bluuebunny/crossref_metadata_2025 huggingface dataset:
Current Status of Endoscopic Laser Surgery in Head and Neck Surgical Oncology
Authors: Eckel Hans Edmund
Published: April 2003

This review of the Cologne University Medical School experience with oncological laser surgery evaluates the potential role of transoral laser surgery for oral, oropharyngeal, laryngeal and hypopharyngeal carcinoma by reporting the treatment modalities and results in large, unselected cohorts of consecutive patients from a university-based referral center that prefers transoral laser surgery over open surgical approaches for all head and neck cancer cases if such an approach is considered feasible and oncologically sound by the contributing surgeons at our department. It seeks to determine the proportion of all oncological cases that can be managed using a transoral approach and to describe survival, local control and organ preservation rates with endoscopic CO2 laser surgery. The data presented in this study suggest that transoral laser surgery is no longer a treatment modality that should be restricted to highly selected patients, but may well become a major treatment option for most infiltrating laryngeal and oral carcinomas, for important subgroups of pharyngeal cancer, and for practically all carcinomas in situ and verrucous carcinoma. Additional treatment options are required for the neck if suspect lymph nodes are detectable at the time of primary treatment or if the neck is considered to be at risk for regional metastases. In light of the recent literature on treatment modalities for head and neck carcinoma, the future may bring new roles for surgery and radiotherapy: organ-sparing surgery, including transoral laser surgery, may become a more widespread approach to early-stage disease, while organ preservation programs based on sequential or concomitant chemotherapy and radiotherapy may replace surgery as the most important treatment modality in advanced but resectables stages.
Growth Pattern of T3 and T4 Piriform Sinus Carcinomas: Implications for Microendoscopic Laser Surgery
Authors: Zbären P. , Stauffer E.
Published: April 2003

Objective: Carcinomas of the piriform sinus have an unfavourable prognosis despite aggressive treatments. Most authors are therefore increasingly hesitant to offer patients treatment options including total laryngectomy. There is a tendency to treat piriform sinus carcinomas in a manner that preserves the larynx, whether by radiochemotherapy (sequential or concomitant), classic organ-preserving surgery, microendoscopic laser surgery, or a combination of these treatment options. The value of laser surgery in the treatment of more extensive carcinomas has not yet been precisely defined, unlike that of classic function-preserving surgery. An attempt has been made in this study to evaluate the possibilities and limits of microendoscopic laser surgery in the treatment of cT3 and cT4 carcinomas, based on a histological analysis of the patterns of spread. Methods: A total of 70 specimens obtained by pharyngolaryngectomy were subjected to a whole-organ section study. The carcinomas were also evaluated in respect of possible classic organ-preserving surgery on the basis of established selection criteria, and an attempt was made to define selection criteria for the use of microendoscopic laser surgery on the basis of the histopathological pattern of spread. Results: On the basis of the established selection criteria, such as fixation of the vocal fold, cricoid infiltration, spread of the tumour to the retrocricoid region and infiltration of the pre-epiglottic space, only very few T3 and T4 carcinomas of the piriform sinus can be treated with classic function-preserving surgery. Laser surgery is primarily determined by the pattern of spread and less by given anatomical landmarks. Selection criteria, such as have been established for classic function-preserving surgery, are not helpful for laser surgery. The main problem in microendoscopic laser surgery is the optimal exposure of the tumour. Conclusions: Assuming correct exposure of the tumour, function-preserving treatment by laser surgery can be carried out on more T3 and T4 carcinomas than would be possible with classic function-preserving surgery. The contraindication criteria for classic function-preserving surgery are not applicable to laser surgery because this form of surgery is determined by the tumour extension and not by anatomical landmarks.
Laser Surgery for T2 Glottic Carcinoma
Authors: Werner J.A. , Dünne A.A. , Folz B.J. , Lippert B.M.
Published: April 2003

Background: Surgical therapy for T2 glottic carcinoma still is a topic of controversial discussion. The value of laser therapy in this stage of disease is difficult to determine due to selection bias. Data of comparative analyses have usually been collected from retrospective studies which are more prone to selection bias. Patients and Methods: A total number of 14 patients suffering from T2 glottic carcinoma were treated by transoral laser microsurgery. Results: During the median follow-up of 24 months, 2 patients developed recurrent disease in the anterior commissure, and 12 patients remained free of disease. Conclusion: Endoscopic laser therapy should be considered after weighing up the indication thoroughly. The sometimes extremely difficult conditions in transoral laser surgery are tightly bound to the experience of the operating surgeon and in cases of doubt, conventional partial laryngectomy should be preferred.
Selenium in Breast Cancer
Authors: Lopez-Saez Juan-Bosco , Senra-Varela Avelino , Pousa-Estevez Lorenzo
Published: April 2003

