bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa
Authors: Fraczek Monika , Kurpisz Maciej
Published: February 2007

ABSTRACT: Epidemiological studies regarding male infertility have revealed that more and more infertile men suffer from acute or chronic inflammation of the genitourinary tract, which often occurs without any symptoms. The inflammatory reactions within the male genital tract are inevitably connected with oxidative stress. Growing evidence indicates that imbalance between prooxidative and anti‐oxidative substances in semen leads to metabolic and functional disorders of male germ cells and may be a primary cause of some types of infertility. The infectious factor and local tissue damage can lead to the infiltration of leukocytes to the inflammatory site. This is in an obvious way connected to the production and release of large amounts of reactive oxygen species (ROS), which trigger immune responses directed against the infectious agent, and the simultaneous secretion of numerous biological substances, thereby escalating the inflammation. Some of these factors are proteases and proinflammatory cytokines. Extended exposure of spermatozoa to ROS may lead to the peroxidation of sperm membrane lipids. Many studies point to the combined activities of inflammatory mediators in exerting toxic effects on spermatozoa. The local influences of biologically active substances released by activated leukocytes in the course of the inflammatory response and the mutual interactions of various factors (bacteria, leukocytes, proinflammatory cytokines) at the site represent a complex puzzle.
Spermatozoa Have Decreased Antioxidant Enzymatic Capacity and Increased Reactive Oxygen Species Production During Aging in the Brown Norway Rat
Authors: Weir Cameron P. , Robaire Bernard
Published: February 2007

ABSTRACT: As the proportion of aged males attempting to reproduce continues to rise, so does the concern regarding the quality of spermatozoa from aged men. An imbalance between the generation of reactive oxygen species (ROS) and cellular antioxidant defenses, as occurs in aging, ultimately leads to decreased protein, lipid, and DNA quality. Spermatozoa are highly susceptible to oxidative damage, and thus an age‐related shift in redox status may have serious implications for fertility. Therefore, we examined the effect of age on antioxidant enzymatic activity, ROS production, and extent of lipid peroxidation in both caput and cauda epididymal spermatozoa from young (4‐month‐old) and old (21‐month‐old) Brown Norway rats. Glutathione peroxidase (Gpx1, Gpx4) and superoxide dismutase (SOD) enzymes had decreased activity in aging spermatozoa. Immunofluorescence studies indicated that Gpx4 expression was decreased in both the head and midpiece regions of spermatozoa in aged animals. The decrease in nuclear Gpx4 points to a novel potential mechanism that may explain the previously noted decreased levels of protamine disulfide bonds in aged sperm nuclei. Further, hydrogen peroxide (H2O2) and superoxide (O2•–) production were increased significantly in aging spermatozoa. Finally, lipid peroxidation was found to be drastically increased in aged spermatozoa. Taken together, these results suggest a decreased capacity for aged spermatozoa to handle oxidative stress and provide a potential basis for understanding the underlying cause of decreased quality of spermatozoa during aging.
Frontal Sinus Surgery: Endoscopic Technique and Preliminary Results
Authors: Friedman Michael , Landsberg Roee , Schults Roman A. , Tanyeri Hasan , Caldarelli David D.
Published: February 2007

Endoscopic frontal sinus surgery, once the last frontier in the evolution of endoscopic sinus surgery. is considered difficult, risky to the patient. and likely to result in a high failure rate. We clarify the surgical anatomy for frontal sinus surgery that, based on a review of our data, provides safe and predictable access to the frontal sinus. We studied 200 consecutive patients with respect to indications, endoscopic and radiographic findings, results. and complications. The study will describe the technique in detail, including the following points: 1) computed tomography identification of the superior attachment of the uncinate process; 2) complete removal of the uncinate process, including its superior attachments, by using the microdebrider; 3) removal of the agger nasi cell, if present; and 4) verification of an open frontal sinus by a transillumination or image-guided system. Postoperative assessment of patients’ symptoms and the confirmation of a patent frontal sinus by office endoscopy and transillumination indicated a 90% patency for short-term follow-up (average 12.2 months). There were no major complications. Postoperative complications included frontal recess stenosis, polypoid mucosa occluding the frontal recess, and middle turbinate lateralization. All of these situations may lead to recurrence of infection and symptoms. In-depth understanding of anatomic variations of the uncinate process and precise surgical removal of its superior attachments provide surgical access to the frontal sinus that is based on the natural ostia and is, therefore, more likely to remain patent.
Acanthamoeba Rhinosinusitis: Charactetization, Diagnosis, and Treatment
Authors: Teknos Theodoros N. , Poulin Mark D. , Laruentano Arthur M. , Li Kasey K.
Published: February 2007

Nasal and paranasal sinus manifestations are among the most common presentations of the acquired immunodeficiency syndrome (AIDS). Several studies cite that as many as 70% of patients with this disease have symptoms referable to the head and neck, including a 30% prevalence of sinusitis. Although the bacteriology of sinusitis in this population is largely considered comparable to that of immunocompetent patients, several opportunistic pathogens have been identified, particularly when T-cell counts are low. This report identifies Acanthamoeba as a potentially fatal cause of rhinosinusitis in immunosuppressed patients. The pathogenesis, diagnosis. and treatment of this rare entity will be discussed and the literature reviewed.
Endoscopic Sinus Surgery in Patients with Cystic Fibrosis: An Analysis of Complications
Authors: Albritton Ford D. , Kingdom Todd T.
Published: February 2007

