bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma hyperosmolality augments peripheral vascular response to baroreceptor unloading during heat stress
Authors: Ito Tomoyuki , Itoh Toshiyuki , Hayano Takashi , Yamauchi Katsuya , Takamata Akira
Published: April 2005

The aim of this study was to elucidate the interactive effect of central hypovolemia and plasma hyperosmolality on regulation of peripheral vascular response and AVP secretion during heat stress. Seven male subjects were infused with either isotonic (0.9%; NOSM) or hypertonic (3.0%; HOSM) NaCl solution and then heated by perfusing 42°C (heat stress; HT) or 34.5°C water (normothermia; NT) through water perfusion suits. Sixty minutes later, subjects were exposed to progressive lower body negative pressure (LBNP) to −40 mmHg. Plasma osmolality (Posmol) increased by ∼11 mosmol/kgH2O in HOSM conditions. The increase in esophageal temperature before LBNP was much larger in HT-HOSM (0.90 ± 0.09°C) than in HT-NOSM (0.30 ± 0.07°C) ( P < 0.01) because of osmotic inhibition of thermoregulation. During LBNP, mean arterial pressure was well maintained, and changes in thoracic impedance and stroke volume were similar in all conditions. Forearm vascular conductance (FVC) before application of LBNP was higher in HT than in NT conditions ( P < 0.001) and was not influenced by Posmol within the thermal conditions. The reduction in FVC at −40 mmHg in HT-HOSM (−9.99 ± 0.96 units; 58.8 ± 4.1%) was significantly larger than in HT-NOSM (−6.02 ± 1.23 units; 44.7 ± 8.1%) ( P < 0.05), whereas the FVC response was not different between NT-NOSM and NT-HOSM. Plasma AVP response to LBNP did not interact with Posmol in either NT or HT conditions. These data indicate that there apparently exists an interactive effect of Posmol and central hypovolemia on the peripheral vascular response during heat stress, or peripheral vasodilated conditions, but not in normothermia.
Effects of gravity and blood volume shifts on cardiogenic oscillations in respired gas
Authors: Montmerle Stéphanie , Linnarsson Dag
Published: April 2005

During the cardiac cycle, cardiogenic oscillations of expired gas ( x) concentrations (COS[ x]) are generated. At the same time, there are heart-synchronous cardiogenic oscillations of airway flow (COSflow), where inflow occurs during systole. We hypothesized that both phenomena, although primarily generated by the heartbeat, would react differently to the cephalad blood shift caused by inflation of an anti-gravity (anti-G) suit and to changes in gravity. Twelve seated subjects performed a rebreathing-breath-holding-expiration maneuver with a gas mixture containing O2 and He at normal (1 G) and moderately increased gravity (2 G); an anti-G suit was inflated to 85 mmHg in each condition. When the anti-G suit was inflated, COSflow amplitude increased ( P = 0.0028) at 1 G to 186% of the control value without inflation (1-G control) and at 2 G to 203% of the control value without inflation (2-G control). In contrast, the amplitude of COS of the concentration of the blood-soluble gas O2 (COS[O2/He]), an index of the differences in pulmonary perfusion between lung units, declined to 75% of the 1-G control value and to 74% of the 2-G control value ( P = 0.0030). There were no significant changes in COSflow or COS[O2/He] amplitudes with gravity. We conclude that the heart-synchronous mechanical agitation of the lungs, as expressed by COSflow, is highly dependent on peripheral-to-central blood shifts. In contrast, COS[blood-soluble gas] appears relatively independent of this mechanical agitation and seems to be determined mainly by differences in intrapulmonary perfusion.
Exercise-induced intrapulmonary shunting of venous gas emboli does not occur after open-sea diving
Authors: Dujić Željko , Palada Ivan , Obad Ante , Duplančić Darko , Brubakk Alf O. , Valic Zoran
Published: April 2005

Paradoxical arterializations of venous gas emboli can lead to neurological damage after diving with compressed air. Recently, significant exercise-induced intrapulmonary anatomical shunts have been reported in healthy humans that result in widening of alveolar-to-arterial oxygen gradient. The aim of this study was to examine whether intrapulmonary shunts can be found following strenuous exercise after diving and, if so, whether exercise should be avoided during that period. Eleven healthy, military male divers performed an open-sea dive to 30 m breathing air, remaining at pressure for 30 min. During the bottom phase of the dive, subjects performed mild exercise at ∼30% of their maximal oxygen uptake. The ascent rate was 9 m/min. Each diver performed graded upright cycle ergometry up to 80% of the maximal oxygen uptake 40 min after the dive. Monitoring of venous gas emboli was performed in both the right and left heart with an ultrasonic scanner every 20 min for 60 min after reaching the surface pressure during supine rest and following two coughs. The diving profile used in this study produced significant amounts of venous bubbles. No evidence of intrapulmonary shunting was found in any subject during either supine resting posture or any exercise grade. Also, short strenuous exercise after the dive did not result in delayed-onset decompression sickness in any subject, but studies with a greater number of participants are needed to confirm whether divers should be allowed to exercise after diving.
The Pathogenesis of Gastrointestinal Bacterial Overgrowth
Authors: Husebye Einar
Published: April 2005

