bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis
Authors: Wood Patricia A. , Bove Kathleen , You Shaojin , Chambers Ann , Hrushesky William J.M.
Published: September 2005

The frequency of breast cancer metastatic spread is affected by the menstrual cycle phase of its resection. Breast cancer growth, post-resection spread, and cure frequency are each modulated by the estrous cycle in C3HeB/FeJ mice. Tumor metastases are 2- to 3-fold more frequent when the resection is done during diestrus as compared with estrus. Tumor angiogenesis is essential for both cancer growth and lethal metastatic cancer spread. The balance between vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) modulates new blood vessel formation and blood vessel permeability. Sex hormones modulate the expression of these key angiogenesis regulators in the endometrium and uterus. We, therefore, asked whether the estrous cycle modulates the density of CD31-positive vessels within the tumor, the permeability of tumor blood vessels, levels of VEGF and bFGF immunoreactive protein in normal breast and breast cancer, and whether expression of these genes are modulated by the estrous cycle stage in C3HeB/FeJ mice. We find that tumor blood vessel density and blood volume do not vary throughout the cycle; however, tumor capillary permeability is regulated by the estrous cycle being highest in diestrus, the cycle stage associated with the highest cancer growth rate and the highest frequency of post-resection cancer metastasis. VEGF protein levels in breast cancer are >100-fold higher than in normal breast. VEGF protein in this mammary tumor varies with the estrus cycle with highest levels in proestrus. In a non-breast tumor, methylcholantrenene A sarcoma, from CD2F1 mice, tumor VEGF protein also varies with the estrus cycle with highest levels in proestrus and diestrus. VEGF gene expression in the mammary tumor does not change significantly across the cycle, but is modulated by the cycle in normal breast tissue. bFGF protein concentration is 6-fold higher in normal breast than in breast cancer. bFGF protein pattern in both tumor and breast are similar, opposite to VEGF, and affected by oophorectomy. bFGF message is modulated by the cycle in both breast cancer and normal breast. The changes in breast cancer capillary permeability, VEGF, and bFGF that occur during each fertility cycle, in breast tissue and breast cancer, putatively in response to cyclical changes in sex hormones, might contribute, at least in part, to both the modulation of cancer growth and post-resection breast cancer spread by the fertility cycle. These fertility cycle–induced effects on tumor biology also seem to extend to non–breast cancer biology.
Selenium disrupts estrogen receptor α signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells
Authors: Shah Yatrik M. , Al-Dhaheri Mariam , Dong Yan , Ip Clement , Jones Frank E. , Rowan Brian G.
Published: September 2005

Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 μmol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10−7 mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Δ16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ERα mRNA and protein without an effect on ERβ levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE2e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ERα levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
The antiproliferative agent MLN944 preferentially inhibits transcription
Authors: Byers Sarah A. , Schafer Blanca , Sappal Darshan S. , Brown Jeffery , Price David H.
Published: September 2005

MLN944 is a novel compound currently being codeveloped by Millennium Pharmaceuticals and Xenova Ltd. as a cancer therapeutic and is in a phase I clinical trial for solid tumors. Although MLN944 was originally proposed to function as a topoisomerase I and II inhibitor, more recent data has shown that it is a DNA-intercalating agent that does not inhibit the catalytic activity of topoisomerase I or II. We show here that MLN944 inhibits incorporation of radiolabeled precursors into RNA preferentially over incorporation into DNA and protein in HCT116 and H460 cells. To determine if MLN944 inhibits transcription, a human RNA polymerase II in vitro transcription system was used. MLN944 inhibited initiation when added before or after the formation of preinitiation complexes and inhibited elongation at higher concentrations. The preferential inhibition of initiation differentiates MLN944 from actinomycin D, which more strongly inhibits elongation. Transcription of all RNA polymerases was inhibited in nuclei isolated from HeLa cells treated with low concentrations of MLN944. Our data are consistent with transcription as the target of the potent cytotoxic effects of MLN944.
Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers
Authors: Dong Yan , Zhang Haitao , Gao Allen C. , Marshall James R. , Ip Clement
Published: September 2005

Our previous report showed that methylseleninic acid (MSA) significantly decreases the expression of androgen receptor and prostate-specific antigen (PSA) in LNCaP cells. The present study extended the above observations by showing the universality of this phenomenon and that the inhibitory effect of MSA on prostate cancer cell growth and cancer-specific biomarkers is mediated through androgen receptor down-regulation. First, MSA decreases the expression of androgen receptor and PSA in five human prostate cancer cell lines (LNCaP, LAPC-4, CWR22Rv1, LNCaP-C81, and LNCaP-LN3), irrespective of their androgen receptor genotype (wild type versus mutant) or sensitivity to androgen-stimulated growth. Second, by using the ARE-luciferase reporter gene assay, we found that MSA suppression of androgen receptor transactivation is accounted for primarily by the reduction of androgen receptor protein level. Third, MSA inhibition of five androgen receptor–regulated genes implicated in prostate carcinogenesis (PSA, KLK2, ABCC4, DHCR24, and GUCY1A3) is significantly attenuated by androgen receptor overexpression. Fourth, transfection of androgen receptor in LNCaP cells weakened noticeably the inhibitory effect of MSA on cell growth and proliferation. Androgen receptor signaling has been documented extensively to play an important role in the development of both androgen-dependent and -independent prostate cancer. Our finding that MSA reduces androgen receptor availability by blocking androgen receptor transcription provides justification for a mechanism-driven intervention strategy in using selenium to control prostate cancer progression.
Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells
Authors: Xiao Danhua , Pinto John T. , Gundersen Gregg G. , Weinstein I. Bernard
Published: September 2005

