bluuebunny/crossref_metadata_2025 huggingface dataset:
Dispelling Inhibition for Laparoscopic Surgery in Younger Children with Cushing’s Syndrome
Authors: Srivastava Anand , Sinha Tapan , Karan S.C. , Sandhu A.S. , Sethi G.S. , Talwar R. , Narang V.
Published: April 2006

Laparoscopic adrenalectomy (LA) is now the gold standard for the treatment of small, benign adrenal tumors in adults. In Cushing’s syndrome (CS), LA is difficult and seldom done, especially in younger children. A 6-year-old girl was diagnosed with CS due to a juxtaadrenal tumor. She underwent LA and made an uneventful recovery. The histopathology was reported as paraganglioma which is a very rare cause of CS. LA is seldom done in younger children with CS owing to extreme obesity, abundant perinephric fat and a high incidence of pre- and postoperative complications.
Primary Adrenal Tuberculosis: Role of Computed Tomography and CT-Guided Biopsy in Diagnosis
Authors: Liatsikos E.N. , Kalogeropoulou C.P. , Papathanassiou Z. , Tsota I. , Athanasopoulos A. , Perimenis P. , Barbalias G.A. , Petsas T.
Published: April 2006

A case of isolated, bilateral, adrenal tuberculosis is presented. A 25-year-old male was admitted to the hospital due to lumbar pain, fever, weight loss and anorexia. Abdominal ultrasonography and computed tomography demonstrated bilateral adrenal enlargement. Laboratory investigations were remarkable for adrenal insufficiency. The Mantoux reaction was positive but there was no evidence of lung or urinary infection. CT-guided biopsy of the left adrenal gland was performed and established the diagnosis of adrenal tuberculosis.
Enhanced Frequency of CD18- and CD49b-Expressing T Cells in Peripheral Blood of Asthmatic Patients Correlates with Disease Severity
Authors: Rahmoun Massilva , Foussat Arnaud , Groux Hervé , Pène Jérôme , Yssel Hans , Chanez Pascal
Published: April 2006

Background: Results from a transcriptome analysis of human CD4+ T regulatory type 1 (Tr1) clones have indicated that transcripts for the integrins CD18 and CD49b are overexpressed in these cells. The aim of this study was to investigate whether the presence of T cells concomitantly expressing these molecules could be detected in asthmatic patients and represent Tr1 cells. Methods:Expression of CD18 and CD49b was analyzed by flow cytometry on peripheral blood mononuclear cells from asthmatic patients of various severity and healthy subjects. The cytokine production profile of purified CD4+ CD18high CD49b+ T cells was analyzed by ELISA. The effect of glucocorticoid treatment on the expression of CD18 and CD49b was determined. Results: The frequency of peripheral blood CD18high CD49b+ T cells was significantly elevated in severe asthmatic patients, as compared with both mild asthmatic and healthy donors, and was diminished in asthmatic patients with a controlled status of the disease. Neither short-course oral glucocorticoid treatment of asthmatic patients ex vivo, nor culture of their peripheral blood mononuclear cells with dexamethasone in vitro, increased the frequency of CD18high CD49b+ T cells, indicating that their presence seems to be independent from recent anti-inflammatory treatment. However, purified CD4+ CD18high CD49b+ T cells from these patients, in contrast to those from healthy donors, lacked the production of the immunosuppressive cytokine interleukin-10. Conclusion: In contrast to healthy donors, peripheral blood CD18high CD49b+ T cells of asthmatic patients do not fulfill the phenotypic criteria of Tr1 cells. Nevertheless, the presence of elevated numbers of peripheral blood CD18high CD49b+ T cells is characteristic for patients with severe and uncontrolled asthma.
Cancer and Pregnancy Share Similar Mechanisms of Immunological Escape
Authors: Wilczynski Jacek R.
Published: April 2006

Background: Despite the fact that trophoblasts and cancer are both immunogenic, they are able to escape from host immunosurveillance, andthe precise mechanisms involved in this process are surprisingly similar in both situations. Methods: A literature review of studies on immunological changes occurring during normal pregnancy and cancer was performed. Results: Loss or downregulation of classical HLA antigens as well as the presence of non-classical HLA-G molecules, a Th2 cytokine activity shift, secretion of immunosuppressive factors and blocking antibodies and finally induction of apoptosis in immunocytes seem to be the most effective mechanisms of immunological escape in pregnancy and cancer. Conclusions: The process of immunological escape in cancer and pregnancy is based on similar mechanisms.
Neural Effects of Nicotine during Auditory Selective Attention in Smokers: An Event-Related Potential Study
Authors: Knott Verner , Blais Crystal , Scherling Carole , Camarda Jordan , Millar Anne , Fisher Derek , McIntosh Judy
Published: April 2006

