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PubMed2005

The histrelin implant: a novel treatment for central precocious puberty.

OBJECTIVE: Standard treatment of central precocious puberty (CPP) consists of intramuscular or subcutaneous administration of a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) at 3- to 4-week intervals. Although generally effective in suppressing clinical and laboratory parameters of puberty, GnRHa injections are painful, and the need for monthly clinic visits may contribute to poor compliance. Recently, a subcutaneous implant was developed that releases the GnRHa histrelin at an average rate of 65 microg/day. The aims of this study were to determine if a histrelin implant would suppress gonadotropin and estradiol (E2) in girls with CPP for 1 year and to compare the suppression to standard treatment. METHODS: We studied 11 girls with CPP to determine if the histrelin implant can maintain long-term gonadotropin suppression. Mean age at diagnosis was 6 years (range: 2-9 years). GnRH (100 microg intravenously) stimulation tests (GnRH-STs) showed peak luteinizing hormone and follicle-stimulating hormone responses of 23 +/- 28 (mean +/- SD) and 20 +/- 25 mIU/mL, respectively. All subjects were initially treated with depot intramuscular GnRHa triptorelin embonate. Implants were inserted subcutaneously under local anesthesia, and depot GnRHa treatment was discontinued. Six girls were followed for 15 months after insertion (group A). For the remaining 5 girls, the implant was removed after 9 months, and a new implant was inserted at the same incision site (group B). GnRH-STs were performed before depot GnRHa treatment, immediately before implant insertion, at the 6- and 9-month visits for each patient and the 12- and 15-month visit for those girls followed for 15 months. RESULTS: In all girls, breast development regressed, growth velocity decreased, and bone-age advancement was slowed. Basal gonadotropins and their responses to GnRH-STs and E2 levels were suppressed. Peak luteinizing hormone and follicle-stimulating hormone responses to GnRH-STs at preinsertion versus 9 months were 1.30 +/- 1.34 vs 0.25 +/- 0.08 and 1.68 +/- 1.08 vs 1.13 +/- 0.55 mIU/mL, respectively. Basal and stimulated gonadotropin levels and E2 level remained suppressed in all 6 patients followed for 15 months after implant insertion. Patients and parents reported less pain and discomfort and less interference with school activity and work with the implant compared with standard monthly injections. CONCLUSIONS: The histrelin implant consistently suppresses clinical and laboratory parameters of puberty for 1 year and is a promising new technique for treating CPP without the pain and inconvenience of monthly injections.

Child↗

PubMed2002

Association of rectal toxicity with thermal dose parameters in treatment of locally advanced prostate cancer with radiation and hyperthermia.

PURPOSE: Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer. METHODS AND MATERIALS: Thirty patients with T2b-T3b disease (1992 American Joint Committee On Cancer criteria) enrolled in a Phase II study of external beam radiation +/- androgen-suppressive therapy with two transrectal ultrasound hyperthermia treatments were assessed for rectal toxicity. Prostatic and anterior rectal wall temperatures were monitored for all treatments. Rectal wall temperatures were limited to 40 degrees C in 19 patients, 41 degrees C in 3 patients, and 42 degrees C in 8 patients. Logistic regression was used to estimate the log hazard of developing National Cancer Institute Common Toxicity Criteria Grade 2 toxicity based on temperature parameters. The following were calculated: hazard ratios, 95% confidence intervals, p values for statistical significance of each parameter, and proportion of variability explained for each parameter. RESULTS: Gastrointestinal toxicity was limited to Grade 2. The rate of acute Grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40 degrees C. In this group, 7 of 11 patients experienced acute Grade 2 proctitis, as opposed to 3 of 19 patients in the group with rectal wall temperatures limited to 40 degrees C (p = 0.004). Preliminary assessment of long-term toxicity revealed no differences in toxicity. Hazard ratios for acute Grade 2 proctitis for allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax were 9.33 (p = 0.01), 3.66 (p = 0.03), and 2.29 (p = 0.08), respectively. A model combining these three parameters explained 48.6% of the variability among groups. CONCLUSION: Rectal toxicity correlates with maximum allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax for patients undergoing transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer. Further definition of this association of thermal dose parameters with rectal toxicity in treatment of pelvic malignancies with hyperthermia should advance the goal of delivering thermal therapy in an effective yet safe manner.

Digestive System↗

PubMed2000

The use of stimulus-biased assay systems to detect agonist-specific receptor active states: implications for the trafficking of receptor stimulus by agonists.

The quantitative comparison of the relative potency of agonists is a standard method of receptor and agonist classification. If agonist potency ratios do not correspond in two given tissues, this is used as presumptive data to conclude that the receptors in those two tissues are different. This article presents data to show that a single receptor can demonstrate varying agonist potency ratios in different host cells. These data are described in terms of the production of more than one agonist-selective receptor active state and the interaction of these different active states with multiple G proteins in the membrane to produce cellular response. Stable host human embryonic kidney 293 cells with enhanced quantities of the respective Galpha-protein were created. Wild-type and Galpha-subunit enriched cells were then transiently transfected with human calcitonin receptor type 2 (hCTR2). Binding did not detect differences in the G protein-enriched cells versus wild-type cells. In contrast, functional studies did show differences between the host cell lines and Galpha-subunit enriched cell lines. The relative potency of eight calcitonin agonists was measured in studies of calcium fluorescence in transfected cells containing human calcitonin receptor type 2 by comparing pEC(50) (-log molar concentration producing half-maximal response) values. In Galphas-enriched cells, the relative order of potency of the agonists changed. The host-cell dependent differences in potency ratios ranged from 2-fold to more than 46-fold. This finding is not consistent with the idea that all of the agonists produce response in the same manner (i.e., through a common active state of the receptor). These data are consistent with the idea that these different agonists produce arrays of active states that differentially use G proteins. This idea is discussed in terms of the design of stimulus-bias assay systems to detect agonist-selective receptor active states with resulting potential for increased selectivity of agonists.

