bluuebunny/crossref_metadata_2025 huggingface dataset:
Does preoperative abduction value affect functional outcome of combined muscle transfer and release procedures in obstetrical palsy patients with shoulder involvement?
Authors: Aydin Atakan , Ozkan Turker , Onel Defne
Published: August 2004

Background

Obstetric palsy is the injury of the brachial plexus during delivery. Although many infants with plexopathy recover with minor or no residual functional deficits, some children don't regain sufficient limb function because of functional limitations, bony deformities and joint contractures. Shoulder is the most frequently affected joint with internal rotation contracture causing limitation of abduction, external rotation. The treatment comprises muscle release procedures such as posterior subscapularis sliding or anterior subscapularis tendon lengtening and muscle transfers to restore the missing external rotation and abduction function.

Methods

We evaluated whether the preoperative abduction degree affects functional outcome. Between 1998 and 2002, 46 children were operated on to restore shoulder abduction and external rotation. The average age at surgery was 7.6 years and average follow up was 40.8 months. We compared the postoperative results of the patients who had preoperative abduction less than 90° (Group I: n = 37) with the patients who had preoperative abduction greater than 90° (Group II: n = 9), in terms of abduction and external rotation function with angle measurements and Mallet classification. We inquired whether patients in Group I needed another muscle transfer along with latissimus dorsi and teres major transfers.

Results

In Group I the average abduction improved from 62.5° to 131.4° (a 68.9° ± 22.9°gain) and the average external rotation improved from 21.4° to 82.6° (a 61.1° ± 23°gain). In Group II the average abduction improved from 99.4°to 140°(a40.5° ± 16°gain) and the average external rotation improved from 33.2°to 82.7° (a 49.5° ± 23.9° gain). Although there was a significant difference between Group I and II for preoperative abduction (p = 0.000) and abduction gain in degrees (p = 0.001), the difference between postoperative values of both groups was not significant (p = 0.268). There was also no significant difference between the two groups in the preoperative external rotation, the external rotation gain and the postoperative external rotation (p = 0.163, p = 0.181 and p = 0.803, respectively).

Conclusions

Obstetric palsy patients with shoulder sequela who had a preoperative abduction less than 90°hadas good functional results using latissimus dorsi, teres major muscle transfer and subscapularis muscle release as the patients who hada preoperative abduction greater than 90°.
DLQI scores in vitiligo: reliability and validity of the Persian version
Authors: Aghaei Shahin , Sodaifi Manouchehr , Jafari Peyman , Mazharinia Nazila , Finlay Andrew Y
Published: August 2004

Background

The objective of this study was to translate and to test the reliability and validity of the 10-item Dermatology Life Quality Index (DLQI) questionnaire in Iranian patients with vitiligo.

Methods

Using a standard "forward-backward" translation procedure, the English language version of the questionnaire was translated into Persian (the Iranian official language) by two bilinguals. Seventy patients with vitiligo attending the Department of Dermatology, Saadi Hospital, Shiraz, Iran, were enrolled in this study.

The reliability and internal consistency of the questionnaire were assessed by Cronbach's alpha coefficient and Spearman's correlation, respectively. Validity was performed using convergent validity.

Results

In all, seventy people entered into the study. The mean age of respondents was 28.3 (SD = 11.09) years. Scores on the DLQI ranged from 0 to 24 (mean ± SD, 7.05 ± 5.13). Reliability analysis showed satisfactory result (Cronbach's α coefficient = 0.77). There were no statistically significant differences between daily activity (DA) and personal relationship (PR) scale mean scores in generalized versus focal-segmental involvement in sufferers (P = 0.056, P = 0.053, respectively). There were also strong differences between the mean scores of the PR (personal relationship) scale with the involvement of covered only and covered/uncovered areas (P= 0.016) that was statistically significant in the second group.

Conclusions

The study findings showed that the Persian version of the DLQI questionnaire has a good structural characteristic and is a reliable and valid instrument that can be used for measuring the effects of vitiligo on quality of life.
The effect of Fucus vesiculosus, an edible brown seaweed, upon menstrual cycle length and hormonal status in three pre-menopausal women: a case report
Authors: Skibola Christine F
Published: August 2004

Background

Rates of estrogen-dependent cancers are among the highest in Western countries and lower in the East. These variations may be attributable to differences in dietary exposures such as higher seaweed consumption among Asian populations. The edible brown kelp, Fucus vesiculosus (bladderwrack), as well as other brown kelp species, lower plasma cholesterol levels. Since cholesterol is a precursor to sex hormone biosynthesis, kelp consumption may alter circulating sex hormone levels and menstrual cycling patterns. In particular, dietary kelp may be beneficial to women with or at high risk for estrogen-dependent diseases. To test this, bladderwrack was administered to three pre-menopausal women with abnormal menstrual cycling patterns and/or menstrual-related disease histories.

Case Presentation

Intake of bladderwrack was associated with significant increases in menstrual cycle lengths, ranging from an increase of 5.5 to 14 days. In addition, hormone measurements ascertained for one woman revealed significant anti-estrogenic and progestagenic effects following kelp administration. Mean baseline 17β-estradiol levels were reduced from 626 ± 91 to 164 ± 30 pg/ml (P = 0.04) following 700 mg/d, which decreased further to 92.5.0 ± 3.5pg/ml (P = 0.03) with the1.4 g/d dose. Mean baseline progesterone levels rose from 0.58 ± 0.14 to 8.4 ± 2.6 ng/ml with the 700 mg/d dose (P = 0.1), which increased further to 16.8 ± 0.7 ng/ml with the 1.4 g/d dose (P = 0.002).