The normal indigenous intestinal microflora consists of about 1015 bacteria that under physiological conditions reside mainly in the lower gastrointestinal tract. Bacterial overgrowth implies abnormal bacterial colonization of the upper gut, resulting from failure of specific defense mechanisms restricting colonization under physiological conditions. At present two types of bacterial overgrowth with defined pathogenesis can be distinguished: (1) gastric overgrowth with upper respiratory tract microflora resulting from selective failure of the gastric acid barrier, and (2) gastrointestinal overgrowth with Gram-negative bacilli (enteric bacteria) resulting from failure of intestinal clearance. Helicobacter pylori-induced gastritis of the oxyntic mucosa is the main cause of acquired failure of the gastric acid barrier, which is common among the healthy elderly. Intestinal clearance may fail as the result of impaired intestinal peristalsis or anatomical abnormalities that alter luminal flow. Impaired peristalsis is associated with conditions interfering with intestinal neuromuscular function including myopathic, neuropathic, autoimmune, infectious, inflammatory, metabolic, endocrine, and neoplastic diseases. Anatomical abnormalities are mainly the result of gastrointestinal surgery, intestinal diverticula or fistula. Combined failure of intestinal clearance and the gastric acid barrier results in more severe colonization with Gram-negative bacilli. Gram-negative bacilli are uncommon in the upper gut of otherwise healthy individuals with gastric hypochlorhydria, being acquired (H. pylori) or drug-induced. Significant bacterial overgrowth with Gram-negative bacilli is a rational in the search for an explanation to optimize clinical management. The clinical significance of colonization with upper respiratory tract microflora remains unclear. Translocation of live bacteria, their metabolic products, or antigens from a small bowel colonized by Gram-negative bacilli play a role in the pathogenesis of spontaneous bacterial peritonitis in hepatic disease and in certain types of sepsis, indicating that further studies can point to new patient populations with potential benefit from medical treatment.
Pathophysiology and Impact of Enteric Bacterial and Protozoal Infections: New Approaches to Therapy
Authors: Brito Gerly A.C. , Alcantara Cirle , Carneiro-Filho Benedito A. , Guerrant Richard L.
Published: April 2005

Despite numerous scientific advances in the past few years regarding the pathogenesis, diagnostic tools and treatment of infectious enteritis, enteric infections remain a serious threat to health worldwide. With globalization of the food supply, the increase in travel, mass food processing and antibiotic resistance, infectious diarrhea has become a critical concern for both developing and developed countries. Oral rehydration therapy has been cited as the most important medical discovery of the century due to the millions of lives that have been saved. However, statistics concerning diarrhea-induced mortality and the highly underestimated morbidity continue to demonstrate the severity of the problem. A more complete understanding of the pathogenesis of infectious diarrhea and potential new vaccines and effective treatments are badly needed. In addition, public health preventive actions, such as early detection of outbreaks, care with food, water and sanitation and, where relevant, immunization, should be considered a priority. This article provides an overview of the epidemiological impact, pathogenesis and new approaches to the management of enteric infections.
Rifaximin in the Treatment of Infectious Diarrhea
Authors: Ericsson Charles D. , DuPont Herbert L.
Published: April 2005

Rifaximin matches the criteria for an ideal agent for the treatment of infectious diarrhea. It has excellent activity against a broad range of enteropathogens. It is nonabsorbable, which may help explain its excellent side effect profile and lack of emergence of resistance because of high stool levels that are not likely to reach subinhibitory levels before the target Gram-negative bacilli are killed. It has shown excellent efficacy in numerous clinical trials of bacterial diarrhea. Because of the lack of systemic absorption and minimal adverse reactions, rifaximin should be useful in treating hosts such as pregnant women in whom the currently favored fluoroquinolones are contraindicated. Uses limited to enteric indications and its inherently low propensity to induce sustainable resistance among Gram-negative flora favor the sustained usefulness of rifaximin in the treatment of enteric infectious syndromes.
Antibiotic-Associated Diarrhea and Pseudomembranous Colitis: Are They Less Common with Poorly Absorbed Antimicrobials?
Authors: Surawicz Christina M.
Published: April 2005

Diarrhea is a well-known complication of antibiotic therapy. Rates of antibiotic-associated diarrhea (AAD) vary from 5 to 25%. Some antibiotics are more likely to cause diarrhea than others, specifically, those that are broad spectrum and those that target anaerobic flora. This paper reviews the effects of antibiotics on the fecal flora as well as host factors which contribute to AAD. Clinical features and treatment of AAD are also described. Prevention of AAD rests on wise antibiotic policies, the use of probiotics and prevention of acquisition in the hospital setting. Data from clinical trials suggest that poorly absorbed antimicrobials might have a decreased risk of causing AAD and Clostridium difficile-associated disease, as concluded from studies of antibiotics used for preoperative bowel decontamination and poorly absorbed antibiotics used for traveler’s diarrhea. Controlled trials would prove this but are not yet available. Probiotics may be a good adjunct to poorly absorbed antibiotics to minimize the risk of diarrhea associated with antibiotics.
Management of Hepatic Encephalopathy: Role of Rifaximin
Authors: Zeneroli Maria Luisa , Avallone Rossella , Corsi Lorenzo , Venturini Ivo , Baraldi Claudia , Baraldi Mario
Published: April 2005