Acute nicotine has been found to improve task performance in smokers after smoking abstinence, but the attentional processes mediating these improvements are unclear. Since scalp-recorded event-related potentials (ERPs) have been shown to be sensitive indicators of selective attention, the effects of acutely administered nicotine were examined on ERPs and concomitant behavioural performance measures in an auditory selective attention task. Ten (6 males) overnight smoking-abstinent cigarette smokers received nicotine gum (4 mg) in a randomized, double-blind, placebo-controlled, crossover design. In a dichotic listening task [which required participants to attend and detect (target) deviant stimuli in one ear and to ignore similar stimuli in the other ear] which included ERP recordings and assessment of response speed and accuracy measures, nicotine gum failed to alter behavioural performance or amplitudes of ERP components sensitive to selective attention [reflected in the N100 and negative difference (Nd) component] or to pre-attentive detection of acoustic change [reflected in the mismatch negativity (MMN) component]. However, nicotine did influence the speed of these voluntary selective processes, as reflected by shortened latencies of the early Nd component. The findings are discussed in relation to the stimulus filter theory of smoking, and with respect to nicotine’s actions on involuntary and controlled aspects of selective attention processes.
Luteolin, a Flavonoid, Inhibits CD40 Ligand Expression by Activated Human Basophils
Authors: Hirano Toru , Arimitsu Junsuke , Higa Shinji , Naka Tetsuji , Ogata Atsushi , Shima Yoshihito , Fujimoto Minoru , Yamadori Tomoki , Ohkawara Tomoharu , Kuwabara Yusuke , Kawai Mari , Kawase Ichiro , Tanaka Toshio
Published: April 2006

Background: We have previously shown that flavonoids such as luteolin, apigenin and fisetin inhibit interleukin 4 and interleukin 13 production. In this study, we investigated whether luteolin can suppress CD40 ligand expression by basophils. Methods: A human basophilic cell line, KU812, was stimulated with A23187 and phorbol myristate acetate (PMA) with or without various concentrations of luteolin or other flavonoids for 12 h, and CD40 ligand expression was analyzed by FACS. The effect of luteolin on CD40 ligand mRNA expression was studied by semiquantitative reverse transcription PCR analysis. In addition, CD40 ligand expression was also measured in purified basophils that had been stimulated for 12 h with A23187 plus PMA with or without various concentrations of luteolin. Results: CD40 ligand expression by KU812 cells was enhanced noticeably in response to A23187 and even more strikingly augmented by A23187 plus PMA. The expression was significantly suppressed by 10 or 30 µM of luteolin, whereas myricetin failed to inhibit. Reverse transcription PCR analyses demonstrated that luteolin inhibited CD40 ligand mRNA expression by stimulated KU812 cells. Of the six flavonoids examined, luteolin, apigenin, fisetin and quercetin at 30 µM showed a significant inhibitory effect on CD40 ligand expression. The incubation of purified basophils with A23187 plus PMA significantly enhanced CD40 ligand expression, and the presence of luteolin again had an inhibitory effect. Conclusions: Luteolin inhibits CD40 ligand expression by activated basophils.
Should Men with Serum Prostate-Specific Antigen ≤4 ng/ml and Normal Digital Rectal Examination Undergo a Prostate Biopsy?
Authors: Pepe Pietro , Panella Paolo , D’Arrigo Letterio , Savoca Francesco , Pennisi Michele , Aragona Francesco
Published: April 2006

The clinical significance of a prostate cancer (PCa) cannot be determined solely by tumor volume (≤0.5 cm3), as small tumors of higher Gleason grade and tumors occurring in younger men may become clinically significant even though the initial volume at diagnosis is small. A certain number of these minimal cancers are likely to remain clinically insignificant; however, it is unpredictable how many can progress beyond the curable stage by the time there is a rise in serum prostate-specific antigen (PSA) values. Compared to clinically detected PCa, PCa detected exclusively by PSA screening (clinical stage T1c) are less likely to be advanced but no more likely to be insignificant in terms of volume, pathologic stage, and Gleason pattern. Only 10–15% of PSA-detected cancers have the features of PCa found at autopsy or in cystoprostatectomy specimens. Actually, 25–30% of PCa are detected with PSA values between 2.5 and 4 ng/ml, and most of these cancers are clinically significant. Evidence from both retrospective and longitudinal studies has shown that the risk of a PCa is dependent on the patient’s age and the initial serum PSA. This allows an individualized approach to PCa screening programs, and PSA cutoff values for biopsy indication may be lowered in selected patients.
Chinese Literature
Authors: Deshpande G.P.
Published: April 2006

This article attempts a wide ranging survey of Chinese literature. It begins this survey with the Book of Odes or Songs and brings the story of the Chinese literature to nearly contemporary times. It leaves out the rich tradition of writing on aesthetics and literary criticism. The article concerns itself primarily with the genres of creative literature as we have come to know them in modern times. The article rasies some questions about the categories of historical analysis of literary concepts and indeed the very notion of history of literature. The basic concern of this survey is to examine if the ideas generated by the Greek and the Hegelian traditions are adequate or indeed relevant in the understanding and theorisation of the history of classical Chinese, or Indian for that matter, literary traditions. The article also briefly discusses some typical translations of classical Chinese poetry.
Japan's Policy Towards East and Southeast Asia
Authors: Varma Lalima
Published: April 2006