We previously reported that the garlic-derived compound S-allylmercaptocysteine (SAMC) causes growth inhibition, mitotic arrest, and induction of apoptosis in SW480 human colon cancer cells by inducing microtubule depolymerization and c-Jun NH2 terminus kinase-1 activation. In the present study, we compared the aforementioned effects of SAMC to those of a series of garlic-derived and other organosulfur compounds. Among the 10 compounds tested, only SAMC, diallyl disulfide (DADS), and S-trityl-L-cysteine (trityl-cys) cause significant inhibition of cell growth with IC50 values of 150, 56, and 0.9 μmol/L, respectively. These three compounds also induce G2-M cell cycle arrest and apoptosis. Further studies reveal that, like SAMC, the garlic-derived compound DADS exerts antiproliferative effects by binding directly to tubulin and disrupting the microtubule assembly, thus arresting cells in mitosis and triggering mitochondria-mediated signaling pathways that lead to apoptosis. However, the synthetic compound trityl-cys exerts its effect on M-phase arrest and growth inhibition by mechanisms that involve spindle impairment but do not involve disruption of microtubule structure or dynamics. Furthermore, trityl-cys does not induce marked loss of mitochondrial membrane potential or release of cytochrome c, but it does induce caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Structure-function analysis suggests that both the allyl and the disulfide moieties are important features for the antiproliferative effects of SAMC and DADS. These findings may be useful in the identification, synthesis, and development of organosulfur compounds that have anticancer activity.
Overexpression of 15-Lipoxygenase-1 Induces Growth Arrest through Phosphorylation of p53 in Human Colorectal Cancer Cells
Authors: Kim Jong-Sik , Baek Seung Joon , Bottone Frank G. , Sali Tina , Eling Thomas E.
Published: September 2005

To investigate the function of 15-lipoxygenase-1 (15-LOX-1) in human colorectal cancer, we overexpressed 15-LOX-1 in HCT-116 human colorectal cancer cells. Clones expressing the highest levels of 15-LOX-1 displayed reduced viability compared with the HCT-116-Vector control cells. Further, by cell cycle gene array analyses, the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and MDM2 genes were up-regulated in 15-LOX-1-overexpressing cells. The induction of p21WAF1/CIP1 and MDM2 were linked to activation of p53 by 15-LOX-1, as there was a dramatic induction of phosphorylated p53 (Ser15) in 15-LOX-1-overesxpressing cells. However, the 15-LOX-1 metabolites 13(S)-hydroxyoctadecadienoic acid and 15(S)-hydroxyeicosatetraenoic acid failed to induce phosphorylation of p53 at Ser15, and the 15-LOX-1 inhibitor PD146176 did not inhibit the phosphorylation of p53 at Ser15 in 15-LOX-1-overexpressing cells. Nonetheless, the growth-inhibitory effects of 15-LOX-1 were p53 dependent, as 15-LOX-1 overexpression had no effect on cell growth in p53 (−/−) HCT-116 cells. Finally, treatment of HCT-116-15-LOX-1 cells with different kinase inhibitors suggested that the effects of 15-LOX-1 on p53 phosphorylation and activation were due to effects on DNA-dependent protein kinase. Collectively, these findings suggest a new mechanism to explain the biological activity of 15-LOX-1, where 15-LOX plays a stoichiometric role in activating a DNA-dependent protein kinase–dependent pathway that leads to p53-dependent growth arrest.
An Acute Bronchodilator Test with Tiotropium or Salmeterol Does Not Allow a Subdivision of Patients according to Responses
Authors: Matera M.G. , Sanduzzi A. , Ponticiello A. , Vatrella A. , Salzillo A. , Cazzola M.
Published: September 2005

Background: The possibility that individual chronic obstructive pulmonary disease (COPD) patients respond better to either tiotropium or salmeterol has been suggested and an acute bronchodilator test might help to guide the choice of therapy. Objectives: We explored the responses to tiotropium and salmeterol within the first 3 h using the recommended dosages (18 µg for tiotropium and 50 µg for salmeterol) in order to verify whether there are differences in the short-term bronchodilator effects between these two long-acting bronchodilators in patients with stable COPD. Moreover, we investigated whether these differences could discriminate between the two agents. Methods: Forty consecutive patients with COPD, but in a stable phase of the disease, participated in this double-blind, double-dummy, randomized crossover study. The study involved a screening visit and 2 study days separated by at least 1 week. For determination of the onset of action, we measured FEV1 at 10, 20, 30, 60 and 90 min, and again 2 and 3 h after inhalation of single study drug. Results: At all time points, both tiotropium and salmeterol caused significant (p< 0.001) changes from baseline. A mean increase of 12% above baseline was reached 66 min (95% CI: 45–87) after tiotropium and 59 min (95% CI: 41–77) after salmeterol. Nine patients after tiotropium and 5 patients after salmeterol did not have this type of improvement. A mean increase of 200 ml above baseline was reached 76 min (95% CI: 52–101) after tiotropium and 76 min (95% CI: 52–100) after salmeterol. Eighteen patients after tiotropium and 15 patients after salmeterol did not have this improvement. Twenty-one patients after tiotropium and 24 patients after salmeterol reached an improvement that was at the same time 12% and 200 ml greater than baseline. Conclusions: These data clearly show that the bronchodilator effects of tiotropium and salmeterol within the first hours after their acute administration are similar in patients with stable COPD when they are evaluated as mean changes from baseline in FEV1. Therefore, they question the direct therapeutic relevance of a subdivision of patients according to bronchodilator responses to tiotropium or salmeterol.
Once-Daily Administration of Fluticasone Propionate Does Not Worsen Controlled Airway Hyperresponsiveness in Patients with Asthma
Authors: Shigyo M. , Inoue H. , Honda Y. , Takata S. , Iwanaga T. , Koto H. , Takahashi N. , Ichiki H. , Aizawa H.
Published: September 2005

