bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive Impairment in Schizophrenia: A Life Span Perspective
Authors: O'Donnell Brian F.
Published: October 2007

Cognitive impairment is a core Feature oF schizophrenia. The evolution oF cognitive impairment over the liFe span may clariFy whether schizophrenia is best characterized as a neurodevelopmental or neurodegenerative disorder. Children who later develop schizophrenia show delayed language acquisition, intellectual impairment, and poorer academic perFormance than peers. These premorbid intellectual deFicits may worsen beFore illness onset. Although patients show pervasive intellectual impairment at First episode, this deFicit does not appear to worsen through middle age. Gerontological patients remain poorly characterized, but a subset oF chronic, institutionalized patients may show Further intellectual and Functional decline in old age. From a cognitive perspective, schizophrenia may be best viewed as a neurodevelopmental disorder initiated by genetic or environmental Factors in the prenatal period. These early changes may contribute to premorbid cognitive impairment and to subsequent disturbances oF neural connectivity and transmission.
Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 epression in monocyte-derived dendritic cells
Authors: Mezger Markus , Steffens Michael , Beyer Melanie , Manger Carolin , Eberle Johannes , Toliat Mohammad-Reza , Wienker Thomas F. , Ljungman Per , Hebart Holger , Dornbusch Hans Jürgen , Einsele Hermann , Loeffler Juergen
Published: October 2007

Patients after allogeneic stem-cell transplantation (alloSCT) have an increased risk for invasive aspergillosis (IA). Here, recipients of an allograft with IA (n = 81) or without IA (n = 58) were screened for 84 single nucleotide polymorphisms in 18 immune relevant genes. We found 3 markers in chemokine (C-X-C motif) ligand 10 (CXCL10, 4q21, 11 101 C > T, P = .007; 1642 C < G, P = .003; −1101 A < G, P = .001) significantly associated with an increased risk of developing IA. Furthermore, immature dendritic cells (iDCs) exposed to Aspergillus fumigatus germlings showed markedly higher CXCL10 expression, if carrying the wild type genotype, compared with the “CGAG” high risk haplotype. In addition, serum from patients with proven/probable IA showed increased serum levels of CXCL10, compared with immunocompromised patients without IA. Thus, polymorphisms in CXCL10 determine chemokine secretion by iDCs upon exposure to A fumigatus and most likely thereby genetically determine the risk of IA after alloSCT.
Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia
Authors: Gattei Valter , Bulian Pietro , Del Principe Maria Ilaria , Zucchetto Antonella , Maurillo Luca , Buccisano Francesco , Bomben Riccardo , Dal-Bo Michele , Luciano Fabrizio , Rossi Francesca M. , Degan Massimo , Amadori Sergio , Del Poeta Giovanni
Published: October 2007

CD49d/α4-integrin is variably expressed in chronic lymphocytic leukemia (CLL). We evaluated its relevance as independent prognosticator for overall survival and time to treatment (TTT) in a series of 303 (232 for TTT) CLLs, in comparison with other biologic or clinical prognosticators (CD38, ZAP-70, immunoglobulin variable heavy chain (IGHV) gene status, cytogenetic abnormalities, soluble CD23, β2-microglobulin, Rai staging). Flow cytometric detection of CD49d was stable and reproducible, and the chosen cut-off (30% CLL cells) easily discriminated CD49dlow from CD49dhigh cases. CD49d, whose expression was strongly associated with that of CD38 (P < .001) and ZAP-70 (P < .001), or with IGHV mutations (P < .001), was independent prognosticator for overall survival along with IGHV mutational status (CD49d hazard ratio, HRCD49d = 3.52, P = .02; HRIGHV = 6.53, P < .001) or, if this parameter was omitted, with ZAP-70 (HRCD49d = 3.72, P = .002; HRZAP-70 = 3.32, P = .009). CD49d was also a prognosticator for TTT (HR = 1.74, P = .007) and refined the impact of all the other factors. Notably, a CD49dhigh phenotype, although not changing the outcome of good prognosis (ZAP-70low, mutated IGHV) CLL, was necessary to correctly prognosticate the shorter TTT of ZAP-70high (HR = 3.12; P = .023) or unmutated IGHV (HR = 2.95; P = .002) cases. These findings support the introduction of CD49d detection in routine prognostic assessment of CLL patients, and suggest both pathogenetic and therapeutic implications for CD49d expression in CLL.
BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2 −938A>C promoter single nucleotide polymorphism
Authors: Majid Aneela , Tsoulakis Olga , Walewska Renata , Gesk Stefan , Siebert Reiner , Kennedy D. Ben J. , Dyer Martin J. S.
Published: October 2007