The application of endoscopic sinus surgery (ESS) for the management of paranasal sinus disease in patients with cystic fibrosis (CF) has been well described. Due to underlying medical issues such as acquired coagulopathies and advanced pulmonary, disease, perioperative morbidity is assumed to be higher in this group. The incidence and type of complications associated with CF patients undergoing ESS has not been previously described. We reviewed 52 consecutive endoscopic procedures in 41 patients with CF performed by a single surgeon over a 34-month period. This review focused on perioperative and postoperative complications. Additional clinical data gathered included estimated blood loss, length of procedure, coagulation laboratory studies, the presence of nasal polyposis, the use of nasal packing, pulmonary function status, and average hospitalization time. A total of six complications were identified-four immediate and two delayed. The perioperative or immediate complications included two cases of epistaxis, one case of periorbital ecchymosis, and one case of pulmonary hemorrhage. Delayed complications include one case of epistaxis and one case of intranasal scarring. In two of these six patients, length of hospitalization was prolonged for management of the associated complications. No study has specifically addressed complications of ESS in the CF patient. Our review demonstrates a complication rate of 11.5%, which compares favorably with the non-CF ESS complication rates of 0-17% reported in the literature. Critical to successful management of these patients is coordinated care delivered by the pediatrician or internist, the pulmonary specialist, the anesthesia team, and the otolaryngologist. In addition to a review of current literature, we discuss the overall management approach adopted at our institution and highlight elements thought to minimize morbidity.
The Effect of Corticosteroids in the Treatment of Experimental Sinusitis
Authors: Cable Benjamin B. , Wassmuth Zachary , Mann Eric A. , Hommer Dean , Connely George , Klem Christopher , Quance-Fitch Fonzie J. , Bolger William E.
Published: February 2007

Emerging evidence indicates that medically recalcitrant sinusitis may be associated with a prolonged and excessive state of inflammation rather than a simple bacterial infection. Corticosteroids have been anecdotally reported to be helpful in treating patients with sinusitis; however, there are no scientific studies documenting the safety and efficacy of corticosteroid therapy in sinusitis. To resolve the controversy over whether corticosteroids promote or inhibit the resolution of sinusitis, we present a prospective study of 80 rabbits with surgically introduced pseudomonal sinusitis that were then treated in one of four arms: control, ceftazidime, methylprednisolone, and ceftazidime with methylprednisolone. Sinus cavities were then evaluated after 5, 14, 21, and 28 days of treatment both by histologic inflammation grading and bacterial quantification. Results showed a significant decrease in bacterial loads in both the antibiotic and antibiotic with steroid arms over control animals, although no difference was seen between the two. Histologic grading showed a similar trend, although statistical significance was not obtained. Overall, this study demonstrated no clear advantage of steroids in the treatment of sinus infections using this model. At the same point, no significant reduction in the effectiveness of antibiotic therapy was seen with concurrent steroid use. A number of limitations of the animal model are noted and the need for human studies in this area is discussed.
Nasal Hyperreactivity to Methacholine Measured by Acoustic Rhinometry in Asymptomatic Allergic and Perennial Nonallergic Rhinitis
Authors: Márquez F. , Sastre J. , Hernández G. , Cenjor C. , Sanchez-Hernandez J. M. , Sánchez J. , Gutiérrez R. , Sanabria J.
Published: February 2007

This study was carried out to assess nasal response to different doses of methacholine and to evaluate the diagnostic possibilities of this test. Thirty-seven patients with allergic rhinitis induced by pollen (out of season), 16 with nonallergic rhinitis, and 25 normal subjects were evaluated. After provocation with saline, increasing doses of methacholine, ranging from 0.5 to 16 mg/mL, were applied. Nasal obstruction was assessed by acoustic rhinometry 10 minutes after each dose, the minimum cross-sectional area and the nasal volume in both fossae were obtained. Ipratropium bromide was applied after the last dose of methacholine to evaluate reversibility. After methacholine challenge with 0.5, 1, 2, and 4 mg/mL there was a statistically significant decrease (p < 0.05) in nasal area and volume in a dose-dependent manner in patients with allergic and nonallergic rhinitis in comparison with controls. A ROC (receiver-operating characteristic) analysis showed that a decrease in nasal volume ≥20% at methacholine concentration of 2 mg/mL is able to predict the presence of rhinitis (positive predicted value 93%, negative predicted value 79%) in 75% of subjects. The clinical relevance of this finding suggests that patients with symptomatic nonallergic rhinitis or even asymptomatic patients with allergic rhinitis out of pollen season present a nasal hyperreactivity to methacholine, and that a decrease of nasal volume >20% by acoustic rhinometry after challenge with methacholine at 2 mg/mL is able to discriminate these patients from normal subjects. This method seems to be a suitable tool in the diagnosis of rhinitis.
The Frontal Sinus Rescue Procedure: Early Experience and Three-Year Follow-Up
Authors: Kuhn Frederick A. , Javer Amin R. , Nagpal Kalpana , Citardi Martin J.
Published: February 2007

The frontal sinus rescue (FSR), first described in 1997, has now been performed on 24 patients (32 sides) over a period of three years. It is a functional endoscopic surgical approach to correct an iatrogenically scarred and obstructed frontal recess, which cannot be successfully opened via a normal endoscopic frontal sinusotomy approach. It is utilized primarily for patients whose only remaining option is either a Draf-type drill-out (modified intranasal Lothrop) procedure or frontal sinus obliteration. The FSR is a technically challenging procedure, but faster, less difficult, and less destructive for the patient than a “drill-out” or frontal sinus obliteration. Once learned, it can save the patient from undergoing the more radical drill-out or obliterative procedure. The early experience and three-year follow-up with this new endoscopic procedure is presented in our first 24 patients (32 sides).
Endoscopic Ligation of the Sphenopalatine Artery for Refractory Posterior Epistaxis
Authors: Wormald Peter John , Wee Desmond T. H , van Hasselt C. Andrew
Published: February 2007

