bluuebunny/crossref_metadata_2025 huggingface dataset:
Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody
Authors: Dewan M. Zahidunnabi , Galloway Ashley E. , Kawashima Noriko , Dewyngaert J. Keith , Babb James S. , Formenti Silvia C. , Demaria Sandra
Published: August 2009

Purpose: This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti–CTLA-4 antibody.

Experimental Design: TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a “primary” site that was irradiated and a “secondary” site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy × 1, 8 Gy × 3, or 6 Gy × 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model.

Results: In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-γ production was proportional to the inhibition of the secondary tumor.

Conclusions: Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti–CTLA-4 antibody in two preclinical carcinoma models. (Clin Cancer Res 2009;15(17):5379–88)
Humanized Anti-Interleukin-6 Receptor Antibody Suppresses Tumor Angiogenesis and In vivo Growth of Human Oral Squamous Cell Carcinoma
Authors: Shinriki Satoru , Jono Hirofumi , Ota Kazutoshi , Ueda Mitsuharu , Kudo Mareina , Ota Tomoko , Oike Yuichi , Endo Motoyoshi , Ibusuki Mutsuko , Hiraki Akimitsu , Nakayama Hideki , Yoshitake Yoshihiro , Shinohara Masanori , Ando Yukio
Published: August 2009

Purpose: The biological effect of interleukin-6 (IL-6) signaling in oral squamous cell carcinoma (OSCC) and whether IL-6 receptor (IL-6R)-mediated signaling can be a therapeutic target for OSCC are unclear. The aim of this study was to investigate the effects of inhibition of IL-6R–mediated signaling on OSCC progression and to evaluate the availability of tocilizumab, a humanized antihuman IL-6R antibody, as a therapeutic agent for OSCC.

Experimental Design: We evaluated expression levels of IL-6 and IL-6R in 58 OSCC tissues and 4 OSCC cell lines by real-time quantitative reverse transcription-PCR and/or immunohistochemstry. We investigated the effects of tocilizumab on OSCC growth in vitro and in xenografts. Xenografts were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Ki-67, and CD31, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay was done.

Results: Expression levels of IL-6 at both mRNA and protein levels in OSCC tissues were significantly higher than those in normal mucosal tissues. In addition, OSCC cell lines expressed higher levels of both IL-6 and IL-6R mRNA than did HaCaT keratinocytes. Tocilizumab significantly reduced in vivo growth of SAS cells with a drastic reduction of STAT3 phosphorylation in tumor cells in mice. Inhibition of IL-6 signaling significantly decreased vascular endothelial growth factor mRNA expression in SAS, and microvessel density and vessel diameter in SAS tumors in tocilizumab-treated mice.

Conclusions: Therapeutic approaches targeting IL-6R by tocilizumab may be effective for OSCC treatment by at least inhibiting angiogenesis. (Clin Cancer Res 2009;15(17):5426–34)
Decreased Blood Flow with Increased Metabolic Activity: A Novel Sign of Pancreatic Tumor Aggressiveness
Authors: Komar Gaber , Kauhanen Saila , Liukko Kaisa , Seppänen Marko , Kajander Sami , Ovaska Jari , Nuutila Pirjo , Minn Heikki
Published: August 2009

Purpose: To study blood flow (BF) and metabolism in normal pancreas and in different pancreatic lesions. We then determined the effect of these biomarkers on outcome in patients with pancreatic cancer.

Experimental Design: Oxygen-15–labeled water and fluorodeoxyglucose positron emission tomography/computed tomography scans were used in 26 patients with a suspicion of pancreatic cancer to measure pancreatic BF and metabolism. In addition, the ratio of standardized uptake value to BF (SUV/BF) was calculated. Patients were divided into three groups: patients with a finding of normal pancreas (n = 7), benign lesions (n = 8), and malignant tumors (n = 11).

Results: Patients with benign and malignant pancreatic tumors had decreased BF of the lesion by 48% and 60%, respectively, compared with patients with normal pancreatic tissue. SUVmax was 3-fold higher in malignant tumors compared with both benign lesions and normal pancreas (P < 0.05). In contrast, the SUVmax of patients with benign lesions and normal pancreas did not differ. The SUV/BF ratio was significantly higher in malignant lesions than in benign lesions or in patients with normal pancreas (P < 0.05). In patients with cancer, high SUV/BF ratio was a stronger predictor of poor survival compared with high metabolism or lower-than-normal pancreatic BF.

Conclusions: BF in pancreatic cancer is significantly reduced compared with the normal pancreas, which may in part explain the poor success of both radiotherapy and chemotherapy. We suggest that the composite measurement of BF and metabolism in pancreatic cancer could serve as a novel tool in the planning of treatments targeting vasculature. (Clin Cancer Res 2009;15(17):5511–7)
A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies
Authors: Chien Amy J. , Illi Julie A. , Ko Andrew H. , Korn Wolfgang M. , Fong Lawrence , Chen Lee-may , Kashani-Sabet Mohammed , Ryan Charles J. , Rosenberg Jonathan E. , Dubey Sarita , Small Eric J. , Jahan Thierry M. , Hylton Nola M. , Yeh Benjamin M. , Huang Yong , Koch Kevin M. , Moasser Mark M.
Published: August 2009

Purpose: Systemic chemotherapy fails to access much of the tumor burden in patients with advanced cancer, significantly limiting its efficacy. In preclinical studies, brief high doses of tyrosine kinase inhibitors (TKI) targeting the human epidermal growth factor receptor (HER) family can prime tumor vasculature for optimal chemotherapeutic delivery and efficacy. This study investigates the clinical relevance of this approach.