Conclusions

These pilot data suggest that dietary bladderwrack may prolong the length of the menstrual cycle and exert anti-estrogenic effects in pre-menopausal women. Further, these studies also suggest that seaweed may be another important dietary component apart from soy that is responsible for the reduced risk of estrogen-related cancers observed in Japanese populations. However, these studies will need to be performed in well-controlled clinical trials to confirm these preliminary findings.
The ECOS-16 questionnaire for the evaluation of health related quality of life in post-menopausal women with osteoporosis
Authors: Badia Xavier , Díez-Pérez Adolfo , Lahoz Raquel , Lizán Luis , Nogués Xavier , Iborra Jordi
Published: August 2004

Background

The aim of this study is to validate the questionnaire ECOS-16 (Assessment of health related quality of life in osteoporosis) for the evaluation of health related quality of life (HRQoL) in post-menopausal women with osteoporosis.

Methods

An observational, prospective and multi-centre study was carried out among post-menopausal women with osteoporosis in primary care centres and hospital outpatient clinics. All patients attended 2 visits: at baseline and at 6 months. In addition, the subgroup of outpatients attended another visit a month after the baseline to assess the test-retest reliability. The psychometric properties of the questionnaire were evaluated in terms of feasibility, validity (content validity and construct validity) and internal consistency in baseline, and in terms of test-retest reliability and responsiveness to change in visit at month and visit at 6 months, respectively. In all visits, ECOS-16, EUROQoL-5D (EQ-5D) and four 7-point items about health status (general health status, back pain, limitation in daily activities and emotional status) were administered, whereas only outpatients were given MINI-OQLQ (Mini Osteoporosis Quality of Life Questionnaire), besides all clinical variables; and sociodemographic variables at baseline.

Results

316 women were consecutively included, 212 from primary care centres and 104 from hospital outpatient clinics. Feasibility: 94.3% of patients answered all items of the questionnaire. The mean administration time was 12.3 minutes. Validity: factor analysis suggested that the questionnaire was unidimensional. In the multivariate analysis, patients with vertebral fractures, co-morbidity and a lower education level showed to have worse HRQoL. Moderate to high correlations were found between the ECOS-16 score and the other health status questionnaires (0.47–0.82). Reliability: internal consistency (Cronbach's α) was 0.92 and test-retest reliability (ICC) was 0.80. Responsiveness to change: ECOS-16 scores increased according to change perceived by the patient, as well as the effect size (ranges between 1.35 to 0.43), the greater the perception of change in patients' general health status, the greater the changes in patients' scores. The Minimal Clinically Important Difference (MCID) suggested a change of 0.5 points in the ECOS-16 score, representing the least improvement in general health status due to their osteoporosis: "slightly better".

Conclusion

ECOS-16 has been proven preliminarily to have good psychometric properties, so that it can be potentially a useful tool to evaluate HRQoL of post-menopausal women with osteoporosis in research and routine clinical practice.
The AMC Linear Disability Score project in a population requiring residential care: psychometric properties
Authors: Holman Rebecca , Lindeboom Robert , Vermeulen Marinus , de Haan Rob J
Published: August 2004

Background

Currently there is a lot of interest in the flexible framework offered by item banks for measuring patient relevant outcomes, including functional status. However, there are few item banks, which have been developed to quantify functional status, as expressed by the ability to perform activities of daily life.

Method

This paper examines the psychometric properties of the AMC Linear Disability Score (ALDS) project item bank using an item response theory model and full information factor analysis. Data were collected from 555 respondents on a total of 160 items.

Results

Following the analysis, 79 items remained in the item bank. The remaining 81 items were excluded because of: difficulties in presentation (1 item); low levels of variation in response pattern (28 items); significant differences in measurement characteristics for males and females or for respondents under or over 85 years old (26 items); or lack of model fit to the data at item level (26 items).

Conclusions

It is conceivable that the item bank will have different measurement characteristics for other patient or demographic populations. However, these results indicate that the ALDS item bank has sound psychometric properties for respondents in residential care settings and could form a stable base for measuring functional status in a range of situations, including the implementation of computerised adaptive testing of functional status.
Construction of a questionnaire measuring outpatients' opinion of quality of hospital consultation departments
Authors: Gasquet Isabelle , Villeminot Sylvie , Estaquio Carla , Durieux Pierre , Ravaud Philippe , Falissard Bruno
Published: August 2004

Background

Few questionnaires on outpatients' satisfaction with hospital exist. All have been constructed without giving enough room for the patient's point of view in the validation procedure. The main objective was to develop, according to psychometric standards, a self-administered generic outpatient questionnaire exploring opinion on quality of hospital care.

Method

First, a qualitative phase was conducted to generate items and identify domains using critical analysis incident technique and literature review. A list of easily comprehensible non-redundant items was defined using Delphi technique and a pilot study on outpatients. This phase involved outpatients, patient association representatives and experts. The second step was a quantitative validation phase comprised a multicenter study in 3 hospitals, 10 departments and 1007 outpatients. It was designed to select items, identify dimensions, measure reliability, internal and concurrent validity. Patients were randomized according to the place of questionnaire completion (hospital v. home) (participation rate = 65%). Third, a mail-back study on 2 departments and 248 outpatients was conducted to replicate the validation (participation rate = 57%).