Aim: Controversy surrounds the hypothetical relationship between low serum levels of selenium and reduced activity of selenium-dependent enzymes, such as glutathione peroxidase, and an increased risk of cancer in humans. This study investigated serum concentrations of selenium in women with and without breast cancer. Methods: In this case-control study, we compared serum concentrations of selenium in women with breast cancer (n = 200), healthy women (n = 100), and women with chronic diseases (n = 100). Patients with breast cancer were divided into premenopausal (n = 99) and postmenopausal subjects (n = 101). Results: Mean serum concentrations of selenium were 81.1 µg/l in women with breast cancer and 98.5 µg/l in women with non-tumoral disease (p < 0.001). Conclusion: Alterations in serum concentrations of selenium in women with breast cancer appear to be a consequence, rather than a cause of cancer. In accordance with the hypothesis, the findings suggest that very low selenium status could be due to the nature of cancer.
Pain and Its Treatment in Patients with Cancer in Korea
Authors: Hyun Myung Soo , Lee Jae Lyun , Lee Kyung Hee , Shin Sei One , Kwon Ki Young , Song Hong Suk , Kim Ok Bae , Sohn Sang Kyun , Lee Kyu Bo , Rhu Hun Mo , Park Gun Wook , Shin Dong Gun , Lee Jeong Lim
Published: April 2003

Substantial pain is experienced by a lot of patients with cancer, and undertreated pain significantly undermines their quality of life. Despite international and national guidelines on cancer pain management, the practical effectiveness of management is still problematic. We did a prospective cross-sectional survey on pain prevalence, pain intensity, its impact on daily activity, and adequacy of pain management in 823 patients treated by medical oncologists and radiologic oncologists. At the time of the survey, 29.7% of the patients had pain that was moderate or severe. Performance status and tumor extent were significant predictors of pain presence and its intensity. Pain severity and the proportion of the patients whose function is impaired are highly associated. Among the patients with pain, only 37% rated pain relief as satisfactory. Forty-one percent of the patients with pain received inadequate pain management. Physicians did not adjust the analgesic prescription in about 53% of the patients who reported severe pain. These results demonstrate the alarming degree of undertreatment of pain in patients with cancer in Korea, and indicate the need to improve the management of cancer-related pain. Future research should elucidate the factors that impede adequate pain management in order to overcome obstacles to adequate treatment.
Significant Hybridization Differences in Comparative Genomic Hybridization due to Nucleotides Used for DNA Labelling and to DNA Chosen for Cohybridization
Authors: Wilkens Ludwig , Tchinda Joelle , Burkhardt Dagmar , Kreipe Hans Heinrich
Published: April 2003

Objective: Comparative genomic hybridization (CGH) has been established as an informative technique in genetic analysis. However, differences in the ratio of hybridization intensities were reported for particular chromosomes, which may affect CGH results. The aim of this study was to define these differences in more detail. For this purpose, CGH results of 70 samples of bone marrow cells (BMC) with normal karyotype in conventional cytogenetics (CC) were evaluated using seven different reference DNAs and two different DNA labeling systems. Methods and Results: CGH using fluorochrome-conjugated nucleotides for DNA labeling indicated signal deviations in 21/70 BMC samples. Deviations affected chromosomes 1 (n = 21), 2 (n = 11), 4 (n = 11), 5 (n = 9), 6 (n = 7), 7 (n = 2), 8 (n = 2), 12 (n = 5), 13 (n = 15), 14 (n = 1), 16 (n = 17), 17 (n = 11), 19 (n = 21), 20 (n = 12), and/or 22 (n = 17). None of the imbalances were confirmed by fluorescence in situ hybridization (FISH). Using digoxigenin and biotin-conjugated nucleotides in exemplary cases (n = 5) led to the disappearance of the signal deviations. Repeated CGH experiments using seven different reference DNAs showed remarkable variations in the signal deviations. Conclusion: Hybridization differences depend not only on the hapten or fluorochrome-labeled nucleotides used for DNA labeling, but also on the reference DNA chosen. Therefore, close control of CGH experiments is mandatory, and additional techniques such as FISH should be performed to confirm the results obtained by CGH.
Preventive (Evidence-Based) Approach to Quality General Dental Care
Authors: Elderton Richard J.
Published: April 2003

Restorative and scaling treatments have not generally provided an effective method for managing dental caries and periodontal diseases. Rather, restorative treatment has often covered up the disease processes in the short term and created a new problem: that of maintenance and re-restoration of restored teeth. Thus, standard invasive dental treatments that are commonly provided fail to address the fundamental bacterial nature of the diseases. Indeed, these treatments rather readily generate and perpetuate a totally unacceptable chain of events. This chain embraces many shortcomings, which themselves nurture what may be described as the repeat restorative cycle. The time has come to correct this iniquity. Dental caries and periodontal diseases are dynamic conditions which need ‘managing’ with a focused cocktail of preventive and refined restoration care. Much more emphasis should be placed upon the assessment of each and every caries or periodontal lesion, with a view to implementing specific preventive measures and allowing the natural arrest of disease processes to occur. The universal adoption of a preventive (evidence-based) approach to making dental treatment decisions could be by far the most powerful factor in reducing the restorative burden of dental services. It is clear that dental education and practice need to rise proactively to the challenge, or changes will be forced upon them while they are in a defensive position. There is a need to move wholeheartedly and contentedly into the preventive era.
Dental Education and Dentistry System in Iran
Authors: Pakshir Hamid Reza
Published: April 2003