High-level BCL2 expression is seen in most patients with chronic lymphocytic leukemia (CLL) in the absence of BCL2 chromosomal translocation. A single nucleotide polymorphism (SNP; −938C>A) within an inhibitory region of the BCL2 promoter has been reported to regulate BCL2 protein expression and to be associated with adverse prognostic features in CLL. We screened 276 patients with CLL for this SNP and 100 patients by quantitative Western blot for BCL2 expression. In contrast to the previous report, we found no association with BCL2 protein levels or with any clinical or laboratory parameters. BCL2 protein levels remained constant in 10 individual patients at different time points. A total of 19 patients with the lowest levels of BCL2 protein expression were biologically and clinically heterogeneous; 5 patients exhibited high-level BCL2 RNA expression and 4 were fludarabine resistant. BCL2 protein levels in CLL reflect a complex interplay of transcriptional and posttranscriptional controls, but do not appear to be associated with the −938C>A promoter SNP.
Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis
Authors: Murray Fiona , Darzentas Nikos , Hadzidimitriou Anastasia , Tobin Gerard , Boudjogra Myriam , Scielzo Cristina , Laoutaris Nikolaos , Karlsson Karin , Baran-Marzsak Fanny , Tsaftaris Athanasios , Moreno Carol , Anagnostopoulos Achilles , Caligaris-Cappio Federico , Vaur Dominique , Ouzounis Christos , Belessi Chrysoula , Ghia Paolo , Davi Fred , Rosenquist Richard , Stamatopoulos Kostas
Published: October 2007

Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).
Human intrathymic lineage commitment is marked by differential CD7 expression: identification of CD7− lympho-myeloid thymic progenitors
Authors: Hao Qian-Lin , George Aswathi A. , Zhu Judy , Barsky Lora , Zielinska Ewa , Wang Xiuli , Price Mary , Ge Shundi , Crooks Gay M.
Published: October 2007

The identity and lineage potential of the cells that initiate thymopoiesis remain controversial. The goal of these studies was to determine, at a clonal level, the immunophenotype and differentiation pathways of the earliest progenitors in human thymus. Although the majority of human CD34+lin− thymocytes express high levels of CD7, closer analysis reveals that a continuum of CD7 expression exists, and 1% to 2% of progenitors are CD7−. CD34+lin− thymocytes were fractionated by CD7 expression and tested for lineage potential in B-lymphoid, T-lymphoid, and myeloid-erythroid conditions. Progressive restriction in lineage potential correlated with CD7 expression, that is, the CD7hi fraction produced T and NK cells but lacked B and myelo-erythroid potential, the CD7int (CD10+) fraction produced B, T, and NK cells, but lacked myelo-erythroid potential. The CD7− fraction produced all lymphoid and myelo-erythroid lineages and expressed HSC-associated genes. However, CD34+lin−CD7− thymocytes also expressed early T lymphoid genes Tdt, pTα, and IL-7Rα and lacked engraftment capacity, suggesting the signals that direct lymphoid commitment and corresponding loss of HSC function are rapidly initiated on arrival of HSC in the human thymus. Thus, differential levels of CD7 identify the progressive stages of lineage commitment in human thymus, initiated from a primitive CD7− lympho-myeloid thymic progenitor.
Cost-effectiveness analysis of guidelines for antihypertensive care in Finland
Authors: Booth Neill , Jula Antti , Aronen Pasi , Kaila Minna , Klaukka Timo , Kukkonen-Harjula Katriina , Reunanen Antti , Rissanen Pekka , Sintonen Harri , Mäkelä Marjukka
Published: October 2007

Background

Hypertension is one of the major causes of disease burden affecting the Finnish population. Over the last decade, evidence-based care has emerged to complement other approaches to antihypertensive care, often without health economic assessment of its costs and effects. This study looks at the extent to which changes proposed by the 2002 Finnish evidence-based Current Care Guidelines concerning the prevention, diagnosis, and treatment of hypertension (the ACCG scenario) can be considered cost-effective when compared to modelled prior clinical practice (the PCP scenario).

