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PubMed2002

Atherogenic progression of carotid stenosis associates selectively with monocyte fraction in circulating leukocytes.

Humoral biomarkers of inflammation appear to correlate with future cardiovascular events warranting investigation of more specific associations between phenotypic subclasses of circulating cellular immunity and atherogenic progression of carotid stenosis. Retrospective study of carotid stenosis progression based on archived serial carotid duplex ultrasonography examinations in 100 patients. Predictors of atherogenic progression of carotid stenosis were sought using univariate and multivariate analysis of age, gender, hypertension, diabetes mellitus, smoking, peripheral blood leukocyte count and leukocyte differential profile, platelets, diastolic and systolic and mean arterial blood pressure, pulse pressure, creatinine, glucose, total-, HDL-, and LDL-cholesterol, triglycerides, and body mass index. Atherogenic progression of carotid stenosis was limited to patients with carotid stenosis at baseline (41/100) and exhibited a sporadic episodic temporal course. Univariate predictors of stenosis progression were diabetes mellitus, smoking, percent monocytes, and absolute monocyte count. Logistic regression demonstrated that monocytes as a percentage of circulating leukocytes [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.06-1.47, P=0.0093] and smoking (OR 7.09, 95% CI 1.97-25.43, P=0.0027) were independently associated with atherogenic epochs. A selective association between the fraction of monocytes among leukocytes in peripheral blood and atherogenic progression of carotid stenosis is described.

Aged↗
PubMed1998

Endogenous EGF-family growth factors are necessary for the progression from the G1 to S phase in human keratinocytes.

Recently several endogenous epidermal growth factor (EGF)-family growth factors (transforming growth factor-alpha, amphiregulin, and heparin-binding EGF-like growth factor) have been identified in human keratinocytes. These factors are known to play an important role in the regulation of cell proliferation. Here we show that the interaction between these factors and EGF receptor are key factors in the progression from the G1 phase to the S phase (the G1/S progression) in human keratinocytes. In this study, human keratinocytes were cultured in serum-free MCDB153 medium and then partially synchronized by isoleucine deprivation. After synchronization, the number of S phase cells increased and reached a maximum after 18-24 h. The immediate addition of anti-EGF receptor blocking antibody (1 microg per ml) to synchronized cells decreased S phase cells by 42.5% compared with untreated keratinocytes at 18 h. By contrast, the addition of anti-EGF receptor antibodies at 12 h or later did not alter the percentage of S phase cells. Northern blot analysis of synchronized cells demonstrated that mRNA expression of transforming growth factor-alpha, amphiregulin, heparin-binding EGF-like growth factor, and EGF receptor reached a maximum within 0.5-3 h after synchronization, when many cells initiated progression from the G1 to the S phase. The results show that anti-EGF receptor antibodies block the G1/S progression and the rapid increase of mRNA expression of endogenous EGF-family growth factors and EGF receptor during G1/S progression. These findings indicate that growth factor binding and EGF receptor activation are involved in the G1/S cell cycle progression of human keratinocytes.

Amphiregulin↗
PubMedDate not supplied

[HIT-LGG: effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report].

BACKGROUND: The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children with progressive low grade glioma at an age under 5 years and in older children upon individual decision. PATIENTS AND METHOD: Until October 10th., 1999, 402 patients from 69 hospitals were registered. 130 children with progressive tumors were treated after a median observation time of 5 months: 46 patients received primary radiotherapy and 84 primary chemotherapy. A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1, 4, 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53. RESULTS: Of 84 patients in the chemotherapy arm of the study (49 male, 35 female, 23 NF I, median age 2.99 years) 36 received treatment at diagnosis and 43 after a median observation time of 19.7 months. 94.3% achieved a clinical and neuroradiological response according to protocol criteria (5 CR, 30 PR/OR, 31 SD) after a median of 5.1 months. 4 tumors showed primary progression (9 too early, 5 not known). Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy, after a median delay of 25.6 months at a median age of 6.0 years. At a median observation time of 21.0 months, 6 children are in CR, 11 in PR, 48 have SD, 4 tumors are progressive and 3 children died of their tumor. (9 too early, 3 not known). PFS is at 72% after 36 months. 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely. CONCLUSIONS: Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children with progressive low-grade glioma. The high rate of hypersensitivity reactions has to prompt future modifications of treatment.