The management of patients with posterior epistaxis remains a challenging problem for the ENT surgeon. In most units, failure of conservative management results in more invasive techniques, involving either major artery ligation or percutaneous embolization of the internal maxillary artery. However, there are complications in more than 25% of patients undergoing these techniques. Endoscopic ligation of the sphenopalatine artery (ELSPA) is emerging as a minimally invasive alternative. We report our experience of ELSPA in 13 patients with a mean follow-up of 13 months. Epistaxis was controlled in 92% and to date no complications have been associated with the procedure. We conclude that ELSPA is a treatment option that is easy to perform and is safe and effective for patients with refractory posterior epistaxis.
Effects of Fibrin Sealant-Containing Antibiotics in a Rabbit Model of Chronic Sinusitis
Authors: Schlosser Rodney J. , Spotnitz William D. , Rodeheaver George , Scheld W. Michael , Iezzoni Julia , Gross Charles W.
Published: February 2007

Postoperative complications of sinus surgery include bleeding, infection, and synechiae. Improved subjective outcomes in humans treated with fibrin sealant (FS) after endoscopic sinus surgery (ESS) have been reported. Streptococcus pneumoniae was used to initiate chronic sinusitis in occluded rabbit sinuses in order to evaluate the role of FS in mucosal healing. Six weeks later, all animals had maxillary antrostomies. Homologous FS-containing ciprofloxicin (100 mg/mL) and clindamycin (15 mg/mL) was applied topically to treatment rabbits (n = 9). Control rabbits (n = 10) received no antibiotics. Two weeks into the recovery phase after antrostomies, all animals were re-examined. Mucociliary transport velocity (mean ± standard deviation in mm/minute) was measured in all sinuses (n = 38) during healthy (100% measurable, 13.82 ± 4.16), infected (18% measurable, 4.74 ± 0.42), and recovery phases (5% measurable, 6.30 ± 4.67). In both groups, mucopurulent discharge was present in the majority of sinuses (control group 18/20, FS group 16/18). In addition, there was no significant difference in the recovery phase between the two groups when comparing changes in the size of antrostomies, light microscopy, or culture clearance. Scanning electron microscopy did suggest a possible improvement in ciliary regeneration in the FS group. Application of FS-containing antibiotics did not appear to improve healing after ESS in our rabbit model of chronic sinusitis.
Allergic Fungal Sinusitis: Learning from Our Failures
Authors: Marple Bradley F. , Mabry Richard L.
Published: February 2007

For more than five years, patients referred to the Department of Otolaryngology–Head and Neck Surgery at the University of Texas Southwestern Medical Center at Dallas with allergic fungal sinusitis (AFS) have been managed using a regimen combining surgery, perioperative corticosteroids, and immunotherapy for relevant antigens (fungal and non-fungal). The initial success of this program has been previously reported. Continued experience with this treatment plan, however, has yielded some cases of recurrence of AFS. Careful review of these cases implicate two major factors associated with treatment failure: (1) lack of compliance with immunotherapy, and (2) inadequate initial surgical extirpation of all allergic mucin. These cases and associated factors will be discussed.
Endoscopic Diagnosis of Sarcoidosis in a Patient Presenting with Bilateral Exophthalmos and Pansinusitis
Authors: Damrose Edward J. , Huang Robert Y. , Abemayor Elliot
Published: February 2007

Sarcoidosis is a chronic granulomatous disease of unknown etiology. Otolaryngologic and ophthalmologic manifestations occur in 15 to 55% of afflicted individuals, respectively. Neck masses, parotid enlargement, and facial nerve palsy are the most common presenting otolaryngologic complaints, while lacrimal gland enlargement, uveitis, and upper eyelid masses often call the attention of the ophthalmologist. Biopsy reveals non-caseating granulomas, while the angiotensin converting enzyme (ACE) level may be elevated. We report an unusual case of a patient who presented with severe bilateral exophthalmos as the sole initial complaint. A prior workup included a negative conjunctival biopsy. On magnetic resonance imaging (MRI) and computed tomography (CT), the patient had pansinusitis. Endoscopic ethmoidectomies with tissue analysis revealed sarcoidosis. Further evaluation revealed no evidence of systemic disease, and all symptoms resolved with a course of oral steroids. Thus, nasal endoscopy and biopsy of affected paranasal sinus mucosa may prove a useful adjunct to the diagnosis of sarcoidosis, particularly in atypical cases.
Vermischte physikalische Bemerkungen
Authors: Parrot
Published: March 2007

Gänzliche Umschaffung der Hygrometrie; neue auf bewährte Versuche gegründete Theorie der wässerigen Meteore; jetziger Zustand und fernere Bearbeitung der Meteorologie. ‐ 2. Ueber Berthollet's Vertheidigung des Phosphor‐Eudiometers gegen Hrn. von Humboldt; Parrot's verbessertes Phosphor‐Oxygenometer und dessen Gebrauch; eine gasförmige Phosphorsäure; und den wahren Sauerstoffgehalt der atmosphärischen Luft. ‐ 3. Wie liessen sich Gewitter unschädlich machen?
High Frequency of Chimerism in Transplanted Livers
Authors: Ng Irene Oi-Lin , Chan Kok-Lung , Shek Wai-Hung , Lee Joyce Man-Fong , Fong Daniel Yee-Tak , Lo Chung-Mau , Fan Sheung-Tat
Published: March 2007