Binding, Competitive↗

PubMed2004

Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States.

BACKGROUND: The aim of this study was to determine the frequency and the severity of pancreatitis after EUS-guided FNA of solid pancreatic masses. A survey of centers that offer training in EUS in the United States was conducted. METHODS: A list of centers in which training in EUS is offered was obtained from the Web site of the American Society for Gastrointestinal Endoscopy. Designated program directors were contacted via e-mail. The information requested included the number of EUS-guided FNA procedures performed for solid pancreatic masses, the number of cases of post-procedure pancreatitis, and the method for tracking complications. For each episode of pancreatitis, technical details were obtained about the procedure, including the location of the mass, the type of fine needle used, the number of needle passes, and the nature of the lesion. RESULTS: Nineteen of the 27 programs contacted returned the questionnaire (70%). In total, 4909 EUS-guided FNAs of solid pancreatic masses were performed in these 19 centers over a mean of 4 years (range 11 months to 9 years). Pancreatitis occurred after 14 (0.29%): 95% CI[0.16, 0.48] procedures. At two centers in which data on complications were prospectively collected, the frequency of acute pancreatitis was 0.64%, suggesting that the frequency of pancreatitis in the retrospective cohort (0.26%) was under-reported (p=0.22). The odds that cases of pancreatitis would be reported were 2.45 greater for the prospective compared with the retrospective cohort (95% CI[0.55, 10.98]). The median duration of hospitalization for treatment of pancreatitis was 3 days (range 1-21 days). The pancreatitis was classified as mild in 10 cases, moderate in 3, and severe in one; one death (proximate cause, pulmonary embolism) occurred after the development of pancreatitis in a patient with multiple comorbid conditions. CONCLUSIONS: EUS-guided FNA of solid pancreatic masses is infrequently associated with acute pancreatitis. The procedure appears to be safe when performed by experienced endosonographers. The frequency of post EUS-guided FNA pancreatitis may be underestimated by retrospective analysis.

Acute Disease↗

PubMed2002

Lack of radiation dose response for patients with low-risk clinically localized prostate cancer: a retrospective analysis.

PURPOSE: The need for dose escalation for patients with low-risk clinically localized prostate cancer remains controversial. In this study, we report our pooled institutional experience of low-risk patients treated with a range of "standard" radiation doses to assess outcome in regard to biochemical failure and to determine whether a dose-response relationship exists within this conventional dose range. METHODS AND MATERIALS: Patients with low-risk clinically localized prostate cancer (T1 or T2a, Gleason grade 6660 cGy). To ensure that any differences in biochemical failure between patients at the lower and higher ends of the dose range used were not masked by analysis of the entire cohort, patients receiving or=6800 cGy were subsequently analyzed separately. Biochemical failure was defined per the ASTRO consensus definition. The log-rank test was used to assess for differences in follow-up and time to biochemical failure. A Kaplan-Meier plot of time to biochemical failure for the initial 3 subgroups was generated. RESULTS: A total of 264 patients were identified. Sixteen patients whose dose was not recorded in the database were excluded from analysis. The median follow-up was 35 months. No significant differences were found in baseline prostate-specific antigen, Gleason grade, or clinical stage among the groups. The overall actuarial rate of 5-year freedom from biochemical failure was 80.2%. By dose level, the 5-year biochemical failure-free rate was 79.2%, 78.4%, and 84.5% for <6660 cGy, 6660 cGy, and >6660 cGy, respectively. These differences were not significant. Subsequently, 45 patients receiving or=6800 cGy. The difference between these groups was not significant. The 5-year freedom from biochemical failure rate for the patients receiving <or=6500 cGy was 89.9%. CONCLUSION: Within a range of doses considered standard for treatment of low-risk clinically localized prostate cancer during an 8-year period, no improvement in biochemical freedom from failure was noted with the higher doses. The overall 5-year rate of freedom from biochemical failure is consistent with that reported by others with standard and escalated external beam doses used in this low-risk population. A prospective randomized study is necessary to define the optimal dose in this patient population.

Cohort Studies↗

PubMed2000

Time at confluence for human RPE cells: effects on the adherens junction and in vitro wound closure.