Before 1979, there were only 5 undergraduate dental schools in Iran with a total admission of 200 students per year, and only 2,000 dentists and about 50 specialists practicing in the country. Currently, there are 18 dental schools with a total admission of 750 undergraduate students, 5 postgraduate programs in 10 disciplines with a total of 100 students, more than 11,000 dentists (1 dentist per 5,500 population) and nearly 1,000 specialists in the country. Two new schools have recently begun offering specialty training courses in 2 disciplines. The length of the dentistry curriculum is 6 years. Students take general and basic science courses during the first 2 years, then continue on the predental and dental courses for the remaining 4 years. The curriculum has been revised over the past 20 years to establish intership and specialty programs and introduce courses reflecting current trends in the dental profession. Dental services in Iran are provided by both public and private sectors. Oral health care was integrated into the Public Health Care network by 1997, and 4 levels of a Dental Health Care Delivery System were established. The first level is concerned with primary prevention at ‘health houses’, where auxiliary health workers called ‘behvarzes’ provide periodic examinations, referrals, and oral health education. At the next level, oral hygienists and dentists in ‘health centers’ perform basic oral health care services such as fillings, scaling, and extraction. At the third level, dentists manage and treat oral diseases in ‘urban health centers’, while the last level is for advanced treatment by specialists in university health centers in the cities.
Long-Term Outcome after Stroke due to Atrial Fibrillation
Authors: Mattle Heinrich P.
Published: April 2003

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF is paroxysmal or persistent and becomes permanent when it does not convert to sinus rhythm spontaneously or when attempted cardioversion fails. The prevalence of AF is 0.4% in the general population and increases with age up to 6–8% in octogenarians. In men, the age-adjusted prevalence is generally higher than in women. During AF, synchronous mechanical atrial activity is disturbed, resulting in haemodynamic impairment. This can give rise to thrombus formation and embolism to the systemic circulation. Thrombus associated with AF arises most frequently in the left atrial appendage. Cerebrovascular emboli in AF patients most often manifest as transient ischaemic attacks or ischaemic strokes. The overall rate of ischaemic stroke among patients with nonrheumatic AF averages 5% per year, but the rate increases with age. Patients with AF are at higher risk of cerebrovascular events from all causes. Of all strokes, one in every six occurs in patients with AF. Including transient ischaemic attacks and silent strokes detected radiographically, the overall rate of all cerebrovascular events in AF patients rises to more than 7% per year, although approximately one third of these are due to causes that are only secondarily or incidentally associated with AF or related anticoagulant therapy. Antiarrhythmic therapy is useful to improve cardiac rate and function in AF. However, to reduce first or recurrent emboli, antithrombotic therapy is of paramount importance. Results from several randomized clinical trials of antithrombotic therapies have shown that adjusted-dose warfarin reduces first or recurrent stroke by about 60% compared with placebo. When patients with nonvalvular AF are anticoagulated, the odds against ischaemic stroke and intracranial bleeding favour an INR between 2.0 and 3.0. Acetylsalicylic acid is less efficacious than warfarin in AF patients, reducing the risk of stroke by about 20%. Therefore, this antiplatelet agent should be used only for AF patients at low risk. Anticoagulation is the current treatment modality in AF patients at high or intermediate risk, i.e. patients with history of transient ischaemic attack or stroke, those aged >65 years, those with a history of hypertension, diabetes, heart failure or structural heart disease, valvular disease or significant systolic dysfunction. The benefit of dual antiplatelet regimens in AF patients is unknown, and combining antiplatelet agents with different mechanisms of action is an important topic for future investigation.
Plasma Testosterone Levels in Patients with Combat-Related Posttraumatic Stress Disorder
Authors: Spivak Baruch , Maayan Rachel , Mester Roberto , Weizman Abraham
Published: April 2003

Background: An abnormal level of androgens has been reported in various psychiatric disorders and the important role of androgens in the regulation of human sexuality, aggression, cognition, emotions and personality have been described. Previous studies in the area of stress and the hypothalamic-pituitary-gonadal (HPG) system in humans indicate that circulating testosterone levels are suppressed by physical and psychological stress. However, there is also evidence that plasma levels of testosterone can increase during potentially stressful events and may be elevated in combat-related posttraumatic stress disorder (CR-PTSD) in comparison with normal subjects and major depressive disorder patients. Methods: The aim of the present study was to examine the possible involvement of the HPG system in chronic untreated CR-PTSD. To this end, we assessed the morning plasma levels of testosterone and cortisol in never-treated chronic CR-PTSD outpatients compared with normal healthy controls. Results: There were no statistically significant differences between the CR-PTSD patients and healthy control subjects in morning plasma testosterone (547.8 ± 152.2 ng/dl vs. 565.6 ± 122.4 ng/dl; p = 0.7) and cortisol (19.0 ± 8.5 µg/dl vs. 15.4 ± 5.1 µg/dl; p = 0.1) levels. However, a significant correlation between plasma testosterone level and avoidance symptom scores of the Impact of Events Scale (IES) was found in the CR-PTSD patients (r = 0.43, p < 0.05). Conclusions: The findings of plasma testosterone levels comparable with normal controls in CR-PTSD patients may indicate that the previously described reduction in testosterone levels in normal subjects under stressful conditions may reflect the acute stress response of the HPG axis, in contrast to an adaptation of the HPG axis under chronic psychological stress.
Endocrine and Cardiovascular Responses to Corticotropin-Releasing Hormone in Patients with Posttraumatic Stress Disorder: A Role for Atrial Natriuretic Peptide?
Authors: Kellner Michael , Yassouridis Alexander , Hübner Renate , Baker Dewleen G. , Wiedemann Klaus
Published: April 2003