Recent studies have shown that primitive stem cells can mobilize and differentiate into hepatocytes. We investigated the time and extent in which cells of recipient origins could differentiate into hepatocytes and other cells in human liver allografts. Microsatellite analysis, which can assess quantitatively the proportions of recipient and donor DNA, was performed in posttransplantation liver biopsy specimens from 17 patients at various times. Combined fluorescence in situ hybridization (FISH) for Y chromosome and immunofluorescence for different cell types was also performed in 10 of these cases with sex mismatch. Organ chimerism in the transplanted livers was found to be of variable extent, and the recipients' DNA in the posttransplantation liver biopsy specimens (excluding portal tracts) amounted up to 50%. The recipient DNA in the posttransplantation liver biopsy specimens increased after liver transplantation by as early as 1 week, peaked at around 30 to 40 weeks, and could be shown 63 weeks after transplantation. Most (64%-75%) of the recipientderived cells showed macrophage/Kupffer cell differentiation. Only up to 1.6% of the recipient–derived cells in the liver grafts showed hepatocytic differentiation in the liver grafts and made up 0.62% of all hepatocytes of both donor and recipient origins. These livers had mild or minimal injury histologically. In conclusion, our results show that most of the recipient–derived cells in the liver allografts were macrophages/Kupffer cells and only a small proportion of hepatocytes was recipient derived. However, with regard to recipient–derived hepatocytes, our data cannot distinguish between transdifferentiation and cell fusion. (Hepatology 2003;38:989-998).
Effects of tilting on central hemodynamics and homeostatic mechanisms in cirrhosis
Authors: Møller Søren , Nørgaard Annette , Henriksen Jens H. , Frandsen Erik , Bendtsen Flemming
Published: March 2007

Patients with cirrhosis have a hyperdynamic circulation and an abnormal blood volume distribution with central hypovolemia, an activated sympathetic nervous system (SNS) as well as the renin-angiotensin-aldosterone system (RAAS). As the hyperdynamic circulation in cirrhosis may be present only in the supine patient, we studied the humoral and central hemodynamic responses to changes with posture. Twenty-three patients with alcoholic cirrhosis (Child-Turcotte-Pugh classes A/B/C: 2/13/8) and 14 healthy controls were entered. Measurements of central hemodynamics and activation of SNS and RAAS were taken in the supine position, after 30° head-down tilting, and after 60° passive head-up tilting for a maximum of 20 minutes. After the head-up tilting, the central blood volume (CBV) decreased in both groups, but the decrease was significantly smaller in patients than in controls (−19% vs. −36%, P < .01). Central circulation time increased only in the patients (+30% vs. −1%, P < .01). The absolute increases in circulating norepinephrine and renin after head-up tilting were significantly higher in the patients than in the controls (P < .05 and P < .01, respectively). In patients with cirrhosis, changes in SNS and RAAS were related to changes in arterial blood pressure, systemic vascular resistance, heart rate, non-CBV, plasma volume, and arterial compliance. In conclusion, cardiovascular and humoral responses to changes in posture are clearly abnormal in patients with cirrhosis. Head-up tilting decreases the CBV less in patients with cirrhosis, and the results suggest a differential regulation of central hemodynamics in patients with cirrhosis. (Hepatology 2004;40:811-819).
Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population
Authors: Piasecki Barbara A. , Lewis James D. , Reddy Rajender K. , Bellamy Scarlett L. , Porter Steven B. , Weinrieb Robert M. , Stieritz Donald D. , Chang Kyong-Mi
Published: March 2007

Hepatitis C virus (HCV) is spontaneously cleared in 15% to 45% of individuals during primary infection. To define the role of alcohol, race, and HBV or HIV coinfections in natural HCV clearance, we examined these parameters in 203 spontaneously HCV-recovered subjects (HCV Ab+/RNA- subjects without prior antiviral therapy) and 293 chronically HCV-infected patients (HCV Ab+/RNA+). Subjects were identified from 1,454 HCV antibody-seropositive US veterans tested for HCV RNA between January 2000 and July 2002 at the Philadelphia Veterans Affairs Medical Center. In univariate analysis, alcohol use disorder (odds ratio [OR] 0.52; 95% CI, 0.31-0.85; P = .006) and black race (OR 0.65; 95% CI, 0.44-0.96; P = .024) were both associated with decreased likelihood of spontaneous HCV clearance. In multivariate analyses adjusting for race, HIV infection, age, and alcohol use disorder, alcohol remained strongly associated with reduced HCV clearance (OR 0.49; 95% CI, 0.30-0.81; P = 0.005). In contrast, the association between black race and viral clearance was no longer statistically significant (adjusted OR 0.72; 95% CI, 0.48-1.09; P = .125). HIV coinfection was negatively associated with HCV clearance (OR 0.37; 95% CI, 0.16-0.83; P = .016), while HBV coinfection was positively associated with HCV clearance (unadjusted OR 5.0; 95% CI, 1.26-28.6; P = .008). In conclusion, the likelihood of spontaneous clearance of HCV may be influenced by alcohol and viral coinfections. (Hepatology 2004;40:892-899).
Peptide antibiotic human beta-defensin-1 and −2 contribute to antimicrobial defense of the intrahepatic biliary tree
Authors: Harada Kenichi , Ohba Kazuo , Ozaki Satoru , Isse Kumiko , Hirayama Toshiya , Wada Akihiro , Nakanuma Yasuni
Published: March 2007