Background: Inhaled steroids are currently the most important drugs for asthma patients, but compliance tends to be low. Compliance could be improved by reducing the number of daily administrations. Objectives: In the present study, we compared once- and twice-daily administration of fluticasone propionate (FP) to determine the differences in efficacy. Methods: Subjects were 40 patients diagnosed with bronchial asthma with stable symptoms and pulmonary functions who were on twice-daily FP administration of 100 µg. There were 14 men and 26 women ranging from 29 to 72 years of age. After a 4-week observation period, subjects were randomized into two administration groups by the envelope method and followed for 8 weeks: group A, once-daily administration (200 µg of FP at night), and group B, twice-daily administration (100 µg of FP in the morning and at night). Clinical symptoms, pulmonary functions and airway responsiveness were compared between these two groups. Results: No significant deterioration in clinical symptoms, pulmonary functions and airway responsiveness were observed in group A compared with group B. Conclusions: These results demonstrate that once-daily FP administration is as effective as twice-daily administration, and that it may improve the compliance for inhaled steroids.
C-Reactive Protein in Lymphocytic Pleural Effusions: A Diagnostic Aid in Tuberculous Pleuritis
Authors: Garcia-Pachon Eduardo , Soler Maria J. , Padilla-Navas Isabel , Romero Victor , Shum Conrado
Published: September 2005

Background:C-reactive protein (CRP) pleural fluid levels have been found to be higher in tuberculosis and parapneumonic effusions than in other causes of pleural effusion. Objective:The aim of this study was to analyze whether CRP (a simple and inexpensive test) may be a diagnostic aid for tuberculosis in lymphocytic pleural effusions. Methods:One hundred and forty-four patients with a lymphocytic pleural effusion (more than 50% lymphocytes in the differential white blood cell count) were included. The patients were 93 men (65%) and 51 women (35%), aged 64 ± 18 years (mean ± SD). The diagnoses were as follows: tuberculosis, 20; pleural effusion associated with malignancy, 69; transudates, 38; other benign exudates, 17. Results: The CRP pleural fluid level was higher in tuberculous pleuritis (54 ± 24 mg/l) than in lymphocytic effusions of other origin (21 ± 16 mg/l; p < 0.001). High CRP levels (≧50 mg/l) have a high specificity for tuberculosis (95%), and low levels (<30 mg/l) have a high sensitivity (95%) for excluding disease. Conclusions: CRP pleural fluid level determination is useful in the diagnostic workup of lymphocytic pleural effusions. High CRP levels are very suggestive of tuberculous pleuritis, and low CRP levels make this diagnosis unlikely.
Evaluation of Tracheal Imaging by Optical Coherence Tomography
Authors: Han Sukgu , El-Abbadi Naglaa H. , Hanna Nevine , Mahmood Usama , Mina-Araghi Reza , Jung Woong-Gyu , Chen Zhongping , Colt Henri , Brenner Matthew
Published: September 2005

Background: Optical coherence tomography (OCT) is a new technology capable of generating high resolution cross-sectional images of complex tissue in real time. Analogous to ultrasound, OCT measures backscattered light intensity using coherence interferometery to construct topographical images of complex tissue. Since OCT uses infrared light rather than acoustic waves, its spatial resolution is exceptionally high (2–10 µm). Recent advances in data acquisition, analysis, and processing enable real-time imaging, and make OCT a potentially valuable tool for pulmonary airway diagnostic applications, including assisting directed airway biopsies. Objective: This study evaluates feasibility of OCT for delineating proximal airway microstructures in various animal as well as human tracheas. Methods: Excised trachea samples from New Zealand white rabbits, Duroc pigs, and human trachea were imaged using a compact, 1,300-nm broad-band superluminescent-diode-based prototype fiber OCT device we constructed. The resulting structural OCT images were compared to conventional hematoxilin and eosin (HE) stained histological sections from the same samples. Results: OCT was able to delineate microstructures such as the epithelium, mucosa, cartilage, and glands in all samples. Conclusion: These findings suggest that integration of OCT with flexible fiberoptic bronchoscopy could enhance pulmonary diagnostic medicine and detection of pathologic tissue changes in various respiratory diseases.
The Lung, an Organ for Absorption?
Authors: von Wichert Peter , Seifart Carola
Published: September 2005

