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PubMed2000

Modulation of urokinase-type and tissue-type plasminogen activator occurs at an early stage of progressing stages of chronic venous insufficiency.

Chronic venous insufficiency (CVI) progresses through a series of clinical stages, from healthy skin to poorly healing leg ulcers. The aim of this study was to analyse the distribution pattern and activity level of urokinase-type (uPA) and tissue-type plasminogen activators (tPA) in normal skin and in tissue biopsies of progressing stages of CVI, prior to and including venous ulceration. Biopsies 6 mm thick were taken from 14 healthy volunteers and 37 patients with 5 different stages of CVI: telangiectases; stasis dermatitis; hyperpigmentation; lipodermatosclerosis; and leg ulcer. Changes in the enzymatic activity and spatial localization of uPA and tPA during the progression of CVI were examined using in situ histological zymography. Normal skin and skin with telangiectases showed a punctate PA activity, consisting of both uPA and tPA activity. As CVI progressed, an increase in the distribution of uPA and a decrease in tPA activity was observed. The spatial localization of uPA was widespread within the dermis of biopsies from stasis dermatitis and lipodermatosclerosis and was associated in particular with the dermoepidermal junction. Hyperpigmented skin revealed a pattern of PA expression similar to that of healthy skin. However, leg ulcer specimens exhibited peak levels of uPA with little tPA. Furthermore, a plasminogen-independent protease activity that was not present in any of the earlier stages of CVI appeared. Our results indicate that there are profound changes in PA activity during the progression of CVI and that these changes begin early in CVI, for example, in stasis dermatitis. We hypothesize that the balance or imbalance of the PA activity in the later stages of CVI is an important pathogenic factor for the development of venous leg ulcer.

Adult↗

PubMed1989

Eicosanoids and multistage carcinogenesis in NMRI mouse skin: role of prostaglandins E and F in conversion (first stage of tumor promotion) and promotion (second stage of tumor promotion).

When applied to NMRI mouse skin in vivo, phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) have been found to induce two early waves of prostaglandin E2 (PGE2) synthesis after 15 and 90 min and a delayed accumulation of prostaglandin F2 alpha (PGF2 alpha) after 2 h. With respect to PGF2 alpha formation different activities of both agents were observed, in that TPA but not RPA induced additional PGF2 alpha waves after 4 and 17 h. Functionally, PGE2 was previously shown to be an endogenous mediator of the TPA- or RPA-induced epidermal hyperproliferation and hyperplasia. A functional role of PGF2 alpha could be attributed to the post-initiation stages of tumor development in initiated mouse skin, i.e. the conversion stage (stage I of tumor promotion) elicited by two TPA applications and the promotion stage (stage II of promotion) brought about repetitive RPA treatments. PGF2 alpha, appearing as one distinct biosynthetic wave 3-4 h after TPA application seems to be critically involved in the conversion steps since (i) inhibition of its accumulation by indomethacin led to an inhibition of tumor formation, (ii) the inhibitory effect of indomethacin could be reversed by PGF2 alpha and (iii) RPA was not able to give rise to the accumulation of PGF2 alpha 4 h after application as obtained by TPA treatment. Moreover, RPA-induced promotion of DMBA- and TPA-treated mouse skin was inhibited by indomethacin. The inhibitory effect of indomethacin on papilloma formation was again reversed by PGF2 alpha treatment concomitant with RPA.

Animals↗

PubMedDate not supplied

Morphological and molecular characteristics of living human fetuses between Carnegie stages 7 and 23: developmental stages in the post-implantation embryo.

Determination of embryonic age groups or stages has been based on the Carnegie Institute collection started in 1887. Improved technology has enabled the building of a new collection of embryos of < 9 weeks gestation; these were then used to compare with the original Carnegie collection. The results suggest that in providing definitive stages that are rigidly bound by developmental events, limitations are placed on categorizing the embryo. Allocation of embryos to a specific stage can assist in identifying post-ovulatory age but overlaps between stages could lead to classification into an incorrect stage.

Embryo, Mammalian↗

PubMed2006

Stage-related increase in the proportion of apoptotic germ cells and altered frequencies of stages in the spermatogenic cycle following gestational, lactational, and direct exposure of male rats to p-nonylphenol.