Results

A 27-item questionnaire comprising 4 subscales (appointment making, reception facilities, waiting time and consultation with the doctor). The factorial structure was satisfactory (loading >0.50 on each subscale for all items, except one item). Interscale correlations ranged from 0.42 to 0.59, Cronbach α coefficients ranged from 0.79 to 0.94. All Item-scale correlations were higher than 0.40. Test-retest intraclass coefficients ranged from 0.69 to 0.85. A unidimensional 9-item version was produced by selection of one third of the items within each subscale with the strongest loading on the principal component and the best item-scale correlation corrected for overlap. Factors related to satisfaction level independent from departments were age, previous consultations in the department and satisfaction with life. Completion at hospital immediately after consultation led to an overestimation of satisfaction. No satisfaction score differences existed between spontaneous respondents and patients responding after reminder(s).

Conclusion

Good estimation of patient opinion on hospital consultation performance was obtained with these questionnaires. When comparing performances between departments or the same department over time scores need to be adjusted on 3 variables that influence satisfaction independently from department. Completion of the questionnaire at home is preferable to completion in the consultation facility and reminders are not necessary to produce non-biased data.
A dual function fusion protein of Herpes simplex virus type 1 thymidine kinase and firefly luciferase for noninvasive in vivoimaging of gene therapy in malignant glioma
Authors: Söling Ariane , Theiß Christian , Jungmichel Stephanie , Rainov Nikolai G
Published: August 2004

Background

Suicide gene therapy employing the prodrug activating system Herpes simplex virus type 1 thymidine kinase (HSV-TK)/ ganciclovir (GCV) has proven to be effective in killing experimental brain tumors. In contrast, glioma patients treated with HSV-TK/ GCV did not show significant treatment benefit, most likely due to insufficient transgene delivery to tumor cells. Therefore, this study aimed at developing a strategy for real-time noninvasive in vivo monitoring of the activity of a therapeutic gene in brain tumor cells.

Methods

The HSV-TK gene was fused to the firefly luciferase (Luc) gene and the fusion construct HSV-TK-Luc was expressed in U87MG human malignant glioma cells. Nude mice with subcutaneous gliomas stably expressing HSV-TK-Luc were subjected to GCV treatment and tumor response to therapy was monitored in vivo by serial bioluminescence imaging. Bioluminescent signals over time were compared with tumor volumes determined by caliper.

Results

Transient and stable expression of the HSV-TK-Luc fusion protein in U87MG glioma cells demonstrated close correlation of both enzyme activities. Serial optical imaging of tumor bearing mice detected in all cases GCV induced death of tumor cells expressing the fusion protein and proved that bioluminescence can be reliably used for repetitive and noninvasive quantification of HSV-TK/ GCV mediated cell kill in vivo.

Conclusion

This approach may represent a valuable tool for the in vivo evaluation of gene therapy strategies for treatment of malignant disease.
Fleet Performance and Capability in the Eighteenth-Century Royal Navy
Authors: Willis S. B.A.
Published: August 2004

The peculiar nature of fleet capability and performance was a defining characteristic of sea warfare in the eighteenth century, determining both tactics and strategy. While this significance has time and again captured the attention of historians, the accuracy of the facts themselves has escaped scrutiny. S.B.A. Willis draws on contemporary sources to demonstrate that our accepted understanding of fleet capability and performance in the eighteenth-century navy is in need of revision.
Russian Military Intelligence, 1905-1917: The Untold Story behind Tsarist Russia in the First World War
Authors: Marshall Alex
Published: August 2004

The role of military intelligence in the First World War has been relatively neglected compared with the revelations that have wholly altered the historiography of the Second World War since the 1970s. The role of Russian military intelligence in that first conflict has in particular been an enigma for many decades, because of the difficulty of archival access. Now, however, a new generation of Russian, European and American scholars are uncovering the role of Russian military intelligence in the First World War, and a series of fresh discoveries combined with the reprint of previously rare biographical material allows one to reach new and more informed conclusions both on Russian military intelligence of the period and on the nature of the Russian revolution itself.
Regulation of Bone Mass and Bone Turnover by Neuronal Nitric Oxide Synthase
Authors: van’t Hof Robert J. , MacPhee Jeny , Libouban Helene , Helfrich Miep H. , Ralston Stuart H.
Published: August 2004