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, which develops in patients with acute or chronic liver failure. It is widely accepted to be due to impairment of hepatic clearance of toxic products from the gut such as ammonia. Accumulation of ammonia induces a glutamate neurotoxicity leading to an increased tone of the γ-aminobutyric acid A (GABA-A) receptor system in the brain which results in HE. Factors either increasing the ammonia levels (protein load, constipation, sepsis, or gastrointestinal bleeding) or potentiating the functional activity of the GABAergic system [natural benzodiazepine-like compounds (NBZDs) or exogenous benzodiazepines] may act as precipitating factors of HE. NBZDs are present in trace amounts in the blood of normal subjects and have been found to be increased in the blood of patients with liver cirrhosis, with or without HE. These compounds may derive either from the diet since they have been found in plants, vegetables and animals or from gut bacteria. The observation that intestinal bacterial flora is involved in the production of both primary agent of HE (ammonia) and precipitating factors (NBZDs) suggests that the use of nonabsorbable antibiotics such as rifaximin may be useful in preventing episodes of HE in patients with liver cirrhosis.
Treatment of Small Intestine Bacterial Overgrowth and Related Symptoms by Rifaximin
Authors: Di Stefano Michele , Corazza Gino Roberto
Published: April 2005

The treatment of small intestine bacterial overgrowth should address different aims: the removal of the predisposing condition, guarantee of adequate nutritional support to reintegrate both caloric and vitamin requirements and, obviously, suppression of the contaminating bacterial flora, which represents the major goal. The polymicrobic nature of contaminating flora suggests the administration of wide-spectrum antibiotics, but until now there has been no conclusive information on the most effective therapeutic approach. In this paper, the efficacy of the different therapeutic approaches used is reviewed.
Management of Diverticular Disease: Is There Room for Rifaximin?
Authors: Papi Claudio , Koch Maurizio , Capurso Lucio
Published: April 2005

Treatment of symptomatic diverticular disease of the colon is aimed at the relief of symptoms and the prevention of major complications. The efficacy of fiber supplementation and of anticholinergic and spasmolytic agents remains controversial. Antibiotics are commonly used in the treatment of inflammatory complications of diverticular disease. Data from open labelled and randomized controlled trials do suggest the efficacy of rifaximin in obtaining symptomatic relief in patients with diverticular disease. Approximately 30% therapeutic gain compared to fiber supplementation only can be expected after one year of intermittent treatment with rifaximin. Considering the safety and tolerability of rifaximin, this drug can be recommended for patients with symptomatic uncomplicated diverticular disease.
Rifaximin, a Peculiar Rifamycin Derivative: Established and Potential Clinical Use Outside the Gastrointestinal Tract
Authors: Pelosini Iva , Scarpignato Carmelo
Published: April 2005

Rifaximin is a poorly absorbed semisynthetic rifamycin derivative with a broad spectrum of antibacterial activity including Gram-positive and Gram-negative bacteria, both aerobes and anaerobes. Although originally developed for the treatment of infectious diarrhea, the appreciation of the pathogenic role of gut bacteria in several organic and functional gastrointestinal diseases has increasingly broadened its clinical use. The availability of a topical formulation (a cream containing 5% of the drug) and the lack of transcutaneous absorption pointed out in both animal and human studies has allowed its topical use in skin infections. Furthermore, since the spectrum of antibacterial action of rifaximin includes many organisms (e.g. Bacteroides bivius-disiens, Gardnerella vaginalis, Haemophilus ducreyi) causing genital infections, including Trichomonas vaginalis and Chlamydia trachomatis, its local application in the treatment of bacterial vaginosis (BV) has been attempted. Finally, since periodontal disease, caused by plaque (an aggregate of various bacteria), can be considered a ‘local’ infection, intrapocket rifaximin was tried in the treatment of periodontal infections. While the efficacy in pyogenic infections of the skin has been confirmed by several investigations, which showed an improvement of both subjective and objective parameters significantly better than that of the reference drug (i.e. chlortetracycline or oxytetracycline), the usefulness of rifaximin in BV and periodontal disease needs to be further studied in well-designed clinical trials.
Vertiginous Complaints: Usual Presentation in Private Practice and Concrete Aspects of Care and Management
Authors: Toupet Michel , Chassany Olivier , Rothoft Jean-Marie , Bremaud des Ouillères Lucie
Published: April 2005

Context: Vertiginous complaints represent a frequent cause for consultations in the general practice. This symptom may result from a variety of disorders. They are often repetitive and invalidating. A rigorous diagnostic approach is required, based on interrogation and clinical examination. The relevant literature supplies surprisingly few data describing the problem in the daily practice, and no study exists in France. Aim: This survey describes the presentation mode of vertiginous complaints faced by general practitioners (GPs), their frequency, type (vertigo or disequilibrium), epidemiology and repercussions on the patients’ quality of life. It analyses also the diagnostic and therapeutic strategies used by GPs. Methods: A survey of 870 GPs was carried out in October and November 2001. Information was gathered by means of a questionnaire containing 11 items. Results: 699 questionnaires were selected for statistical analysis. The average number of consultations for vertiginous complaints is 4.9/week. In two thirds of cases, patients reported disequilibrium. The age of patients suffering from disequilibrium was significantly higher (61.06 ± 9.47) than that of patients suffering from vertigo (50.89 ± 10.21). In cases of vertigo, GPs first performed neurological and ENT investigations, while they performed vascular and then neurological and ENT investigations in cases of disequilibrium. Patients were referred to a specialist in 37% of cases, mainly due to the severity and permanence of symptoms. The most common therapeutic forms were medicinal followed by physiotherapeutic. A high impact upon all aspects of the patient’s life was observed and that vertigo could mask other severe illnesses due to its invalidating nature. Conclusion: Vertigo and disequilibrium represent the complaints of 5% of the patients seen by GPs in France. Further studies are needed to assess more specifically the repercussions of vertiginous complaints on the patient’s quality of life.
Chondrosarcoma of the Thyroid Cartilage
Authors: Yiotakis John , Ferekidis Eleutherios , Papadimitriou Nikolaos , Zervoudakis Dimitrios , Korres Stavros , Tzagaroulakis Antonios
Published: April 2005