The cumulative effects of environmental toxicants, for example, the alkylphenol, para-nonylphenol (p-NP) are of concern. Our previous study showed that p-NP reduced several testicular morphometric parameters, including sperm counts. The present study reexamined material collected in that study to determine the mechanistic basis of p-NP action on spermatogenic development in the offspring. Seven-day pregnant Sprague-Dawley rats were treated with vehicle or 100 or 250 mg/kg p-NP through gestation, lactation and afterward directly to all male offspring until 10 weeks of age. Both doses of p-NP significantly (P < 0.02) increased the number of germ cells with in situ end-labeled fragmented DNA (TUNEL positive) by 1.9-fold and 1.7-fold, respectively, and specifically in stages XII-XIV and I-III. TUNEL-labeling was, however, selective, and excluded labeling of basal cells with apoptotic morphology. Cleaved caspase-3 immunohistochemistry strongly labeled basal cells (spermatogonia and early spermatocytes) with condensed marginated chromatin but not degenerate germ cells lacking definitive nuclear material found throughout the epithelium. Only the caspase index (ratio of number of caspase positive to number of degenerate cells) of the 100-mg/kg p-NP group was significantly (p < 0.05) threefold greater than controls. Whereas both doses and either 250 or 100 mg/kg treatment alone significantly (p < 0.002) reduced the frequencies (duration) of stages I-III, VII-VIII, and late VIII-IX (spermiating and recently spermiated tubules), respectively, both doses significantly (p < 0.002) increased the frequencies of stages IV-VI and all stages containing late-stage spermatocytes (XII-XIII) and meiotic cell divisions (XIV). Thus, p-NP, an environmentally persistent xenoestrogen, insidiously alters the spermatogenic cycle and spermatogenic process in male offspring.

Animals↗

PubMed1987

Predictive value of staging investigations in patients with clinical stage I malignant melanoma.

We reviewed the charts of 393 consecutive patients referred to the Toronto-Bayview Regional Cancer Centre and the Ontario Cancer Institute between January 1, 1978, and December 31, 1982, with clinical stage I malignant melanoma to determine the predictive value of routine staging investigations. The investigations reviewed included physical examination, liver function tests, radionuclide liver-spleen and bone scans, chest x-ray, whole-lung tomograms, CT chest scans, CT brain scans, and bipedal lymphangiograms. The clinical stage of nine patients was changed, eight as a result of physical examination and one as a result of lymphangiogram. No other investigations detected metastatic melanoma at referral. We recommend that staging investigations for patients referred with clinical stage I malignant melanoma be restricted to a complete physical examination and a baseline chest x-ray for all patients.

Humans↗

PubMed1992

One-stage versus two-stage anterior and posterior spinal reconstruction in adults. Comparison of outcomes including nutritional status, complications rates, hospital costs, and other factors.

Twenty-four patients undergoing anterior and posterior spinal fusion were preoperatively assessed and at weekly intervals during their hospitalization for the following: serum albumin, transferrin, total lymphocyte count, skin anergy and anthropometric measurements. Eleven patients underwent staged anterior and posterior spinal reconstruction and 13 patients underwent similar procedures in a combined fashion. The groups were similar in age, sex, diagnosis, and number of levels fused. Results of these tests were kept as well as operative time, blood loss, transfusion requirements, wound healing problems, infection, length of hospital stay, patient satisfaction, and total cost. All 24 patients had normal preoperative nutritional parameters. Seven patients in the staged group and ten in the combined group became malnourished after surgery. No patient in the combined group developed infection or a wound healing problem. Wound infections developed in two of the seven patients in the staged group after their second procedure. The average number of units of blood transfused and the operating time were similar for both groups. The average length of hospital stay for the staged group was 20 days compared to 13 days for the combined group. Total hospital bills averaged 30% less in the combined group. All patients stated that they preferred to have the procedures done under the same anesthetic. The authors conclude that protein and calorie malnutrition develops to an appreciable extent in adults undergoing anterior and posterior spinal reconstructive procedures. It therefore increases the postoperative morbidity if staged surgical procedures are performed too close together as is currently done by many spine surgeons.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2004

The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding rat.