Nitric oxide (NO) is produced by NO synthase (NOS) and plays an important role in the regulation of bone cell function. The endothelial NOS isoform is essential for normal osteoblast function, whereas the inducible NOS isoform acts as a mediator of cytokine effects in bone. The role of the neuronal isoform of NOS (nNOS) in bone has been studied little thus far. Therefore, we investigated the role of nNOS in bone metabolism by studying mice with targeted inactivation of the nNOS gene. Bone mineral density (BMD) was significantly higher in nNOS knockout (KO) mice compared with wild-type controls, particularly the trabecular BMD (P < 0.01). The difference in BMD between nNOS KO and control mice was confirmed by histomorphometric analysis, which showed a 67% increase in trabecular bone volume in nNOS KO mice when compared with controls (P < 0.001). This was accompanied by reduced bone remodeling, with a significant reduction in osteoblast numbers and bone formation surfaces and a reduction in osteoclast numbers and bone resorption surfaces. Osteoblasts from nNOS KO mice, however, showed increased levels of alkaline phosphatase and no defects in proliferation or bone nodule formation in vitro, whereas osteoclastogenesis was increased in nNOS KO bone marrow cultures. These studies indicate that nNOS plays a hitherto unrecognized but important physiological role as a stimulator of bone turnover. The low level of nNOS expression in bone and the in vitro behavior of nNOS KO bone cells indicate that these actions are indirect and possibly mediated by a neurogenic relay.
Development and Application of a Rat Ovarian Gene Expression Database
Authors: Jo Misung , Gieske Mary C. , Payne Charles E. , Wheeler-Price Sarah E. , Gieske Joseph B. , Ignatius Ignatius V. , Curry Thomas E. , Ko CheMyong
Published: August 2004

The pituitary gonadotropins play a key role in follicular development and ovulation through the induction of specific genes. To identify these genes, we have constructed a genome-wide rat ovarian gene expression database (rOGED). The database was constructed from total RNA isolated from intact ovaries, granulosa cells, or residual ovarian tissues collected from immature pregnant mare serum gonadotropin (PMSG)/human chorionic gonadotropin-treated rats at 0 h (no PMSG), 12 h, and 48 h post PMSG, as well as 6 and 12 h post human chorionic gonadotropin. The total RNA was used for DNA microarray analysis using Affymetrix Rat Expression Arrays 230A and 230B (Affymetrix, Santa Clara, CA). The microarray data were compiled and used for display of individual gene expression profiles through specially developed software. The final rOGED provides immediate analysis of temporal gene expression profiles for over 28,000 genes in intact ovaries, granulosa cells, and residual ovarian tissue during follicular growth and the preovulatory period. The accuracy of the rOGED was validated against the gene profiles for over 20 known genes. The utility of the rOGED was demonstrated by identifying six genes that have not been described in the rat periovulatory ovary. The mRNA expression patterns and cellular localization for each of these six genes (estrogen sulfotransferase, synaptosomal-associated protein 25 kDa, runt-related transcription factor, calgranulin B, α1-macroglobulin, and MAPK phosphotase-3) were confirmed by Northern blot analyses and in situ hybridization, respectively. The current findings demonstrate that the rOGED can be used as an instant reference for ovarian gene expression profiles, as well as a reliable resource for identifying important yet, to date, unknown ovarian genes.
Mechanisms of Hemorrhage-Induced Hepatic Insulin Resistance: Role of Tumor Necrosis Factor-α
Authors: Ma Yuchen , Toth Balazs , Keeton Adam B. , Holland LaWanda T. , Chaudry Irshad H. , Messina Joseph L.
Published: August 2004

Hemorrhage, sepsis, burn injury, surgical trauma and critical illness all induce insulin resistance. Recently we found that trauma and hemorrhage acutely induced hepatic insulin resistance in the rat. However, the mechanisms of this hemorrhage-induced acute hepatic insulin resistance are unknown. Here we report on the mechanisms of this hepatic insulin resistance. Protein levels and phosphorylation of the insulin receptor and insulin receptor substrate-1/2 (IRS-1/2) were measured, as was the association between IRS-1/2 and phosphatidylinositol 3-kinase (PI3K). Also examined were the hepatic expression of TNFα and TNFα-induced serine phosphorylation of IRS-1. Insulin receptor and IRS-1/2 protein levels and insulin-induced tyrosine phosphorylation of the insulin receptor were unaltered. In contrast, insulin-induced tyrosine phosphorylation of IRS-1/2 and association between IRS-1/2 and PI3K were dramatically reduced after hemorrhage. Hepatic levels of TNFα mRNA and protein were increased as was phosphorylation of IRS-1 serine 307 after hemorrhage. Our data provide the first evidence that compromised IRS-1/2 tyrosine phosphorylation and their association with PI3K contribute to hemorrhage-induced acute hepatic insulin resistance. Increased local TNFα may play a role in inducing this hepatic insulin resistance after trauma and hemorrhage.
Triiodothyronine Stimulates Food Intake via the Hypothalamic Ventromedial Nucleus Independent of Changes in Energy Expenditure
Authors: Kong Wing May , Martin Niamh M. , Smith Kirsty L. , Gardiner James V. , Connoley Ian P. , Stephens David A. , Dhillo Waljit S. , Ghatei Mohammad A. , Small Caroline J. , Bloom Stephen R.
Published: August 2004