This review summarizes information concerning the mechanisms of absorption of substances across the pulmonary epithelium. Inhalation is now increasingly used as a route of administration, although the scientific understanding of these mechanisms is rather limited. The aim of this study is to draw attention to these questions.
Prevention of Infectious Complications in Surgical Patients: Potential Role of Probiotics
Authors: Besselink Marc G.H. , Timmerman Harro M. , van Minnen L. Paul , Akkermans Louis M.A. , Gooszen Hein G.
Published: September 2005

Infectious complications in surgical patients often originate from the intestinal microflora. In the critically ill patient, small bowel motility is disturbed, leading to bacterial overgrowth and subsequent bacterial translocation due to dysfunction of the gut mucosal barrier. The optimal prophylactic strategy should act on all these factors, but such a strategy is not yet available. For several decades, antibiotic prophylaxis to prevent translocation of pathogenic bacteria has been studied with conflicting results. Selective decontamination of the digestive tract has shown good results, but fear for bacterial multiresistance has prevented worldwide implementation. In recent years, probiotics, living bacteria with a potential beneficial effect to their host, have shown promising results in several randomized placebo-controlled trials. Currently, in vitro and experimental research focuses on the effects of probiotics on the microflora responsible for gut-derived infections, structural mucosal barrier function and the immune system.
VEGF as a Target of Therapy in Gastrointestinal Oncology
Authors: Los Maartje , Voest Emile E. , Borel Rinkes Inne H.M.
Published: September 2005

The last decade has seen enormous progress in understanding the development of cancer. It is now recognized that tumor growth is a multistep process that may take years to become clinically relevant. Angiogenesis is an absolute requirement for tumors to become clinically detectable. The importance of angiogenesis for tumor growth is supported by several clinical studies that showed a positive correlation between tumor angiogenesis and tumor stage. In animal studies, inhibition of angiogenesis caused impressive reduction of tumor growth. The aim of antivascular therapy in the treatment of cancer is to attack the tumor through its vasculature. Antivascular therapy can be divided in two different areas: (1) inhibition of angiogenesis with the aim to prevent formation of new blood vessels and (2) vascular targeting agents with the goal to destroy the existing tumor vasculature. Vascular endothelial growth factor (VEGF) has been recognized as one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. This review focuses mainly on the inhibition of angiogenesis in gastrointestinal tumors by blocking the VEGF receptor/ligand signaling. We will discuss the biology of the VEGF receptor/ligand signaling system and give an overview of the current approaches for therapy in gastrointestinal cancer targeting the VEGF signaling pathway.
Renal Handling of Aluminium
Authors: Shirley D.G. , Lote C.J.
Published: September 2005

Aluminium (Al) is absorbed from a variety of foodstuffs and medications. Its major route of elimination from the body is in the urine. However, current knowledge concerning its glomerular filtration and, more particularly, its reabsorption/secretion is fragmentary. Most (80–90%) of Al in the plasma is normally bound to protein (mainly transferrin) and is therefore unfilterable; the remainder is bound to low molecular mass compounds, of which citrate appears to be the most important. In vitro determinations using artificial membranes indicate that ∼10% of Al is filtered at normal plasma concentrations. However, when plasma Al is raised experimentally, its filterability falls, unless the excess Al is complexed with citrate; the aluminium citrate complex appears to be freely filtered. Information on tubular Al reabsorption at normal plasma concentrations is inconsistent. Filtered Al appears to be at least partially reabsorbed, although the reabsorptive mechanisms remain speculative. A consensus is emerging that elevated plasma Al concentrations result in a fall in fractional Al reabsorption, and a recent micropuncture study indicates that under these circumstances the only significant site of Al reabsorption is the loop of Henle.
Syphilitic Coronary Artery Ostial Stenosis Resulting in Acute Myocardial Infarction and Death
Authors: Kennedy Jamie L.W. , Barnard Jeffrey J. , Prahlow Joseph A.
Published: September 2005

Cardiovascular abnormalities are well-known manifestations of tertiary syphilis infections. Most notable in this regard is syphilitic aortitis, which tends to result in aortic root dilatation and its associated complications. A less common manifestation of syphilitic aortitis is coronary artery ostial narrowing related to aortic wall thickening. Herein, we present the case of a 32-year-old female who died of a myocardial infarct due to coronary artery ostial stenosis secondary to syphilitic aortitis.
Arterial Wall Response to ex vivo Exposure to Oscillatory Shear Stress
Authors: Gambillara Veronica , Montorzi Gabriela , Haziza-Pigeon Christelle , Stergiopulos Nikos , Silacci Paolo
Published: September 2005