In recent years Japan's definition of Asia has been undergoing a significant change. So farfor Japan, Asia meant mainly China, the two Koreas and the Southeast Asian countriesAfter the events of 11 September, the US invasion of Afghanistan, the war in Iraq, the massivanti-Japan movement in China and South Korea and other developments Japan was impelleto strengthen its relations with other Asian countries which so far had been on the peripherof its Asia policy. In addition to this, Japan's Asia policy to a great extent is also guided bthe rising stature of China, although changes in Japan's policy towards Asian countries ialso often influenced by the changes in its relations with the US. While Japan realizes tharelations with the US form the cornerstone of its foreign policy, it still makes attempts tconvince both the US and China that it wants to play a prominent and independent role iAsia. Changes in Japan's Asia policy are also based on the realization of the fact that tcounter its delicate relations with China and South Korea, it must play an important politicarole in the region and that its Asia policy must factor the growing influence of other countrielike India rather than focussing on just China, the two Koreas and Southeast Asian countries
“Noble Thoughts Come from All Directions”
Authors: Berry John W.
Published: April 2006

Professor Durganand Sinha was a cross–cultural psychologist with wide–ranging interests and yet firmly rooted in the culture of India. He was the chief proponent of the ecocultural framework which considers human diversity (both cultural and psychological) to be a set of collective and individual adaptations to the given context. From this perspective, it is considered that individuals are born into some extant set of social and cultural arrangements, and that their constant interaction with their ecological surroundings leads to both psychological and cultural changes. Sinha maintained a delicate balance between the cross–cultural comparative and the culturally–rooted character of psychology in his work. Sinha's scholarship was fundamentally driven by social concerns, both within India and outside.
Senior/Junior Recipient Status and Reward Allocation
Authors: Krishnan Lilavati , Carment D.W.
Published: April 2006

This study examines senior/junior recipient status as a possible determinant of perceived fairness of given allocations and allocation preference. Considering status as a feature associated with the cultural dimension of power distance, female university students from India (a high power distance, relatively collectivistic culture) and Canada (a low power distance, individualistic culture) were compared with regard to perceived fairness and allocation preferences in scenarios involving an organisational or an academic setting, with varying senior/junior recipient status, allocation rule combinations, nature of allocation, and the allocator/recipient role. Overall, recipient status effects were incongruent with the expected power distance differences. Further, Canadians perceived more fairness and less unfairness than Indians. They favoured seniority to a greater extent than Indians, possibly because they treated seniority as a component of merit. Indians manifested an equality orientation, and gave variable responses to seniority depending on the nature of allocation, allocator/recipient role, rule combination and their interactive effects. Allocation preferences were affected more by rule combination than by recipient status in both cultures. The need to examine status effects with a modified research design was underlined.
Adolescents’ Identification with the National Group
Authors: Ng-Tseung Caroline
Published: April 2006

Adolescents' identification with the national and ethnic categories was investigated within the multiethnic context of Mauritius. A sample of 202 subjects (107 girls, 95 boys) in age group of 12-16 years answered the self-report questionnaire. The study aimed to (a) assess the nature of national identity along cognitive, affective and evaluative lines, (b) investigate whether there were links between national and ethnic identities, and (c) explore ethnic, sex and age differences in national identity. Results revealed only sex differences on the dimensions of national identity, with boys reporting higher levels of national identity than girls. There was a significant positive correlation between identification with the national category and identification with the ethnic category. The results were discussed in terms of nested identities, the peculiarities of the social context, and social representations theory.
Subordinates’ Perception of Leadership Styles and Their Work Behaviour
Authors: Suar Damodar , Tewari Hare R. , Chaturbedi Kostubh R.
Published: April 2006

The study examines subordinates’ perception of leadership styles and their work behaviour in the Indian Air Force. A self–reported questionnaire was used to collect data from 287 airmen and 75 officers. The results revealed that the leaders of airmen had a predominantly authoritarian style and the leaders of officers had a nurturant–task style. Regarding work behaviour, officers were more committed and satisfied with the job than airmen. Officers accepted challenging tasks, showed better performance, achieved targets on time and expressed less desire to quit the defence services compared to airmen. Airmen and officers’ commitment to the organisation and job satisfaction decreased, and stress effect and intention to quit the services increased under an authoritarian leader. Conversely, airmen and officers felt committed, satisfied with the job, accepted challenging tasks, showed higher job performance, and expressed unwillingness to quit the organisation under nurturant–task and participative leaders.
Acculturation and Integration Patterns among Indian and African University Students in South Africa
Authors: Naidoo Josephine C. , Mahabeer Manorunjunie
Published: April 2006