Adolescent↗
PubMed2002

Determinants of early carotid atherosclerosis progression in young patients with type 1 diabetes mellitus.

The results of cross-sectional studies addressing early preintrusive atherosclerosis in type 1 diabetic patients are conflicting. In an observational longitudinal study we determined the course of carotid artery intima-media thickness (IMT) over a period of 2.5 years in mean. A total of 102 patients with type 1 diabetes mellitus (age < or = 40 years, diabetes duration > or = 2 years at baseline examination) who were participants of the baseline examination was studied again in a follow-up. HbA1c, albumin excretion rate (AER), lipids, systolic and diastolic blood pressure, retinopathy, and current smoking status were assessed at baseline and follow-up. The IMT of the common carotid artery was measured by high-resolution ultrasound, the maximum IMT was evaluated. The annual progression rate (APR) was calculated from the difference between baseline and follow-up IMT reading and the time between both examinations. The follow-up IMT was significantly higher, compared to the baseline measurement: 0.65 +/- 0.18 vs. 0.57 +/- 0.14 mm (p < 0.001), the mean APR was 0.033 mm/year. The APR was correlated with age (r = 0.337, p < 0.01), diabetes duration (r = 0.252, p < 0.05), hypertension (r = 0.225, p < 0.05), and systolic blood pressure (r = 0.281, p < 0.05) at the baseline examination. Comparing subgroups, defined according to APR tertiles, with no IMT progression (first tertile, mean APR - 0.012 mm/year), mild progression (second tertile, mean APR 0.037 mm/year), and advanced progression (third tertile, mean APR 0.088 mm/year), patients with advanced progression significantly (p < 0.05) more often had hypertension and nephropathy than subjects with mild progression. In a multiple linear regression analysis, the changes of plaque frequency and of the nephropathy status between baseline and follow-up examinations were independent predictors of the APR.

Adult↗
PubMed1983

Unstable angina and progression of coronary atherosclerosis.

We studied the progression of atherosclerotic coronary lesions in 38 patients who had previously undergone angiography and were later hospitalized for an episode of unstable angina pectoris, and in 38 matched patients with stable angina who had also undergone prior catheterization. Patients with unstable angina and those with stable angina were similar in terms of age (mean, 49 and 50 years, respectively), number of risk factors (1.5 per patient in both groups), interval between studies (mean +/- S.D., 44 +/- 31 and 35 +/- 31 months, respectively), number of diseased vessels on the first angiogram (1.52 in both groups), and initial ejection fraction (65 and 63 per cent, respectively). Progression of coronary lesions was demonstrated in 29 of the 38 patients with unstable angina, as compared with 12 of the 38 with stable angina (P less than 0.0005). Progression to 70 per cent or more stenosis was recorded in 21 of the patients with unstable angina but in only 5 of those with stable angina (P less than 0.0005). Also more frequent in the patients with unstable angina were multifocal progression (11 vs. 2, P less than 0.01) and progression of the left main or preseptal left anterior descending artery or both (9 vs. 1, P less than 0.01). Thus, we have demonstrated by angiography that unstable angina is associated with progression in the extent and severity of coronary atherosclerosis.

Adult↗
PubMed1984

Grade I Reye's syndrome--outcome and predictors of progression to deeper coma grades.

We studied 83 biopsy-proved cases of Grade I Reye's syndrome to determine the outcome, possible clinical or laboratory predictors of progression to deeper coma grades, and hepatic ultrastructural findings. Seventy-eight patients had no change in coma grade during hospitalization, whereas five (6 per cent) had progression to deeper coma grades. All the patients survived without sequelae except one who sustained severe brain damage. The mean (+/- S.E.) level of serum ammonia on admission was significantly higher (P = 0.005) in patients whose disease progressed to deeper neurologic grades (291 +/- 42 micrograms per deciliter) than in those whose disease did not so progress (53 +/- 5 micrograms per deciliter), and the corrected prothrombin time was significantly more prolonged (P = 0.005) in patients with progressing coma (3.9 +/- 0.5 seconds) than in those whose coma grade did not change (1.6 +/- 0.2 seconds). The combination of a prothrombin time 3 seconds or longer than that of the control and a serum level of ammonia on admission of 100 micrograms per deciliter or more correctly predicted progression in 71.5 per cent of the cases (sensitivity, 100 per cent; specificity, 97.6 per cent). Our findings suggest that the prognosis is excellent for survival without sequelae in Grade I Reye's syndrome (98.8 per cent) when management includes hospital surveillance and intravenous glucose and electrolyte infusion.