Increased food intake is characteristic of hyperthyroidism, although this is presumed to compensate for a state of negative energy balance. However, here we show that the thyroid hormone T3 directly stimulates feeding at the level of the hypothalamus. Peripheral administration of T3 doubled food intake in ad libitum-fed rats over 2 h and induced expression of the immediate early gene, early growth response-1, in the hypothalamic ventromedial nucleus (VMN), whereas maintaining plasma-free T3 levels within the normal range. T3-induced feeding occurred without altering energy expenditure or locomotion. Injection of T3 directly into the VMN produced a 4-fold increase in food intake in the first hour. The majority of T3 in the brain is reported to be produced by tissue-specific conversion of T4 to T3 by the enzyme type 2 iodothyronine deiodinase (D2). Hypothalamic D2 mRNA expression showed a diurnal variation, with a peak in the nocturnal feeding phase. Hypothalamic D2 mRNA levels also increased after a 12- and 24-h fast, suggesting that local production of T3 may play a role in this T3 feeding circuit. Thus, we propose a novel hypothalamic feeding circuit in which T3, from the peripheral circulation or produced by local conversion, stimulates food intake via the VMN.
Small-Molecule Insulin Mimetic Reduces Hyperglycemia and Obesity in a Nongenetic Mouse Model of Type 2 Diabetes
Authors: Strowski Mathias Z. , Li Zhihua , Szalkowski Deborah , Shen Xiaolan , Guan Xiao-Ming , Jüttner Stefan , Moller David E. , Zhang Bei B.
Published: August 2004

Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor-γ agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPARγ agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.
Dissecting Linear and Conformational Epitopes on the Native Thyrotropin Receptor
Authors: Ando Takao , Latif Rauf , Daniel Samira , Eguchi Katsumi , Davies Terry F.
Published: August 2004

The TSH receptor (TSHR) is the primary antigen in Graves’ disease. In this condition, autoantibodies to the TSHR that have intrinsic thyroid-stimulating activity develop. We studied the epitopes on the native TSHR using polyclonal antisera and monoclonal antibodies (mAbs) derived from an Armenian hamster model of Graves’ disease. Of 14 hamster mAbs analyzed, five were shown to bind to conformational epitopes including one mAb with potent thyroid-stimulating activity. Overlapping conformational epitopes were determined by cell-binding competition assays using fluorescently labeled mAbs. We identified two distinct conformational epitopes: epitope A for both stimulating and blocking mAbs and epitope B for only blocking mAbs. Examination of an additional three mouse-derived stimulating TSHR-mAbs also showed exclusive binding to epitope A. The remaining nine hamster-derived mAbs were neutral or low-affinity blocking antibodies that recognized linear epitopes within the TSHR cleaved region (residues 316–366) (epitope C). Serum from the immunized hamsters also recognized conformational epitopes A and B but, in addition, also contained high levels of TSHR-Abs interacting within the linear epitope C region. In summary, these studies indicated that the natively conformed TSHR had a restricted set of epitopes recognized by TSHR-mAbs and that the binding site for stimulating TSHR-Abs was highly conserved. However, high-affinity TSHR-blocking antibodies recognized two conformational epitopes, one of which was indistinguishable from the thyroid-stimulating epitope. Hence, TSHR-stimulating and blocking antibodies cannot be distinguished purely on the basis of their conformational epitope recognition.
Regulation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT1-Dependent Genes by RET/PTC (Rearranged in Transformation/Papillary Thyroid Carcinoma) Oncogenic Tyrosine Kinases
Authors: Hwang Eun Suk , Kim Dong Wook , Hwang Jung Hwan , Jung Hye Sook , Suh Jae Mi , Park Young Joo , Chung Hyo Kyun , Song Jung Hun , Park Ki Cheol , Park Su Hyeon , Yun Hwan-Jung , Kim Jin Man , Shong Minho
Published: August 2004

Chimeric RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncoproteins are constitutively active tyrosine kinases found in thyroid papillary carcinoma and nonneoplastic Hashimoto’s thyroiditis. Although several proteins have been identified to be substrates of RET/PTC kinases, the pathogenic roles played by RET/PTC in malignant and benign thyroid diseases and the molecular mechanisms that are involved are not fully understood. We found that RET/PTC expression phosphorylates the Y701 residue of STAT1, a type II interferon (IFN)-responsive protein. RET/PTC-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation requires RET/PTC kinase activity to be intact but other tyrosine kinases, such as Janus kinases or c-Src, are not involved. RET/PTC-induced STAT1 transcriptional activation was not inhibited by suppressor of cytokine signaling-1 or -3, or protein inhibitors of activated STAT3 [(protein inhibitor of activated STAT (PIAS3)], but PIAS1 strongly repressed the RET/PTC-induced transcriptional activity of STAT1. RET/PTC-induced STAT1 activation caused IFN regulatory factor-1 expression. We found that STAT1 and IFN regulatory factor-1 cooperated to significantly increase transcription from type IV IFN-γresponsive promoters of class II transactivator genes. Significantly, cells stably expressing RET/PTC expressed class II transactivator and showed enhanced de novo membrane expression of major histocompatibility complex (MHC) class II proteins. Furthermore, RET/PTC1-bearing papillary thyroid carcinoma cells strongly expressed MHC class II (human leukocyte-associated antigen-DRα) genes, whereas the surrounding normal tissues did not. Thus, RET/PTC is able to phosphorylate and activate STAT1. This may lead to enhanced MHC class II expression, which may explain why the tissues surrounding RET/PTC-positive cancers are infiltrated with lymphocytes. Such immune response-promoting activity of RET/PTC may also relate to the development of Hashimoto’s thyroiditis.
Hypoxic survival strategies in two fishes: extreme anoxia tolerance in the North European crucian carp and natural hypoxic preconditioning in a coral-reef shark
Authors: Nilsson Göran E. , Renshaw Gillian M. C.
Published: August 2004

Especially in aquatic habitats, hypoxia can be an important evolutionary driving force resulting in both convergent and divergent physiological strategies for hypoxic survival. Examining adaptations to anoxic/hypoxic survival in hypoxia-tolerant animals may offer fresh ideas for the treatment of hypoxia-related diseases. Here, we summarise our present knowledge of two fishes that have evolved to survive hypoxia under very different circumstances.