Hypothalamic-pituitary-adrenocortical (HPA) axis data, such as low plasma cortisol concentrations in spite of increased corticotropin-releasing hormone (CRH) levels in patients with posttraumatic stress disorder (PTSD), are difficult to interpret. Atrial natriuretic peptide (ANP) may be an explanatory link in the neuroendocrine pathophysiology of the disorder, since it is a neuromodulator with antianxiety effects that inhibits HPA activity at multiple levels. Seventeen patients with chronic PTSD and 17 healthy control subjects were given 100 µg of human CRH at 3 p.m. ANP, adrenocorticotropic hormone (ACTH), and cortisol levels in plasma as well as blood pressure and heart rate were measured during basal conditions and after CRH stimulation. Basal ANP levels were significantly lower in PTSD patients in comparison with normal controls, but the response to CRH was undistinguishable. In contrast to our expectation, no significant differences in basal or CRH-stimulated ACTH or cortisol parameters could be observed. Systolic and diastolic blood pressures at baseline and after CRH were significantly elevated in PTSD patients. All group differences remained significant after controlling for basal blood pressure and/or body mass index. Our data do not support a role of ANP in abnormal HPA axis regulation in PTSD. However, the persistently low ANP plasma levels in PTSD patients despite elevated blood pressure may serve to facilitate anxiety behavior and have adverse long-term cardiovascular consequences. Further studies to assess ANP secretion in PTSD patients and to clarify its pathophysiological impact are needed.
Temporal Relationship between Nocturnal Erections and Rapid Eye Movement Episodes in Healthy Men
Authors: Mann Klaus , Pankok Justus , Connemann Bernhard , Röschke Joachim
Published: April 2003

The exact temporal relationship between spontaneous nocturnal erections and rapid eye movement (REM) sleep was studied in healthy men with the aim of creating a basis for a more sophisticated analysis of nocturnal erection measurements in physiological research and clinical applications. The vast majority of erectile events was coupled to REM episodes, where the latency between the beginning of erections and REM episodes showed a large variability. Moreover, a correlation analysis revealed a highly significant decrease of the latency over the course of the night. The time variant properties of the coupling between erections and REM sleep point to more complex dynamics of the central control of erections with regard to sleep regulation, indicating that REM sleep and REM-related erections are not completely interdependent. Beside the possibility of obtaining further insight into the physiological mechanisms underlying erectile function, the consideration of dynamic aspects in the assessment of nocturnal erection measurements might have potential clinical implications regarding both the diagnosis and the evaluation of therapies for erectile dysfunction.
Loading-Related Subjective Symptoms during a Vocal Loading Test with Special Reference to Gender and Some Ergonomic Factors
Authors: Vintturi Juha , Alku Paavo , Sala Eeva , Sihvo Marketta , Vilkman Erkki
Published: April 2003

Vocal loading-related subjective symptoms were studied in a day-long vocal loading test. The voices of 40 female and 40 male voluntary young students were loaded by having them read aloud a novel for five times 45 min. The subjective symptoms that occurred during the vocal loading session were reported by filling in a questionnaire after each session. The responses loaded on five factors in a factor analysis: (1) ‘central fatigue’; (2) ‘symptoms of the neck, shoulders and back’; (3) ‘drying in the mouth and throat’; (4) ‘symptoms of the throat’; (5) ‘symptoms of the voice’. The exposure groups (5 females and 5 males per cell) consisted of eight combinations of the following factors: (1) low (25 ± 5%) or high (65 ± 5%) relative humidity of ambient air; (2) low [<65 dB(SPL)] or high [>65 dB(SPL)] speech output level of vocal loading; (3) sitting or standing posture during vocal loading. The lowest mean score for symptoms pooled over the test were found in ‘symptoms of the neck, shoulders and back’ and the highest mean symptom score in ‘drying in the mouth and throat’ and ‘symptoms of the throat’. Most symptoms were at their minimum during the first loading session and increased statistically significantly to a peak mean value after three or five vocal loading sessions. Statistically significant differences in the mean level between the gender or exposure groups emerged for ‘central fatigue’ (humidity had clear effects) and ‘symptoms of the neck, shoulders and back’ (gender, humidity and posture had clear effects). In these cases, females had more symptoms than males; the low-humidity group had more symptoms than the high-humidity group, and the standing subjects had more symptoms than the sitting subjects.
A Psychological Cascade Model for Persisting Voice Problems in Teachers
Authors: de Jong F.I.C.R.S. , Cornelis B.E. , Wuyts F.L. , Kooijman P.G.C. , Schutte H.K. , Oudes M.J. , Graamans K.
Published: April 2003