BACKGROUND: Autoimmune diabetes of the diabetes-resistant biobreeding (DRBB) rat shares similarities with diabetes in humans and has stages of diabetes that can be controlled and compared. FTY720 is an immunomodulator that has been efficacious in transplant and autoimmune models without inducing an immunosuppressed state. We determined the stages of diabetes that are affected by FTY720 in the DRBB rat. METHODS: Autoimmune diabetes was induced with RT6.1 T-cell-depleting antibody and polyIC starting at 4 weeks of age. FTY720 (1 mg/kg/d) was started at day 0, 5, 7, and 14 following the start of depletion. The rats that did not develop diabetes were maintained for 60 d following the last dose of FTY720 before undergoing a second course of depletion. RESULTS: FTY720 starting at day 0, 5, 7, and 14 of depletion prevented diabetes in 100, 100, 50, and 20% of the DRBB rats compared to 0% of the control rats. The surviving rats in the 5-, 7-, and 14-d groups developed diabetes after FTY720 treatment was stopped. Histological examination indicated insulitis in the control rats between day 7 and 11 of depletion and end-stage insulitis by day 18 of depletion compared to negligible insulitis in rats without diabetes. Redepletion in the surviving day 0 rats resulted in development of diabetes in 25% of these rats compared to none of the age-matched controls. SUMMARY: FTY720 can prevent autoimmune diabetes, if administered before and/or during stimulation and expansion of the autoreactive T cells or in the early stages of insulitis. The effectiveness diminishes with each successive stage of diabetes.

Adjuvants, Immunologic↗

PubMed2005

Molecular staging in stage II and III melanoma patients and its effect on long-term survival.

PURPOSE: To assess the prognostic value of serial reverse transcriptase polymerase chain reaction (RT-PCR) -based measurements of tyrosinase mRNA in peripheral blood of stage II and III melanoma patients. PATIENTS AND METHODS: During routine follow-up of American Joint Committee on Cancer stage II and III melanoma patients, serial testing for tyrosinase transcripts in peripheral blood was performed by RT-PCR. The PCR results were compared with the clinical data collected during the follow-up. RESULTS: Over a period of 3 years, 111 patients (78 stage II and 33 stage III patients) were enrolled, and tyrosinase determinations were carried out. The 6-year disease-specific survival probability was 97% for patients always showing negative RT-PCR results and 67% for patients who tested positive at least once. In a Cox proportional hazards model, the prognostic value of sex, age, site of primary tumor, histologic subtype, stage, Breslow's tumor thickness, Clark level, and the time-dependent variable PCR result was assessed. Patients with a positive RT-PCR test had a distinctly higher risk of dying from melanoma, with a hazard ratio of 12.6 (95% CI, 3.4 to 46.3; P < .001). CONCLUSION: Our study shows a strong association between PCR and disease-specific survival time. Detection of tyrosinase mRNA in peripheral blood may be of similar importance for the clinical course of melanoma as the detection of micrometastatic disease in the sentinel lymph node. Whether a combination of these two factors leads to a better definition of the prognosis of melanoma patients is under investigation in current studies.

Adult↗

PubMed2000

A staging scheme for assessing development in vitro of organogenesis stage embryos of the stripe-faced dunnart, Sminthopsis macroura (Marsupialia: dasyuridae).

The inaccessibility of mammalian organogenesis stage embryos has precluded their widespread use in embryological and teratological studies. As organogenesis occurs during the last 1.5 days of the 10. 7 days of gestation in the stripe-faced dunnart (Sminthopsis macroura), the aim of the present study was to investigate whether day 9 and day 10 embryos and fetuses could be grown to term in vitro. High glucose Dulbecco's modified Eagle's medium with 10% fetal calf serum (FCS) supported embryonic growth for various periods of time, some to within 5 h of the predicted time of parturition. A roller culture system maintained at 35 degrees C was used to incubate organogenesis stage embryos (n = 43). Nine unincubated (control) embryos were either fixed for microscopic analysis or frozen for microprotein determination. The results of the present study indicate that with some optimization of the culture conditions (increasing oxygen in the gas phase in the culture tubes, replacing FCS with rat serum), it might be possible for organogenesis stage S. macroura embryos to be grown to term. A scoring scheme for assessing morphological development was devised for use as a standard in staging organogenesis stage embryos. This scheme reflects the highly compressed schedule of developmental events that occurs mainly during day 9 of gestation in S. macroura embryos. In comparison, during embryogenesis in Didelphis virginiana these developmental events occur from day 8 to day 10.5 of gestation, and birth occurs on day 13.