The crucian carp (Carassius carassius) is of particular interest because of its extreme anoxia tolerance. During the long North European winter, it survives for months in completely oxygen-deprived freshwater habitats. The crucian carp also tolerates a few days of anoxia at room temperature and, unlike anoxia-tolerant freshwater turtles, it is still physically active in anoxia. Moreover, the crucian carp does not appear to reduce neuronal ion permeability during anoxia and may primarily rely on more subtle neuromodulatory mechanisms for anoxic metabolic depression.

The epaulette shark (Hemiscyllium ocellatum) is a tropical marine vertebrate. It lives on shallow reef platforms that repeatedly become cut off from the ocean during periods of low tides. During nocturnal low tides, the water [O2] can fall by 80% due to respiration of the coral and associated organisms. Since the tides become lower and lower over a period of a few days, the hypoxic exposure during subsequent low tides will become progressively longer and more severe. Thus, this shark is under a natural hypoxic preconditioning regimen. Interestingly, hypoxic preconditioning lowers its metabolic rate and its critical PO2. Moreover, repeated anoxia appears to stimulate metabolic depression in an adenosine-dependent way.
Oxidants, antioxidants and the ischemic brain
Authors: Warner David S. , Sheng Huaxin , Batinić-Haberle Ines
Published: August 2004

Despite numerous defenses, the brain is vulnerable to oxidative stress resulting from ischemia/reperfusion. Excitotoxic stimulation of superoxide and nitric oxide production leads to formation of highly reactive products,including peroxynitrite and hydroxyl radical, which are capable of damaging lipids, proteins and DNA. Use of transgenic mutants and selective pharmacological antioxidants has greatly increased understanding of the complex interplay between substrate deprivation and ischemic outcome. Recent evidence that reactive oxygen/nitrogen species play a critical role in initiation of apoptosis, mitochondrial permeability transition and poly(ADP-ribose) polymerase activation provides additional mechanisms for oxidative damage and new targets for post-ischemic therapeutic intervention. Because oxidative stress involves multiple post-ischemic cascades leading to cell death, effective prevention/treatment of ischemic brain injury is likely to require intervention at multiple effect sites.
Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury
Authors: Giffard Rona G. , Xu Lijun , Zhao Heng , Carrico Whitney , Ouyang Yibing , Qiao Yanli , Sapolsky Robert , Steinberg Gary , Hu Bingren , Yenari Midori A.
Published: August 2004

Chaperones, especially the stress inducible Hsp70, have been studied for their potential to protect the brain from ischemic injury. While they protect from both global and focal ischemia in vivo and cell culture models of ischemia/reperfusion injury in vitro, the mechanism of protection is not well understood. Protein aggregation is part of the etiology of chronic neurodegenerative diseases such as Huntington's and Alzheimer's, and recent data demonstrate protein aggregates in animal models of stroke. We now demonstrate that overexpression of Hsp70 in hippocampal CA1 neurons reduces evidence of protein aggregation under conditions where neuronal survival is increased. We have also demonstrated protection by the cochaperone Hdj-2 in vitro and demonstrated that this is associated with reduced protein aggregation identified by ubiquitin immunostaining. Hdj-2 can prevent protein aggregate formation by itself, but can only facilitate protein folding in conjunction with Hsp70. Pharmacological induction of Hsp70 was found to reduce both apoptotic and necrotic astrocyte death induced by glucose deprivation or oxygen glucose deprivation. Protection from ischemia and ischemia-like injury by chaperones thus involves at least anti-apoptotic,anti-necrotic and anti-protein aggregation mechanisms.
Negotiating brain anoxia survival in the turtle
Authors: Lutz Peter L. , Milton Sarah L.
Published: August 2004

The turtle brain's extraordinary ability to tolerate anoxia is based on constitutive and expressed factors. Constitutive factors that predispose for anoxia tolerance include enhanced levels of glycogen stores, increased densities of protective receptors, elevated antioxidant capacities and elevated heat shock protein. However, to survive an anoxic insult, three distinct phases must be negotiated successfully. (1) A coordinated downregulation of ATP demand processes to basal levels. This phase, which takes 1–2 h, includes a reduction in voltage-gated K+ (Kv)channel transcription and a substantial increase in Hsp72 and Hsc73 levels. During this period, adenosine and KATP channels mediate several key events including channel arrest initiation and a reduction in the release of excitatory amino acids (EAAs). (2) Long-term survival (days) at basal levels of ATP expenditure. Neuronal network integrity is preserved through the continued operation of core activities. These include periodic electrical activity, an increased release of GABA and a continued release of glutamate and dopamine. Adenosine and GABA modulate the glutamate release. There is a further increase in Hsc73, indicating a `housekeeping' role for this protein during this period. (3) A rapid upregulation of neuronal processes when oxygen becomes available to restore full function, together with the activation of protection mechanisms against reperfusion-generated reactive oxygen species.
Hypoxia–ischemia in the immature brain
Authors: Vannucci Susan J. , Hagberg Henrik
Published: August 2004