PURPOSE: To determine how time at confluence affects the properties of cultured human retinal pigment epithelium (RPE) cells, with emphasis on the adherens junction. METHODS: Cultures were maintained at confluence without passage for intervals to several months. Adherens junction proteins (N-cadherin, E-cadherin, alpha-catenin, beta-catenin, plakoglobin, and actin) and the proliferation marker Ki-67 were localized in the cultures by fluorescence microscopy, and in vitro wound healing was compared. Adherens junctions were analyzed for protein solubility in detergent buffers and sensitivity to disruption by treatment with anti-cadherin antibodies and low calcium conditions. RESULTS: Compared with cultures in early-confluence (2-3 days), postconfluent cultures (weeks) had more mature adherens junctions characterized by a circumferential (rather than linear) actin organization, and a zonular (rather than punctate) distribution of more detergent resistant cadherin and catenins. Postconfluent cultures also had fewer Ki-67-positive cells and a higher cell packing density. Early-confluence cells migrated into in vitro wounds as dissociated single cells, whereas postconfluent cells moved as contiguous sheets, retaining an intact junction during wound-induced cell migration and proliferation. Mature junctions were not disrupted by treatment of living cells with N-cadherin antibodies, which bound to and remained detectable at junctions for several days. Calcium withdrawal displaced N-cadherin from mature junctions and rendered it more soluble, but the dominant circumferential pattern of actin was stable. Restoration of medium calcium resulted in a rapid (hours) recovery of a nearly complete zonular pattern of insoluble N-cadherin. CONCLUSIONS: Over long postconfluent periods, cultured RPE cells became more growth quiescent, and intercellular cadherin adhesions became more stable, exhibiting increased resistance to calcium removal and greater retention of junctional integrity during in vitro wound closure. Consideration should be given to whether the behavior of RPE cells in postconfluent cultures, where intercellular adhesions are more mature, more closely simulates RPE cells in situ than cells in early-confluence cultures, which are more commonly used for analysis.

Adolescent↗

PubMed2005

Adenosine A2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation.

BACKGROUND: Reperfusion injury continues to significantly affect patients undergoing lung transplantation. Isolated lung models have demonstrated that adenosine A 2A receptor activation preserves function while decreasing inflammation. We hypothesized that adenosine A 2A receptor activation by ATL-146e during the initial reperfusion period preserves pulmonary function and attenuates inflammation in a porcine model of lung transplantation. METHODS: Mature pig lungs preserved with Viaspan (Barr Laboratories, Pomona, NY) underwent 6 hours of cold ischemia before transplantation and 4 hours of reperfusion. Animals were treated with (ATL group, n = 7) and without (IR group, n = 7) ATL-146e (0.05 microg kg -1 . min -1 ATL-146e administered intravenously for 3 hours). With occlusion of the opposite pulmonary artery, the animal was maintained for the final 30 minutes on the allograft alone. Recipient lung physiology was monitored before tissue evaluation of pulmonary edema (wet-to-dry weight ratio), myeloperoxidase assay, and tissue tumor necrosis factor alpha by means of enzyme-linked immunosorbent assay. RESULTS: When the ATL group was compared with the IR group, the ATL group had better partial pressure of carbon dioxide (43.8 +/- 4.1 vs 68.9 +/- 6.3 mm Hg, P < .01) and partial pressure of oxygen (272.3 +/- 132.7 vs 100.1 +/- 21.4 mm Hg, P < .01). ATL-146e-treated animals exhibited lower pulmonary artery pressures (33.6 +/- 2.1 vs 47.9 +/- 3.5 mm Hg, P < .01) and mean airway pressures (16.25 +/- 0.08 vs 16.64 +/- 0.15 mm Hg, P = .04). ATL-146e-treated lungs had lower wet-to-dry ratios (5.9 +/- 0.39 vs 7.3 +/- 0.38, P < .02), lower myeloperoxidase levels (2.9 x 10 -5 +/- 1.2 x 10 -5 vs 1.3 x 10 -4 +/- 4.0 x 10 -5 DeltaOD mg -1 . min -1 , P = .03), and a trend toward decreased lung tumor necrosis factor alpha levels (57 +/- 12 vs 96 +/- 15 pg/mL, P = .06). The ATL group demonstrated significantly less inflammation on histology. CONCLUSION: Adenosine A 2A activation during early reperfusion attenuated lung inflammation and preserved pulmonary function in this model of lung transplantation. ATL-146e and similar compounds could play a significant role in improving outcomes of pulmonary transplantation.

Adenosine A2 Receptor Agonists↗

PubMedDate not supplied

Nutritional and cognitive status in elderly subjects living in service flats, and the effect of nutrition education on personnel.

BACKGROUND: There is limited knowledge about the nutritional and cognitive status in elderly and chronically ill subjects living in sheltered housing. OBJECTIVE: To perform a 6-month follow-up study in order to investigate (1) nutritional status and its relationship to cognitive function in elderly people living in service flats, and (2) the effect of a 9-hour educational program given to personnel working in the service flats. METHODS: Of 93 eligible subjects, 28 agreed to participate (age 81 +/- 7 years, 75% women). Body mass index (BMI), triceps skin fold (TSF), arm muscle circumference (AMC), appetite, Subjective Global Assessment (SGA), serum albumin, serum insulin-like growth factor-1 (IGF-1) and Mini Mental Test (MMT) were assessed on two occasions with a 6-month interval. The staff of the service flats answered a questionnaire before and 6 months after an educational program. RESULTS: At the start, BMI, TSF and AMC were within the normal ranges, e.g. BMI 26.6 +/- 3.1 for men and 25.6 +/- 3.2 for women. Three subjects were suspected to be malnourished and 2 were malnourished according to SGA. Among 20 randomly selected subjects who chose not to participate in the investigation, age, sex, BMI, weight loss and appetite were not significantly different from those values in participants. However, none of the latter had a BMI <20 compared to 10% in non-participants. The MMT results suggested cognitive dysfunction in 41% of the subjects. On the first test occasion, MMT correlated with BMI (r = 0.43, p < 0.03), weight loss (r = 0.4, p < 0.05) and age (r = -0.38, p < 0.05). The ability of the personnel to suggest suitable nutrition for fictitious patient cases appeared to have improved after the educational program. At the 6-month follow-up, the BMI in men rose to 27.0 +/- 3.4 (p < 0. 05), while other anthropometric measurements remained unchanged. Serum IGF-1 lay within the normal range, as did serum albumin which, however, rose from 39.1 +/- 2.9 to 41.2 +/- 3.5 g/l (p < 0.01). CONCLUSION: Fifteen to twenty percent of the individuals studied in the service flats displayed definite or possible signs of malnutrition. Cognitive function correlated with BMI, weight loss and age. The educational program appeared to increase the nutritional knowledge in personnel working in the service flats. At the 6-month follow-up, the nutritional status of the residents had not deteriorated.