Human beta-defensins (hBDs) are important antimicrobial peptides that contribute to innate immunity at mucosal surfaces. This study was undertaken to investigate the expression of hBD-1 and hBD-2 in intrahepatic biliary epithelial cells in specimens of human liver, and 4 cultured cell lines (2 consisting of biliary epithelial cells and 2 cholangiocarcinoma cells). In addition, hBD-1 and hBD-2 were assayed in specimens of bile. hBD-1 was nonspecifically expressed immunohistochemically in intrahepatic biliary epithelium and hepatocytes in all patients studied, but expression of hBD-2 was restricted to large intrahepatic bile ducts in 8 of 10 patients with extrahepatic biliary obstruction (EBO), 7 of 11 with hepatolithiasis, 1 of 6 with primary biliary cirrhosis (PBC), 1 of 5 with primary sclerosing cholangitis (PSC), 0 of 6 with chronic hepatitis C (CH-C), and 0 of 11 with normal hepatic histology. hBD-2 expression was evident in bile ducts exhibiting active inflammation. Serum C reactive protein levels correlated with biliary epithelial expression of hBD-2. Real-time PCR revealed that in all of 28 specimens of fresh liver, including specimens from patients with hepatolithiasis, PBC, PSC, CH-C and normal hepatic histology, hBD-1 messenger RNA was consistently expressed, whereas hBD-2 messenger RNA was selectively expressed in biliary epithelium of patients with hepatolithiasis. Immunobloting analysis revealed hBD-2 protein in bile in 1 of 3 patients with PSC, 1 of 3 with PBC, and each of 6 with hepatolithiasis; in contrast, hBD-1 was detectable in all bile samples examined. Four cultured biliary epithelial cell lines consistently expressed hBD-1; in contrast these cell lines did not express hBD-2 spontaneously but were induced to express hBD-2 by treatment with Eschericia coli, lipopolysaccharide, interleukin-1β or tumor necrosis factor-α. In conclusion, these findings suggest that in the intrahepatic biliary tree, hBD-2 is expressed in response to local infection and/or active inflammation, whereas hBD-1 may constitute a preexisting component of the biliary antimicrobial defense system. Supplementary material for this article can be found on the Hepatology website (http:/interscience.wley.com/jpages/0270-9139/suppmat/index.html). (Hepatology 2004;40:925-932).
Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP
Authors: Ledda-Columbano Giovanna M. , Pibiri Monica , Cossu Costanza , Molotzu Francesca , Locker Joseph , Columbano Amedeo
Published: March 2007

It has been shown that the magnitude of DNA synthesis and the time at which maximal DNA synthesis occurs after two-thirds partial hepatectomy (PH) is greatly reduced in the liver of aged rodents compared to young animals. This reduction could represent an intrinsic defect in proliferation or a more specialized change in the response to PH. We therefore evaluated the proliferative capacity of hepatocytes in aged animals, following treatment with primary liver mitogens. We show that treatment of 12-month-old CD-1 mice with the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) caused an increase in hepatocyte proliferation similar to that seen in young (8-week-old) mice. The labeling index was 82% in the livers of aged mice versus 76% in young animals. Histological observation demonstrated that the number of hepatocytes entering mitoses was similar in both groups; the mitotic indices were 2.5 per thousand and 2.7 per thousand, respectively. Additional experiments showed that the timing of DNA synthesis and M phase were nearly identical in both aged and young mice. Stimulation of hepatocyte DNA synthesis was associated with increased expression of several cell cycle-associated proteins (cyclin D1, cyclin A, cyclin B1, E2F, pRb, and p107); all were comparable in aged mice and young mice. TCPOBOP treatment also increased expression of the Forkhead Box transcription factor m1b (Foxm 1b) to a similar degree in both groups. In conclusion, hepatocytes retain their proliferative capacity in old age despite impaired liver regeneration. These findings suggest that therapeutic use of mitogens would alleviate the reduction in hepatocyte proliferation observed in the elderly. (Hepatology 2000;40:981-988).
Reduced oncotic necrosis in fas receptor-deficient C57BL/6J- lpr mice after bile duct ligation
Authors: Gujral Jaspreet S. , Liu Jie , Farhood Anwar , Jaeschke Hartmut
Published: March 2007

Neutrophils aggravate cholestatic liver injury after bile duct ligation (BDL). Recently, it was suggested that hepatocellular apoptosis might be critical for liver injury in this model. To test the hypothesis that apoptosis could be a signal for neutrophil extravasation and injury, we assessed parameters of apoptosis and inflammation after BDL using 2 different approaches: (1) wild-type and Fas receptor-deficient lpr mice of the C57BL/6J or C3H/HeJ strains, and (2) treatment with the pancaspase inhibitor z-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk)in C3HeB/FeJ mice. After BDL for 3 days, total cell death was estimated to be between 10% and 50% of all cells evaluated. However, less than 0.1% of hepatocytes showed apoptotic morphology in all 3 strains. Processing of procaspase-3, caspase-3 enzyme activities, and immunohistochemical staining for cytokeratin 18 cleavage products indicated no activation of caspases. Real-time reverse-transcriptase polymerase chain reaction analysis revealed increased expression of many inflammatory mediators but no effect on proapoptotic genes. More than 50% of all accumulated neutrophils were extravasated and colocalized with foci of oncotic hepatocytes and chlorotyrosine adducts. z-VAD-fmk treatment had no effect on apoptosis or liver injury after BDL but eliminated apoptosis after galactosamine/endotoxin in C3HeB/FeJ mice. In Fas receptor-deficient lpr mice (C57BL/6J), expression of inflammatory mediators, neutrophil accumulation and extravasation, chlorotyrosine adduct formation, and liver injury were reduced. This protection was not observed in lpr mice of the endotoxin-resistant C3H/HeJ strain. In conclusion, liver injury (oncotic necrosis) after BDL correlated with the severity of the inflammatory response. The minimal amount of apoptosis had no effect on inflammation or on the overall injury. (Hepatology 2004;40:998-1007).
Outfoxing liver cancer with p19ARF tumor suppressor?
Authors: Thorgeirsson Snorri S.
Published: March 2007

