during gestation (as detected by reduced width of the epaxial muscles). Protein mobilization entailed a significant functional loss that was illustrated by decrements in tests of strength and constriction after parturition. In wild situations, such effects are likely to decrease the snakes' ability to forage and apprehend prey. Hence, the time period needed to recover from reproduction can be extended not only because the female must compensate losses of both fat stores and functional muscle, but also because the ability to do so may be compromised. Performance alteration is likely to be of equal or greater importance than reduced energy stores in the physiological mediation of elevated post-reproduction mortality rates and infrequent reproductive bouts (e.g. biannual or triannual), two common ecological traits of female snakes.

Animals↗

PubMed1992

Density dependent polarized secretion of a prostatic epithelial cell line.

The polarized secretions (apical/basal) of newly synthesized total protein and proteases from prostatic epithelial sheets of PA-III cells grown in dual compartment chambers were investigated at various cell densities and culture conditions. PA-III cells grown in a serum free defined medium (SFDM) form morphologically polarized monolayers of epithelial cells. These cells secreted their 35S-methionine labeled total protein in a predominantly apical direction (apical/basal ratio, 4-8 fold), with a lesser proportion of protein secreted apically at lower cell densities of the PA-III cell monolayer. PA-III cells grown in 5% fetal calf serum (FCS) are morphologically squamous, comparable to the anaplastic phenotype, and exhibited an inversion of polarized total protein secretion (apical/basal ratio, 0.4-0.9 fold), with an increased proportion of total protein secreted in a basal direction at lower cell densities. Since the culture of PA-III cells in FCS may approximate the anaplastic phenotype we investigated the polarized secretion of proteases from these cells at various cell densities, and compared them with the secretory pattern of protease secretion from polarized PA-III cells cultured in SFDM. At lower cell densities of the PA-III cells grown in FCS the polarity of protease secretion was inverted such that metalloproteinases, tissue type plasminogen activator, and a 72 kD gelatinase were secreted in a predominantly basal direction, as well as urokinase and a gelatinase of 26 kD that were secreted more or less equally into the apical and basal compartments of the chambers. On the other hand, for cultures of PA-III cells grown in SFDM the aforementioned proteases exhibited predominantly an apically directed polarity of secretion. These results suggest that the anaplastic phenotype characterized by a loss of polarized structure may also be characterized by a functional loss or inversion of polarized secretion. The consequences of such a loss or inversion of polarized secretion would be to increase the localized concentrations of proteases along the basal domain of cells thereby facilitating degradation of the basement membrane and interstitial tissue in vivo.

Adenocarcinoma↗

PubMed1999

Age-related changes in the cerebellum: parallel fibers.

Between the ages of 3 and 23 months, the cerebella of NIH Fischer 344 rats lose 30% of the thickness of the molecular layer, 60% of the length of parallel fibers, and 80% of the synaptic varicosities along parallel fibers. Nearly 60% of these synaptic varicosities disappear between 3 and 9 months. Thus, the loss of cerebellar synapses is unusual, may have begun early in life, and continue into old age, causing profound synaptic losses in older rats. In addition to serious implications to functional losses, we speculate that these synaptic losses may trigger other age-related cellular losses in the cerebellum.

Aging↗

PubMed2001

Chromatic and achromatic defects in patients with progressing glaucoma.

To evaluate the pattern of losses associated with glaucomatous injury in patients with progressing glaucoma, functional losses were examined in 14 patients with progressing glaucoma using tests for which detection should be selectively mediated by one of three psychophysical mechanisms. Red-on-white increments, blue-on-white increments and critical flicker frequency were used to isolate the responses of the red-green chromatic mechanism, the blue-on chromatic mechanism, and the high-frequency flicker achromatic mechanism. For our 3.1 degrees circular stimuli, chromatic defects were found in a greater number of the patients with glaucoma than were achromatic defects. We evaluated these defects in terms of two existing hypotheses: preferential loss and reduced redundancy. The greater sensitivity to glaucomatous injury of chromatic tests, compared to achromatic tests, found in this and other studies and the apparent discrepancy between anatomical and psychophysical studies can be parsimoniously explained by differences in cortical summation of ganglion cell responses for the chromatic and achromatic pathways.

Aged↗

PubMed2004

How to interpret normal electromyographic findings in patients with an alleged history of polio.

OBJECTIVE: In some patients with a history of polio, the electromyography is normal, not showing the typical neurogenic signs. The aim of this study was to explain the normal findings in electromyography, especially in paralytic polio. DESIGN: Retrospective study. SUBJECTS/METHODS: Concentric needle electromyography, macro electromyography (including single fibre electromyography) and neurography were performed in various combinations in 688 patients with an alleged history of polio. RESULTS: Thirty-five patients with paralytic polio had normal or minimally abnormal neurophysiology. In 6 patients the diagnosis of polio was rejected and was instead found to be other diagnoses. Three patients had a very atypical history. Of the 26 with possible paralytic polio, 17 showed a strong suspicion of previous paralytic polio without any neurophysiological signs of degeneration of the anterior horn cells. CONCLUSION: If neurophysiological findings are normal in patients with a history of polio, the original diagnosis may be incorrect. However, the absence of electromyography changes does not entirely exclude a previous history of polio with transient functional loss without degeneration of anterior horn cells vulnerable for later functional impairment.