Experimental Design: A phase I clinical study of escalating doses of the HER TKI lapatinib given as a 2-day pulse before a weekly infusion of nab-paclitaxel (100 mg/m2) was conducted in patients with advanced solid tumors.

Results: Twenty-five patients were treated. Treatment was associated with grade 1 to 2 toxicities including diarrhea, nausea, rash, neutropenia, neuropathy, fatigue, alopecia, and anemia. The two dose-limiting toxicities were grade 3 vomiting and grade 4 neutropenia, and the maximum tolerated dose of lapatinib was defined as 5250 mg/day in divided doses. Lapatinib concentrations increased with increasing dose. Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse. Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory.

Conclusion: A 2-day pulse of high-dose lapatinib given before weekly nab-paclitaxel is a feasible and tolerable clinical regimen, suitable for testing this novel vascular-priming chemosensitization hypothesis developed in preclinical models. (Clin Cancer Res 2009;15(17):5569–75)
[11C]Choline Positron Emission Tomography in Estrogen Receptor–Positive Breast Cancer
Authors: Contractor Kaiyumars B. , Kenny Laura M. , Stebbing Justin , Al-Nahhas Adil , Palmieri Carlo , Sinnett Dudley , Lewis Jacqueline S. , Hogben Katy , Osman Safiye , Shousha Sami , Lowdell Charles , Coombes R. Charles , Aboagye Eric O.
Published: August 2009

Purpose: Novel radiotracers could potentially allow the identification of clinically aggressive tumor phenotypes. As choline metabolism increases during malignant transformation and progression of human mammary epithelial cells, we examined the ability of [11C]choline (CHO) positron emission tomography imaging to detect clinically aggressive phenotype in patients with estrogen receptor (ER)–positive breast cancer in vivo.

Experimental Design: CHO positron emission tomography was done in 32 individuals with primary or metastatic ER–positive breast cancer. Semiquantitative (standardized uptake value) and fully quantitative (net irreversible transfer rate constant of CHO, Ki) estimates of CHO uptake in the tumors were calculated and compared with tumor grade, size, involved nodes, and also ER, progesterone receptor, Ki-67, and human epidermal growth factor receptor-2 scores.

Results: Breast tumors were well visualized in 30 of 32 patients with good tumor background ratios. A wide range of uptake values were observed in primary and metastatic tumors. CHO uptake variables correlated well with tumor grade. For most imaging variables, a poor association was found with tumor size, ER, progesterone receptor, human epidermal growth factor receptor-2, Ki-67, and nodal status.

Conclusions: CHO showed good uptake in most breast cancers and merits further investigation as a breast cancer imaging agent. (Clin Cancer Res 2009;15(17):5503–10)
Complexity Made Simple in Diffuse Large B-Cell Lymphoma
Authors: Aster Jon , Kutok Jeffery
Published: August 2009

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease and response to therapy is difficult to predict. An algorithm to sort DLBCL cases using a series of five immunohistochemical markers (GCET1, CD10, BCL6, MUM1, FOXP1) accurately predicts survival in patients treated with current chemotherapeutic regimens. (Clin Cancer Res 2009;15(17):5291–3)
NF-κB activation in endothelial cells is critical for the activity of angiostatic agents
Authors: Tabruyn Sebastien P. , Mémet Sylvie , Avé Patrick , Verhaeghe Catherine , Mayo Kevin H. , Struman Ingrid , Martial Joseph A. , Griffioen Arjan W.
Published: August 2009

In tumor cells, the transcription factor NF-κB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. From these data, a protumorigenic role of NF-κB has emerged. Here, we examined in endothelial cells whether NF-κB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-κB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-κB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-κB activity was required for the angiostatic activity, because inhibition of NF-κB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-κB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-κB inhibitors may therefore be revisited because NF-κB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer. [Mol Cancer Ther 2009;8(9):2645–54]
Do Chinese Speakers Need a Specialized Cochlear Implant System?
Authors: Tong Michael Chi-Fai , Lee Kathy Yuet-Sheung
Published: August 2009

Background: Cochlear implants are a standard treatment option for the profoundly deaf, but have only recently become a treatment option in China. Chinese is a tonal language, and a change in the lexical tone almost always changes the meaning of a word. Methods: A critical review of the strategies for improving the outcome of cochlear implantation in Chinese speakers was made. Results: The introduction of cochlear implantation in China has stimulated the development of new speech perception tests, which are specific to Chinese, for adults and children. Research undertaken over the last decade in Hong Kong has demonstrated the successful acquisition of tones in adults and children who have received cochlear implants. Surgical approaches have been developed to address specific issues, including post-irradiation and infected ears. New areas of research into the enhancement of speech understanding through signal processing have been established. Conclusions: The findings in these new areas will form the basis of a cochlear implant system for Chinese people in the near future.
Cochlear Implantation in China: Review of 1,237 Cases with an Emphasis on Complications
Authors: Ding Xiuyong , Tian Hao , Wang Weiwei , Zhang Daoxing
Published: August 2009