Activities of Daily Living↗

PubMed2000

High levels of E-/P-cadherin: correlation with decreased apical polarity of Na/K ATPase in bovine RPE cells in situ.

PURPOSE: The adherens junction protein E-cadherin induces a basolateral polarity of Na/K ATPase in most epithelial cells that express it, whereas in retinal pigment epithelium (RPE) cells, Na/K ATPase is largely apical. The purpose of this study was to determine whether the distribution of Na/K ATPase differs in RPE cells in situ, that differ in levels of junctional E-cadherin. METHODS: Bovine RPE cells in situ were immunostained with an E-cadherin antibody (which has some cross-reactivity with the closely related epithelial cadherin P-cadherin), and RPE cells with different levels of junctional stain were identified. RPE cells with low and high E-/P-cadherin were costained in various combinations with Na/K ATPase and interacting proteins of the membrane cytoskeleton (ankyrin, fodrin, and actin) and analyzed by confocal imaging. RESULTS: Individual RPE cells within the same monolayer differed in amount of Na/K ATPase, with a lower frequency of high expressing cells in the area centralis. High expressing Na/K ATPase cells were found among cells with both low and high E-/P-cadherin levels. In cells with low E/P-cadherin, Na/K ATPase localized to apical microvilli, whereas in high E-/P-cadherin cells, Na/K ATPase was on basolateral surfaces in addition to microvilli. Actin staining showed that microvillar domains were smaller and that lateral membrane domains were taller in high E-/P-cadherin cells. In high but not low E-/P-cadherin cells, ankyrin and fodrin levels varied among cells, with a subset of cells showing distinctly higher expression. Both ankyrin and fodrin had complex subcellular distribution patterns, although they tended to be enriched basal to rather than apical to the adherens junction. Cells with high Na/K ATPase did not necessarily have commensurately higher levels of ankyrin or fodrin. Where both Na/K ATPase and ankyrin were high, they codistributed weakly in apical microvilli but more prominently on the basal cell surface. CONCLUSIONS: Within the same RPE monolayer, the polarity of Na/K ATPase differs among cells, with a more basal polarity found in cells with high levels of junctional E-/P-cadherin. The increased basal Na/K ATPase was due to a combination of a smaller microvillar domain, a taller lateral domain, and more basolateral staining for Na/K ATPase, perhaps because of an enrichment of a basal ankyrinfodrin membrane cytoskeleton with which Na/K ATPase is known to associate.

Actins↗

PubMed2004

Routine mechanical ventricular assist following the Norwood procedure--improved neurologic outcome and excellent hospital survival.

BACKGROUND: Although excellent survival following the Norwood procedure for palliation of hypoplastic left heart syndrome (HLHS) is being achieved by some, most centers, especially the ones with small surgical volume and limited experience, continue to struggle with initial results. Survivors often showed evidence of significant neurologic injury. The early postoperative care is labor-intensive as attempts are made to balance the systemic and pulmonary circulation for these infants. We report our experience with routine use of mechanical circulatory assist to support the increased cardiac output requirements present following Norwood procedure. METHODS: Eighteen consecutive infants undergoing Norwood operation for HLHS (Oregon Health & Science University [OHSU] 13; University of Louisville [UL] 5) were placed on a ventricular assist device (VAD) immediately following modified ultrafiltration in the operating room using the cardiopulmonary bypass (CPB) cannulas that were in the right atrium and the neoaorta. VAD flows were maintained at approximately 200 mL x kg(-1) x min(-1) and the patients were transported to the intensive care unit (ICU). Patients operated at OHSU also received neurodevelopmental testing before their Glenn procedure, approximately 4 to 6 months following their Norwood operation. RESULTS: All patients were stable on VAD support and no attempt was made to balance the systemic and pulmonary circulation. The ventilator was manipulated to achieve systemic Pa0(2) between 30 and 45 mm Hg and PaC0(2) between 35 and 45 mm Hg. Evidence of hypoperfusion (increasing lactates) was managed by increasing the VAD flow. Lactates normalized [< 2 mmol/L]) by 1.8 +/- 1.1 days following surgery. Average time of VAD support was 3.1 +/- 1.0 (range, 2 to 5 days) and average time until chest closure was 3.4 +/- 1.5 (range, 2 to 8 days). There were two cases of postoperative bleeding (11.1%) requiring reexploration and one case of mediastinitis (5.5%) in a patient who has now gone on to successful Glenn. Sixteen of the eighteen patients survived (hospital survival mean 89% with a 95% confidence interval of 63.9% to 98.1%; 12/13 OHSU [92.3%]; 4/5 UL [80%]). Neurodevelopmental testing using the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scale were normal for all infants tested. CONCLUSIONS: Routine postoperative use of VAD can support the increased cardiac output demands of infants following Norwood operation and results in a stable postoperative convalescence that does not require aggressive ventilator or inotrope manipulation. Although not a panacea, this strategy can simplify postoperative management, lead to excellent hospital survival, and possibly augment cerebral oxygen delivery, resulting in improved neurologic outcomes for this challenging group of patients.