Diagnosis, Differential↗

PubMed1989

Crush injuries of the foot with compartment syndrome: immediate one-stage management.

Severe crush injuries with compartment syndrome were treated in five patients by an immediate one-stage procedure. This procedure included the assessment of skin flap viability with accurate debridement of devascularized tissues. It was performed according to the split-thickness skin excision technique. Compartment pressures were measured and the fasciotomies were performed through open wounds or separate medial and lateral incisions. The medial incision was extended to release the tarsal tunnel. Fractures were reduced and internally fixed and exposed bones were covered with locally transposed muscles. Skin grafts, taken earlier for the skin viability assessment, were meshed and applied to replace skin loss. All wounds and fractures healed uneventfully with no major functional loss. In multiple trauma, the physician should maintain a high index of suspicion for early diagnosis and treatment of severe foot injuries. Early treatment leads to more desirable results, shorter hospitalization, and faster rehabilitation.

Adult↗

PubMed2002

Nitrogen in aquatic ecosystems.

Aquatic ecosystems respond variably to nutrient enrichment and altered nutrient ratios, along a continuum from fresh water through estuarine, coastal, and marine systems. Although phosphorus is considered the limiting nutrient for phytoplankton production in freshwater systems, the effects of atmospheric nitrogen and its contribution to acidification of fresh waters can be detrimental. Within the estuarine to coastal continuum, multiple nutrient limitations occur among nitrogen, phosphorus, and silicon along the salinity gradient and by season, but nitrogen is generally considered the primary limiting nutrient for phytoplankton biomass accumulation. There are well-established, but nonlinear, positive relationships among nitrogen and phosphorus flux, phytoplankton primary production, and fisheries yield. There are thresholds, however, where the load of nutrients to estuarine, coastal and marine systems exceeds the capacity for assimilation of nutrient-enhanced production, and water-quality degradation occurs. Impacts can include noxious and toxic algal blooms, increased turbidity with a subsequent loss of submerged aquatic vegetation, oxygen deficiency, disruption of ecosystem functioning, loss of habitat, loss of biodiversity, shifts in food webs, and loss of harvestable fisheries.

Animals↗

PubMedDate not supplied

Loss of physical functioning among patients with cancer: a longitudinal view.

This study investigated, in a convenience sample of 279 patients with cancer, the trajectories of symptoms and loss of physical functioning over time, the relationships of these variables to age and co-morbidity, and differences existing according to cancer site (breast, lung, colorectal/gastrointestinal, urinary/reproductive, lymphoma, and "other"). The patients were surveyed twice; at intake (wave I, n = 279) and 6 months later (wave II, n = 160). Findings indicated, at wave I, that age and co-morbidity were significantly correlated, and loss of physical functioning was associated primarily with symptoms and, to a lesser degree, with age. Loss of function scores varied significantly according to cancer site, with higher levels for patients with lung cancer and lower levels for patients with breast or colorectal/gastrointestinal cancer. The most frequently occurring symptoms were fatigue, insomnia, pain, and nausea. Average levels of symptoms and loss of physical functioning were lower at wave II, indicative of a possible treatment-related effect (at wave II, a smaller percentage of patients had recently undergone treatment). Although co-morbidity was only modestly correlated with symptoms and loss of function for the total sample, it was highly correlated with both symptoms and loss of physical functioning for the younger patients (those younger than 60 years of age). The significant link that was identified between symptoms and loss of physical functioning has important implications for physicians, nurses, and other healthcare providers caring for patients with cancer as they deal with symptom management and quality-of-life issues.

Activities of Daily Living↗

PubMed1995

The Glenn A. Fry Award Lecture. Early losses of visual function in glaucoma.

Getting back to the questions raised by Dr. Enoch 12 years ago, I believe that we have made significant progress in the early psychophysical detection of glaucoma and that we are either on the right track or considerably closer to it. The continuing progress in conventional automated perimetry has improved the overall quality of visual field testing in the ophthalmic community, as well as providing standardization and state-of-the-art analysis procedures for everyone. We have certainly not solved the problem of early detection of glaucoma, but we now have more sensitive procedures that are available for existing clinical instrumentation. SWAP has clearly shown that it is able to detect glaucomatous losses several years before they are evident by conventional automated perimetry, and results from the other test procedures mentioned earlier are also very encouraging. Thus, although we may not yet have the pot of gold, we have been able to pick up a few valuable nuggets along the way. This leads me to believe that the current approaches are on the right track. However, Dr. Enoch's message should also serve to remind us that there are few panaceas for early detection of functional loss in glaucoma. Our progress to date has been influenced by our greater understanding of the properties of visual mechanisms and the pathophysiology of glaucoma. It has also been driven by clever and innovative approaches and new test procedures, as well as advances in technology. However, it has also been based on a considerable amount of research effort in the form of long-term prospective longitudinal studies of large populations of normal observers, patients with various stages of glaucomatous damage, and patients at risk of developing glaucoma. Answers to all of the issues pertaining to the ultimate clinical value of psychophysical procedures for early detection of glaucoma do not come quickly, but they are of vital importance to ocular health care. I hope that my brief discussion of new developments in psychophysical detection of glaucoma has convinced you that significant progress has been made, and that some of you will be motivated to join in this important research endeavor.

Awards and Prizes↗