Objective: The purpose of this study is to retrospectively review the complications of patients who underwent cochlear implantation at 51 hospitals in mainland China over a decade. Methods: A retrospective analysis of 1,237 patients who underwent cochlear implantation from February 1998 to December 2008. The patients were reviewed for demographic information, type of hearing loss, abnormal findings on temporal CT scans, cochlear implant device, procedure time, and complications that included meningitis, hematoma (intracranial and extracranial), wound infection and implant extrusion, cerebrospinal fluid leak and facial palsy. Results: A total of 1,237 patient records were identified, and pertinent clinical information was reviewed. Of the patients, 59.6% were male, and 98.9% were prelingually deaf. The most common etiologies of hearing loss were: ototoxicity (28.1%), non-syndromic congenital hearing loss (14.8%), and inner ear malformation (18.5%). Inner ear malformations included: enlarged vestibular aqueduct (9.4%), Mondini defect (5.4%), common cavity (2.8%), cochlear ossification (3.9%), round window dysplasia (0.4%), and narrow internal auditory meatus (1.2%). The most common intraoperative complications were: gusher (5%) and electrode kinking (2.3%). The most common postoperative complications were hematoma (1.7%), wound infection and implant extrusion (0.5%), and device failure (0.9%). No CSF leakage or permanent facial palsy occurred. Conclusions: Cochlear implantation is a safe and reliable otosurgical procedure in China, and the rate of complications is similar to developed countries. Carefully preoperative preparation and standardization of the procedure are important for the development of cochlear implant programs in developing countries.
Integrated Profile to Assess Auditory Nerve-Auditory Pathway Integrity
Authors: Kong Wei-Jia , Cheng Hua-Mao , Wang Yan-Jun , Zhang Su-Lin , Liu Wei , Ma Hui , Han Ping , Kong Xiang-Quan
Published: August 2009

Purpose: To evaluate the Integrated Cochlear Profile for Assessing Auditory Nerve-Auditory Pathway Integrity (ICP-API), as proposed by our group, in the selection of cochlear implant candidates. Procedures: The API of the candidates for cochlear implantation were assessed with the ICP-API, which consists of 5 categories including: audiological testing; radiological imaging study; ear-canal electric response audiometry; response to environmental sounds; speech development level. The auditory rehabilitation effects of the cochlear implantation receivers were evaluated postoperatively. Results: Sixty-six of 68 candidates who met the criteria of the ICP-API received cochlear implantation with improved hearing and speech development postoperatively. The remaining 2 of the 68 candidates were diagnosed with bilateral auditory nerves aplasia, and therefore failed cochlear implants were avoided. Conclusion: The ICP-API is valuable and feasible for the selection of cochlear implant candidates. The API should be considered as one of the most important criteria for cochlear implant candidate selection.
Sensitivity and Fidelity of a Novel Piezoelectric Middle Ear Transducer
Authors: Chi Fang-Lu , Wu Yongzhen , Yan Qin-Bo , Shen Yi-Hu , Jiang Ye , Fan Bao-Hua
Published: August 2009

Objective: A novel implantable piezoelectric transducer has been developed in this laboratory. The transfer functions of the transducer were assessed in anesthetized acutely implanted cats, and were compared with the microphone of a cochlear implant’s speech processor. Methods: The piezoelectric transducer was fixed to the head of the malleus of the cat. Pure tone signals of 97 dB SPL ranging from 250 to 8,000 Hz delivered from a loudspeaker placed beside the auricle of the cat were used to vibrate the tympanic membrane. The frequency response of the transducer was measured by monitoring the output signal of the transducer with an oscilloscope. The transfer functions of the transducer were then compared with the standard external microphone receiving the same tonal stimulus. Results: The average sensitivity of the implantable piezoelectric transducer was –38.7 dB re 1 V/Pa at 1,000 Hz. The frequency-response curve of the transducer mirrored that of the external microphone, even with high-frequency stimuli. Conclusion: The implantable piezoelectric transducer developed in this laboratory transmits tonal stimuli with high fidelity.
Simulated Phase-Locking Stimulation: An Improved Speech Processing Strategy for Cochlear Implants
Authors: Chen Jing , Wu Xihong , Li Liang , Chi Huisheng
Published: August 2009

The continuous interleaved sampling (CIS) speech-processing strategy has been widely used for cochlear implants to extract speech envelope information without preserving phase information. In this study, a novel simulated phase-locking stimulation (SPLS) strategy, which detects zero-crossing times of the narrow-band signal of each band, was developed to extract both phase and amplitude-envelope information from a bank of frequency bands of speech sounds. The advantage of the SPLS strategy over the CIS strategy was confirmed by the results of our psychophysical experiments, showing that normal-hearing Chinese listeners’ performance in recognizing SPLS-processed Chinese speech was significantly better than their performance of recognizing CIS-processed Chinese speech under quiet, noise-masking, or speech-masking conditions. Thus, the results suggest that if the SPLS strategy is used to modulate the interval of electrical stimulation pulses in cochlear-implant devices according to extracted phase information, the speech-processing functions of cochlear implant devices would be improved for Chinese cochlear implant users.
Treatment and Outcome of Traumatic Endophthalmitis in Open Globe Injury with Retained Intraocular Foreign Body
Authors: Yang Chang-Sue , Lu Chao-Kung , Lee Fenq-Lih , Hsu Wen-Ming , Lee Yi-Fen , Lee Shui-Mei
Published: August 2009