South Africa is a country in transition. Apartheid, akin to “ethnic cleansing”, created a siege ingroup mentality. The 1994 democratic elections ushered in the “Rainbow” nation. In this historical context, this exploratory study of acculturation and integration to western culture by young people of non–western origins was conducted. A sample of 63 African and 106 Indian, male and female students at the University of Durban–Westville (now part of the University of KwaZulu–Natal) was administered the Berry Acculturation Scale (1986), Naidoo Measure of Value Preferences (1986), and Triandis Individualism–Collectivism Scale (1990). Questions posed were: (a) What mode of acculturation to western culture do African and Indian students prefer; (b) what values do they admire and adopt from the dominant western individualistic value systems; (c) do these cultural groups retain ancestral collectivist values; and (d) what intergroup social/work contacts occur. Significant findings were obtained based on appropriate ANOVAS for data derived from the two ethnic groups and genders for the three measures used. Both groups shared commonalities, favouring integration of ancestral collectivist and western individualistic values; both expressed selectivity to western values. Both groups desired western education, careers, and opportunity for all, but also wanted to retain core collectivist family values. Indians felt strongly about the retention of religious values; Africans were staunch Christian. Women participants looked to the western culture for new feminist values. Indians had lost their ancestral languages but both shared English. The implications of the commonalities for ethno–gender co–existence in “Rainbow” South Africa have been discussed.
Child Maltreatment Trends in the 1990s: Why Does Neglect Differ From Sexual and Physical Abuse?
Authors: Jones Lisa M. , Finkelhor David , Halter Stephanie
Published: April 2006

Substantiated cases of child maltreatment have declined more than 20% since a peak in 1993. However, although sexual abuse and physical abuse showed significant declines during the 1990s (47% and 36%, respectively), neglect fluctuated, with only a small overall decline during this period (7%). Available data suggest that at least part of the declines in sexual and physical abuse is likely to be real. Some evidence also suggests that a decline in neglect may have been masked in some states. Possible sources for declines in child maltreatment include direct prevention efforts, economic improvements, more aggressive criminal justice efforts, dissemination of psychiatric medication, and generational changes. Public health models suggest that population-level prevention initiatives are the most promising options for further reducing maltreatment rates. However, better epidemiological and evaluation research will be needed to identify the key factors.
Attributional Style as a Mediator Between Parental Abuse Risk and Child Internalizing Symptomatology
Authors: Rodriguez Christina M.
Published: April 2006

This study examined a model wherein children’s attributional style mediates the relationship between parental physical child-abuse risk and children’s internalizing problems. Using structural equation modeling, three indices of abuse risk were selected (child abuse potential, physical discipline use, and dysfunctional parenting style) and two indices of children’s internalizing problems (depression and anxiety). The sample included 75 parent-child dyads, in which parents reported on their abuse risk and children independently completed measures of depressive and anxious symptomatology and a measure on their attributional style. Findings supported the model that children’s attributional style for positive events (but not negative events) partially mediated the relationship between abuse risk and internalizing symptoms, with significant direct and indirect effects of abuse risk on internalizing symptomatology. Future directions to continue evaluating additional mediators and other possible contextual variables are discussed.
Discipline Practices Among Biological and Foster Parents
Authors: Linares L. Oriana , Montalto Daniela , Rosbruch Nicole , Li MinMin
Published: April 2006

In a sample of 124 parents (62 pairs of biological and foster parents) of children who were maltreated (M age = 6.2 years), this study compared self-reports of discipline practices between biological and foster parents toward a target child and explored the role of child, parent, and foster care ecology factors on discipline practices. Controlling for parental age, psychological distress, and marital status, biological and foster parents reported using similar levels of positive, appropriate, and harsh discipline. For biological and foster parents, child characteristics (being female, younger, and having more conduct problems) were associated with parental self-reports of less effective discipline. The study also found a positive association between parent-to-parent cooperation and effective discipline. These findings suggest that parenting interventions may need to move beyond simple presumption of deficits in parenting knowledge, and that children could benefit from enhancement of supportive relationships between biological and foster parents involved in the foster care system.
Foster Children’s Diurnal Production of Cortisol: An Exploratory Study
Authors: Dozier Mary , Manni Melissa , Gordon M. Kathleen , Peloso Elizabeth , Gunnar Megan R. , Stovall-McClough K. Chase , Eldreth Diana , Levine Seymour
Published: April 2006

Young children in foster care have often experienced inadequate early care and separations from caregivers. Preclinical studies suggest that early inadequate care and separations are associated with long-term changes in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the daytime pattern of cortisol production was examined among 55 young children who had been placed into foster care and 104 children who had not. Saliva samples were taken at wake-up, in the afternoon, and bedtime for 2 days. Average salivary cortisol values for each time of day were computed. A group (foster vs. comparison) time (morning, afternoon, night) interaction emerged, reflecting less decline in levels across the day for foster than comparison children. Daytime patterns were categorized as typical, low, or high. Children who had been in foster care had higher incidences of atypical patterns of cortisol production than children who had not. These differences suggest that conditions associated with foster care interfere with children’s ability to regulate neuroendocrine functioning.
Sexual Revictimization: The Role of Sexual Self-Esteem and Dysfunctional Sexual Behaviors
Authors: Van Bruggen Lisa K. , Runtz Marsha G. , Kadlec Helena
Published: April 2006