Ammonia↗
PubMed2001

A novel KIT mutation results in piebaldism with progressive depigmentation.

Piebaldism is an autosomal dominant disorder of melanocyte development characterized by white skin (leukoderma) and white hair (poliosis). In general, piebaldism has been distinguished from vitiligo by the presence of lesions from birth, the hyperpigmented macules of depigmented and normal skin, and the static course. We hypothesized that an 8-year-old girl and her mother who had unusual piebaldism of a progressive nature would have a novel mutation of the KIT gene, the gene that is altered in patients with piebaldism, or of the MITF (microphthalmia activating transcription factor) gene, which would be expected to cause type II Waardenburg syndrome, but is associated with a phenotype of progressive depigmentation in mice. Genomic DNA was extracted from the blood of affected and unaffected family members, and the KIT and MITF genes were sequenced. Genetic analysis of genomic DNA from both the mother and daughter with progressive piebaldism revealed a novel Val620Ala (1859T>C) mutation in the KIT gene, which was not detected in family members without progressive piebaldism or in 52 normal control individuals. This KIT mutation affects the intracellular tyrosine kinase domain and thus predicts a severe phenotype, as was the case in this family. Although other KIT mutations in the vicinity of codon 620 lead to the standard phenotype of static piebaldism, the Val620Ala mutation is novel and may result in a previously undescribed phenotype with melanocyte instability, leading to progressive loss of pigmentation as well as the progressive appearance of the hyperpigmented macules.

Adult↗
PubMed2001

High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy.

BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. METHODS: Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 microg/dL in patients during the responsive phase and more than or equal to 89 microg/dL during disease progression, with 1 exception (P < .0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S.

Adrenalectomy↗
PubMed2000

Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I.

The transactivator protein Tax of human T-cell leukemia virus type I plays an important role in the development of adult T-cell leukemia probably through modulation of growth regulatory molecules including p16(INK4a). The molecular mechanism of leukemogenesis induced by Tax has yet to be elucidated. We analyzed Tax function in the cell cycle using an interleukin-2 (IL-2)-dependent human T-cell line (Kit 225) that can undergo cell cycle arrest at G(0)/G(1) phase by deprivation of IL-2. Tax activated endogenous E2F activity in IL-2-starved Kit 225 cells, resulting in activation of E2F site-carrying promoters of genes involved in G(1) to S phase transition in a cell type-dependent and p16(INK4a)-independent manner. The ability of Tax mutants to activate E2F coincided with that to activate nuclear factors kappaB and AT, sole expression of which, however, did not activate E2F, suggesting involvement of another pathway in activation of E2F. Introduction of Tax by a recombinant adenovirus induced cell cycle progression to G(2)/M phase in resting Kit 225 cells accompanied by endogenous cyclin D2 gene expression. Similarly, Tax-induced cell cycle progression was seen with peripheral blood lymphocytes prestimulated with phytohemagglutinin. Analyses with Tax mutants did not allow Tax-induced cell cycle progression to be differentiated from Tax-dependent activation of E2F, suggesting that Tax induces cell cycle progression presumably through activation of E2F. Nevertheless, infection with an E2F1-expressing virus, which is sufficient for induction of S phase in serum-starved fibroblasts, was not sufficient for either E2F activation or cell cycle progression in IL-2-starved Kit 225 cells, implying differential regulation of E2F activation and cell cycle progression in T-cells that is activated by Tax.

Binding Sites↗
PubMed2001

Control of SV-40 transformed RCE cell proliferation by growth-factor-induced cell cycle progression.