Objectives: In the present case report, we describe a rare laryngeal chondrosarcoma of the thyroid cartilage in a woman to emphasize the specific clues that can lead the clinician to an early and accurate diagnosis. Methods: The clinical course of a 49-year-old female is presented and discussed. The up-to-date literature on the diagnosis, clinical behaviour, follow-up and treatment of this tumour is reviewed. Results and Conclusions: Laryngeal chondrosarcoma of the thyroid cartilage is a rare entity, especially in women. It is a slowly growing tumour easily confused with benign chondroma. The symptomatology depends on the pattern of growth. Hoarseness, dyspnoea, dysphagia and palpable neck mass are the symptoms most frequently encountered. A significant minority of the patients have no formal complaints. Special precautions during tissue sampling enable a reliable histological confirmation. Calcification within the cartilage in the CT should also alert the clinician to a possible chondrosarcoma. Organ preservation procedures are feasible and curative in early-stage disease.
Cancer-Related Anemia: Pathogenesis, Prevalence and Treatment
Authors: Birgegård Gunnar , Aapro Matti S. , Bokemeyer Carsten , Dicato Mario , Drings Peter , Hornedo Javier , Krzakowski Maciej , Ludwig Heinz , Pecorelli Sergio , Schmoll Hans-Joachim , Schneider Maurice , Schrijvers Dirk , Shasha Daniel , van Biesen Simon
Published: April 2005

Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin <12.0 g/dl) at enrollment, although the rate varied according to tumor type, disease status, and cancer treatment status. Of the patients who were not anemic at enrollment and started cancer treatment during the survey, those undergoing chemotherapy – either alone or in combination with radiotherapy – had the highest incidence of anemia (63 and 42%, respectively). Low hemoglobin levels correlated with poor performance status and only 40% of patients who were anemic at some time during the survey received treatment for their anemia. These findings are noteworthy, since a growing body of clinical evidence indicates that the treatment of anemia can significantly improve patients’ quality of life and may also improve the clinical outcome.
Cancer-Related Anemia: Biological Findings, Clinical Implications and Impact on Quality of Life
Authors: Blohmer Jens-Uwe , Dunst Jürgen , Harrison Louis , Johnston Patrick , Khayat David , Ludwig Heinz , O’Brien Mary , van Belle Simon , Vaupel Peter
Published: April 2005

Anemia is a common symptom in cancer patients. The relationship among anemia, cancer progression and clinical outcomes of cancer treatment is complex and much remains to be elucidated. One hypothesis for an etiological link is that anemia contributes to the development of tumor hypoxia, which in turn has been shown to induce proteomic and genomic changes within the tumor cells that ultimately favor malignant progression and treatment resistance. A substantial body of clinical data indicates that anemia can be a significant independent prognostic factor for treatment response and survival in cancer patients treated with chemotherapy or radiotherapy. In addition, studies have shown a correlation between anemia and decline in quality of life (QOL) in cancer patients. Of the many factors that impact cancer patients’ QOL, fatigue has emerged as the most prevalent, troubling, under-recognized and under-treated of all symptoms experienced by anemic cancer patients. Systematic correction of anemia with appropriate supportive therapies prior to or during chemotherapy or radiotherapy may enhance patients’ QOL.
Standard of Care for Cancer-Related Anemia: Improving Hemoglobin Levels and Quality of Life
Authors: Cortesi Enrico , Gascón Pere , Henry David , Littlewood Timothy , Milroy Robert , Pronzato Paolo , Reinhardt Uwe , Shasha Daniel , Thatcher Nicholas , Wilkinson Peter
Published: April 2005

The introduction of recombinant human erythropoietin (rHuEPO) has proven to be a major advance in the therapeutic options available for managing anemia in cancer patients. The results of placebo-controlled clinical trials and large, community-based, open-label studies have confirmed that epoetin alfa, a recombinant human erythropoietin, significantly reduces transfusion requirements, and reliably increases hemoglobin (Hb) levels in anemic (Hb level <12 g/dl) cancer patients undergoing chemotherapy. Increased Hb improves patients’ energy level and their ability to perform the activities of daily living, as well as their overall quality of life (QOL). These findings are independent of tumor type and disease status and are comparable in patients receiving nonplatinum- and platinum-based chemotherapeutic regimens. Furthermore, more than a decade of use in clinical trials and by physicians in routine clinical practice has demonstrated that epoetin alfa is safe and well tolerated when used to treat cancer patients with anemia. The availability of epoetin alfa as an alternative to transfusion has changed practices in anemia management; physicians can now treat anemia with the goal of achieving adequate Hb levels to relieve anemia-related fatigue, a major symptom contributing to decreased QOL in cancer patients. Incremental benefit analysis has shown that increasing Hb level from 11 g/dl to 12 g/dl yields the greatest improvement in QOL per 1 g/dl increase in Hb. The demonstrated efficacy of epoetin alfa for increasing Hb levels and improving patient QOL have made this agent a rationale choice for management of cancer-related anemia. Ongoing research will continue to provide new insights into best management of anemia with epoetin alfa in cancer patients.
Serum CA19-9 Measurement Increases the Effectiveness of Staging Laparoscopy in Patients with Suspected Pancreatic Malignancy
Authors: Connor S. , Bosonnet L. , Alexakis N. , Raraty M. , Ghaneh P. , Sutton R. , Neoptolemos J.P.
Published: April 2005