Disproportionately high rates of sexual revictimization have been noted among former victims of child sexual abuse (CSA), yet researchers have yet to determine the source of this apparent vulnerability to reexperience sexual violence. This study explores this issue by examining sexual self-esteem, sexual concerns, and sexual behaviors among 402 university women. Compared to women without a history of CSA (n = 348), women with a history of CSA (n = 54) had lower sexual self-esteem, poorer sexual adjustment, and were 2 times more likely to have experienced sexual assault since the age of 14 years. Structural equation modeling indicated that the relationship between child abuse (i.e., CSA and child psychological maltreatment) and sexual revictimization was partially mediated by sexual self-esteem, sexual concerns, and high-risk sexual behaviors. This study emphasizes the need for further research on child maltreatment, revictimization, and women’s sexual adjustment.
OCT-1–mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib
Authors: White Deborah L. , Saunders Verity A. , Dang Phuong , Engler Jane , Zannettino Andrew C. W. , Cambareri Antony C. , Quinn Steven R. , Manley Paul W. , Hughes Timothy P.
Published: April 2006

Intrinsic sensitivity of newly diagnosed chronic myeloid leukemia (CML) patients to imatinib (IC50imatinib) correlates with molecular response. IC50imatinib is defined as the in vitro concentration of drug required to reduce phosphorylation of the adaptor protein Crkl by 50%. We now show that interpatient variability in IC50imatinib is mainly due to differences in the efficiency of imatinib intracellular uptake and retention (IUR). In 25 untreated CML patients, the IC50imatinib strongly correlated (R2 = –0.484, P = .014 at 2 μM imatinib) with the IUR of [14C]imatinib. The addition of prazosin, a potent inhibitor of OCT-1 cellular transporter, reduced the IUR and eliminated interpatient variability. IC50 values for the more potent BCR-ABL inhibitor nilotinib (AMN107) did not correlate with IC50imatinib (R2 =–0.0561, P > .05). There was also no correlation between IC50nilotinib and the IUR for [14C]nilotinib (R2 = 0.457, P > .05). Prazosin had no effect on nilotinib IUR, suggesting that influx of nilotinib is not mediated by OCT-1. In conclusion, whereas OCT-1–mediated influx may be a key determinant of molecular response to imatinib, it is unlikely to impact on cellular uptake and patient response to nilotinib. Determining interpatient and interdrug differences in cellular uptake and retention could allow individual optimization of kinase inhibitor therapy.
Autoreactive MZ and B-1 B-cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance
Authors: Qian Ye , Conway Kara L. , Lu Xiangdong , Seitz Heather M. , Matsushima Glenn K. , Clarke Stephen H.
Published: April 2006

Murine autoreactive anti-Smith (Sm) B cells are negatively regulated by anergy and developmental arrest, but are also positively selected into the marginal zone (MZ) and B-1 B-cell populations. Despite positive selection, anti-Sm production occurs only in autoimmune-prone mice. To investigate autoreactive B-cell activation, an anti-Sm transgene was combined with the lpr mutation, a mutation of the proapoptotic gene Fas (Faslpr), on both autoimmune (MRL) and nonautoimmune backgrounds. Faslpr induces a progressive and autoantigen-specific loss of anti-Sm MZ and B-1 B cells in young adult Faslpr and MRL/Faslpr mice that does not require that Faslpr be B-cell intrinsic. This loss is accompanied by a bypass of the early pre–plasma cell (PC) tolerance checkpoint. Although the MRL bkg does not lead to a progressive loss of anti-Sm MZ or B-1 B cells, it induces a robust bypass of the early pre-PC tolerance checkpoint. Faslpr mice have a high frequency of apoptotic lymphocytes in secondary lymphoid tissues and a macrophage defect in apoptotic cell phagocytosis. Since Sm is exposed on the surface of apoptotic cells, we propose that anti-Sm MZ and B-1 B-cell activation is the result of a Faslpr-induced defect in apoptotic cell clearance.
The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes
Authors: Sesti Giorgio , Laratta Emanuela , Cardellini Marina , Andreozzi Francesco , Del Guerra Silvia , Irace Concetta , Gnasso Agostino , Grupillo Maria , Lauro Renato , Hribal Marta Letizia , Perticone Francesco , Marchetti Piero
Published: April 2006

Context: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking.

Objective: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure.

Design: Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia.

Setting: The study was conducted in an ambulatory care facility.

Patients: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study.

Intervention: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment.

Main Outcome Measure: Secondary failure was the main outcome measure.

Results: Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01–2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02–2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant.

Conclusions: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.
Larger Testes and Higher Inhibin B Levels in Finnish than in Danish Newborn Boys
Authors: Main Katharina M. , Toppari Jorma , Suomi Anne-Maarit , Kaleva Marko , Chellakooty Marla , Schmidt Ida M. , Virtanen Helena E. , Boisen Kirsten A. , Kai Claudia M. , Damgaard Ida N. , Skakkebæk Niels E.
Published: April 2006

Context: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland.