In 76 teachers with persisting voice problems, the maintaining factors and coping strategies were examined. Physical, functional, psychological and socioeconomic factors were assessed. A parallel was drawn to a psychological cascade model designed for patients with chronic back pain. The majority of the patients were found to be in a deadlocked situation (phase 1 of the cascade model), for which the combination of externalization and unawareness of the situation is the main risk factor. Subjective rating of the voice problem was assessed by the Voice Handicap Index (VHI) and a visual analogue scale (VAS). Patients in phase 1 of the cascade model showed higher VHI and VAS scores compared with the other patients. For a high VHI score, the combination of socioeconomic factors and being in phase 1 was the most important risk factor. Socioeconomic factors were the most important risk factors for a high VAS score. We introduce the term ‘chronicity’, which means that the problems are maintained, the patient finds himself in a deadlocked situation, and is sliding down into a chronic disease. ‘Chronicity’ is essentially different from ‘chronic’, which refers only to the duration of the disease. We consider maintaining factors and (inadequate) coping factors, which consist of emotional/psychological, physical and socioeconomic aspects, as indicators for chronicity.
Caspase-Dependent Cell Death Mediates the Early Phase of Aortic Hypertrophy Regression in Losartan-Treated Spontaneously Hypertensive Rats
Authors: Marchand Eve-Lyne , Der Sarkissian Shant , Hamet Pavel , deBlois Denis
Published: April 2003

Blockade of angiotensin type 1 (AT
1
) receptors induces smooth muscle cell (SMC) death and regression of aortic hypertrophy in spontaneously hypertensive rats (SHR). We postulated that SMC death and vascular remodeling in this model may be attenuated by z-Val-Ala-Asp(OMe)-CH
2
F (z-VAD-fmk), a tripeptide inhibitor of caspase enzymes mediating apoptosis. To determine the time course of SMC death and aortic remodeling, SHR were treated with losartan (30 mg/kg per day) for up to 9.5 days. Transient SMC apoptosis occurred in the aortic media with a peak around day 5 of treatment, with increases in the Bax to Bcl-2 protein ratio (>3-fold), in active caspase-3 (5.6-fold), in TUNEL-positive nuclei (19-fold), preceding by 24 hours the peak activation of capase-9 (3.8-fold), and significant reductions in SMC number (46%) and aortic cross-sectional area (8.5%) at 5.5 days. The decrease in total aortic DNA reached significance at 6.5 days (29%). Blood pressure reduction with losartan was progressive and reached significance at day 7 of treatment. Next, we examined the causal link between vascular apoptosis and remodeling. SHR received placebo or losartan (30 mg/kg per day) for 6 days. During the last 24 hours, a subgroup of losartan-treated rats received 3 IV injections of z-VAD-fmk (cumulative dose: 4.4 mg · kg
−1
). All other rats received the vehicle, DMSO. The 24-hour cotreatment with z-VAD-fmk effectively prevented losartan-induced caspase-3 activation and internucleosomal DNA fragmentation, as well as SMC depletion and the reductions in aortic mass and DNA content. Together, these data suggest that caspase-dependent SMC death mediates the early phase of vascular remodeling in response to AT
1
receptor blockade in this model of hypertension.
A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes
Authors: Candido Riccardo , Forbes Josephine M. , Thomas Merlin C. , Thallas Vicki , Dean Rachael G. , Burns Wendy C. , Tikellis Christos , Ritchie Rebecca H. , Twigg Stephen M. , Cooper Mark E. , Burrell Louise M.
Published: April 2003

The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.
Chronic SR Ca
2+
-ATPase Inhibition Causes Adaptive Changes in Cellular Ca
2+
Transport
Authors: Brittsan Angela G. , Ginsburg Kenneth S. , Chu Guoxiang , Yatani Atsuko , Wolska Beata M. , Schmidt Albrecht G. , Asahi Michio , MacLennan David H. , Bers Donald M. , Kranias Evangelia G.
Published: April 2003

Phospholamban, the critical regulator of the cardiac SERCA2a Ca
2+
affinity, is phosphorylated at Ser
16
and Thr
17
during β-adrenergic stimulation (eg, isoproterenol). To assess the impact of nonphosphorylatable phospholamban, a S16A, T17A double-mutant (DM) was introduced into phospholamban knockout mouse hearts. Transgenic lines expressing DM phospholamban at levels similar to wild types (WT) were identified. In vitro phosphorylation confirmed that DM phospholamban could not be phosphorylated, but produced the same shift in EC
50
of SERCA2a for Ca
2+
as unphosphorylated WT phospholamban. Rates of basal twitch [Ca
2+
]
i
decline were not different in DM versus WT cardiomyocytes. Isoproterenol increased the rates of twitch [Ca
2+
]
i
decline in WT, but not DM myocytes, confirming the prominent role of phospholamban phosphorylation in this response. Increased L-type Ca
2+
current (
I
Ca
) density, with unaltered characteristics, was the major compensation in DM myocytes. Consequently, the normal β-adrenergic–induced increase in
I
Ca
caused larger dynamic changes in absolute
I
Ca
density. Isoproterenol increased Ca
2+
transients to a comparable amplitude in DM and WT. There were no changes in myofilament Ca
2+
sensitivity, or the expression levels and Ca
2+
removal activities of other Ca
2+
-handling proteins. Nor was there evidence of cardiac remodeling up to 10 months of age. Thus, chronic inhibition of SERCA2a by ablation of phospholamban phosphorylation (abolishing its adrenergic regulation) results in a unique cellular adaptation involving greater dynamic
I
Ca
modulation. This
I
Ca
modulation may partly compensate for the loss in SERCA2a responsiveness and thereby partially normalize β-adrenergic inotropy in DM phospholamban mice.
MAP Kinase Kinase 6–p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes In Vitro and In Vivo
Authors: Degousee Norbert , Martindale Joshua , Stefanski Eva , Cieslak Martin , Lindsay Thomas F. , Fish Jason E. , Marsden Philip A. , Thuerauf Donna J. , Glembotski Christopher C. , Rubin Barry B.
Published: April 2003