Cardiac Surgical Procedures↗

PubMed2002

Programmable microchip monitoring of post-stroke pyrexia: effects of aspirin and paracetamol on temperature and infarct size in the rat.

BACKGROUND: Recent studies have demonstrated spontaneous and prolonged hyperthermia following stroke in both humans and rodents. However, a full characterization of these pyretic changes and the effects of anti-pyretic drugs on outcome is not available. METHODS: The aims of this study were to monitor conscious body temperature (n=10 per group) using programmable microchips for up to 24 h in rats following either permanent (p) or 90 min transient (t) middle cerebral artery occlusion (MCAO) or sham surgery, and to evaluate the relationship to hypothalamic damage. Also, the effects of anti-pyretic drug therapy on body temperature and infarct volume were evaluated in animals treated with vehicle, optimal doses of either aspirin or paracetamol (250 mg/kg i.p.) following pMCAO (n=10 per group). RESULTS: At 1 h, body temperature significantly (P<0.01) increased to 38.6+/-0.2 degrees C following tMCAO and 38.9+/-0.1 degrees C following pMCAO compared with sham-operated animals (37.1+/-0.1 degrees C). Sustained hyperthermia (> or =38.1 degrees C) was observed for up to 24 h following pMCAO but approached baseline within 30 min (37.6+/-0.2 degrees C) following tMCAO with reperfusion. The post-stroke pyrexia was related to the degree of ischemia where hypothalamic damage was observed in (80%) of the animals undergoing pMCAO and (0%) in the tMCAO group (P<0.05). Treatment with paracetamol (250 mg/kg i.p.) significantly attenuated (P<0.05) but did not normalize core body temperature up to 2 h (38.2+/-0.4 degrees C) compared with vehicle treated animals (39.3+/-0.1 degrees C). Aspirin had no effect on temperature under these conditions. Hypothalamic damage and lesion volume were not different between animals treated with paracetamol (253.3+/-8.5 mm(3)), aspirin (264.0+/-11.6 mm(3)) or vehicle (274.4+/-8.2 mm(3)). CONCLUSIONS: This study is the first to demonstrate the utility of programmable microchips to monitor serial changes in post-stroke hyperthermia. The sustained post-stroke pyrexia and negative effects of antipyretic treatment may be attributed to the extensive hypothalamic injury suggesting that better pharmacologic approaches to reduce body temperature should be identified and evaluated for brain protection in severe experimental stroke.

Acetaminophen↗

PubMed2004

Clinicopathologic significance of histologic vascular invasion in papillary and follicular thyroid carcinomas.

BACKGROUND: The association of angioinvasion with tumor aggressiveness in follicular and papillary thyroid carcinoma remains unclear. This study addresses this problem focusing on clinicopathologic relevance of angioinvasion in the treatment of papillary thyroid carcinoma and follicular thyroid carcinoma. METHODS: From a university hospital database, 358 patients with papillary thyroid carcinoma or follicular thyroid carcinoma were randomly selected. Their charts were retrospectively analyzed and divided into papillary thyroid carcinoma and follicular thyroid carcinoma groups. Each group was subdivided into angioinvasive and nonangioinvasive tumor subgroups. All data were analyzed using Student's t-test, Mann-Whitney rank sum test, chi-square test, and Fisher's exact test. RESULTS: There were 289 women and 69 men, ages 18 to 89 years. Papillary thyroid carcinoma (86%) was more frequent than follicular thyroid carcinoma. Most patients had nonangioinvasive tumor (90.2%). After a mean followup of 43.6 months, there were no significant differences between papillary thyroid carcinoma subgroups for local recurrence (p = 0.69), persistent elevated serum thyroglobulin (p = 0.568), and distant metastasis rates (p = 0.422). No death related to the cancer was observed in both papillary thyroid carcinoma subgroups (p = 1), except for one death resulting from a concomitant nasopharyngeal cancer. The longterm prognosis was less favorable for angioinvasive papillary thyroid carcinoma based on AJCC (American Joint Committee on Cancer staging), AMES (age, distant metastasis, tumor extent, and size), and MACIS (distant metastasis, age, completeness of primary tumor resection, local invasion, and tumor size), but the angioinvasive papillary thyroid carcinoma were larger than nonangioinvasive papillary thyroid carcinomas. The short-term clinical outcomes in both follicular thyroid carcinoma, after a mean followup of 72.3 months, were comparable in terms of local recurrence (p = 0.34), persistent elevated serum thyroglobulin (p = 1), and distant metastasis (p = 0.597). There was no death related to cancer in both follicular thyroid carcinoma subgroups (p = 1). There were no significant differences between both follicular thyroid carcinoma subgroups for longterm prognosis. CONCLUSIONS: Our results indicate that angioinvasion does not adversely influence short-term outcomes or longterm prognosis in follicular thyroid carcinoma and short-term outcomes in papillary thyroid carcinoma. Angioinvasion is a postoperative pathologic finding that does not justify an ominous prognosis or drastic therapeutic measures.