Background/Aims: Staging laparoscopy for suspected pancreatic neoplasia is not widely accepted due to its low yield. The aim of this study was to determine if serum carbohydrate antigen (CA19-9) levels could be used to improve the selection of patients for staging laparoscopy. Methods: The data from a prospectively collected database (1997–2004) with 159 patients who had computed tomography-predicted resectable disease and who had undergone laparoscopic staging were analysed to determine if a low preoperative CA19-9 level (≤150 kU/l, or ≤300 kU/l with a bilirubin >35 µmol/l) identified patients in whom laparoscopy was not useful. Results: The CA19-9 level was >150 kU/l in 96 patients of whom 75 (78%) were considered resectable following laparoscopic assessment. There were 63 patients with a CA19-9 ≤150 kU/l of whom 60 (95%) were considered resectable following laparoscopic assessment. The sensitivity, specificity, positive predictive value and negative predictive value for CA19-9 ≤150 kU/l in predicting that laparoscopic assessment would judge patients as resectable were 44, 88, 95 and 22%, respectively. A cut-off level of ≤300 kU/l in patients with a bilirubin >35 µmol/l produced values of 30, 94, 94 and 28%, respectively. By using CA19-9 ≤150 kU/l, laparoscopy could have been avoided in 40% of patients, increased to 55% of patients with adjustment for the presence of jaundice; concomitantly, the yield from laparoscopy would have been increased from 15 to 22 and 25%, respectively. Conclusion: Use of serum CA19-9 levels would increase the efficiency of laparoscopic staging in patients with suspected pancreatic malignancy.
Cellular Transfection to Deliver Alanine-Glyoxylate Aminotransferase to Hepatocytes: A Rational Gene Therapy for Primary Hyperoxaluria-1 (PH-1)
Authors: Koul Sweaty , Johnson Thomas , Pramanik Saroj , Koul Hari
Published: April 2005

Background: Primary hyperoxaluria-type 1 (PH-1) is a rare autosomal recessive disorder of glyoxalate metabolism caused by deficiency in the liver-specific peroxisomal enzyme alanine-glyoxalate transaminase 1 (AGT) resulting in the increased oxidation of glyoxalate to oxalate. Accumulation of oxalate in the kidney and other soft tissues results in loss of renal function and significant morbidity. The present treatment options offer some relief in the short term, but they are not completely successful. In the present study, we tested the feasibility of corrective gene therapy for this metabolic disorder. Methods: A cDNA library was made from HepG2 cells. PCR primers were designed for the AGT sequence with modifications to preclude mistargeting during gene delivery. Amplified AGT cDNA was cloned as a fusion protein with green fluorescent protein (GFP) using the vector EGFP-C1 (Clontech) for monitoring subcellular distribution. Sequence and expression of the fusion protein was verified. Fusion protein vectors were transfected into hepatocytes by liposomal transfection. AGT expression and subcellular distribution was monitored by GFP fluorescence. Results: HepG2 cells express full-length mRNA coding for AGT as confirmed by insert size as well as sequence determination. Selective primers allowed us to generate a modified recombinant GFP-AGT fusion protein. Cellular transfections with Lipofectamine resulted in transfection efficiencies of 60–90%. The recombinant AGT did localize to peroxisomes as monitored by GFP fluorescence. Conclusions: The results demonstrate preliminary in vitro feasibility data for AGT transfection into the hepatocytes. To the best of our knowledge, this is the first study to attempt recombinant AGT gene therapy for treatment of primary hyperoxaluria-1.
Esophageal Adenocarcinomas in Heterotopic Gastric Mucosa: Review and Report of a Case with Complete Response to Neoadjuvant Radiochemotherapy
Authors: von Rahden Burkhard H.A. , Stein Hubert J. , Becker Karen , Rüdiger Siewert J.
Published: April 2005