Background: The aim of this study was to analyze the arterial wall response to plaque-prone hemodynamic environments, known to occur mainly in areas of arterial trees such as bifurcations and branching points. In these areas, the vasculature is exposed to cyclically reversing flow that induces an endothelial dysfunction predisposing thus arteries to local development of atherosclerotic plaques. Methods: We used an ex vivo perfusion system that allows culturing arterial segments under different hemodynamic conditions. Porcine carotid arteries were exposed for 3 days to unidirectional high and low shear stress (6 ± 3 and 0.3 ± 0.1 dyn/cm2) as well as to oscillatory shear stress (0.3 ± 3 dyn/cm2). This latter condition mimics the hemodynamics present at plaque-prone areas. At the end of the perfusion, the influence of different flow patterns on arterial metabolism was assessed in terms of matrix turnover as well as of smooth muscle cell function, differentiation and migration. Results: Our results show that after 3 days of perfusion none of the applied conditions influence smooth muscle cell phenotype retaining their full contraction capacity. However, an increase in the expression level of matrix metalloproteinase-2 and -9, as well as a decrease in plasminogen activator inhibitor-1 expression were observed in arteries exposed to oscillatory shear stress when compared to arteries exposed to unidirectional shear stress. Conclusion: These observations suggest that plaque-prone hemodynamic environment triggers a vascular wall remodelling process and promotes changes in arterial wall metabolism, with important implication in atherogenesis.
Dementia with Lewy Bodies: Current Concepts
Authors: Buracchio Teresa , Arvanitakis Zoe , Gorbien Martin
Published: September 2005

As life expectancy continues to increase over time, dementia is becoming an increasingly more common problem and a major cause of disability in older persons. It is now more important than ever to identify and manage common causes of dementia given variations in disease course, treatments and the possibility for modification of risk factors. Dementia with Lewy bodies (DLB) is a dementia syndrome characterized by progressive cognitive decline, with fluctuating cognition, recurrent detailed and well-formed hallucinations, and parkinsonism. This article aims to provide an overview of current concepts of DLB, including a description of the key clinical features and neuropathology, neurochemistry, and genetics of DLB, then a discussion of the relationship of DLB with Alzheimer’s disease and Parkinson’s disease, and, finally, a summary of current management strategies available for this disorder.
Effects of Desipramine and Escitalopram on Postprandial Symptoms Induced by the Nutrient Drink Test in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Talley Nicholas J. , Camilleri Michael , Chitkara Denesh K. , Bouras Ernest , Locke III G. Richard , Burton Duane , Rucker Mary Jo , Thapa Prabin , Zinsmeister Alan R.
Published: September 2005

Background: Antidepressants are widely used to treat functional gastrointestinal disorders but their effect on postprandial symptoms remains unstudied. We hypothesized that desipramine and escitalopram would enhance the maximum tolerated volume of nutrient ingested and decrease postprandial symptoms. Methods: Healthy participants (n = 45) all underwent an assessment of symptoms, anxiety and depression, and a standard nutrient drink test (Ensure). Participants were randomized to 11 days of desipramine (50 mg once daily), escitalopram (10 mg once daily) or identical placebo. Results: The maximum tolerated gastric volumes were not significantly different on day 11 for desipramine (1,136 ± 478 ml, mean ± SD), escitalopram (1,198 ± 422 ml) and placebo (1,231 ± 318 ml). A univariate analysis indicated significant treatment group effects on total symptom scores (p = 0.049), but after adjusting for age, gender, BMI and baseline scores, treatment effects were no longer significant (p = 0.15). Conclusions: While this study does not rule out a beneficial effect of tricyclics or selective serotonin reuptake inhibitors in functional dyspepsia, neither desipramine nor escitalopram significantly altered the nutrient volume ingested or symptoms induced by the nutrient drink test in healthy volunteers.
Adenosquamous Carcinoma of the Pancreas
Authors: Hsu Jun-Te , Yeh Chun-Nan , Chen Yi-Ru , Chen Han-Ming , Hwang Tsann-Long , Jan Yi-Yin , Chen Miin-Fu
Published: September 2005

Background/Aims: Adenosquamous carcinoma (ASC) of the pancreas is rare and correct preoperative diagnosis is difficult. Case reports of ASC of the pancreas are sporadic and have typically employed small series. This study investigated the clinicopathological features of 7 cases of ASC of the pancreas and reviewed the pertinent literature to elucidate this rare disease. Methodology: Seven patients (4 men and 3 women; age range 38–79 years; median 66 years) with ASC of the pancreas who underwent surgical treatment at Chang Gung Memorial Hospital between February 1993 and April 2000 were retrospectively reviewed. Results: Symptoms of ASC were as follows: abdominal pain (85.7%), body weight loss (85.7%), jaundice (42.9%) and anorexia (42.9%). The tumors were located at the head of the pancreas in 4 patients (57.1%), at the body in 2, and at the tail in 2. One patient had ASC at the body and tail. Most cases (5/7, 71.4%) were anemic. Seven (100%) and 5 patients (71.4%) had elevated serum CEA and CA19-9 levels, respectively. Curative pancreaticoduodenectomy was performed on 2 patients, bypass surgery on 3, and exploratory laparotomy on 2. Two patients underwent intraoperative radiotherapy. Three patients received postoperative adjuvant chemotherapy. No surgical mortality or morbidity occurred. Five of 7 patients (71.4%) died within 6 months after surgery. The median survival of the 7 patients was 4.41 months (range 1.12–22.42). Conclusions: Patients with ASC present symptoms similar to those of adenocarcinoma of the pancreas. Most patients had dismal prognosis despite aggressive surgery with or without adjuvant therapy.
Biphasic Effect of Prostaglandin E2 in a Rat Model of Esophagitis Mediated by EP1 Receptors: Relation to Pepsin Secretion
Authors: Yamato Masanori , Nagahama Kenji , Kotani Tohru , Kato Shinichi , Takeuchi Koji
Published: September 2005