Animals↗

PubMed1980

Reduced responses of renin release to three different stimuli in essential hypertensive patients of stage II (WHO stage classification).

The responses of renin release to three different stimuli, such as 1) head-up tilt, 2) administration of loop diuretics(bumetanide) and 3) low sodium diet + administration of bumetanide + ambulation were examined in essential hypertensive patients and normotensive subjects. Essential hypertensive patients were classified as stage I and II according to WHO stage classification. Groups studied were age-matched. The responses of renin release to three stimuli did not significantly differ in normotensive subjects (n = 13, 42 +/- 2(SEM) years old) and essential hypertensive patients of stage I (n = 15, 44 +/- 2). However, essential hypertensive patients of stage II (n = 20, 44 +/- 1) showed significantly lower responses of renin release to all three stimuli than essential hypertensive patients of stage I and normotensive subjects. The results suggest that the suppression of renin release is related in part to the development of hypertension.

Adult↗

PubMedDate not supplied

Survey of nutritional status in newly hospitalized patients with stage III or stage IV pressure ulcers.

OBJECTIVE: To examine the nutritional status of newly hospitalized patients with Stage III or Stage IV pressure ulcers. DESIGN: Descriptive survey. STUDY PARTICIPANTS: 405 newly admitted hospitalized non-ICU patients were eligible for inclusion in the study. Patients included in the study had Stage III or Stage IV pressure ulcers on their trunk, had weight indices available, and had prealbumin levels measured. One hundred and twenty patients were included in the analysis. INTERVENTIONS AND MAIN OUTCOME MEASURES: Measurements of weight, prealbumin and albumin levels, nutritional intake, type of diet, gender, age, type of pressure ulcer, and type of residence prior to admission. RESULTS: Analysis of the data revealed that a majority of the patients were elderly, had a Stage III sacral ulcer, were below their usual body weight, had a low prealbumin level, and were not taking in enough nutrition to meet their needs. CONCLUSION: The results of this study suggest that a majority of newly hospitalized patients with severe pressure ulcers are malnourished and aggressive nutritional therapy may be warranted.

Aged↗

PubMed1975

A reappraisal of staging and therapy for patients with cancer of the rectum. I. Development of two new systems of staging.

Existing systems of staging for patients with rectal cancer depend almost exclusively on anatomic evidence. Consequently, the stages cannot be determined in advance of therapeutic decisions and cannot be used for patients treated without surgery. Furthermore, the stages contain no provision for important prognostic distinctions, that cannot be discerned from anatomic data. After preparing a taxonomy for hiterto unclassified medical data, we developed and tested two new systems of staging in a cohort if 318 patients. The first system which can be applied before treatment, is divided into four composite stages that contain elements of symptomatic, chronometric, co-morbid, and para-morbid data, as well as information obtained from physical examination, sigmoidoscopy, and roentgenography. The second system, applicable to patients with resected tumors, is based on a combination of pre-therapeutic clinical information and post-surgical anatomic evidence. The two systems produce prognostic gradients that are clinically distinctive and statistically efficacious.

Humans↗

PubMed1987

Inhibition of both stage I and stage II mouse skin tumour promotion by retinoic acid and the dependence of inhibition of tumor promotion on the duration of retinoic acid treatment.