Purpose: Our aim was to evaluate the incidence, risk factors, pathogens, use of systemic and intravitreal antibiotics, and outcome of traumatic endophthalmitis after open globe injury with retained intraocular foreign body (RIOFB). Methods: Patients with open globe injury and RIOFB complicated by endophthalmitis were enrolled and retrospectively studied in Taiwan over a 20-year-period from 1981 to 2002. Results: There were 125 patients, who sustained open globe injury and RIOFB, which required surgical management. In 15 patients (12%) traumatic endophthalmitis was identified. Thirteen (87%) of these 15 cases had signs of endophthalmitis at their initial presentation. The patients’ mean age was 41 years; all of them were male. Invading micro-organisms were isolated in 8 patients, and the positive culture rate was 53%. Gram-negative bacteria were the most commonly isolated organisms in 6 patients and 1 eye with multiple organisms. One eye with culture-proven Bacillus cereus had a very fulminant course and ended with phthisis bulbi. All 15 patients received topical and systemic intravenous antibiotic treatment; 9 eyes (60%) were given intravitreal antibiotic injection with broad-spectrum combined vancomycin and ceftazidime in 5 eyes. Pars plana vitrectomy was performed in 9 patients, with successful removal of RIOFB. The final visual acuity improved in 8 patients (53.5%), was unchanged in 1 (6.7%) and worse in 6 (40.0%). Five patients (33%) got a visual outcome of 6/60 or better. There were also 5 patients (33%) with a poor outcome of no light perception. Eleven (73%) of 15 patients had treatment delayed for >24 h after injury, and 5 out of these 11 patients had a very poor visual outcome (1 hand motion, 4 no light perception). Delay of presentation for >24 h after injury was associated with a tendency to increased risk of endophthalmitis [11/71 (15.5%) vs. 4/54 (7.4%)]. Conclusions: Early intravitreal antibiotics and prompt vitrectomy to remove the contaminating IOFB may salvage useful vision in some patients with traumatic endophthalmitis with RIOFB. Delay of treatment for >24 h was associated with increased risk of traumatic endophthalmitis.
A Psychoneuroendocrinology Service
Authors: Sonino Nicoletta , Peruzzi Pio
Published: August 2009

Background: Research evidence has highlighted the relevance of endocrine/metabolic abnormalities in psychiatry and of psychosocial implications in endocrinology. However, the value of interdisciplinary expertise has not been implemented in clinical practice. We have therefore designed a new outpatient clinic, called the Psychoneuroendocrinology Service, to apply the principles of current psychosomatic medicine and report here on the first 100 referrals. Methods and Results: Of the first 100 patients (74 females/26 males; mean age 44 ± 13.8 years), the sources of referral were the Mental Health Center (n = 41), specialists (n = 37) and primary care physicians (n = 22). The main reasons for referral were endocrine assessment (n = 40), unexplained medical symptoms (n = 18) and poor response to treatment (n = 17). The most frequent medical diagnoses were obesity/overweight (n = 22), hypertension (n = 20) and hypothyroidism (n = 11). The most frequent psychiatric diagnoses were major depression (n = 15), schizophrenia/schizoaffective disorder (n = 13) and bipolar disorder (n = 12). Subclinical symptoms (Diagnostic Criteria for Psychosomatic Research) found were persistent somatization (n = 18), demoralization (n = 14) and irritable mood (n = 7). Therapeutic strategies included lifestyle modifications (n = 45), explanatory therapy (n = 30), low-dose clonazepam (n = 23) and modifications of existing treatment with psychotropic drugs (n = 16). Conclusions: In this highly selected population, several difficult patients could be appropriately managed by virtue of a holistic view. Such an approach must involve experienced clinicians with a broad-spectrum training in psychoneuroendocrinology and psychosomatic medicine. If confirmed in its efficacy and cost-effectiveness, this model might be further expanded.
Tick-Borne Encephalitis Virus Infection of Cultured Mouse Macrophages
Authors: Ahantarig Arunee , Růžek Daniel , Vancová Marie , Janowitz Anna , Št'astná Hana , Tesařová Martina , Grubhoffer Libor
Published: August 2009