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)–p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38α and p38β2 MAPK mRNA in rat cardiac myocytes. Interleukin-1β induced the phosphorylation of p38α and p38β2 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E
2
(PGE
2
) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38β2 MAPK inhibited interleukin-1β–induced p38 MAPK activation, COX-2 gene expression, and PGE
2
release. Treatment with the p38α and p38β2 MAPK inhibitor, SB202190, attenuated interleukin-1β–induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38β2 MAPK, in the absence of interleukin-1β, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1β–induced cardiac myocyte COX-2 gene expression and PGE
2
biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.
ABRAHAM'S INCESTUOUS MARRIAGE WITH SARAH: A VIOLATION OF THE HOLINESS CODE
Authors: Hepner Gershon
Published: April 2003

Verbal resonances suggest that Abraham's claim that Sarah is his half-sister in Gen. xx 13 indicates that he violates the prohibition of sibling incest in Lev. xx 17. This observation links Abraham not only to Amnon who has an incestuous relationship with his half-sister Tamar but to David who has an incestuous relationship with his halfsister Abigail after the death of her husband Nabal. The narrative of the conception of Moab, the son born to Lot after his unwitting incestuous relationship with his younger daughter, precedes the narrative in which Abraham admits that Sarah is his half-sister and is followed by the birth of Isaac, suggesting that the Torah implies that Isaac is no less the product of an incestuous relationship that violates the Holiness Code than Moab, an ancestor of David and Perez who is born as a result of an unwitting incestuous relationship between Judah and Tamar.
Translational control of maternal glp-1 mRNA by POS-1 and its interacting protein SPN-4 in Caenorhabditis elegans
Authors: Ogura Ken-ichi , Kishimoto Norihito , Mitani Shohei , Gengyo-Ando Keiko , Kohara Yuji
Published: April 2003

The translation of maternal glp-1 mRNAs is regulated temporally and spatially in C. elegans embryos. The 3′ UTR (untranslated region) of the maternal glp-1 mRNA is important for both kinds of regulation. The spatial control region is required to suppress translation in the posterior blastomeres. The temporal one is required to suppress translation in oocytes and one-cell stage embryos. We show that a CCCH zinc-finger protein, POS-1, represses glp-1 mRNA translation by binding to the spatial control region. We identified an RNP-type RNA-binding protein, SPN-4, as a POS-1-interacting protein. SPN-4 is present developmentally from the oocyte to the early embryo and its distribution overlaps with that of POS-1 in the cytoplasm and P granules of the posterior blastomeres. SPN-4 binds to a subregion of the temporal control region in the 3′ UTR and is required for the translation of glp-1 mRNA in the anterior blastomeres. We propose that the balance between POS-1 and SPN-4 controls the translation of maternal glp-1 mRNA.
A novel method for finding tRNA genes
Authors: TSUI VICKIE , MACKE TOM , CASE DAVID A.
Published: April 2003

We describe a novel procedure for generating and optimizing pattern descriptors that can be used to find structural motifs in DNA or RNA sequences. This combines a pattern-description language (based primarily on secondary structure alignment and conservation of some key nucleotides) with a scoring function that relies heavily on estimated folding free energies for the secondary structure of interest. For the cloverleaf secondary structure characteristic of tRNA, we show that a fairly simple pattern descriptor can find almost all known tRNA genes in both bacterial and eukaryotic genomes, and that false positives (sequences that match the pattern but that are probably not tRNAs) can be recognized by their high estimated folding free energies. A general procedure for optimizing descriptors (and hence for finding new structural motifs) is also described. For six bacterial, four eukaryotic, and four archaea genome sequences, our results compare favorably with those of the more complex and specialized tRNAscan-SE algorithm. Prospects for using this general approach to find other RNA structural motifs are discussed.
Elevated activity of the large form of ADAR1 in vivo: Very efficient RNA editing occurs in the cytoplasm
Authors: WONG SWEE KEE , SATO SHUJI , LAZINSKI DAVID W.
Published: April 2003