We investigated the roles of prostaglandin (PG) E2 and cyclooxygenase (COX) isoenzymes in the mucosal defense of the esophagus, using subtype-selective EP agonists and antagonists as well as various COX inhibitors, in an acute rat esophagitis model. The animals were used after fasting for 18 h. Acid reflux esophagitis was induced by ligating both the pylorus and the transitional region between the forestomach and the glandular portion under ether anesthesia, and the damage was examined 3 or 4 h later. The esophageal lesions were significantly aggravated by prior administration of indomethacin and SC-560 (a selective COX-1 inhibitor) but not rofecoxib (a selective COX-2 inhibitor). PGE2 prevented these lesions at lower doses, yet the protective effect disappeared at a high dose. This biphasic effect was mimicked by 17-phenyl PGE2 (EP1 agonist) and antagonized by ONO-AE-829 (EP1 antagonist), while neither EP2, EP3, nor EP4 agonists had any effect on the esophageal lesions. PGE2 and 17-phenyl PGE2 had no effect on the acid secretion, but significantly increased the pepsin secretion, in a dose-dependent manner. The development of the esophageal lesions was totally prevented by pepstatin, a specific inhibitor of pepsin, and markedly aggravated by exogenous pepsin. We conclude that endogenous PGs derived from COX-1 are involved in the mucosal defense of the esophagus and that PGE2 has a biphasic influence on esophageal injury, depending on the dose: a protective effect at low doses and a deleterious effect at high doses, both mediated by EP1 receptors – the latter effect of PGE2 may be brought about by stimulation of the pepsin secretion.
Effect of Inhibition of Farnesylation and Geranylgeranylation on Renal Fibrogenesis in vitro
Authors: Masterson Rosemary , Kelynack Kristen , Hewitson Tim , Becker Gavin
Published: September 2005

Background: The Ras and Rho family of GTPases serve as essential molecular switches in the downstream signalling of many cytokines involved in the regulation of renal fibroblast activity. Prenylation is a post-translational process critical to the membrane localization and function of these GTPases. We studied the effects of a farnesyltransferase inhibitor BMS-191563 and geranylgeranyltransferase inhibitor GGTI-298 on renal fibrogenesis in vitro. Methods: Functional studies examined the effects of BMS-191563 and GGTI-298 on rat renal fibroblast kinetics, collagen synthesis and collagen gel contraction. Pro-collagen α1(I) mRNA expression was measured by Northern analysis and CTGF expression by Western blotting. Results: Fibroblast proliferation was significantly reduced by both agents. Exposure of fibroblasts to BMS-191563 resulted in a significant reduction in total collagen production and pro-collagen α1(I) mRNA expression, an effect also observed but to a lesser degree with GGTI-298. Both agents significantly reduced CTGF protein expression. Fibroblast-mediated collagen I lattice contraction was decreased at 48 h by GGTI-298, an effect not observed with BMS-191563. Consistent with this finding, marked actin filament disassembly was evident by phalloidin staining of fibroblasts exposed to GGTI-298. Conclusion: BMS-191563 and GGTI-298 exhibit different effects on renal fibroblast function reflecting their predominant roles in inhibiting prenylation of Ras or Rho proteins respectively. Further studies are warranted to establish their potential therapeutic application in the treatment of progressive renal disease.
Effects of Recombinant Human Thyrotropin on Heart Rate Variability and Blood Pressure in Patients on l-Thyroxine-Suppressive Therapy for Differentiated Thyroid Carcinoma
Authors: Murialdo G. , Casu M. , Cappi C. , Patrone V. , Repetto E. , Copello F. , Minuto F. , Giusti M.
Published: September 2005

Background: Recombinant human thyrotropin (rhTSH) is now currently used for the follow-up of patients with differentiated thyroid carcinoma (DTC) after total thyroid ablation. Side effects after rhTSH could involve the autonomic system and TSH receptors are possibly expressed in the heart and coronary arteries. Methods:Heart rate variability (HRV), studied by power spectral analysis of low (LF) and high frequency (HF) powers, blood pressure (BP) and their responses to orthostatism were investigated before and 3, 6, 9 days after the first of two administrations of rhTSH on alternate days in 11 patients on chronic l-thyroxine (l-T4) suppressive therapy for DTC and in 31 healthy controls. Results: A transient asymptomatic decrease in systolic and mean BP was observed during the rhTSH test, but rhTSH did not modify sympathovagal control of HRV and the lying to standing responses. Decreased LF power and LF/(LF + HF) and LF/HF ratios in DTC patients versus healthy controls indicated a sympathetic failure ascribed to the TSH-suppressive therapy with l-T4 rather than to direct effects of rhTSH. Conclusions: These findings allowed us to confirm the cardiovascular safety of rhTSH and the absence of its effects on sympathovagal control of HRV when used in the follow-up of patients with normal heart function after thyroid ablation for DTC.
A Clinical Study of Endoscopic Sinus Surgery for Sinusitis in Patients with Bronchial Asthma
Authors: Dejima Kenji , Hama Takemitsu , Miyazaki Makoto , Yasuda Shigenobu , Fukushima Kazuto , Oshima Akihiro , Yasuda Makoto , Hisa Yasuo
Published: September 2005