The interactions of tick-borne encephalitis virus (TBEV) with mouse macrophages were studied at the electron microscopic level. The cultured mouse macrophages were sensitive to infection with TBEV strain Hypr (a highly neuroinvasive and neurovirulent strain for laboratory mice) and produced relatively high virus titers. However, these macrophage cells remained morphologically inactivated. Viral particles were located mainly in the ER but were also present in other exocytic compartments. No virus production was observed in cells infected with the attenuated, non-neuroinvasive TBEV strain 263. In this case, the infection led to a clear morphological activation of the macrophages. In conclusion, the virus replication process in mouse macrophage cells might be different from that in other mammalian cell lines since the smooth membrane structures, which are thought to be the sites for flavivirus replication, were not observed. Moreover, different TBEV strains exhibited a different interaction with the host macrophages. The inability of strain 263 to replicate in mouse macrophages as the first site of significant viral replication in vivo could be associated with the inability of this strain to establish a serious infection in mice.
Effects of Atorvastatin on Carotid Atherosclerotic Plaques: A Randomized Trial for Quantitative Tissue Characterization of Carotid Atherosclerotic Plaques with Integrated Backscatter Ultrasound
Authors: Yamada Kiyofumi , Yoshimura Shinichi , Kawasaki Masanori , Enomoto Yukiko , Asano Takahiko , Minatoguchi Shinya , Iwama Toru
Published: August 2009

Background: Instability of carotid plaques has been reported to be associated with stroke and other cerebrovascular events. The purpose of this study was to examine whether cholesterol-lowering therapy with atorvastatin in nonhypercholesterolemic patients reduces carotid plaque instability as assessed by ultrasound integrated backscatter (IBS) analysis. Methods: Consecutive non- or slightly hypercholesterolemic patients with moderate carotid artery stenosis were randomly assigned to a diet group (n = 20) or a statin group (atorvastatin; n = 20). Carotid plaques were monitored by measuring intima media thickness (IMT) and IBS values at baseline and after 6 months. Results: Three-dimensional IBS imaging showed that relative lipid volume of carotid plaques significantly decreased from 58.4 ± 25.6 to 47.8 ± 23.5% in the statin group (p < 0.01), whereas there was no significant decrease in the diet group. Significant regression of IMT was not observed in either group. The changes of IBS values and relative lipid volume between baseline and 6 months were correlated with the change in low-density lipoprotein cholesterol (r = 0.31, p < 0.05, and r = 0.34, p < 0.05, respectively). Conclusions: Lipid-lowering therapy by atorvastatin decreased relative lipid volume without significant regression of plaque volume during short-term follow-up in patients with moderate carotid artery stenosis. Quantitative assessment of carotid plaques by IBS analysis was clinically useful for monitoring atherosclerotic lesions.
Alpha-Lipoic Acid Attenuates Cisplatin-Induced Tubulointerstitial Injuries through Inhibition of Mitochondrial Bax Translocation in Rats
Authors: Lee Young Mo , Bae So Yon , Won Nam Hee , Pyo Heui Jung , Kwon Young Joo
Published: August 2009

Background: Renal tubule cell apoptosis plays a pivotal role in cisplatin-induced nephrotoxicity. α-Lipoic acid (LA), a thiol antioxidant, is well known to be cytoprotective in various cell death models through its involvement in the death receptor apoptosis pathway. However, we hypothesized that LA would attenuate cisplatin-induced nephrotoxicity through inhibition of mitochondrial bax translocation in rats. Methods and Materials: Sprague-Dawley rats were treated with cisplatin (7 mg/kg) with or without pretreatment with LA (100 mg/kg × 3 times). Renal function was evaluated based on blood urea nitrogen (BUN), serum creatinine, and fractional excretion of sodium. Tubular necrosis scores were assessed by light microscopy findings and apoptotic cell deaths by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Cytosolic bax, mitochondrial bax, cytochrome c, caspase-9 and caspase-3 were investigated using Western blot in each group. Results: LA pretreatment significantly decreased both BUN and serum creatinine. Morphologically, both tubular necrosis and apoptosis of tubular cells were decreased significantly with LA pretreatment. LA attenuated the translocation of mitochondrial bax, reduced the release of cytochrome c, and decreased the expression of caspase-3 and caspase-9 serially in cisplatin nephrotoxicity. Conclusion: We demonstrated that LA attenuates cisplatin-induced renal tubular damages by inhibition of mitochondrial bax translocation in vivo.
Aging-Related Differences in Maximum Force, Unloaded Velocity and Power of Human Leg Multi-Joint Movement
Authors: Yamauchi Junichiro , Mishima Chizuko , Nakayama Satoshi , Ishii Naokata
Published: August 2009

Background: Because many of our movements of daily living are multi-joint movements and lower limb performance decreases with aging, it is important to understand the influence of aging on muscle functions of lower limb multi-joint movements. Objective: To investigate aging-related differences in the maximum force, unloaded velocity and power of muscles that control leg multi-joint movements. Methods: 285 recreationally active men (n = 142) and women (n = 143) aged between 18 and 82 years volunteered for the study. Lower limb muscle function was measured with a servo-controlled dynamometer and the maximum isometric force (Fmax), unloaded velocity (Vmax) and power (Pmax) were determined by the force-velocity and force-power relations. Results: With increasing age, Fmax/body mass significantly declines in both men (r = –0.400, p <0.001) and women (r = –0.587, p < 0.001), while Vmax/leg length does not change with age in either men (r = –0.033, p > 0.05) or women (r = –0.040, p > 0.05). Pmax significantly declines with age in both men (r = –0.370, p < 0.001) and women (r = –0.446, p < 0.001). Conclusions: Aging does not have effects on the shortening velocity, although it causes a decrease in maximum force and power of leg multi-joint movements. This finding suggests that decreases in muscle force-generating capacity and power may primarily lead to the loss of mobility and a reduced capability of accelerating and decelerating the body mass during the movements in elderly individuals.
Use of Excised Human Skin to Assess the Bioequivalence of Topical Products
Authors: Franz T.J. , Lehman P.A. , Raney S.G.
Published: August 2009