Adenocarcinoma, Follicular↗

PubMed2005

Risk factors for and outcomes of bloodstream infection caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species in children.

OBJECTIVE: The increasing prevalence of infections caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species (ESBL-EK) has become a growing concern in the hospitalized patient population. Previous studies on risk factors for infection with ESBL-EK have mainly focused on adult populations, and these findings may not be relevant among the pediatric population that experiences a unique set of health care exposures and underlying conditions. The objective of this study was to define the risk factors and outcomes associated with ESBL-EK bloodstream infections in children. METHODS: We conducted a nested case-control study using data from the Children's Hospital of Philadelphia from May 1, 1999, to September 30, 2003. Eligible patients were identified from the hospital database of microbiology laboratory records. All patients with ESBL-EK bloodstream infections were compared to a random sample of patients with non-ESBL-EK bloodstream infections. Risk factors analyzed included prior antimicrobial use, comorbid conditions, and demographic characteristics. Pulsed-field gel electrophoresis was performed to determine genetic relatedness of the ESBL-EK isolates. RESULTS: Thirty-five cases and 105 control subjects were included in the study. The median age among the cases was 2 years (interquartile range: 0-11), compared with 1 year (interquartile range: 0-8) among control subjects. Patients with ESBL-EK infections were 5.8 times (95% confidence interval: 1.9-17.7) more likely to have had exposure to an extended-spectrum cephalosporin in the 30 days before infection than those with non-ESBL-EK infections. Other independent predictors of ESBL-EK infection were being female, infection with a Klebsiella species, and steroid use in the 30 days before infection. All ESBL-EK isolates were susceptible to carbapenem antibiotics. Pulsed-field gel electrophoresis analysis revealed that the ESBL-EK isolates were polyclonal. Although a substantially higher proportion of children with ESBL-EK died (in-hospital mortality: 36% vs 13%), this difference was not statistically significant. CONCLUSIONS: Receipt of extended-spectrum cephalosporins in the 30 days before infection by an Escherichia coli or Klebsiella species is significantly associated with having an ESBL-EK infection in hospitalized children. Curtailed use of cephalosporins among high-risk groups may reduce the occurrence of ESBL-EK infections. Future studies on identifying high-risk children and investigating the impact of curtailed third-generation cephalosporin use to limit additional emergence of ESBL-EK infections should be undertaken.

Analysis of Variance↗

PubMed2004

Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy.

OBJECTIVE: Because mesenchymal stem cells can differentiate into chondrocyte-like cells, we ask the question, can mesenchymal stem cells commit to the nucleus pulposus phenotype? BACKGROUND: Back pain, a significant source of morbidity in our society, is linked to degenerative changes of the intervertebral disc. Absence of suitable graft tissue limits therapeutic approaches for repair of disc tissue. For this reason, there is considerable interest in developing "tissue engineering" strategies for the regeneration of the nucleus pulposus. METHODS: Rat mesenchymal stem cells were immobilized in 3-dimensional alginate hydrogels and cultured in a medium containing transforming growth factor-beta1 under hypoxia (2% O2) and normoxia (20% O2). Mesenchymal stem cells were examined by confocal microscopy to evaluate their viability and metabolic status after labeling with Celltracker green, a thiol sensitive dye, and Mitotracker red, a dye sensitive to the mitochondrial membrane potential. Flow cytometry, semiquantitative reverse transcription polymerase chain reaction and Western blot analysis were carried out to evaluate phenotypic and biosynthetic activities and the signaling pathways involved in the differentiation process. RESULTS: Under hypoxic conditions, mesenchymal stem cells formed large aggregates and exhibited positive Celltracker and Mitotracker signals. Glucose transporter-3, matrix metalloproteinase-2, collagen type II and type XI, and aggrecan mRNA and protein expression was upregulated, whereas there was no change in the levels of decorin, biglycan, fibromodulin, and lumican. Hypoxia maintained the expression of CD44 (hyaluronan receptor), ALCAM (CD166), and endoglin (transforming growth factor-beta receptor). Likewise, expression of beta3 and alpha2 integrin was upregulated. Transforming growth factor-beta treatment increased MAPK activity and Sox-9, aggrecan, and collagen type II gene expression. Basal levels of the phosphorylated MAPK isoform ERK1/2, but not p38, were higher under hypoxic conditions than normoxia, and its activation was further augmented by treatment of cells with transforming growth factor-beta. In hypoxia, transforming growth factor-beta sustained phosphorylated p38 expression for an extended time period. Pharmacological inhibition of ERK1/2 and p38 enzymatic activity resulted in a decrease in Sox-9, aggrecan, and collagen type II mRNA levels. CONCLUSIONS: Our results indicate that hypoxia and transforming growth factor-beta drive mesenchymal stem cell differentiation towards a phenotype consistent with that of the nucleus pulposus. Measurement of selected signaling molecules and response to specific inhibitors suggest involvement of MAPK signaling pathways. It is concluded that mesenchymal stem cells could be used to repopulate the damaged or degenerate intervertebral disc.

Animals↗

PubMed1997

Apoptosis of N-type neuroblastoma cells after differentiation with 9-cis-retinoic acid and subsequent washout.