The immature brain has long been considered to be resistant to the damaging effects of hypoxia and hypoxia–ischemia (H/I). However, it is now appreciated that there are specific periods of increased vulnerability, which relate to the developmental stage at the time of the insult. Although much of our knowledge of the pathophysiology of cerebral H/I is based on extensive experimental studies in adult animal models, it is important to appreciate the major differences in the immature brain that impact on its response to, and recovery from, H/I. Normal maturation of the mammalian brain is characterized by periods of limitations in glucose transport capacity and increased use of alternative cerebral metabolic fuels such as lactate and ketone bodies, all of which are important during H/I and influence the development of energy failure. Cell death following H/I is mediated by glutamate excitotoxicity and oxidative stress, as well as other events that lead to delayed apoptotic death. The immature brain differs from the adult in its sensitivity to all of these processes. Finally, the ultimate outcome of H/I in the immature brain is determined by the impact on the ensuing cerebral maturation. A hypoxic–ischemic insult of insufficient severity to result in rapid cell death and infarction can lead to prolonged evolution of tissue damage.
Protective role of neuronal KATP channels in brain hypoxia
Authors: Ballanyi Klaus
Published: August 2004

During severe arterial hypoxia leading to brain anoxia, most mammalian neurons undergo a massive depolarisation terminating in cell death. However,some neurons of the adult brain and most immature nervous structures tolerate extended periods of hypoxia–anoxia. An understanding of the mechanisms underlying this tolerance to oxygen depletion is pivotal for developing strategies to protect the brain from consequences of hypoxic-ischemic insults. ATP-sensitive K+ (KATP) channels are good subjects for this study as they are activated by processes associated with energy deprivation and can counteract the terminal anoxic-ischemic neuronal depolarisation. This review summarises in vitro analyses on the role of KATP channels in hypoxia–anoxia in three distinct neuronal systems of rodents. In dorsal vagal neurons, blockade of KATPchannels with sulfonylureas abolishes the hypoxic-anoxic hyperpolarisation. However, this does not affect the extreme tolerance of these neurons to oxygen depletion as evidenced by a moderate and sustained increase of intracellular Ca2+ (Cai). By contrast, a sulfonylurea-induced block of KATP channels shortens the delay of occurrence of a major Cai rise in cerebellar Purkinje neurons. In neurons of the neonatal medullary respiratory network, KATP channel blockers reverse the anoxic hyperpolarisation associated with slowing of respiratory frequency. This may constitute an adaptive mechanism for energy preservation. These studies demonstrate that KATP channels are an ubiquituous feature of mammalian neurons and may, indeed, play a protective role in brain hypoxia.
A unique pathway of cardiac myocyte death caused by hypoxia–acidosis
Authors: Graham Regina M. , Frazier Donna P. , Thompson John W. , Haliko Shannon , Li Huifang , Wasserlauf Bernard J. , Spiga Maria-Grazia , Bishopric Nanette H. , Webster Keith A.
Published: August 2004

Chronic hypoxia in the presence of high glucose leads to progressive acidosis of cardiac myocytes in culture. The condition parallels myocardial ischemia in vivo, where ischemic tissue becomes rapidly hypoxic and acidotic. Cardiac myocytes are resistant to chronic hypoxia at neutral pH but undergo extensive death when the extracellular pH (pH[o]) drops below 6.5. A microarray analysis of 20 000 genes (cDNAs and expressed sequence tags)screened with cDNAs from aerobic and hypoxic cardiac myocytes identified>100 genes that were induced by >2-fold and ∼20 genes that were induced by >5-fold. One of the most strongly induced transcripts was identified as the gene encoding the pro-apoptotic Bcl-2 family member BNIP3. Northern and western blot analyses confirmed that BNIP3 was induced by 12-fold(mRNA) and 6-fold (protein) during 24 h of hypoxia. BNIP3 protein, but not the mRNA, accumulated 3.5-fold more rapidly under hypoxia–acidosis. Cell fractionation experiments indicated that BNIP3 was loosely bound to mitochondria under conditions of neutral hypoxia but was translocated into the membrane when the myocytes were acidotic. Translocation of BNIP3 coincided with opening of the mitochondrial permeability pore (MPTP). Paradoxically,mitochondrial pore opening did not promote caspase activation, and broad-range caspase inhibitors do not block this cell death pathway. The pathway was blocked by antisense BNIP3 oligonucleotides and MPTP inhibitors. Therefore,cardiac myocyte death during hypoxia–acidosis involves two distinct steps: (1) hypoxia activates transcription of the death-promoting BNIP3 gene through a hypoxia-inducible factor-1 (HIF-1) site in the promoter and (2) acidosis activates BNIP3 by promoting membrane translocation. This is an atypical programmed death pathway involving a combination of the features of apoptosis and necrosis. In this article, we will review the evidence for this unique pathway of cell death and discuss its relevance to ischemic heart disease. The article also contains new evidence that chronic hypoxia at neutral pH does not promote apoptosis or activate caspases in neonatal cardiac myocytes.
Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals
Authors: Chen Qiaofang , Haddad Gabriel G.
Published: August 2004