Background: Establishing the bioequivalence of topical drug products is a costly and time-consuming process since, with few exceptions, clinical efficacy trials are required. Objective: To develop a surrogate for clinical bioequivalence testing through evaluation of the kinetics of drug absorption in vitro through excised human skin. Methods: The percutaneous absorption of seven approved generic topical drug products was compared with their corresponding reference products during preclinical development using the Franz diffusion cell. Thereafter, following the conduct of bioequivalence trials and regulatory approval of these products in the United States, clinical data became available to which the in vitro data were compared. Results: In six of the seven cases the in vitro test:reference ratio for total absorption was close to one and indicated that the products were equivalent, in agreement with the clinical data. Results from the seventh case, in which the test:reference ratio was only 0.63, indicated that the in vitro model actually had greater sensitivity than the clinical method to detect small differences between products. Conclusion: These data demonstrate the relevance and predictive power of the in vitro human skin model and strongly support its use as a surrogate for in vivo bioequivalence studies.
Effects of the Aging Process on Respiratory Function
Authors: Britto Raquel Rodrigues , Zampa Camila Camargos , de Oliveira Tatiana Antunes , Prado Lívia Fontes , Parreira Verônica Franco
Published: August 2009

Background: The identification of breathing patterns in healthy elderly individuals and changes in the respiratory system related to the normal aging process is important to detect and prevent respiratory dysfunction. Objectives: To assess and compare respiratory function between adults and elderly individuals according to baseline conditions. Methods: Nineteen adults aged 20–59 years (group 1), 12 elderly aged 60–69 years (group 2) and 12 elderly above 69 years of age (group 3) who were all nonsmokers, untrained and with normal pulmonary function tests were studied using calibrated respiratory inductive plethysmography to assess tidal volume (Vt), respiratory frequency (f), minute ventilation, mean inspiratory flow [Vt/inspiratory time (Ti)], inspiratory duty cycle (Ti/total cycle time), labored breathing index (an asynchrony index measurement), percentage of rib cage motion and abdominal motion. Measurements of the maximal inspiratory pressure (MIP), maximal expiratory pressure and transcutaneous oxygen saturationwere also obtained. Results: The MIP was statistically significantly lower in group 2 (54.58 ± 32.37 cm H2O) and group 3 (54.58 ± 33.61 cm H2O) compared to group 1 (92.11 ± 43.22 cm H2O; p = 0.037). There were no significant differences between the groups regarding breathing patterns, respiratory variables and thoracoabdominal motion. No statistically significant differences between groups 2 and 3 were found for any of the investigated variables. Conclusion: These findings suggest that the aging process of the respiratory system reduces the inspiratory muscle strength but does not have a significant impact on breathing pattern variables.
Cochlear Implantation in Elderly Patients: Surgical and Audiological Outcome
Authors: Migirov Lela , Taitelbaum-Swead Riki , Drendel Michael , Hildesheimer Minka , Kronenberg Jona
Published: August 2009

Background: Deteriorated hearing affects speech perception and speech production, and negatively impacts on social interaction, employment, income, and, as a result, the quality of life of the elderly population. Lack of satisfaction with conventional hearing aids motivated part of them to turn to more sophisticated cochlear device systems. Objective: To investigate the outcome of cochlear implantation (CI) among elderly cochlear implant recipients. Methods: The medical records of 20 postlingual patients aged >65 years at the time of CI, who were followed up for a period of at least 12 months were retrospectively reviewed for age at the time of CI, the cause and duration of deafness, hearing aid experience, comorbidities, complications of the procedure and audiological outcome. Pre- and post-CI speech perception performance was tested using a battery of speech perception tests. Results: In addition to bilateral severe to profound hearing loss, all 20 patients had some comorbidities and 13 had more than 2 pathologies that are associated with hearing impairment. Major complications such as facial nerve paralysis and foreign body reaction were rare (n = 2). Minor complications such as disequilibrium (n = 5) and wound problems (n = 5) resolved spontaneously or were successfully managed conservatively. There were no complications associated with general anesthesia used during the CI procedure. Statistical analysis using the Wilcoxon Signed Rank Test showed significant differences (p < 0.01) between the pre- and postspeech perception categories. No significant correlations were found between the background data: unaided thresholds, aided thresholds, duration of profound deafness, duration of hearing aid use prior to CI, speech perception before CI and speech perception performance after CI using Pearson correlations. Conclusion: CI was found to be associated with significant hearing benefit in elderly candidates. However, every CI candidate must be informed about possible complications associated with the procedure, especially related to the vestibular system. At the same time, it should be made clear that life-threatening conditions are rare and that the surgery is usually safe.
Localization for Solving Noisy Multi-Objective Optimization Problems
Authors: Bui Lam T. , Abbass Hussein A. , Essam Daryl
Published: August 2009