Hepatocellular carcinoma (HCC) is a leading cause of cancerrelated deaths worldwide. Here, we provide evidence that the Forkhead Box (Fox) m1b (Foxm1b or Foxm1) transcription factor is essential for the development of HCC. Conditionally deleted Foxm1b mouse hepatocytes fail to proliferate and are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol. The mechanism of resistance to HCC development is associated with nuclear accumulation of the cell cycle inhibitor p27 Kip1 protein and reduced expression of the Cdk1-activator Cdc25B phosphatase. We showed that the Foxm1b transcription factor is a novel inhibitory target of the p19ARF tumor suppressor. Furthermore, we demonstrated that conditional overexpression of Foxm1b protein in osteosarcoma U2OS cells greatly enhances anchorage-independent growth of cell colonies on soft agar. A p19ARF 26-44 peptide containing nine D-Arg to enhance cellular uptake of the peptide was sufficient to significantly reduce both Foxm1b transcriptional activity and Foxm1b-induced growth of U2OS cell colonies on soft agar. These results suggest that this (D-Arg)9-p19ARF 26-44 peptide is a potential therapeutic inhibitor of Foxm1b function during cellular transformation. Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors.
NMR functional imaging using a tailored RF gradient echo sequence: A true susceptibility measurement technique
Authors: Cho Zang‐Hee , Ro Yong‐Man , Park Sung‐Taek , Chung Sonn‐Chul
Published: March 2007

The tailored radio frequency gradient echo (TRFGE) technique that has been used in venography (Cho et al., Magn. Reson. Med. 28, 25‐38, 1992; Ro, Cho, Magn. Reson. Mod. 28, 237, 1992) is applied to functional imaging. The TRFGE technique has the advantage that it is sensitive to the field gradient created by the susceptibility effect, thereby enhancing only the signals from the regions with local field gradient In addition, the method is insensitive to the in‐flow effect, especially from the arterial blood. The latter further simplifies the functional MRI data analysis. The TRFGE sequence is, therefore, suitable for functional MR imaging for which true susceptibility effect measurements are of prime importance. To examine the TRFGE functional imaging systematically, experiments with various imaging parameters such as flip angle a, repetition time, and echo time were performed and the results were compared with the data obtained from the conventional gradient echo functional MR imaging. The experimental results shown were all obtained from human volunteers with a 2.0T whole body MRI system.
Temperature mapping using water proton chemical shift obtained with 3D‐MRSI: Feasibility in vivo
Authors: Kuroda Kagayaki , Suzuki Yutaka , Ishihara Yasutoshi , Okamoto Kazuya , Suzuki Yoshinori
Published: March 2007

This article discusses the applicability to a living animal of the temperature mapping method using the water proton chemical shift obtained with three‐dimensional magnetic resonance spectroscopic imaging (3D‐MRSI). There are several sources of error in obtaining the spectra with 3D‐MRSI: signal noise, limitation in the frequency resolution due to the finite signal length, intravoxel inhomogeneity in the static magnetic field, and variation in the magnetic field due to the eddy current magnetic field. A spectral estimation method called phase deduction complex Lorentzian fitting (PD‐CLF) was proposed. Numerical simulations demonstrated that this method reduces the error in the chemical shift to one third of that obtained with the simple frequency subtraction method that uses zero‐padded first Fourier transformation (FFT). The temperature images obtained using 3D‐MRSI with PD‐CLF clearly visualized the changes and distribution of temperature in an anesthetized rat.
Proton exchange rates from amino acid side chains— implications for image contrast
Authors: Liepinsh Edvards , Otting Gottfried
Published: March 2007

The proton exchange rates between water and the hydroxyl protons of threonine, serine, tyrosine, the amino protons of lysine, and the guanidinium protons of arginine were measured in the pH range 0.5 to 8.5 and for the temperatures 4°C, 10°C, 20°C, 30°C, and 36°C. The intrinsic exchange rates of the hydroxyl and amino protons at pH 7.0°C and 36°C were found to be in the range 700 to about 10,000 s−1. In addition, the exchange catalysis by phosphate, carbonate, carboxyl‐, and amino‐groups was investigated. The presence of these exchange catalysts at physiological concentrations increased the proton exchange rates from hydroxyl and amino groups several fold. The proton exchange rates are sufficiently fast that the total magnetization transfer between biomolecules and free bulk water is not rate limited by the proton exchange rate, but by the intramolecular cross‐relaxation rates between the exchangeable and nonexchangeable protons of the biomolecules. Since the cross‐relaxation rates between surface hydration water molecules and biomolecules are usually vanishingly small because of too rapid exchange with the free bulk water, it is proposed that the contrast in MR images is a fingerprint of the number of the exchangeable protons from OH and NH groups of the tissue, as far as the contrast depends on the magnetization transfer between biomolecules and water.
Use of nitroxides for assessing perfusion, oxygenation, and viability of tissues: In vivo EPR and MRI studies
Authors: Gallez Bernard , Bacic Goran , Goda Fuminori , Jiang Jinjie , O′Hara Julia A. , Dunn Jeff F. , Swartz Harold M.
Published: March 2007