Objectives: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries.

Design: This was a prospective, longitudinal population-based study.

Setting: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland.

Participants: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age.

Interventions: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed.

Main Outcome Measures: Testicular volume and reproductive hormones were measured.

Results: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm3, respectively; P < 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm3; P < 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P < 0.0001), FSH (1.33 vs. 1.21 IU/liter; P < 0.036), and SHBG (143 vs. 136 nmol/liter; P < 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P < 0.006).

Conclusions: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.
Caldesmon is an integral component of podosomes in smooth muscle cells
Authors: Eves Robert , Webb Bradley A. , Zhou Shutang , Mak Alan S.
Published: April 2006

Podosomes are highly dynamic actin-based structures commonly found in motile and invasive cells such as macrophages, osteoclasts and vascular smooth muscle cells. Here, we have investigated the role of caldesmon, an actin-binding protein, in the formation of podosomes in aortic smooth muscle A7r5 cells induced by the phorbol ester PDBu. We found that endogenous low molecular weight caldesmon (l-caldesmon), which was normally localised to actin-stress fibres and membrane ruffles, was recruited to the actin cores of PDBu-induced podosomes. Overexpression of l-caldesmon in A7r5 cells caused dissociation of actin-stress fibres and disruption of focal adhesion complexes, and significantly reduced the ability of PDBu to induce podosome formation. By contrast, siRNA interference of caldesmon expression enhanced PDBu-induced formation of podosomes. The N-terminal fragment of l-caldesmon, CaD40, which contains the myosin-binding site, did not label stress fibres and was not translocated to PDBu-induced podosomes. Cad39, the C-terminal fragment housing the binding sites for actin, tropomyosin and calmodulin, was localised to stress fibres and was translocated to podosomes induced by PDBu. The caldesmon mutant, CadCamAB, which does not interact with Ca2+/calmodulin, was not recruited to PDBu-induced podosomes. These results show that (1) l-caldesmon is an integral part of the actin-rich core of the podosome; (2) overexpression of l-caldesmon suppresses podosome formation, whereas siRNA knock-down of l-caldesmon facilitates its formation; and (3) the actin-binding and calmodulin-binding sites on l-caldesmon are essential for the translocation of l-caldesmon to the podosomes. In summary, this data suggests that caldesmon may play a role in the regulation of the dynamics of podosome assembly and that Ca2+/calmodulin may be part of a regulatory mechanism in podosome formation.
Evidence for a role of transmembrane protein p25 in localization of protein tyrosine phosphatase TC48 to the ER
Authors: Gupta Vijay , Swarup Ghanshyam
Published: April 2006

T-cell protein tyrosine phosphatase gives rise to two splice isoforms: TC48, which is localized to the endoplasmic reticulum (ER) and TC45, a nuclear protein. The present study was undertaken to identify proteins that are involved in targeting TC48 to the ER. We identified two TC48-interacting proteins, p25 and p23, from a yeast two-hybrid screen. p23 and p25 are members of a family of putative cargo receptors that are important for vesicular trafficking between Golgi complex and ER. Both p23 and p25 associate with overexpressed TC48 in Cos-1 cells as determined by coimmunoprecipitation. A significant amount of TC48 colocalized initially with ERGIC and Golgi complex markers (in addition to ER and nuclear membrane localization) and was then retrieved to the ER. Coexpression with p25 enhanced ER localization of TC48, whereas coexpression with p23 resulted in its trapping in membranous structures. Coexpression of a p25 mutant lacking the ER-localization signal KKxx resulted in enhanced Golgi localization of TC48. Forty C-terminal amino acid residues of TC48 (position 376-415) were sufficient for interaction with p23 (but not with p25) and targeted green fluorescence protein (GFP) to the Golgi complex. Targeting of GFP to the ER required 66 C-terminal amino acid residues of TC48 (position 350-415), which showed interaction with p25 and p23. We suggest that TC48 translocates to the Golgi complex along the secretory pathway, whereas its ER localization is maintained by selective retrieval enabled by interactions with p25 and p23.
Targeting of CTCF to the nucleolus inhibits nucleolar transcription through a poly(ADP-ribosyl)ation-dependent mechanism
Authors: Torrano Verónica , Navascués Joaquín , Docquier France , Zhang Ru , Burke Les J. , Chernukhin Igor , Farrar Dawn , León Javier , Berciano María T. , Renkawitz Rainer , Klenova Elena , Lafarga Miguel , Delgado M. Dolores
Published: April 2006