Adenocarcinomas are exceedingly rare in the cervical esophagus (26 reported cases), where squamous cell cancer (SCC) is the predominant tumor type. Esophageal heterotopic gastric mucosa (HGM) – a frequent remnant of incomplete replacement of the original columnar epithelium during the embryonic period – is suspected as cellular origin of cervical esophageal adenocarcinomas. As in any rare tumor entity, no standard treatment strategy is available for cervical esophageal adenocarcinomas. We herein report about the case of a 52-year-old man with a locally advanced, irresectable cervical esophageal adenocarcinoma originating in HGM. We decided on a neoadjuvant therapy (48.6 Gy + 5-FU/cisplatin) derived from experiences with SCC. Restaging showed an extraordinary good clinical response of the previously irresectable tumor. Subsequently the patient underwent limited cervical esophageal resection, lymphadenectomy and interposition of a free jejunal loop for reconstruction. Postoperative histopathological work-up of the specimen showed no residual tumor tissue, but unchanged HGM. This is the first case with complete response of a rare cervical esophageal adenocarcinoma to a neoadjuvant protocol. On 3-year follow-up the patient is doing fine with no complaints of dysphagia and no evidence of local or systemic recurrence.
At Least 2 Distinct Pathways Generating Reactive Oxygen Species Mediate Vascular Cell Adhesion Molecule-1 Induction by Advanced Glycation End Products
Authors: Basta Giuseppina , Lazzerini Guido , Del Turco Serena , Ratto Gian Michele , Schmidt Ann Marie , De Caterina Raffaele
Published: April 2005

Objective—

The interaction of advanced glycation end products (AGEs) with their main receptor RAGE in endothelial cells induces intracellular generation of reactive oxygen species (ROS) and the expression of vascular cell adhesion molecule (VCAM)-1. We investigated the role of distinct sources of ROS, including the mitochondrial electron transport chain, NAD(P)H oxidase, xanthine oxidase, and arachidonic acid metabolism, in AGE-induced VCAM-1 expression.

Methods and Results—

The induction of ROS and VCAM-1 by AGEs in cultured human umbilical vein endothelial cells was specifically blocked by an anti-RAGE antibody. The inhibition of NAD(P)H oxidase by apocynin and diphenylene iodonium, and of the mitochondrial electron transport system at complex II by thenoyltrifluoroacetone (TTFA), significantly inhibited both AGE-induced ROS production and VCAM-1 expression, whereas these effects were potentiated by rotenone and antimycin A, specific inhibitors of mitochondrial complex I and III, respectively. The inhibition of Cu/Zn superoxide dismutase inhibited both ROS and VCAM-1 induction, indicating that H
2
O
2
by this source is involved as a mediator of VCAM-1 expression by AGEs.

Conclusions—

Altogether, these results demonstrate that ROS generated by both NAD(P)H-oxidase and the mitochondrial electron transport system are involved in AGE signaling through RAGE, and indicate potential targets for the inhibition of the atherogenic signals triggered by AGE-RAGE interaction.
Proapoptotic Effects of Caspase-1/Interleukin-Converting Enzyme Dominate in Myocardial Ischemia
Authors: Syed Faisal M. , Hahn Harvey S. , Odley Amy , Guo Yiru , Vallejo Jesus G. , Lynch Roy A. , Mann Douglas L. , Bolli Roberto , Dorn Gerald W.
Published: April 2005

Caspase-1/interleukin-converting enzyme (ICE) is a cysteine protease traditionally considered to have importance as an inflammatory mediator, but not as an apoptotic effector. Because of the dual functions of this caspase, the pathophysiological impact of its reported upregulation in hypertrophy and heart failure is not known. Here, the consequences of increased myocardial expression of procaspase-1 were examined on the normal and ischemically injured heart. In unstressed mouse hearts with a 30-fold increase in procaspase-1 content, unprocessed procaspase-1 was well tolerated, without detectable pathology. Cardiomyocyte processing and activation of caspase-1 and caspase-3 occurred after administration of endotoxin or with transient myocardial ischemia. In post-ischemic hearts, procaspase-1 overexpression was associated with strikingly increased cardiac myocyte apoptosis in the peri- and noninfarct regions and with 50% larger myocardial infarctions. Tissue culture studies revealed that procaspase-1 processing/activation is stimulated by hypoxia, and that caspase-1 acts in synergy with hypoxia to stimulate caspase-3 mediated apoptosis without activating upstream caspases. These data demonstrate that the proapoptotic effects of caspase-1 can significantly impact the myocardial response to ischemia and suggest that conditions in which procaspase-1 in the heart is increased may predispose to apoptotic myocardial injury under conditions of physiological stress.
Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension
Authors: Yang Xudong , Long Lu , Southwood Mark , Rudarakanchana Nung , Upton Paul D. , Jeffery Trina K. , Atkinson Carl , Chen Hailan , Trembath Richard C. , Morrell Nicholas W.
Published: April 2005

Mutations in the bone morphogenetic protein type II receptor gene (
BMPR2
) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation contributes to the vascular remodeling observed in PAH, the role of BMPs in this process and the impact of
BMPR2
mutation remains unclear. Studies involving normal human pulmonary artery smooth muscle cells (PASMCs) suggest site-specific responses to BMPs. Thus, BMP-4 inhibited proliferation of PASMCs isolated from proximal pulmonary arteries, but stimulated proliferation of PASMCs from peripheral arteries, and conferred protection from apoptosis. These differences were not caused by differential activation of BMP signaling pathways because exogenous BMP-4 led to phosphorylation of Smad1, p38
MAPK
, and ERK1/2 in both cell types. However, the proproliferative effect of BMP-4 on peripheral PASMCs was found to be p38
MAPK
/ERK-dependent. Conversely, overexpression of dominant-negative Smad1 converted the response to BMP-4 in proximal PASMCs from inhibitory to proliferative. Furthermore, we confirmed that proximal PASMCs harboring kinase domain mutations in
BMPR2
are deficient in Smad signaling and are unresponsive to the growth suppressive effect of BMP-4. Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1. We conclude that defective Smad signaling and unopposed p38
MAPK
/ERK signaling, as a consequence of mutation in
BMPR2
, underlie the abnormal vascular cell proliferation observed in familial PAH.
Relation of Parity With Common Carotid Intima-Media Thickness Among Women of the Study of Health in Pomerania
Authors: Wolff Birger , Völzke Henry , Robinson Daniel , Schwahn Christian , Lüdemann Jan , Kessler Christof , John Ulrich , Felix Stephan B.
Published: April 2005

Background and Purpose—

Metabolic and hormonal changes associated with pregnancy and childbirth are assumed to contribute to the development of cardiovascular disease among women. We analyzed the association of parity with common carotid intima-media thickness (IMT), which has a predictive value of subsequent myocardial infarction and stroke.