Methods

A decision analytic model compares the ACCG and PCP scenarios using information synthesised from a set of national registers covering prescription drug reimbursements, morbidity, and mortality with data from two national surveys concerning health and functional capacity. Statistical methods are used to estimate model parameters from Finnish data. We model the potential impact of the different treatment strategies under the ACCG and PCP scenarios, such as lifestyle counselling and drug therapy, for subgroups stratified by age, gender, and blood pressure. The model provides estimates of the differences in major health-related outcomes in the form of life-years and costs as calculated from a 'public health care system' perspective. Cost-effectiveness analysis results are presented for subgroups and for the target population as a whole.

Results

The impact of the use of the ACCG scenario in subgroups (aged 40–80) without concomitant cardiovascular and related diseases is mainly positive. Generally, costs and life-years decrease in unison in the lowest blood pressure group, while in the highest blood pressure group costs and life-years increase together and in the other groups the ACCG scenario is less expensive and produces more life-years. When the costs and effects for subgroups are combined using standard decision analytic aggregation methods, the ACCG scenario is cost-saving and more effective.

Conclusion

The ACCG scenario is likely to reduce costs and increase life-years compared to the PCP scenario in many subgroups. If the estimated trade-offs between the subgroups in terms of outcomes and costs are acceptable to decision-makers, then widespread implementation of the ACCG scenario is expected to reduce overall costs and be accompanied by positive outcomes overall.
The implementation of the Medical Regulation Office and Mobile Emergency Attendance System and its impact on the gravity profile of non-traumatic afflictions treated in a University Hospital: a research study
Authors: Lopes Sérgio LB , dos Santos José Sebastião , Scarpelini Sandro
Published: October 2007

Background

The public health system of Brazil is structured by a network of increasing complexity, but the low resolution of emergency care at pre-hospital units and the lack of organization of patient flow overloaded the hospitals, mainly the ones of higher complexity. The knowledge of this phenomenon induced Ribeirão Preto to implement the Medical Regulation Office and the Mobile Emergency Attendance System. The objective of this study was to analyze the impact of these services on the gravity profile of non-traumatic afflictions in a University Hospital.

Methods

The study conducted a retrospective analysis of the medical records of 906 patients older than 13 years of age who entered the Emergency Care Unit of the Hospital of the University of São Paulo School of Medicine at Ribeirão Preto. All presented acute non-traumatic afflictions and were admitted to the Internal Medicine, Surgery or Neurology Departments during two study periods: May 1996 (prior to) and May 2001 (after the implementation of the Medical Regulation Office and Mobile Emergency Attendance System). Demographics and mortality risk levels calculated by Acute Physiology and Chronic Health Evaluation II (APACHE II) were determined.

Results

From 1996 to 2001, the mean age increased from 49 ± 0.9 to 52 ± 0.9 (P = 0.021), as did the percentage of co-morbidities, from 66.6 to 77.0 (P = 0.0001), the number of in-hospital complications from 260 to 284 (P = 0.0001), the mean calculated APACHE II mortality risk increased from 12.0 ± 0.5 to 14.8 ± 0.6 (P = 0.0008) and mortality rate from 6.1 to 12.2 (P = 0.002). The differences were more significant for patients admitted to the Internal Medicine Department.

Conclusion

The implementation of the Medical Regulation and Mobile Emergency Attendance System contributed to directing patients with higher gravity scores to the Emergency Care Unit, demonstrating the potential of these services for hierarchical structuring of pre-hospital networks and referrals.
Diabetes and pre-diabetes are associated with cardiovascular risk factors and carotid/femoral intima-media thickness independently of markers of insulin resistance and adiposity
Authors: Faeh David , William Julita , Yerly Patrick , Paccaud Fred , Bovet Pascal
Published: October 2007

Background

Impaired glucose regulation (IGR) is associated with detrimental cardiovascular outcomes such as cardiovascular disease risk factors (CVD risk factors) or intima-media thickness (IMT). Our aim was to examine whether these associations are mediated by body mass index (BMI), waist circumference (waist) or fasting serum insulin (insulin) in a population in the African region.