Multiple functions have been reported for the transcription factor and candidate tumour suppressor, CTCF. Among others, they include regulation of cell growth, differentiation and apoptosis, enhancer-blocking activity and control of imprinted genes. CTCF is usually localized in the nucleus and its subcellular distribution during the cell cycle is dynamic; CTCF was found associated with mitotic chromosomes and the midbody, suggesting different roles for CTCF at different stages of the cell cycle. Here we report the nucleolar localization of CTCF in several experimental model systems. Translocation of CTCF from nucleoplasm to the nucleolus was observed after differentiation of K562 myeloid cells and induction of apoptosis in MCF7 breast cancer cells. CTCF was also found in the nucleoli in terminally differentiated rat trigeminal ganglion neurons. Thus our data show that nucleolar localization of CTCF is associated with growth arrest. Interestingly, the 180 kDa poly(ADP-ribosyl)ated isoform of CTCF was predominantly found in the nucleoli fractions. By transfecting different CTCF deletion constructs into cell lines of different origin we demonstrate that the central zinc-finger domain of CTCF is the region responsible for nucleolar targeting. Analysis of subnucleolar localization of CTCF revealed that it is distributed homogeneously in both dense fibrillar and granular components of the nucleolus, but is not associated with fibrillar centres. RNA polymerase I transcription and protein synthesis were required to sustain nucleolar localization of CTCF. Notably, the labelling of active transcription sites by in situ run-on assays demonstrated that CTCF inhibits nucleolar transcription through a poly(ADP-ribosyl)ation-dependent mechanism.
Dramatic Effects of d-Electron Configurations on Vibrational Circular Dichroism Spectra of Tris(acetylacetonato)metal(III)
Authors: Sato Hisako , Taniguchi Tohru , Monde Kenji , Nishimura Shin-Ichiro , Yamagishi Akihiko
Published: April 2006

The VCD spectra of a series of tris(acetylacetonato)metal(III) ([M(acac)3] with M = Co, Cr, Ru, and Rh) have revealed a new aspect concerning the effects of a central metal ion on the vibrational energy levels split by the inter-ligand interactions. Our present view is that the correlated vibrational motions of vicinal ligands are affected by the d-electron configuration of a central metal ion.
Screening Tests for Intended Medication Adherence Among the Elderly
Authors: Raehl Cynthia L , Bond CA , Woods Tresa J , Patry Roland A , Sleeper Rebecca B
Published: April 2006

Background:

Medication nonadherence is increasingly recognized as a cause of preventable adverse events, hospitalizations, and poor healthcare outcomes. While comprehensive medication adherence assessment for the elderly is likely to identify and prevent drug-related problems, it is time consuming for patient and healthcare providers alike.

Objective:

To identify screening tools to predict elderly patients' intended medication adherence that are suitable for primary-care settings and community pharmacies.

Methods:

This study evaluated 57 English-speaking persons aged 65 years and older who were from diverse socioeconomic backgrounds. Intended adherence was quantified, and the relationships to demographic, medical history, socioeconomic, and literacy variables were determined.

Results:

In a multivariate analysis with the composite MedTake Test (a quantitative measure of each subject's intent to adhere to prescribed oral medications) as the dependent variable, independent predictors of intended adherence included: age, car ownership in the last 10 years, receipt of food assistance in the last 10 years, number of over-the-counter (OTC) medicines, and REALM (Rapid Estimate of Adult Literacy in Medicine). The strongest predictor was the REALM word-recognition pronunciation test (β = 0.666; R2 = 0.271; p < 0.001).

Conclusions:

We observed that the REALM word-recognition pronunciation test, along with age, number of OTC drugs, and 2 socioeconomic questions, predicted the intent of seniors to correctly take their own prescribed oral medications.
Atenolol-Induced Breast Pain in a Woman with Hypertension
Authors: Kelleher Julia A
Published: April 2006

Objective:

To describe a case of atenolol-induced breast pain and swelling in a patient receiving atenolol.

Case Summary:

A 54-year-old woman was diagnosed with hypertension with no existing comorbidity. The patient was not taking any prescription medications, but was using an herbal supplement and several other over-the-counter supplements. After diet and exercise failed to control the woman's blood pressure, atenolol 25 mg daily was initiated. She reported symptoms of insomnia 9 days after starting the medication. During a follow-up visit 5 weeks later, the patient reported continued insomnia, as well as a 6 day history of breast pain, swelling, and tenderness. Atenolol was quickly titrated to discontinuation, and a thiazide diuretic was prescribed. Subsequently, the pain and swelling gradually resolved.

Discussion:

Assessment using the Naranjo probability scale revealed that the adverse reaction was probably associated with atenolol. While rare cases of hyperprolactinemia and galactorrhea have been reported with β-blocker use, no reports of breast pain caused by this drug class were identified in the literature.

Conclusions:

Atenolol has many reported adverse reactions, both common and rare; however, until this report, breast pain and swelling had not been documented adverse reactions. Clinicians should be aware that atenolol may be a cause of nonorganic breast pain and swelling in women.
Zn‐Dependent Medium‐Chain Dehydrogenases/Reductases
Authors: Meijers Rob , Cedergren‐Zeppezauer Eila S
Published: April 2006

Medium‐chain dehydrogenases/reductases (MDRs) have about 350 to 390 amino acids and belong to a large superfamily of proteins including the Zn‐dependent alcohol dehydrogenases (ADHs) and several other Zn‐dependent activities. They are dimers or tetramers and utilize either NADH or NADPH as electron carriers referred to as cofactors. The oxidation/reduction process is a 2‐electron/1‐proton (hydride ion, H−) transfer between substrate and cofactor. The compounds oxidized or reduced by these enzymes vary considerably in structure ranging from small primary and secondary alcohols/aldehydes/ketones (aliphatic and aromatic), sugars (sorbitol/fructose, glucose) to large substances like fatty acids, steroids, and retinoids. ADHs are widely distributed in nature and some MDR members are found in all species. An essential Zn ion at the active site is common to all MDRs but some members have two zinc ions per subunit.