BACKGROUND: The overall survival rate for patients with neuroblastoma has improved over the past two decades, but long-term survival for the subgroup of patients with high-risk disease remains low. In recent years, there has been interest in the potential clinical use of drugs able to induce differentiation of neuroblastoma cells. Since 9-cis-retinoic acid induces better and more sustained differentiation of neuroblastoma in vitro than other retinoic acid isomers, this may be a more appropriate retinoid for use in neuroblastoma therapy. PURPOSE: The purpose of this work was to compare the long-term effects of all-trans- and 9-cis-retinoic acid on neuroblastoma differentiation using an N-type (neuroblastic) cell line, SH SY 5Y, as an in vitro model. In addition, we wanted to find out whether 9-cis-retinoic acid would induce programmed cell death (apoptosis) in these N-type neuroblastoma cells and to determine whether the effects of either 9-cis- or all-trans-retinoic acid are dependent on their continued presence in the culture medium. METHODS: SH SY 5Y cells were incubated in either the continued presence of all-trans- or 9-cis-retinoic acid or for 5 days with retinoic acid followed by culture in the absence of retinoid for up to 13 days. Morphologic changes were observed using phase-contrast and scanning electron microscopy. Apoptosis was determined by flow cytometry of propidium iodide-stained cells and by using terminal deoxynucleotidyl transferase to end-label DNA fragments in situ in apoptotic cells. RESULTS: Culture of SH SY 5Y cells with all-trans- or 9-cis retinoic acid for 5 days induced morphologic differentiation and inhibited cell growth. These effects were maintained in the continuous presence of each retinoic acid isomer but were more profound in cells treated with 9-cis-retinoic acid. The differentiation of cells treated with all-trans-retinoic acid was reversible once retinoic acid was removed from the medium. Conversely, apoptosis was induced in cells treated with 9-cis-retinoic acid for 5 days and cultured for 9 days (4 days after washout) but not in cells cultured in the continuous presence of 9-cis-retinoic acid. This effect was specific to 9-cis-retinoic acid. CONCLUSIONS: Previous studies have demonstrated differential responses to all-trans-retinoic acid in N- and S-type (substrate-adherent or Schwann-like) neuroblastoma cells: Apoptosis is induced in S-type cells, whereas differentiation occurs in N-type cells. The present results show that, unlike all-trans-retinoic acid, 9-cis-retinoic acid induces both differentiation and apoptosis in N-type SH SY 5Y neuroblastoma cells. However, apoptosis was dependent on removal of 9-cis-retinoic acid from the culture medium. IMPLICATIONS: Since both differentiation and apoptosis are involved in tumor regression, 9-cis-retinoic acid may be a more appropriate retinoid for clinical trials in neuroblastoma. The dependence of apoptosis on treatment and subsequent removal of 9-cis-retinoic acid implies that drug scheduling may be an important parameter affecting therapeutic efficacy.

Alitretinoin↗

PubMed2006

Enantioselective separation and online affinity chromatographic characterization of R,R- and S,S-fenoterol.

BACKGROUND: rac-Fenoterol is a beta2-adrenoceptor agonist (beta2-AR) used in the treatment of asthma. It has two chiral centers and is marketed as a racemic mixture of R,R'- and S,S'-fenoterol (R-F and S-F). Here we report the separation of the R-F and S-F enantiomers and the evaluation of their binding to and activation of the beta2-AR. METHODS: R-F and S-F were separated from the enantiomeric mixture by chiral chromatography and absolute configuration determined by circular dichroism. Beta2-AR binding was evaluated using frontal affinity chromatography with a stationary phase containing immobilized membranes from HEK-293 cells that express human beta2-AR and standard membrane binding studies using the same membranes. The effect of R-F and S-F on cardiomyocyte contractility was also investigated using freshly isolated adult rat cardiomyocytes. RESULTS: Chiral chromatography of rac-fenoterol yielded separated peaks with an enantioselectivity factor of 1.21. The less retained peak was assigned the absolute configuration of S-F and the more retained peak R-F. Frontal chromatography using membrane-bound beta2-AR as the stationary phase and rac-3H-fenoterol as a marker ligand showed that addition of increasing concentrations of R-F to the mobile phase produced concentration-dependent decreases in rac-3H-fenoterol retention, while similar addition of S-F produced no change in rac-3H-fenoterol retention. The calculated dissociation constant of R-F was 472 nM and the number of available binding sites 176 pmol/column, which was consistent with the results from the membrane binding study 460 +/- 55 nM (R-F) and 109,000 +/- 10,400 nM (S-F). In the cardiomyocytes, R-F increased maximum contractile response from (265 +/- 11.6)% to (306 +/- 11.8)% of resting cell length (P < 0.05) and reduced EC50 from -7.0 +/- 0.270 to -7.1 +/- 0.2 log[M] (P < 0.05), while S-F had no significant effect. DISCUSSION: Previous studies have shown that rac-fenoterol acts as an apparent beta2-AR/G(s) selective agonist and fully restores diminished beta2-AR contractile response in cardiomyocytes from failing hearts of spontaneously hypertensive rats (SHR). Here we report the separation of the enantiomers of rac-fenoterol and that R-F is the active component of rac-fenoterol. Further evaluation of R-F will determine if it has enhanced selectivity and specificity for beta2-AR/G(s) activation and if it can be used in the treatment of congestive heart failure.

Animals↗

PubMed1999

Staging laparoscopic pelvic lymphadenectomy in prostate cancer.