Relative perfusion, pO2, and bioreduction were measured simultaneously in wVo in tissues in mice by following changes in the intensity and shape of the EPR spectra of nitroxides injected directly into the tissues, using low frequency (1.1 GHz) localized EPR spectroscopy. Using normal and blood flow restricted gastrocnemius muscles it was shown that the decrease of the EPR signals of the nitroxides in tissues was due principally to perfusion, which redistributed the nitroxides. Changes in pO2 were reflected by changes of the linewidth; only a perdeuterated nttroxide with a narrow line was an adequate indicator for this parameter. This technique was applied experimental murine tumors (MTG‐B and RIF‐1) to determine the perfusion and pO2 in these relatively hypoxic model tumor systems. Using the paramagnetic properties of the nitroxides to enhance T1‐weighted MR images, heterogeneity in perfusion in individual tumors was demonstrated.
Dynamic uncoupling and recoupling of perfusion and oxidative metabolism during focal brain activation in man
Authors: Frahm Jens , Krüger Gunnar , Merboldt Klaus‐Dietmar , Kleinschmidt Andreas
Published: March 2007

Changes in glucose consumption, lactate production, and blood oxygenation were measured during prolonged neuronal activation (4–6 min) in human primary visual cortex using dynamic magnetic resonance spectroscopy and imaging. A decrease of steady‐state glucose by 40% because of enhanced use by 21% was accompanied by a transient accumulation of lactate with a peak value of 170% 2.5 min after stimulation onset Rapid blood hyperoxygenation indicating „uncoupling”︁ of blood flow and oxidative metabolism was followed by a return to basal levels over 3 min. Thus, initial nonoxidative glucose consumption during functional activation is gradually complemented by a slower adjustment of oxidative phosphorylation that „recouples”︁ perfusion and oxygen consumption at a new equilibrium.
Continuous assessment of relative cerebral blood volume in transient ischemia using steady state susceptibility‐contrast MRI
Authors: Hamberg Leena M. , Boccalini Pia , Stranjalis George , Hunter George J. , Huang Zhihong , Halpern Elkan , Weisskoff Robert M. , Moskowitz Michael A. , Rosen Bruce R.
Published: March 2007

The utility of a noninvasive steady state susceptibility‐contrast MRI technique for continuous measurement of relative cerebral blood volume (rCBV) during global transient ischemia and subsequent hyperemia in a feline ischemia model is demonstrated. The measurements were obtained during a 10‐min period of occlusion and 1‐h period of reperfusion. Maximal hyperemic responses in gray matter, basal ganglia, and white matter (observed at 7,7, and 5 min, respectively) were 1.9 ± 0.5,1.8 ± 0.3, and 1.7 ± 0.6 times greater than baseline CBV (mean ± SEM). Thirty to forty minutes after onset of reperfusion, CBV returned to normal. Thereafter, it decreased below baseline, nearing the control level by 1 h after onset of reperfusion. Steady state susceptibility‐contrast MRI permits continuous, in vivo mapping of alterations in CBV.
Simultaneous multicompartment intracellular Ca2+ measurements in the perfused heart using 19F NMR spectroscopy
Authors: Yanagida Shigeki , Luo Cameron S. , Balschi James A. , Pohost Gerald M. , Pike Martin M.
Published: March 2007

Although Ca2+ transport regulation at subcellular organelles is of great interest, only limited methodology has been available for measuring organellar [Ca2+] levels. The present study employs the 19F NMR resonance frequency of 4F‐BAPTA to measure free [Ca2+]. In 4F‐BAPTA loaded perfused rabbit hearts, two 19F NMR resonances were clearly observed. The frequency of one was consistent with cytosolic [Ca2+] levels. Responses to agents that alter sarcoplasmic reticulum function identified the other resonance as originating from that organelle. The experiments demonstrate the utility of NMR shift indicator methodology in obtaining simultaneous multi‐compartment intracellular [Ca2+] measurements and in enabling organellar [Ca2+] measurements to be made from within intact living tissue.
Myocardial perfusion and function in dogs with moderate coronary stenosis
Authors: Kraitchman Dara L. , Wilke Norbert , Hexeberg Erik , Jerosch‐Herold Michael , Wang Ying , Parrish Todd B. , Chang Cheng‐Ning , Zhang Yi , Bache Robert J. , Axel Leon
Published: March 2007