PURPOSE: To determine in SV40-immortalized rabbit corneal epithelial cells (RCE), whether there is conservation of parent tissue serum growth-factor-stimulated cytokine receptor activation and downstream intracellular signaling events mediating control of cell cycle progression and differentiation. METHODS: Immunostaining and Western blot analysis were used to measure cytokeratin K3 and K12 expression with AE5 and AK12 antibodies. Karyotype analysis was performed based on comparison of the RCE chromosomal complement with its parent tissue. EGF receptor activation was evaluated based on immunochemistry and Western blot analyses of EGF receptor dimerization and phosphorylation. Functional status of EGF receptor was determined through measurements of EGF-induced stimulation of ERK-2 activity, which is a component of the mitogen-activated protein kinase cascade (MAPK). This was done by immunocomplex and kinase assay using anti-ERK antibodies and a specific substrate. EGF-induced increases in proliferation and cell cycle progression were determined based on measurements of [(3)H]-thymidine incorporation, G(2)-specific cyclin B1 expression and cell cycle mapping. RESULTS: From days 7 to 14, K12 expression increased based on marked rises in the levels of a 55 kD band. At day 14, a 64 kD band also appeared indicative of K3 expression. Karyotype analysis showed that there were no chromosomal losses due to SV-40 transformation. Upon exposure to EGF (5 ng/ml) for 1 min, EGF receptors were activated and formed clusters indicating that autophosphorylation and multimerization of the EGF receptor were occurred. In the presence of serum growth factors or EGF, ERK-2 kinase activity was markedly increased with a bell-shaped time-dependent activation pattern. Cell cycle progression was analyzed in G(1)/S boundary synchronized RCE cells. After releasing the cells into modified Supplemented Hormonal Epithelium Medium containing 10% serum and DMEM/F-12 medium, 80% of the cells had entered the S phase within 2 h. In addition, time dependent changes in [(3)H]-hymidine incorporation over 8 h confirmed RCE passage through the G(1)/S checkpoint. There were more RCE cells entered the G(2)/M phase of cell cycle in the 6-8 h interval after their release. Another indication of cell cycle progression into the G(2)/M phase was that at 8-10 h cyclin B(1) expression reached its maximal level. CONCLUSIONS: RCE in passage number 12-20 are a physiologically relevant model for studies on growth factor receptor mediated control of cell cycle progression and differentiation in its parent tissue as each of these phenomena were conserved: 1) EGF-induced EGF receptor activation; 2) EGF-activated ERK signaling; 3) expression of cornea-specific differentiation markers; 4) karyotype profile; and 5) cell cycle control and progression.

Animals↗
PubMed2005

Progress testing with short answer questions.

The concept of progress testing was developed in the 1970s. Significant features of progress tests are that the content is not linked to any specific course or unit, and that it reflects the final objectives of the curriculum as a whole. The questions are taken from a broad domain and cover a range of disciplines. Furthermore, the test is taken repeatedly over a period of time, to monitor students' progress. Known progress tests all use closed format questions. In 2002-2003 the University Medical Center Utrecht initiated a progress test with short answer questions. The test consists of 40 cases, each with a clinical and a basic science short-answer key feature question. This differs from other progress tests that use close format items, but also in the philosophy of mastery level testing and in the deliberate linking of basic science concepts to clinical case vignettes. The first four executions of the test show high internal consistencies (Cronbach's alpha 0.85 to 0.87) and satisfactory item parameters. The effort of marking answers is reasonable, the effort of writing case vignettes with short-answer items is less than writing MC-items if similar test reliabilities are to be achieved.

Education, Medical, Undergraduate↗
PubMed2005

The conceptual process of skill progression development in artistic gymnastics.

In this study, we examined the methods used and knowledge required by 16 elite men's gymnastic coaches in the development of skill progressions. Following in-depth interviews, a conceptual model representing the process of skill progression development was generated. We found that: (1) elite gymnastic coaches developed skill progressions through experimental practice, reflection and critical inquiry; (2) the development of skill progressions was underpinned by the coaches acquiring a mindset based on four further sub-components (i.e. skill progression refinement, current coaching knowledge, mental imagery and biomechanical understanding); and (3) coaches identified the importance of replication of the spatial and temporal characteristics of the final skill. The results are consistent with task analysis, reflective practice and the principle of specificity. Practically, these findings suggest the need to develop coaches with a more objective approach to skill progression development and a greater understanding of the controlling mechanisms inherent in such practices.