Retinoic acid is a potent inhibitor of mouse skin tumor promotion by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). We have further evaluated the effect of retinoic acid on the stages of tumor promotion and also analyzed the effect of duration of retinoic acid treatment on mouse skin tumor promotion by TPA. In a number of independent experiments, either with female CD-1 or SENCAR mice, we failed to observe a specificity of inhibition by retinoic acid of either Stage I or Stage II tumor promotion. In a typical experiment with SENCAR mice, application of 34 nmol of retinoic acid concurrently with each application of either TPA (3.2 nmol) or mezerein (3.2 nmol) to initiated (with 10 nmol 7,12-dimethylbenz(a)anthracene) skin equally inhibited promotion of skin papilloma formation. Furthermore, sustained inhibition of tumor promotion by retinoic acid required a continuous application of retinoic acid in conjunction with each promotional treatment with TPA; if retinoic acid treatment was discontinued, TPA treatment elicited tumor formation. These results indicate: (a) retinoic acid inhibits both Stage I and Stage II of tumor promotion; and (b) inhibition of tumor promotion exhibits retinoic acid dependency.

Animals↗

PubMed1986

Single-stage versus two-stage diversion-cystectomy in treatment of bladder cancer: a comparative study.

We have compared the results of 26 single-stage and 16 two-stage diversion-cystectomies performed for bladder carcinoma at the Helsinki University Central Hospital, Finland in the period December 1974-April 1983. All the patients underwent pre-cystectomy radiation. An ileal conduit urinary diversion was used in every patient. No benefit relative to surgical mortality or early and late complications seemed to be derived from using the staged procedure. The single-stage operation, in addition to sparing the patients the inconveniences of the second operation, saves social expenditure by reducing the total length of hospital stay and the total operating time. The two-stage procedure should, however, be considered for fragile patients and those with serious operative risk factors.

Adult↗

PubMed1995

The stages of exercise scale and stages of exercise behavior in female adults.

Using the Transtheoretical Model of behavior change as a theoretical framework, a Stage of Exercise Scale (SOES) was developed. The ability of the SOES to differentiate between subjects classified into each of the theoretically posited stages was then studied in a sample of 178 female adults. Results showed that the scale was able to significantly and meaningfully differentiate between subjects classified by stage in terms of exercise energy expenditure (p < 0.0001, omega 2 = 0.18), physical activity energy expenditure (p < 0.0001, omega 2 = 0.15), and VO2peak ml/kg/min (p < 0.0001, omega 2 = 0.19). Stage-specific interventions have been successful when applied to other health behaviors and would appear to have promise for increasing our understanding of the exercise initiation and maintenance process. As such, researchers and practitioners may wish to use the SOES to begin testing the efficacy of stage-specific physical activity interventions.

Adult↗

PubMed1993

Anatomic repair of transposition of great arteries with ventricular septal defect and aortic arch obstruction. One-stage versus two-stage procedure.

Between September 1, 1982, and March 1, 1992, 40 patients underwent anatomic repair of transposition of the great arteries, ventricular septal defect, and aortic arch obstruction. In group I, 26 patients (65%) underwent repair in a two-stage procedure, phases A and B. Phase A included repair of the aortic arch obstruction with (16 patients) or without (10 patients) pulmonary artery banding through a left thoracotomy (mean age 18.7 +/- 23.4 days). There were three deaths and three reoperations. Phase B included an arterial switch operation with closure of the ventricular septal defect (mean age 95.5 +/- 122 days). There were five early deaths and two late deaths. Eight patients required reoperation. Mean delay between phase A and phase B was 77.5 +/- 109 days. In group I, there were eight early and two late deaths, and 11 patients required reoperation. The mean stay in the intensive care unit was 24.7 +/- 20 days. Mean follow-up of 59.6 +/- 21.4 months was completed in all survivors. All but one were in New York Heart Association class I without medication. Actuarial survival rate and rate of freedom from reoperation at 5 years were 57.5% and 49.9%, respectively. In group II, 14 patients (35%) had a one-stage procedure through midsternotomy: an arterial switch operation with closure of the ventricular septal defect and repair of the aortic arch obstruction (mean age 10.2 +/- 5.5 days). There were two early deaths (14.2%) and one late death after reoperation for overlooked multiple ventricular septal defects. Two patients required reoperation. The mean stay in the intensive care unit was 11.7 +/- 2.5 days. Mean follow-up of 22.4 +/- 16.7 months was achieved in all survivors. They were all in New York Heart Association class I without medication. Actuarial survival rate and rate of freedom from reoperation at 3 years were 78.5% and 81.5%, respectively. The one-stage procedure allowed complete repair in neonates without the need for multiple operations. We believe that it may decrease early mortality rates (14.2% versus 30.7%), reduce the reoperation rate and cumulative stay in the intensive care unit (11.7 days versus 24.7 days, p = Not significant), and significantly decrease the overall rate of morbidity (p < 0.01). However, requirements for surgical intervention with a one-stage or a two-stage procedure must include accurate assessments of intracardiac and aortic arch anatomy.