Methods—

The Study of Health in Pomerania (SHIP), an epidemiological study of the general population in the northeast of Germany, included 1195 women aged 45 to 79 years. Mean and maximum far-wall IMT of the common carotid arteries were assessed by high-resolution ultrasound. All women were comprehensively characterized as to their reproductive history as well as to socioeconomic, behavioral, and biological risk factors.

Results—

There was a U-shaped association between the number of children (from 0 to ≥4) and mean and maximum IMT. Nulliparous women had the highest age-adjusted mean (0.81 mm [95% CI, 0.78 to 0.84]) and maximum IMT (1.04 mm [95% CI, 1.00 to 1.09]), and women with single parity the lowest (mean IMT, 0.73 [95% CI, 0.72 to 0.74]; maximum IMT, 0.91 mm [95% CI, 0.89 to 0.93];
P
<0.001 versus nulliparity for both parameters). Stepwise multivariate adjustment for socioeconomic factors, lifestyle variables, and biological variables attenuated the magnitude of this association yet significance remained.

Conclusions—

Nulliparity and higher number of children are associated with increased carotid IMT. These findings add support to the hypothesis of a link between the reproductive history of women and cardiovascular disease.
Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine
1A
Receptor–Dependent Mechanism
Authors: Mishima Kenichi , Hayakawa Kazuhide , Abe Kohji , Ikeda Tomoaki , Egashira Nobuaki , Iwasaki Katsunori , Fujiwara Michihiro
Published: April 2005

Background and Purpose—

Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice.

Methods—

Male MCA occluded mice were treated with cannabidiol, abnormal cannabidiol, anandamide, methanandamide, cannabidiol plus capsazepine, and cannabidiol plus WAY100135 before and 3 hours after MCA occlusion. The infarct size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Cerebral blood flow (CBF) was measured at, before and 1, 2, 3, and 4 hours after MCA occlusion.

Results—

Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume. Moreover, the neuroprotective effect of cannabidiol was inhibited by WAY100135, a serotonin 5-hydroxytriptamine
1A
(5-HT
1A
) receptor antagonist but not capsazepine a vanilloid receptor antagonist. Cannabidiol increased CBF to the cortex, and the CBF was partly inhibited by WAY100135 in mice subjected to MCA occlusion.

Conclusions—

Cannabidiol and abnormal cannabidiol reduced the infarct volume. Furthermore, the neuroprotective effect of cannabidiol was inhibited by WAY100135 but not capsazepine, and the CBF increased by cannabidiol was partially reversed by WAY100135. These results suggested that the neuroprotective effect of cannabidiol may be related to the increase in CBF through the serotonergic 5-HT
1A
receptor.
NAD(P)H Oxidases in Rat Basilar Arterial Endothelial Cells
Authors: Ago Tetsuro , Kitazono Takanari , Kuroda Junya , Kumai Yasuhiro , Kamouchi Masahiro , Ooboshi Hiroaki , Wakisaka Masanori , Kawahara Tsukasa , Rokutan Kazuhito , Ibayashi Setsuro , Iida Mitsuo
Published: April 2005

Background and Purpose—

Reactive oxygen species (ROS) may play a critical role in the regulation of vascular tone and development of vascular diseases, such as stroke. NAD(P)H oxidase is a major source of ROS in vascular cells, including endothelial cells. It has been considered that Nox2 and Nox4 are exclusively expressed among Nox homologues in the endothelial cells of noncerebral blood vessels. However, the precise molecular identity of the NAD(P)H oxidase in the endothelial cells of the cerebral arteries is not fully understood. We examined the expression of Nox homologues and their activation mechanism in the endothelial cells of the cerebral arteries.

Methods—

We isolated and cultured basilar artery endothelial cells (BAECs) of Sprague-Dawley rats. Expression of NAD(P)H oxidase was examined by reverse-transcription-polymerase chain reaction (RT-PCR) and immunohistological staining.

Results—

RT-PCR disclosed abundant expression of Nox4 with marginal Nox2 in BAEC. In addition, Nox1 was expressed highly both at mRNA and protein levels in BAECs. Immunohistological staining also showed the prominent expression of Nox1 in the endothelial cells of the basilar artery. With respect to the cytosolic components of NAD(P)H oxidases, BAECs expressed p67

phox

and, to a lesser extent, p47

phox

, Noxo1, and Noxa1. Both NADH and NADPH induced superoxide production of the BAEC membranes. The phagocyte-type cytosolic components, p47

phox

and p67

phox

, significantly enhanced the NADH-induced superoxide production of the BAEC membranes, whereas the components failed to increase the NADPH-induced superoxide production.