Female↗
PubMed2006

What progress have we made with tinnitus? The Tonndorf Lecture 2005.

CONCLUSION: The field of tinnitus research is vibrant and active. Prospects for progress are high, but would be optimized by the growth of inter-disciplinary collaborations. OBJECTIVE: Tinnitus remains a source of urgent scientific investigation, and truly effective treatments continue to be elusive. The Tonndorf Lecture of the International Tinnitus Seminars represents an opportunity to reflect upon progress to date regarding tinnitus, and the actions needed to further that progress in future. METHOD: Progress regarding tinnitus mechanisms is reviewed, with particular regard to the conceptual distinction between ignition sites for tinnitus, and the physiological mechanisms that then promote the tinnitus through the central auditory pathway. The current status of both the Jastreboff neurophysiological model and the psychological model of tinnitus is reviewed. Some concerns regarding each model are raised, and the need for models that integrate the insights of both perspectives is identified as urgent. RESULTS: There are clear indications of progress in tinnitus, specifically regarding mechanisms, models and treatments. For knowledge to progress further, however, there is a pressing need for an inter-disciplinary approach to tinnitus, more involvement in teaching at a postgraduate level, and the development of experimental models of tinnitus that are both congruent with, and represent the complexity of, human experience of tinnitus.

Humans↗
PubMed1997

Progressive atrophy and neuron death for one year following brain trauma in the rat.

Although atrophic changes have been well described following traumatic brain injury (TBI) in humans, little is known concerning the mechanisms or progression of brain tissue loss. In the present study, we evaluated the temporal profile of histopathological changes following parasagittal fluid-percussion (FP) brain injury in rats over 1 year postinjury. Anesthetized 3-4 month-old Sprague-Dawley Rats (n = 51) were subjected to FP brain injury of high severity (2.5-2.9 atm, n = 51) or sham treatment (n = 27). At 1 h, 2 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months and 1 year after brain injury or sham treatment, these animals were humanely euthanized. Brain sections were analyzed with image-processing techniques to determine the extent of cortical tissue loss and shrinkage of the hippocampal pyramidal cell layer. In addition, cell counting was performed to determine the number of neurons in the dentate hilus of the hippocampus, and glial fibrillary acidic protein (GFAP) immunostaining was used to reveal reactive astrocytosis. Examination of the injured brains revealed substantial and progressive tissue loss with concomitant ventriculomegaly in the hemisphere ipsilateral to injury. The regions with the most notable progressive atrophy included the cortex, hippocampus, thalamus, and septum. Quantitative analysis demonstrated a significantly progressive loss of cortical tissue as well as shrinkage of the hippocampal pyramidal cell layer ipsilateral to injury over 1 year following injury. In addition, reactive astrocytosis in regions of atrophy and progressive bilateral death of neurons in the dentate hilus was observed for 1 year following injury. These results suggest that a chronically progressive degenerative process may be initiated by brain trauma. Thus, there is a temporally broad window within which to introduce novel therapeutic strategies designed to ameliorate the short and long-term consequences of brain trauma.

Animals↗
PubMed2006

Effect of linear polarized light irradiation near the stellate ganglion in skin blood flow of fingers in patients with progressive systemic sclerosis.