The 3D Structures of Zn‐dependent MDRs are highly similar and they essentially have the same polypeptide fold. The low sequence identity found sometimes could not immediately reveal this close structural relationship. Now numerous structures have been examined indicating that the evolutionary strategy for MDRs has been to vary amino acids preferably at the reaction center and further away in the substrate binding area. Thus, the size and shape of the substrate channel is adapted for small or large substrates, hydrophilic or hydrophobic substances, modifications attained via few mutations, or significant deletions/additions of amino acids. A further opportunity to create multiplicity has been to vary the control mechanism for the protein conformation change and the oligomeric state. Some enzymes undergo significant structural changes upon cofactor binding, while others do not.

A transition state intermediate of NADH in complex with horse liver alcohol dehydrogenase, resolved to atomic resolution (≈1 Å), has revealed structural modifications of the cofactor associated with the activation process for hydride transfer. This involves an OH−pyridine ring adduct, connected to the zinc center. The distortion of the nicotinamide at the enzyme site, affected by the presence of the negatively charged oxygen ligand, influences three parameters: (i) the puckering of the ring, (ii) a deviation from a standard carbon–carbon double bond length, and (iii) accumulation of negative charge at the C4 atom promoting hydride transfer. The active site Zn‐center of this large enzyme group shows great flexibility with respect to metal–ligand geometry and dynamics. Structural and spectroscopic evidence suggest that Zn‐dependent MDRs should be included in the general family of Zn‐enzymes, which require water and hydroxide ion as reactants during catalysis.
6‐Pyruvoyl‐Tetrahydropterin Synthase
Authors: Nar Herbert
Published: April 2006

The 6‐pyruvoyl‐tetrahydropterin synthase (PTPS), a zinc‐dependent, heat‐stable, homohexameric protein complex of approximately 90 kDa molecular weight catalyzes the conversion of dihydroneopterin triphosphate to 6‐pyruvoyl‐tetrahydropterin, the second of three enzymatic steps in the synthesis of tetrahydrobiopterin from GTP.

The 6‐pyruvoyl‐tetrahydropterin synthetase monomer forms a compact, single‐domain α + β structure containing a sequential, four‐stranded, antiparallel β‐sheet. Oligomerization occurs through association of monomers via their β‐sheets that form a 12‐stranded β‐barrel structure that is duplicated in the functional hexameric form via a head‐to‐head association of two trimers.

The PTPS active site is a 12‐Å deep cavity that is located on the interface of three monomers, two from one trimer and one subunit from the other trimer. The Zn(II) binding site is located at the center of the cavity. The transition metal is bound to the NE2 atoms of the three histidine residues. The role of the catalytic metal is to correctly position the substrate, to polarize the carbon–oxygen bonds for facile proton release from the substrate, and to prevent cleavage of the C1′‐C2′ substrate side‐chain bond.

In addition, PTPS contains an intersubunit catalytic triad motif composed of the amino acid residues CysA42, HisB89, and AspB88 from two neighboring monomers (A and B) that putatively function as a relay system for proton abstraction from substrate and reaction intermediate. Residue GluA133 may represent the key residue for the stereospecificity of the catalyzed reaction.
Cys2His2Zinc Finger Proteins
Authors: Laity John H
Published: April 2006

The Cys2His2(C2H2) zinc finger is one of the simplest independently folded structural domains known, yet the number of proteins with distinct and complex functions that contain the motif is too large to count. The domain consists of a small antiparallel β‐sheet and a single helix that contribute two cysteine and two histidine ligands respectively to coordinate a central Zn(II) ion in a nearly perfect tetrahedral geometry. The C2H2 zinc finger is one of the major DNA binding motifs in eukaryotic transcription factors, and probably the most common protein motif in the human genome. DNA sequence specificity is achieved through residue side‐chain contacts to DNA bases that occur at preferential residue positions located in the N‐terminal region of the zinc finger helix (‘fingertip’) that reside primarily on one surface of the domain. Functional specificity and diversity of C2H2 zinc finger proteins are, paradoxically, both achieved through tandem repeats of the motif separated by short, conserved peptide linkers, where each individual finger is capable of recognizing a distinct DNA subsite. Diversity of the C2H2 motif extends beyond DNA recognition to protein–RNA and protein–protein interactions, although these functions are not well understood. Since the first reported structure of a single finger almost 15 years ago, over 40 C2H2 zinc finger structures have been reported both free and bound to DNA. Detailed molecular aspects of C2H2 zinc finger structure, function, and metal binding are examined.