Conclusions—

Nox1 is highly expressed in the endothelial cells of the cerebral arteries along with Nox2 and Nox4, and the endothelial NAD(P)H oxidase of the cerebral arteries may have a unique activation mechanism by the phagocyte-type cytosolic components.
Unexpected Plural Inflections in Spanish: Reduplication and Metathesis
Authors: Harris James , Halle Morris
Published: April 2005

We examine the puzzling displacement in various Spanish dialects of a plural suffix from a verb where it is motivated semantically, syntactically, and morphologically onto a following clitic. We present previously unreported data and a new analysis of this material that succeeds where earlier efforts fail to provide a unified account of related phenomena. Our solution, which employs recent work on reduplication and metathesis, allows us to account for seemingly disparate phenomena as special cases of a single general framework and demonstrates that these operations are more versatile than previously thought. Directions for future research are indicated.
Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice
Authors: Tanaka Yoshihiko , So Takanori , Lebedeva Svetlana , Croft Michael , Altman Amnon
Published: April 2005

Although c-Maf is crucial for Th2 differentiation and production of interleukin 4 (IL-4), its regulation is poorly understood. We report that Vav1–/– CD4+ T cells display deficient T-cell receptor (TCR)/CD28-induced IL-4 and c-Maf expression and, conversely, enhanced interferon γ (IFN-γ) production and T-bet expression (even when cultured under Th2-polarizing conditions), but intact expression of other Th2 cytokines and GATA-3. Up-regulation of c-Maf was dependent on Ca2+/nuclear factor of activated T cell (NFAT) and, together with IL-4 production, could be rescued in Vav1–/– T cells by Ca2+ ionophore. Deficient IL-4 production was restored by retrovirus-mediated Vav1 expression, but only partially by retroviral c-Maf expression. Similar IL-4 → IFN-γ skewing was observed in intact, antigen-primed Vav1–/– mice. Thus, Vav1 is selectively required for IL-4 and c-Maf expression, a requirement reflecting, at least in part, the dependence of c-Maf expression on Ca2+/NFAT signaling.
PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC
Authors: Hampson Peter , Chahal Hema , Khanim Farhat , Hayden Rachel , Mulder Anneke , Assi Lakhvir Kaur , Bunce Christopher M. , Lord Janet M.
Published: April 2005

Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. We report here that PEP005 also has potent antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Of importance, PEP005 did not induce apoptosis in normal CD34+ cord blood myeloblasts at up to 2-log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent, and PEP005 efficacy correlated with expression of PKC-delta. The delta isoform of PKC plays a key role in apoptosis and is therefore a rational potential target for antileukemic therapies. Transfection of KG1a leukemia cells, which did not express PKC-delta or respond to PEP005, with enhanced green fluorescent protein (EGFP)-PKC-delta restored sensitivity to induction of apoptosis by PEP005. Our data therefore suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005. (Blood. 2005;106:1362-1368)
Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells
Authors: Nilsson Susan K. , Johnston Hayley M. , Whitty Genevieve A. , Williams Brenda , Webb Ryan J. , Denhardt David T. , Bertoncello Ivan , Bendall Linda J. , Simmons Paul J. , Haylock David N.
Published: April 2005

Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized critical role for Opn in regulation of the physical location and proliferation of HSCs. Within marrow, Opn expression is restricted to the endosteal bone surface and contributes to HSC transmarrow migration toward the endosteal region, as demonstrated by the markedly aberrant distribution of HSCs in Opn–/– mice after transplantation. Primitive hematopoietic cells demonstrate specific adhesion to Opn in vitro via β1 integrin. Furthermore, exogenous Opn potently suppresses the proliferation of primitive HPCs in vitro, the physiologic relevance of which is demonstrated by the markedly enhanced cycling of HSC in Opn–/– mice. These data therefore provide strong evidence that Opn is an important component of the HSC niche which participates in HSC location and as a physiologic-negative regulator of HSC proliferation.
PF4/heparin complexes are T cell–dependent antigens
Authors: Suvarna Shayela , Rauova Lubica , McCracken Emily K. E. , Goss Christina M. , Sachais Bruce S. , McKenzie Steven E. , Reilly Michael P. , Gunn Michael Dee , Cines Douglas B. , Poncz Mortimer , Arepally Gowthami
Published: April 2005

Heparin-induced thrombocytopenia (HIT) is a life-threatening, thrombotic disorder associated with development of anti–platelet factor 4 (anti-PF4)/heparin autoantibodies. Little is known about the antigenic and cellular requirements that initiate the immune response to these complexes. To begin to delineate mechanisms of autoantibody formation in HIT, we studied the immunizing effects of murine PF4 (mPF4)/heparin in mice with and without thymic function. Euthymic mice were injected with mPF4/heparin complexes, mPF4, heparin, or buffer. Mice injected with mPF4/heparin, but not mPF4 or heparin alone, developed heparin-dependent autoantibodies that shared serologic and functional characteristics of human HIT antibodies, including preferential binding to mPF4/heparin complexes and causing heparin- and FcRγIIA-dependent platelet activation. In contrast, athymic mice did not develop HIT-like antibodies. Taken together, these studies establish that PF4/heparin complexes are highly immunogenic and elicit self-reacting anti-PF4/heparin antibodies in a T cell–dependent manner.