OBJECTIVE: The purpose of this study is to evaluate the effect of linear polarized light irradiation near the stellate ganglion area on cutaneous blood flow in fingers of patients with progressive systemic sclerosis. BACKGROUND DATA: Sympathetic overactivity is known to be present in patients with progressive systemic sclerosis. Recently introduced linear polarized light irradiation is designed to simulate noninvasive stellate ganglion block to decrease sympathetic output. METHODS: Five patients with progressive systemic sclerosis and three normal healthy controls were studied. Linear polarized light (Super Lizer) was irradiated near the stellate ganglion on the right side of the neck at 358 J/cm(2) for 10 min. Then, laser Doppler flowmetry, laser Doppler imager, and capillary microscopy were used to measure the cutaneous blood flow of the right fourth finger for 30 min. RESULTS: No significant alternations of the skin blood flow between normal controls and patients with progressive systemic sclerosis after linear polarized light irradiation were detected. The effect of linear polarized light on the microcirculation of patients with progressive systemic sclerosis was minimal and transient. CONCLUSION: The effect of linear polarized light in treating patients with progressive systemic sclerosis may not result from the improvement of skin blood flow. Therefore, the use of linear polarized light in those patients to increase cutaneous blood flow should not be overemphasized.

Adult↗
PubMed1999

Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines.

There is evidence that reactive oxygen species (ROS) are important mediators of tumor promotion and progression. The molecular mechanisms involved in ROS-mediated signaling, however, are unclear at present. Using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as model physical and chemical carcinogens, we have malignantly progressed 308 cells, a papilloma-producing mouse keratinocyte cell line, and investigated the molecular alterations in the progressed phenotypes. In this study, we demonstrate that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo. We found increased Erk-1/2 and p38 MAP kinase activities to be important components of ROS-mediated signaling. The pro-oxidant state also contributed to constitutive elevation of AP-1, NFkappaB and cAMP response element transactivation in the malignant phenotype. Our data provide evidence for a functional role of elevated ROS levels in tumor progression and implicate Erk-1/2 and p38 MAP kinase activation in the malignant progression of mouse keratinocytes.

Animals↗
PubMed1999

Taxol, vincristine or nocodazole induces lethality in G1-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression.

In this report, we describe a novel lytic mechanism exploited by antimicrotubule drugs (AMDs) such as Taxol which are frequently used to treat multiple human cancers including breast and ovarian cancers. In cells lacking the G1-arresting capacity due to the defect in retinoblastoma or p53 gene function, AMDs trigger hyperploid progression and death. The hyperploid progression occurs via continued cell-cycle progression without cell division. Blocking hyperploid progression through hydroxyurea or ectopically expressed p27(Kip1), a G1-specific Cdk inhibitor, abrogates AMD cytotoxicity. Thus, AMDs induce lethality in G1-checkpoint-defective cells by triggering hyperploid progression. The phenomenon is reminiscent of that observed previously with bub-1 yeast mutant. The potential significance of this finding lies in that hyperploid progression-mediated death may be exploited to develop a therapy with tumor-specificity at the genetic level. As a large fraction of human cancers are mutated in p53 gene, it may have a wide therapeutic applicability.

Astrocytoma↗
PubMed1996

Progressive versus catastrophic disability: a longitudinal view of the disablement process.

BACKGROUND: There is little epidemiologic data on the development of disability over time in older persons. This study uses prospective data from cohorts followed annually for 6 to 7 years to identify persons who developed severe disability and to characterize the time course of their disabling process and subsequent mortality. METHODS: Incidence rates of severe disability, defined as need for help in three or more activities of daily living (ADLs), were estimated for 6,640 persons who had not reported severe disability at baseline and at the first four annual follow-up visits. Among persons developing severe disability, those who reported no need for help in ADLs in previous interviews were defined as cases of catastrophic disability, and those who had previously reported some disability in ADLs were defined as cases of progressive disability. RESULTS: Overall, 212 subjects developed progressive and 227 developed catastrophic disability. The rates of progressive disability and catastrophic disability were 11.3 and 12.1 cases per 1,000 person-years, respectively. For both types of disability, incidence rates increased exponentially with age, but the increase was steeper for progressive disability. At ages 70-74, less than 25% of severe disability was progressive, while over age 85 progressive disability represented more than half of severe disability. Incidence rates of total and both types of severe disability were similar in men and women. Mortality after severe disability onset was extremely high. Survival was unrelated to age at disability onset and type of disability but was significantly longer in women than in men (median 3.44 vs 2.12 years; p < .0001). CONCLUSION: Tracking the development of disability provides new and important insights into the disability experience in older men and women that are potentially relevant in planning preventive, intervention, and long-term care strategies.

Activities of Daily Living↗