Background: An association between bronchial asthma and sinusitis has long been suspected. Our aim is to study the clinical features of chronic sinusitis associated with bronchial asthma as two manifestations of one airway disease. Methods: We conducted a prospective analysis of the outcome of 88 patients, with or without bronchial asthma, who underwent endoscopic sinus surgery (ESS) for chronic sinusitis. Patients were divided into two groups by the presence or absence of asthma and were evaluated. One surgeon performed the ESS, and the same postoperative treatment was given to both groups. The postoperative outcomes of symptoms and objective findings related to sinusitis were evaluated numerically, with a maximum score of 2 points for each examination item. Twenty-eight patients with asthma symptoms were assessed before and after surgery, using peak flow (liter/second) and medication scores (according to US Food and Drug Administration) to determine whether bronchial asthma was improved by first-time ESS. Results: The outcomes of ESS were signifi- cantly worse in the asthma group, especially the endonasal findings. Patients suffering from chronic sinusitis and bronchial asthma showed improvement following ESS in terms of their asthma symptoms, peak flow and medication score. Patients with a good ESS result tended to have the greatest improvement in their asthma. Conclusions: We conclude that sinusitis and asthma are closely related to each other, acting as two manifestations of one airway disease. We recommend treating cases of sinusitis complicated by asthma as a single disease of the entire respiratory tract.
Psychopathologic Correlates of Suicidal Ideation in Major Depressive Outpatients: Is It All Due to Unrecognized (Bipolar) Depressive Mixed States?
Authors: Akiskal Hagop S. , Benazzi Franco
Published: September 2005

Background: Recent transatlantic concern about suicidality in patients receiving antidepressants prompted us to examine the psychopathologic correlates of suicidal ideation occurring in clinically depressed patients. Methods: The study sample, which consisted of 644 consecutive major depressive outpatients, of which 58.0% had bipolar II disorder (BP-II), was systematically interviewed with the SCID, in order to delineate the diagnostic and psychopathologic correlates of suicidal ideation. Results: Such ideation, which was present in 49.5% [and favoring BP-II vs. major depressive disorder (MDD)] at an odds ratio (OR) of 1.3 (95% confidence interval = 0.98–1.8), was clinically significantly associated with depressive mixed state (racing/crowded thoughts and psychomotor agitation/activation during index depression), mood lability, decreased self-esteem, anorexia, as well as melancholic and psychotic features. Multiple logistic regression of suicidal ideation versus depressive symptoms and intradepressive excitatory symptoms revealed that decreased self-esteem (OR = 3.3), racing/crowded thoughts (OR = 1.5), and psychomotor agitation/activation (OR = 1.4) were independent and clinically significant correlates of suicidal ideation, irrespective of depression severity. Discussion: From a psychopathologic standpoint, suicidality might be conferred by a combination of both the excited (mixed) depressive and agitated (melancholic) clusters. Trait mood lability appears to favor the genesis of these affective clusters. Within the framework of Kraepelinian psychiatry, both clusters represent depressive mixed states. Given that such states are more prevalent in BP-II, our data provide a possible explanation for the greater suicidality in BP-II patients reported in the literature. In light of the higher odds of suicidal ideation in BP-II versus MDD patients, we hypothesize that the higher prevalence of mental and psychomotor activation in BP-II might be one factor among others that favors the greater likelihood of the transition from suicidal ideation to suicidal action in BP-II. Our analyses delineate a mixed depressive substrate at risk for suicidality. To what extent, if any, antidepressant monotherapy might contribute to the genesis of such states and/or suicidality cannot be answered with the methodology of the present study.
Henri Ey’s Neojacksonism and the Psychopathology of Disintegrated Mind
Authors: Farina Benedetto , Ceccarelli Maurizio , Di Giannantonio Massimo
Published: September 2005

The French psychiatrist Henri Ey developed his organo-dynamic theory of the mind function and consciousness 50 years ago incorporating Hughling Jackson’s thinking, along with psychiatric and philosophical theorizations by Janet and Bergson. This model has not received the attention it deserved, but recent advances in neuroscience rekindled interest for Ey’s theory. By overcoming the Cartesian mind-body dualism and treating the mind-body unit as an inseparable whole, this model opens the way for the integrated treatment of mental disorders. Ey’s conceptualization of consciousness as being simultaneously both synchronous and diachronic anticipates current theories of consciousness (Damasio, Edelman, Mesulam).
Peanut-Like 1 (Septin 5) Gene Expression in Normal and Neoplastic Human Endocrine Pancreas
Authors: Capurso Gabriele , Crnogorac-Jurcevic Tatjana , Milione Massimo , Panzuto Francesco , Campanini Nicoletta , Dowen Sally E. , Di Florio Alessia , Sette Claudio , Bordi Cesare , Lemoine Nicholas R. , Delle Fave Gianfranco
Published: September 2005