Mammalian cells express small and large forms of the RNA editing enzyme ADAR1, referred to as ADAR1-S and ADAR1-L, respectively. Here we observed that ADAR1-L was >70-fold more active than was ADAR1-S when assayed with a substrate that could be edited in either the nucleus or cytoplasm, and was also much more active when assayed with a substrate that was generated in the cytoplasm during viral replication. In contrast, when a substrate that could only be edited within the nucleus was assayed, the activity of ADAR1-S was found to be somewhat higher than that of ADAR1-L. We show here not only that editing could occur in the cytoplasm but also that the process was extremely efficient, occurred rapidly, and could occur in the absence of translation. Consistent with the observation that editing in the cytoplasm can be very efficient, deletion of the nuclear localization signal from ADAR2 resulted in a protein with 15-fold higher activity when tested with a substrate that contained an editing site in the mature message. In addition to its potential role in an antiviral response, we propose that ADAR1-L is the form primarily responsible for editing mRNAs in which the editing site is retained after processing.
A quantitative analysis of intron effects on mammalian gene expression
Authors: NOTT AJIT , MEISLIN SHLOMO H. , MOORE MELISSA J.
Published: April 2003

In higher eukaryotes, intron-containing and intronless versions of otherwise identical genes can exhibit dramatically different expression profiles. Introns and the act of their removal by the spliceosome can affect gene expression at many different levels, including transcription, polyadenylation, mRNA export, translational efficiency, and the rate of mRNA decay. However, the extent to which each of these steps contributes to the overall effect of any one intron on gene expression has not been rigorously tested. Here we report construction and initial characterization of a luciferase-based reporter system for monitoring the effects of individual introns and their position within the gene on protein expression in mammalian cells. Quantitative analysis of constructs containing human TPI intron 6 at two different positions within theRenillaluciferase open reading frame revealed that this intron acts primarily to enhance mRNA accumulation. Spliced mRNAs also exhibited higher translational yields than did intronless transcripts. However, nucleocytoplasmic mRNA distribution and mRNA stability were largely unaffected. These findings were extended to two other introns in a TCR-β minigene.
Estimation and prediction with ARMMAX model: a mixture of ARMAX models with common ARX part
Authors: He Li , Kárný Miroslav
Published: April 2003

Bayesian parameter estimation and prediction of a linear‐in‐parameters model with coloured noise is addressed, based on a novel mixture model called ARMMAX. ARMMAX is a finite mixture with its ARMAX components having a common ARX part. It assumes that the common ARX part describes a fixed deterministic input–output relationship and allows for varying characteristics of the driving coloured noise. The ARMMAX model with fixed MA parts is estimated by a specific version of recursive Quasi‐Bayes (ARMMAX‐QB) algorithm. It rests on a classical Bayesian solution that requires no restrictions on MA part allowing it to be even at the stability boundary.

For on‐line use, the ARMMAX model offers flexibility with respect to varying characteristics of the model noise. The flexibility gained is paid by a slight increase of the computational burden when compared with the single ARMAX with known MA part, which is, in this respect, close to recursive least‐squares estimation.

For off‐line use, the ARMMAX model offers the possibility to estimate the unknown MA part in a novel way. Exploiting the natural parallelism of the ARMMAX model, a robust, derivative free multi‐directional search (MDS) is selected to deal with extensive data sets for which universal optimization tools are too cumbersome.

The paper motivates the modelling approach, describes algorithmic ingredients and illustrates the resulting algorithm using a simple example. Copyright © 2003 John Wiley & Sons, Ltd.
Control of induction motors: an adaptive passivity MIMO perspective
Authors: Duarte‐Mermoud Manuel A. , Travieso Juan C.
Published: April 2003

The design of two multiple‐input multiple‐output (MIMO) controllers for induction motors, based on adaptive passivity, is presented in this paper. The controller design method is based on concepts of equivalence passivity via adaptive feedback, previously developed by the authors. Robustness under variations of the motor‐load parameters is guaranteed and the knowledge of such a parameters is not needed in the design. Simple proportional controllers for the torque, rotor flux and stator current control loops are used, due to the control simplification introduced by the use of feedback passive equivalence. A principle called ‘Torque‐Flux Control Principle’ is used in this article introducing a considerable simplification in the resultant controller. Because of the employment of this principle, the control efforts are diminished and rotor flux estimation (or measurement) is avoided. Copyright © 2003 John Wiley & Sons, Ltd.
Unique mosaicism of structural chromosomal rearrangement: Is chromosome 18 preferentially involved?
Authors: de Pater J.M. , Smeets D.F.C.M. , Scheres J.M.J.C.
Published: April 2003

The mentally normal mother of a 4‐year‐old boy with del(18)(q21.3) syndrome was tested cytogenetically to study the possibility of an inherited structural rearrangement of chromosome 18. She was found to carry an unusual mosaicism involving chromosomes 18 and 21. Two unbalanced cell lines were seen as derivatives of a reciprocal translocation t(18;21), resulting in mosaicism of two cell lines, one with partial monosomy 18q and one with partial trisomy 18q. A literature review revealed that mosaicism of two or more cell lines with different unbalanced structural aberrations is extremely rare; moreover, chromosome 18 appeared to be involved in the majority of cases. We discuss possible mechanisms for the origin of this distinctive chromosomal constitution. © 2003 Wiley‐Liss, Inc.
A boy with developmental delay, malformations, and evidence of a connective tissue disorder—possibly a new type of cutis laxa
Authors: Armstrong Linlea , Jimenez Carmencita , Hunter Alasdair G.W.
Published: April 2003