Actuarial Analysis↗

PubMed1998

Prognostic significance of DNA ploidy in patients with stage II and stage III colon carcinoma: a prospective flow cytometric study.

BACKGROUND: The prognostic value of flow cytometric DNA ploidy in colorectal carcinoma has not been defined clearly. Most previous studies were conducted retrospectively using archival formalin fixed, paraffin embedded tumor samples. Conversely, few data on prospective studies employing fresh or frozen tissue specimens are available. There is general agreement that fresh/frozen material is more reliable than paraffin embedded tissue for DNA ploidy analysis by flow cytometry. METHODS: In the current investigation we evaluated the prognostic significance of nuclear DNA content in a prospective series of 191 patients with curatively resected TNM Stage II (n = 107) or Stage III (n = 84) sporadic colon carcinomas. DNA ploidy status was assessed by flow cytometry utilizing multiple frozen tumor samples. Mean follow-up in surviving patients was 48.5 months (median, 46.9 months; range, 29-77 months). The Cox proportional hazards model was used to adjust for several clinical and pathologic covariates. RESULTS: Of the 191 carcinomas examined, 47 (24.6%) were classified as DNA diploid and 144 (75.4%) as DNA aneuploid. DNA ploidy pattern was significantly related to tumor site (P < 0.0001), histologic type (P = 0.0002), and grade of differentiation (P = 0.009), but not to other clinical and pathologic variables. Patients with DNA diploid tumors showed a better disease free (P = 0.013) and overall survival (P = 0.021) than patients with DNA aneuploid adenocarcinomas. In particular, patients with Stage II DNA diploid tumors (n = 30) had an excellent clinical outcome, with an overall 5-year survival rate of 97%. When patients were analyzed according to the anatomic site of the tumor, a significant relationship between DNA ploidy status and disease free and overall survival was observed in the group of patients with carcinomas of the proximal colon (n = 84) (P = 0.004 and P = 0.002, respectively), but not among patients whose tumors were sited distally to the splenic flexure (n = 107). In multivariate analysis, nuclear DNA content was demonstrated to be an independent prognostic variable for both disease free and overall survival. Furthermore, in the group of patients with tumors of the proximal colon, DNA ploidy pattern was the single most important prognostic factor. CONCLUSIONS: Our results confirm that flow cytometric DNA ploidy status is a significant and independent prognostic factor in patients with colon carcinoma. These findings may have clinical implications for the management of affected patients, especially those with Stage II disease.

Adenocarcinoma↗

PubMed1982

An analysis of skin tests and their relationship to recurrence and survival in stage III and stage IV melanoma patients.

One-hundred-two patients with Stage III and IV malignant melanoma were analyzed to determine whether immunologic status in terms of skin testing along with sex and age played a role in recurrence and survival. Before treatment, patients had skin tests with five recall antigens (monilia, mumps, PPD, SK-SD, trichophyton) along with phytohemagglutinin (PHA). Univariate statistical analysis revealed sex as the major significant variable with respect to survival for Stage IVB patients, with female patients surviving longer than males. Patients with resected disease and greater SK-SD skin test reactivity tended to survive longer than those with impaired reactivity. Similarly, reactivity to trichophyton was associated with improved survival among patients with metastases. A multivariate analysis of the patients shows improved remission duration with mumps positivity in Stage III and Stage IVA patients. It appears that certain skin tets analyzed in this fashion have prognostic importance in these patients and should be analyzed with other variables of disease status.

Antigens↗