This paper investigates the use of a framework of local models in the context of noisy evolutionary multi-objective optimization. Within this framework, the search space is explicitly divided into several nonoverlapping hyperspheres. A direction of improvement, which is related to the average performance of the spheres, is used for moving solutions within each sphere. This helps the local models to filter noise and increase the robustness of the evolutionary algorithm in the presence of noise. A wide range of noisy problems we used for testing and the experimental results demonstrate the ability of local models to better filter noise in comparison with that of global models.
A Preference-Based Evolutionary Algorithm for Multi-Objective Optimization
Authors: Thiele Lothar , Miettinen Kaisa , Korhonen Pekka J. , Molina Julian
Published: August 2009

In this paper, we discuss the idea of incorporating preference information into evolutionary multi-objective optimization and propose a preference-based evolutionary approach that can be used as an integral part of an interactive algorithm. One algorithm is proposed in the paper. At each iteration, the decision maker is asked to give preference information in terms of his or her reference point consisting of desirable aspiration levels for objective functions. The information is used in an evolutionary algorithm to generate a new population by combining the fitness function and an achievement scalarizing function. In multi-objective optimization, achievement scalarizing functions are widely used to project a given reference point into the Pareto optimal set. In our approach, the next population is thus more concentrated in the area where more preferred alternatives are assumed to lie and the whole Pareto optimal set does not have to be generated with equal accuracy. The approach is demonstrated by numerical examples.
Structure and Origin of the Quasi-Biweekly Oscillation over the Tropical Indian Ocean in Boreal Spring
Authors: Wen Min , Li Tim , Zhang Renhe , Qi Yanjun
Published: August 2009

The structure and evolution features of the quasi-biweekly (10–20 day) oscillation (QBWO) in boreal spring over the tropical Indian Ocean (IO) are investigated using 27-yr daily outgoing longwave radiation (OLR) and the National Centers for Environment Prediction–National Center for Atmospheric Research (NCEP–NCAR) reanalysis data. It is found that a convective disturbance is initiated over the western IO and moves slowly eastward. After passing the central IO, it abruptly jumps into the eastern IO. Meanwhile, the preexisting suppressed convective anomaly in the eastern IO moves poleward in the form of double-cell Rossby gyres. The analysis of vertical circulation shows that a few days prior to the onset of local convection in the eastern equatorial IO an ascending motion appears in the boundary layer.

Based on the diagnosis of the zonal momentum equation, a possible boundary layer–triggering mechanism over the eastern equatorial IO is proposed. The cause of the boundary layer convergence and vertical motion is attributed to the free-atmospheric divergence in association with the development of the barotropic wind. It is the downward transport of the background mean easterly momentum by perturbation vertical motion during the suppressed convective phase of the QBWO that leads to the generation of a barotropic easterly—the latter of which further causes the free-atmospheric divergence and, thus, the boundary layer convergence. The result suggests that the local process, rather than the eastward propagation of the disturbance from the western IO, is essential for the phase transition of the QBWO convection over the eastern equatorial IO.
Influence of Ice Crystal Aspect Ratio on the Evolution of Ice Size Spectra during Vapor Depositional Growth
Authors: Sheridan Lindsay M. , Harrington Jerry Y. , Lamb Dennis , Sulia Kara
Published: August 2009

The relationship among aspect ratio, initial size, and the evolution of the size spectrum is explored for ice crystals growing by vapor deposition. Ice crystal evolution is modeled based on the growth of spheroids, and the ice size spectrum is predicted using a model that is Lagrangian in crystal size and aspect ratio. A dependence of crystal aspect ratio on initial size is discerned: more exaggerated shapes are shown to result when the initial crystals are small, whereas more isometric shapes are found to result from initially large crystals. This result is due to the nature of the vapor gradients in the vicinity of the crystal surface. The more rapid growth of the smaller crystals is shown to produce a period during which the size distribution narrows, followed by a broadening led by the initially smallest crystals. The degree of broadening is shown to depend strongly on the primary habit and hence temperature.
Do High-Frequency Eddies Contribute to Low-Frequency Teleconnection Tendencies?*
Authors: Athanasiadis Panos J. , Ambaum Maarten H. P.
Published: August 2009

An isentropic potential vorticity (PV) budget analysis is employed to examine the role of synoptic transients, advection, and nonconservative processes as forcings for the evolution of the low-frequency PV anomalies locally and those associated with the North Atlantic Oscillation (NAO) and the Pacific–North American (PNA) pattern. Specifically, the rate of change of the low-frequency PV is expressed as a sum of tendencies due to divergence of eddy transport, advection by the low-frequency flow (hereafter referred to as advection), and the residual nonconservative processes. The balance between the variances and covariances of these terms is illustrated using a novel vector representation.