Peanut-like 1 (PNUTL1) is a septin gene which is expressed at high levels in human brain. There it plays a role in the process of membrane fusion during exocytosis by interacting with syntaxin and synaptophysin. As the secretory apparatus of pancreatic islet cells closely resembles that of neurons, we decided to study the expression of PNUTL1 in the human endocrine pancreas, both in normal islets and in pancreatic endocrine tumors (PETs). Normal pancreatic tissue, purified islets, 11 PETs and two cell lines were used to evaluate the presence of PNUTL1 by RT-PCR and Western blot. The expression of the PNUTL1 protein was also evaluated by immunohistochemistry on normal pancreas, additional 26 PETs, eight pancreatic adenocarcinomas, one mixed endocrine-exocrine pancreatic neoplasm, a specimen of solid papillary pseudomucinous tumor, an adult islet cell hyperplasia and a case of neonatal nesidioblastosis. In addition, a tissue array (LandMark High Density Cancer Tissue MicroArray) comprising 280 various tumor and matched normal specimens was utilized. In PETs, the expression of pancreatic hormones, chromogranin-A, synaptophysin and Ki-67 were also evaluated. In the normal pancreas PNUTL1 expression is almost exclusively confined to the islet cells, weak expression was occasionally seen in some acinar cells, while immunoreactivity was completely absent in the ductal epithelia. PNUTL1 expression is maintained at similar high levels in hyperplastic and neoplastic islet cells, but this did not correlate with any of the clinicopathological data nor with proliferation status in PETs. Weak immunoreactivity was also noted in a proportion of exocrine neoplasms. Our findings describe for the first time the high expression levels of PNUTL1 in human pancreatic endocrine cells that suggests a similar role of this protein in islet cells to that demonstrated in neuronal tissues, and warrants further functional studies of this protein.
Hemorrhoidal Ablation and Fixation: An Alternative Procedure for Prolapsing Hemorrhoids
Authors: Gupta Pravin J.
Published: September 2005

Background: Many new techniques have been evolved to curb the problem of post-operative pain after hemorrhoidectomy. Stapler hemorrhoidopexy and Doppler-guided hemorrhoidal artery ligation are the two methods gaining popularity amongst proctologists. The author proposes another technique called radiofrequency ablation and fixation of hemorrhoids to add to this list. Patients and Methods: The surgical technique and clinical follow-up of 410 patients operated by this technique are presented. An Ellman radiofrequency generator was used for hemorrhoidal ablation at the output power intensity of 80. Post-defecation pain and pain at rest were assessed using a visual analogue scale. Patient satisfaction score was calculated at the mean follow-up of 60 months (range 48–72). The results in terms of mean hospital stay, post-operative pain, post-operative complications, and period of incapacity for work were compared with the published data of results of stapled hemorrhoidopexy and Doppler-guided hemorrhoidal artery ligation. Results: Pain score at first evacuation was 6. The post-defecation pain score in the first week was 4 (range 3–6) and it was 3 (range 2–5) in the second week. The mean pain score at rest in the first week was 2 (range 1–4) and 1 (range 0–2) in the second post-operative week. In the long-term follow-up at a mean of 60 months, this procedure was found in most of the cases to control prolapse, discharge, and bleeding, with no stenosis or incontinence. The recurrence rate was less than 2%. The patient satisfaction score was high. Conclusion: The results of this technique of radiofrequency ablation and fixation of hemorrhoids hold positive promises in terms of less post-operative pain, early discharge from the hospital and faster return to work. The results are comparable to stapled hemorrhoidopexy and are better than Doppler-guided hemorrhoidal artery ligation in terms of effectiveness and symptomatic relief on a long-term basis.
Retrospective Analysis on Chinese Patients Diagnosed with Acute Renal Failure Hospitalized during the Last Decade (1994–2003)
Authors: Wang Yue , Cui Zhuan , Fan Minhua
Published: September 2005

Objectives: To investigate the epidemiology, diagnosis and prognosis of acute renal failure (ARF) in hospitalized Chinese during the last decade. Methods: The diagnosis of patients with ARF in Peking University Third Hospital from January 1994 to December 2003 was reconfirmed and the data of epidemiology, etiology and prognosis were analyzed. Results: Only 209 discharged cases were diagnosed with ARF and all were reconfirmed. Two peak occurrences were found at ages of 35–45 and 60–80 with a male predominance of approximately 59.7%. Patients diagnosed with ARF accounted for 1.19‰ of the admissions in the same period and increased significantly in the last 5 years (p = 0.038). The creatinine level at diagnosis was 345.8 ± 122.6 µmol/l and had no significant change (p > 0.05). The percent of hospital-acquired ARF (HA-ARF) demonstrated a significant increase in 1999–2003 compared to 1994–1998 (p = 0.008). Intrarenal ARF accounted for 73.69% and was multifactorial, with drugs, infections and operations as leading causes. Renal biopsy was performed in 37.32% (78/209) with 53.84% (42/78) having acute interstitial nephritis. Maintenance dialysis was discontinued in 46.41% because their renal function completely or partially recovered. The overall mortality was 37.91% without improvement over time. The mortality was 6.25% for patients in nephrology department, but 65.51% in ICU (p < 0.001), and was 21.6% for patients in community-acquired ARF (CA-ARF), but 63.1% in HA-ARF (p < 0.001). Conclusions: During the past 10 years, the number of patients diagnosed with ARF has been rising in hospitalized Chinese. HA-ARF was the major source, and infections, drugs and operations were the leading causes. The diagnosis and prognosis of acute renal failure did not improve much in this population over the decade studied.