Trehalose is a nonreducing disaccharide in which the two glucose units are linked in an α,α-1,1-glycosidic linkage. The best known and most widely distributed pathway of trehalose synthesis involves the transfer of glucose from UDP-glucose to glucose 6-phosphate to form trehalose-6-phosphate and UDP via the trehalose-6-phosphate synthase (TPS1). Trehalose-6-phosphate phosphatase (TPS2) then converts trehalose-6-phosphate to free trehalose. This sugar is present in a wide variety of organisms,including bacteria, yeast, fungi, insects, invertebrates and plants, and because of its particular physical features, trehalose is able to protect the integrity of cells against a variety of environmental stresses such as desiccation, dehydration, heat, cold and oxidation. Our current studies described here indicate that trehalose protects Drosophila and mammalian cells from hypoxic and anoxic injury. The mechanism of this protection is probably related to a decrease in protein denaturation through protein–trehalose interactions.
Synthesis and Structures of Highly Conducting Charge-Transfer Salts of Selenium Containing TTM-TTP Derivatives
Authors: Ashizawa Minoru , Akutsu Akane , Noda Bunpei , Nii Hirofumi , Kawamoto Tadashi , Mori Takehiko , Nakayashiki Takashi , Misaki Yohji , Tanaka Kazuyoshi , Takimiya Kazuo , Otsubo Tetsuo
Published: August 2004

Selenium-substituted TTM-TTP (2,5-bis[4,5-bis(methylthio)-1,3-dithiol-2-ylidene]-1,3,4,6-tetrathiapentalene) derivatives (1a–1d), in which several 1,3-dithiole rings of the bis-fused TTF framework are replaced by 1,3-diselenole rings, have been prepared. In particular, we have accomplished the first selenium substitution of the inner TTP part (1a). The 1:1 composition iodine salt, (1a)I3, is an insulator constructed of the donor trimers. The 1:1 GaCl4 salt, (1a)GaCl4, has a uniform column isostructural to the sulfur analog, (TTM-TTP)FeBr1.8Cl2.2; it exhibits metallic conduction down to about 60 K, the lowest metal–insulator (M–I) transition temperature in 1:1 salts. The donors 1c and 1d give the iodine salts isostructural to the sulfur analog, (TTM-TTP)(I3)5/3. By the selenium substitution, the M–I transition of (1d)(I3)5/3 is entirely suppressed.
Effects of Cyclodextrins on the Fluorescence of 2-Methylnaphth[2,3-d]oxazole in Aqueous Solution
Authors: Hamai Sanyo
Published: August 2004

In organic solvents, 2-methylnaphth[2,3-d]oxazole (MNO) exhibits a single emission, whereas it exhibits dual emissions (the 350-nm band fluorescence and the longer-wavelength fluorescence) in water (pH 6.1). In acidic aqueous solution, the 350-nm band fluorescence alone is observed with a disappearance of the longer-wavelength fluorescence. In pH 6.1 buffers, α-CD has been found to form a 2:1 inclusion complex with MNO. Upon the addition of α-CD to MNO solution, the longer-wavelength fluorescence is significantly reduced in intensity, relative to the 350-nm band fluorescence. The incorporation of an MNO molecule into the α-CD cavities obstructs the generation of the excited state responsible for the longer-wavelength fluorescence. The longer-wavelength fluorescence is most likely due to the intramolecular charge transfer (ICT) state of MNO, which is induced by water molecules of high polarity. MNO forms a 1:1 inclusion complex with β-CD. In the presence of β-CD, the intensity ratio of the longer-wavelength fluorescence to the 350-nm band fluorescence is decreased. When 1-propanol is added to MNO solution containing β-CD, a ternary inclusion complex is formed among β-CD, MNO, and 1-propanol. In β-CD solution containing 1-propanol, the intensity ratio of the longer-wavelength fluorescence to the 350-nm band fluorescence is slightly reduced. These findings support the conclusion that the longer-wavelength fluorescence of MNO is due to the ICT state, whose generation is promoted by the water environment.
Ternary Complexes from Cu(II)–Oligopeptide and N-Acetyl-l-histidine, as Studied by Circular Dichroism Spectroscopy
Authors: Hanaki Akira , Ueda Jun-ichi , Ikota Nobuo
Published: August 2004

The Cu(II) complexes of oligopeptides, Cu(H−iL); i = 1, 2, or 3, reacted with N-acetyl-l-histidine (AHis) to form ternary complexes, Cu(H−jL)(AHis); j = 1 or 2. The Cu(H−1L) species formed Cu(H−1L)(AHis), which was either dimerized to [Cu(H−1L)]2(AHis−) or converted stepwise to Cu(AHis)n; n = 3, 4. The reaction of the Cu(H−2L) or Cu(H−3L) species with AHis led to the formation of Cu(H−2L)(AHis), and the formation constants of the ternary complexes were small, on the magnitude of 10−1–101 M−1.
19F NMR Study on the Heme Electronic Structure in Oxy and Carbonmonoxy Reconstituted Myoglobins
Authors: Hirai Yueki , Nagao Satoshi , Mita Hajime , Suzuki Akihiro , Yamamoto Yasuhiko
Published: August 2004

A 19F NMR study on myoglobin reconstituted with a ring-fluorinated C2 symmetric heme, 13,17-bis(2-carboxylatoethyl)-2,8,12,18-tetramethyl-3,7-difluoroporphyrinatoiron(II), demonstrated that the porphyrin π system is affected by the bent orientation of the Fe–O–O unit relative to the heme in oxy myoglobin and Fe dπ → CO π* back-donation in carbonmonoxy myoglobin.