MRI studies of first‐pass contrast enhancement with polylysine‐Gd‐DTPA and myocardial tagging using spatial modulation of magnetization (SPAMM) were performed to assess the feasibility of a combined regional myocardial blood flow and 2D deformation exam. Instrumented closed‐chest dogs were imaged at a baseline control state (Cntl) followed by two interventions: moderate coronary stenosis (St) achieved by partial occlusion of the left anterior descending (LAD) and moderate coronary stenosis with dobutamine loading (StD). Hypoperfusion of the anterior region (ANT) of the myocardium (LAD distribution) relative to the posterior wall (POS) based on the upslope of the signal intensity time curve from the contrast‐enhanced MR images was demonstrated only with dobutamine loading (ANT:POS Cntl=1.077 ± 0.15 versus ANT:POS StD=0.477 ± 0.11, P<0.03) and was confirmed with radio‐labeled microspheres measurements (ANT:POS Cntl=1.18 ± 0.2 ml/min/g versus ANT:POS StD=0.44 ± 0.1 ml/min/g; P<0.002). Significant changes in regional myocardial shortening were only seen in the StD state (P<0.02); the anterior region showed impaired myocardial shortening with dobutamine loading (P=NS), whereas the nonaffected POS region showed a marked increase in shortening when compared with Cntl (Cntl=0.964 ± 0.02 versus StD=0.884 ± 0.03; P<0.001). These results demonstrate that an integrated quantitative assessment of regional myocardial function and semiquantitative assessment of myocardial blood flow can be performed noninvasively with ultrafast MRI.
Evaluation of methemoglobin as an autologous intravascular MRI contrast agent
Authors: Duewell Stefan , Kasserra Claudia E. , Jezzard Peter , Balaban Robert S.
Published: March 2007

Methemoglobin (MetHb) was evaluated as an intravascular paramagnetic contrast agent. Methemoglobin formation was induced by 4‐dimethylaminophenol (4‐DMAP), causing a reduction in blood T2* in vitro. The 4‐DMAP generated metHb with a time constant of 62 s. A 4‐DMAP bolus did not decrease measurably the signal intensity in the in vivo rabbit kidney in the first pass. At steady state, a MetHb concentration of 24.8 ± 2.3% resulted in a signal decrease of 9.2 ± 2.6% in the kidney. Methemoglobin is an effective vascular T2* relaxation agent, but the formation of MetHb by 4‐DMAP is too slow for first‐pass imaging. A more effective conversion agent resulting in a bolus of at least 25% MetHb within 5 s would result in a detectable first‐pass signal and a viable contrast technique.
Substrate selection early after reperfusion of ischemic regions in the working rabbit heart
Authors: Solomon Michael A. , Jeffrey F. Mark H. , Storey Charles J. , Sherry A. Dean , Malloy Craig R.
Published: March 2007

Several substrates are available in vivo for oxidation by the myocardium. Although substrate selection has been studied extensively in normoxic myocardium, relatively little is known about substrate preference very early during reperfusion after ischemia. Carbon‐13 isotopomer analysis was used to study substrate usage by nonischemic and reperfused‐ischemic myocardium in a working heart that was subjected to 15 min of regional ischemia and reperfused for 5 min. Compared with nonischemic myocardium, the contribution of acetoacetate to acetyl coenzyme A was increased in the reperfused‐ischemic region, and the contribution of exogenous lactate was decreased. Free fatty acid oxidation, however, was not different in the two regions. These results indicate that (1) early during reperfusion, ketone body oxidation may be more significant than has been emphasized, (2) the relative contribution of fatty acids to acetyl coenzyme A is not sensitive to ischemia followed by reperfusion, and (3) Carbon‐13 magnetic resonance spectroscopy methods may be used for analysis of spatial heterogeneity of metabolism in the heart.
Automated feature extraction for the classification of human in vivo13C NMR spectra using statistical pattern recognition and wavelets
Authors: Tate A. Rosemary , Watson Des , Eglen Stephen , Arvanitis Theodores N. , Thomas E. Louise , Bell Jimmy D.
Published: March 2007

If magnetic resonance spectroscopy (MRS) is to become a useful tool in clinical medicine, it will be necessary to find reliable methods for analyzing and classifying MRS data. Automated methods are desirable because they can remove user bias and can deal with large amounts of data, allowing the use of all the available information. In this study, techniques for automatically extracting features for the classification of MRS in vivo data are investigated. Among the techniques used were wavelets, principal component analysis, and linear discriminant function analysis. These techniques were tested on a set of 75 in vivo 13C spectra of human adipose tissue from subjects from three different dietary groups (vegan, vegetarian, and omnivore). It was found that it was possible to assign automatically 94% of the vegans and omnivores to their correct dietary groups, without the need for explicit identification or measurement of peaks.
Analysis of localized quadratic encoding and reconstruction
Authors: Pipe James G.
Published: March 2007

Localized quadratic (LQ) encoding is a method of collecting multislice MRI data sets with greatly overlapping excited slices in such a way that the slice overlap can be deconvolved. This results in reconstructed data with resolution equal to the center‐to‐center slice spacing, regardless of the amount of excited slice overlap. LQ encoding is analyzed using the modulation transfer function of the encoding and reconstruction process. This allows analysis of many aspects of the technique in a well established theoretical framework. Many different characteristics of the method are explored, including excited slice profiles, required RF magnitudes and specific absorption rate, signal to noise ratio, signal dynamic range, reconstruction artifacts, sensitivity to motion, saturation and inflow effects, modulation transfer function shifting, and off‐resonance artifacts. It is suggested that this technique is best suited for applications currently using multiple thin‐slab three‐dimensional encoding.
Fast dynamic imaging using two reference images
Authors: Hanson Jill M. , Liang Zhi‐Pei , Wiener Erik C. , Lauterbur Paul C.
Published: March 2007

This paper presents a fast dynamic imaging method which is characterized by the acquisition of two high‐resolution reference images and a sequence of low‐resolution dynamic data sets. Image reconstruction is accomplished using a generalized series based algorithm. Experimental results demonstrate that dynamic images with high temporal resolution can be obtained while maintaining excellent spatial resolution. This method will be useful for a variety of dynamic imaging applications including contrast‐enhanced dynamic imaging and functional brain studies.