We report a 7.5‐year‐old boy with loose translucent skin, aortic dilatation, hyperextensible veins, recurrent respiratory problems, pectus excavatum, arthralgias, lax joints, mild epiphyseal dysplasia, and umbilical and inguinal hernias. He also has developmental delay, progressive bilateral sensorineural hearing loss, an unusual facial appearance, terminal digit hypoplasia with unusual radiographic changes in some of the phalanges, glandular hypospadias, shawl scrotum, and undescended testes. Biochemical investigations, including electrophoresis of Types 1 and 3 procollagens and collagens, and quantification of serum copper and ceruloplasmin, are normal. Relative to age‐matched control patients the electron micrographs of the boy's dermis show elastin fibers to be decreased in number, and abnormal in appearance, with a low matrix to microfibril ratio. The organ distribution of abnormalities and the nature of the findings suggest a connective tissue disorder. We contrast and compare this boy's phenotype to those of the classic connective tissue disorders. We conclude that he has cutis laxa with features that distinguish him from previously described types of cutis laxa. © 2003 Wiley‐Liss, Inc.
Chudley‐McCullough syndrome: Expanded phenotype and review of the literature
Authors: Welch Katherine Oelrich , Tekin Mustafa , Nance Walter E. , Blanton Susan H. , Arnos Kathleen S. , Pandya Arti
Published: April 2003

Chudley‐McCullough syndrome is an autosomal recessive condition characterized by profound sensorineural deafness, hydrocephalus secondary to obstruction of the foramen of Monro, and other structural abnormalities of the brain. We describe a family including two brothers and a sister with this condition. Each has profound sensorineural deafness that was either congenital or rapidly progressive in infancy and asymmetric dilatation of the lateral ventricles secondary to obstruction of the foramen of Monro. They also have additional brain abnormalities, including arachnoid cyst, partial agenesis of the corpus callosum, and abnormalities in the migration of cerebellar cells. This report is the fourth description of this condition within four years, suggesting Chudley‐McCullough may not be as rare as once assumed. We, therefore, recommend an audiological assessment for all children with hydrocephalus, especially those with obstruction of the foramen of Monro. © 2003 Wiley‐Liss, Inc.
Professional opportunities and responsibilities in the provision of genetic information to children relinquished for adoption
Authors: Venne Vickie L. , Botkin Jeffrey R. , Buys Saundra S.
Published: April 2003

We report a case involving the disclosure of BRCA1 mutation results to a woman who had placed a child for adoption 30 years prior to learning her mutation status. The disclosure of the mother's genetic test result to the son resulted in unexpected subsequent communications. This article briefly describes the experience and discusses the unique issues that arise in counseling a parent who has relinquished a child who is subsequently at risk to inherit a mutation for an adult onset genetic condition. © 2003 Wiley‐Liss, Inc.
Familial mitral valve prolapse associated with short stature, characteristic face, and sudden death
Authors: James Paul A. , Aftimos Salim , Skinner Jonathan R.
Published: April 2003

Mitral valve prolapse (MVP) is frequently a familial disorder but in few of these inherited cases it does form a prominent component of a multiple congenital anomaly (MCA) syndrome. We report a family in which eight individuals in four generations were affected by a dominantly inherited disorder involving MVP, short stature, a dolicocephalic face, broad forehead, posteriorly angulated ears, long philtrum, thin upper lip, high arched palate, and a small mandible. The proband presented with infective mastoiditis, bacterial endocarditis, and a supraventricular tachycardia. One other family member also had infective mastoiditis and bacterial endocarditis and both the proband's mother and grandmother died suddenly at the age of 30 and 25 years, respectively. © 2003 Wiley‐Liss, Inc.
No association between single nucleotide polymorphisms in DLX6 and piccolo genes at 7q21‐q22 and autism
Authors: Nabi Rafiqun , Zhong Hailang , Serajee Fatema J , Huq AHM Mahbubul
Published: April 2003

Several independent genome scans have revealed excess allele sharing in an overlapping 40 cM region of 7q21‐34 in autism. DLX6 and Piccolo (PCLO) at 7q21‐q22 are two positional and functional candidate genes in autism. We have investigated a single nucleotide polymorphism (SNP) in exon 4 of the PCLO gene and a SNP in intron 1 of the DLX6 gene for linkage and association in autistic disorder using both qualitative and quantitative analyses. One hundred ninety‐six multiplex autistic disorder families were tested using transmission disequilibrium and two‐point affected sib pair linkage analysis. We found no evidence of association or linkage with the two intragenic markers. In addition, there was also no linkage or association between language and stereotypic behavior quantitative traits in autism and the SNPs. In conclusion, our studies suggest that these two SNPs in DLX6 and PCLO genes are not in linkage disequilibrium with autism. © 2003 Wiley‐Liss, Inc.