OBJECTIVE: To assess the results of transperitoneal laparoscopic pelvic lymphadenectomy as a separate staging procedure in patients with early prostate cancer. PATIENTS AND METHODS: The results were reviewed from the first 27 patients with prostate cancer admitted for laparoscopic lymphadenectomy between January 1994 and March 1998. Initially, all patients with a negative bone scan and either a negative computed tomography or negative magnetic resonance scan were admitted for laparoscopic staging. After several reports detailing ways of reducing the number of negative lymphadenectomy operations, from July 1996 only those patients with a preoperative prostate specific antigen (PSA) serum level of >10 ng/mL were admitted to the study. All procedures were performed by one experienced laparoscopic surgeon. A radical retropubic prostatectomy was performed as a separate procedure by a consultant urologist within 2 weeks. The effectiveness of the staging operation was analysed by assessing the nodal yield, and the results, including operative duration, complications and length of stay, were compared with other published series. Further analysis was provided by reviewing the PSA levels, Gleason grade sum and clinical digital staging. RESULTS: The nodal yield was similar to that published in series from other institutions, with a median (range) of 6.5 (0-12). However, the operation was significantly quicker, at a median (range) of 55 (40-110) min for a bilateral dissection. There were only minor complications, with no detectable reduction in complications with experience; the median (range) postoperative stay was 1 (1-4) days. Two of the 27 patients had metastatic disease within the lymph nodes. If a PSA level of >10 ng/mL had been instituted as an entry criteria at the start of the study, six patients would have been excluded and thus the positive lymphadenectomy rate would have been two of 21 patients (10%). Of 54 patients eligible to enter the study, half did not require a lymphadenectomy. CONCLUSIONS: Laparoscopic transperitoneal lymphadenectomy can be performed expeditiously and safely. A two-stage procedure in some patients with prostate cancer is the management of choice. Attention to carefully closing the peritoneum with sutures minimizes any retropubic adhesions and no problems associated with the staging procedure were encountered during subsequent radical retropubic prostatectomy. In efforts to reduce negative staging lymphadenectomies, the exclusion values for staging should not be set too high (PSA and Gleason grading sum). Such practice, despite a relatively safe staging procedure, would lead to unnecessary radical prostatectomy.

Humans↗

PubMed2026

Long-term outcomes of top-down therapy versus a conventional step-up strategy in adults newly diagnosed with Crohn's disease: 5-year follow-up of the PROFILE trial.

BACKGROUND: The PROFILE trial previously reported better 48-week outcomes for patients with Crohn's disease who received top-down anti-TNF treatment from diagnosis, compared with a conventional step-up strategy. Through subsequent follow-up of PROFILE participants, we aimed to assess whether the benefit of top-down treatment from diagnosis results in modification of the long-term disease course. METHODS: PROFILE was a multicentre, open-label, randomised controlled trial completed in 40 hospitals in the UK, which included patients aged 16-80 years with newly diagnosed Crohn's disease. Eligible patients were randomly assigned via a secure online platform to a top-down (infliximab plus immunomodulator) or a step-up protocolised treatment strategy for 48 weeks, after which participants reverted to local standards of care. Objective outcome data were extracted for up to 5 years after the week 48 visit, including need for Crohn's-related abdominal surgery as the primary outcome. Data were analysed based on the original PROFILE randomisation and intention-to-treat population. Participants without long-term follow-up data were censored at the week 48 visit. Time-to-event analyses were performed using the Kaplan-Meier method and Cox proportional hazards model. The trial was registered with the ISRCTN registry, number 11808228 and is complete. FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 483 patients were assessed for inclusion. 389 patients were enrolled and randomly assigned (three patients were excluded due to ineligibility), 193 to top-down treatment and 193 to step-up treatment. Of the 386 participants in the PROFILE primary trial, 358 (93%) had post-week 48 records available for review (182 [51%] top-down and 176 [49%] step-up). Median follow-up was approximately 5 years from randomisation (1809 days [IQR 1300-2101]), by which point 172 (89%) of 193 patients in the step-up group and 191 (99%) of 193 patients in the top-down group had received biological or immunomodulator therapy. Relating to the primary outcome, during follow-up there were 28 Crohn's disease-related abdominal surgeries in 26 patients treated with a step-up approach versus six surgeries in six patients treated with a top-down approach. Time to surgery was shorter in the step-up group than the top-down group (adjusted hazard ratio [aHR] 5·23 [95% CI 1·99-13·76]; p=0·0008). For the secondary outcomes, incidence of Crohn's disease-related hospital admissions was higher in patients originally managed with step-up treatment versus top-down treatment (41 [21%] of 193 patients vs 22 [11%] of 193 patients); and time to first hospital admission was shorter with step-up treatment than with top-down treatment (aHR 2·01 [95% CI 1·18-3·41], p=0·017). Progression to B2 or B3 complications was also more frequent in those originally managed with step-up treatment compared with top-down treatment (32 [17%] of 192 patients vs 13 [7%] of 193 patients); with time to disease progression being shorter in the step-up group than in the top-down group (aHR 2·46 [95% CI 1·25-4·86]; p=0·010). There was no difference in safety outcomes between groups for either serious infections (12 [6%] of 193 step-up patients and 14 [7%] of 193 top-down patients) or malignancies (five patients [3%] and three patients [2%] respectively). INTERPRETATION: Early top-down anti-TNF treatment from diagnosis was associated with improved long-term outcomes at 5 years compared with step-up treatment and is suggestive of a disease-modifying effect in Crohn's disease. FUNDING: Wellcome and Celltrion.

Journal Article↗