It is shown that for most locations, as well as for the PNA pattern, the PV variability is dominantly driven by advection. The eddy forcing explains a small amount of the tendency variance. For the NAO, the role of synoptic eddy fluxes is found to be stronger, explaining on average 15% of the NAO tendency variance. Previous studies have not assessed quantitively how the various forcings balance the tendency. Thus, such studies may have overestimated the role of eddy fluxes for the evolution of teleconnections by examining, for example, composites and regressions that indicate maintenance, rather than evolution driven by the eddies. The authors confirm this contrasting view by showing that during persistent blocking (negative NAO) episodes the eddy driving is relatively stronger.
Pollen-Based Quantitative Reconstruction of Holocene Climate Changes in the Daihai Lake Area, Inner Mongolia, China
Authors: Xu Qinghai , Xiao Jule , Li Yuecong , Tian Fang , Nakagawa Takeshi
Published: August 2009

Vegetation around the Daihai Lake, northern China, is very sensitive to climate changes. In this paper, pollen-based quantitative climate reconstructions using three methods [weighted averaging partial least squares method (WAPLS), modern analog technique (MAT), and pollen response surface method (PRS)] were conducted to obtain robust reconstructions of Holocene climate changes in the Daihai Lake area. The result obtained by the three methods all consistently show the annual precipitation to have been 50–100 mm lower in the early Holocene, 100–200 mm higher in the Mid-Holocene, and 50–100 mm lower again in the late Holocene than at present. The WAPLS and the MAT methods also show quasi-synchronous oscillations of the mean annual temperature (Ta); 1°–2°C lower in the Early Holocene and 1°–3°C higher in the Mid-Holocene than today. The time period from 6200 to 5100 cal yr BP was the wettest and the warmest interval, with an annual precipitation (Pa) greater than 550 mm and mean annual temperature Ta higher than 6.5°C. Several cold and dry events can be identified to occur about 8200, 6000, and 4400 cal yr BP, with an annual precipitation less than 400 mm and a mean annual temperature colder than 4.5°C, respectively. The mean temperature of the warmest month (Tw) as reconstructed using both WAPLS and MAT methods was relatively stable during the Holocene, fluctuating about ±2°C relative to the present level, but the PRS method suggests more varied Tw values in both amplitude and frequency. After 1500 cal yr BP, no consistent pattern can be observed from these three different analyses, probably because of the impact of intensified human disturbances on the natural vegetation. The fluctuations of annual precipitation (Pa) correspond to that observed in Dongge Cave in southern China. The differences might be linked to Indian monsoon and East Asia monsoon climates or caused by the different degree of dating precision, different temporal resolution, and different sensitive response of climate proxies to the climate variations.
Spontaneous Cardiomyopathy in Cynomolgus Monkeys (Macaca Fascicularis)
Authors: Zabka Tanja S. , Irwin Michael , Albassam Mudher A.
Published: August 2009

A previously undescribed spontaneous cardiomyopathy was identified by routine light microscopic examination of the heart from four clinically healthy purpose-bred cynomolgus monkeys that ranged from four to nine years of age and included 2 males and 2 females. Special stains of Sirius red, Masson’s trichrome, and Mallory’s phosphotungstic acid hematoxylin (PTAH); and immunohistochemistry using anti-CD68, troponin-I, and desmin antibodies were used to facilitate lesion characterization and assess cardiomyocyte viability. Microscopically, the apical to mid-ventricular myocardium to subendocardium had foci of cardiomyocyte disarray with cytoplasmic pallor to stippling and karyomegaly, vacuolization of the perimyseal connective tissue, a meshwork of fibrous tissue that concentrated around medium-sized blood vessels and dissected between or less often replaced affected cardiomyocytes; and a minimal, predominantly macrophage infiltrate. The disrupted cardiomyocytes were immunoreactive to desmin and troponin-I antibodies and had a normal cross-striation pattern by PTAH, indicating the chronic cardiomyopathy was not associated with active cardiomyocyte damage. The consistent distribution and morphology of the cardiomyopathy suggested a common etiology and pathogenesis. The features were reminiscent of chronic catecholamine-induced experimental cardiomyopathy and stress cardiomyopathy in monkeys and humans, respectively. This report documents another spontaneous heart lesion in clinically healthy monkeys for consideration during interpretation of toxicology studies.
An Equivalent Relative Utility Metric for Evaluating Screening Mammography
Authors: Abbey Craig K. , Eckstein Miguel P. , Boone John M.
Published: August 2009

Comparative studies of performance in screening mammography are often ambiguous. A new method will frequently show a higher sensitivity or detection rate than an existing standard with a concomitant increase in false positives or recalls. The authors propose an equivalent relative utility (ERU) metric based on signal detection theory to quantify screening performance in such comparisons. The metric is defined as the relative utility, as defined in classical signal detection theory, needed to make 2 systems equivalent. ERU avoids the problem of requiring a predefined putative relative utility, which has limited application of utility theory in receiver operating characteristic analysis. The metric can be readily estimated from recall and detection rates commonly reported in comparative clinical studies. An important practical advantage of ERU is that in prevalence matched populations, the measure can be estimated without an independent estimate of disease prevalence. Thus estimating ERU does not require a study with long-term follow-up to find cases of missed disease. The approach is applicable to any comparative screening study that reports results in terms of recall and detection rates, although the authors focus exclusively on screening mammography in this work. They derive the ERU from the definition of utility given in classical treatments of signal detection theory. They also investigate reasonable values of relative utility in screening mammography for use in interpreting ERU using data from a large clinical study. As examples of application of ERU, they reanalyze 2 recently published reports using recall and detection rates in screening mammography.