Methods

Major CVD risk factors (systolic blood pressure, smoking, LDL-cholesterol, HDL-cholesterol,) were measured in a random sample of adults aged 25–64 in the Seychelles (n = 1255, participation rate: 80.2%).

According to the criteria of the American Diabetes Association, IGR was divided in four ordered categories: 1) normal fasting glucose (NFG), 2) impaired fasting glucose (IFG) and normal glucose tolerance (IFG/NGT), 3) IFG and impaired glucose tolerance (IFG/IGT), and 4) diabetes mellitus (DM). Carotid and femoral IMT was assessed by ultrasound (n = 496).

Results

Age-adjusted levels of the major CVD risk factors worsened gradually across IGR categories (NFG < IFG/NGT < IFG/IGT < DM), particularly HDL-cholesterol and blood pressure (p for trend < 0.001). These relationships were marginally attenuated upon further adjustment for waist, BMI or insulin (whether considered alone or combined) and most of these relationships remained significant. With regards to IMT, the association was null with IFG/NGT, weak with IFG/IGT and stronger with DM (all more markedly at femoral than carotid levels). The associations between IMT and IFG/IGT or DM (adjusted by age and major CVD risk factors) decreased only marginally upon further adjustment for BMI, waist or insulin. Further adjustment for family history of diabetes did not alter the results.

Conclusion

We found graded relationships between IGR categories and both major CVD risk factors and carotid/femoral IMT. These relationships were only partly accounted for by BMI, waist and insulin. This suggests that increased CVD-risk associated with IGR is also mediated by factors other than the considered markers of adiposity and insulin resistance. The results also imply that IGR and associated major CVD risk factors should be systematically screened and appropriately managed.
Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: A randomized clinical trial
Authors: Namutangula Beatrice , Ndeezi Grace , Byarugaba Justus S , Tumwine James K
Published: October 2007

Background

Several reports have suggested that raised intracranial pressure (ICP) is a major contributor to death among children with cerebral malaria. Mannitol, an osmotic diuretic, effectively lowers ICP and is used to treat post-traumatic raised ICP. It is not clear whether intravenous mannitol given to children with cerebral malaria improves clinical outcome. The objective of this study was to determine the effect of mannitol as adjunct therapy on the clinical outcome of children with cerebral malaria.

Methods

This randomized double-blind placebo controlled clinical trial was carried out at the Emergency Paediatric ward of Mulago Hospital, Uganda's national referral and teaching hospital. One hundred and fifty six children aged 6 to 60 months with cerebral malaria were randomized to either one dose of mannitol 1 g/kg or placebo, in addition to intravenous quinine. Main outcome measures included coma recovery time; time to sit unsupported, begin oral intake; duration of hospitalization; death and adverse effects.

Results

Time to regain consciousness (p = 0.11), sit unsupported (p = 0.81), time to start oral intake (p = 0.13) and total coma duration (p = 0.07) were similar in both groups. There was no significant difference in the mortality between the placebo (13/80 or 16.3%) and mannitol (10/76 or 13.2%) groups: RR = 1.2 (CI 0.5–2.7). No adverse effects were observed after administration of mannitol.

Conclusion

Mannitol had no significant impact on clinical outcome of cerebral malaria. It is difficult to recommend intravenous mannitol as adjunct therapy for childhood cerebral malaria.

Clinical registration number

ClinicalTrials.gov ID: NCT00113854
Poor follow-up rates at a self-pay northern Indian tertiary AIDS clinic
Authors: Maru Duncan Smith-Rohrberg , Khakha Deepika C , Tahir Mohammad , Basu Sanjay , Sharma Surendra K
Published: October 2007

Background

In many developing countries, out-of-pocket payment remains a primary mechanism by which patients infected with HIV access treatment. In India, this has been changing as the National AIDS Control Organization (NACO) has been rolling out free antiretroviral therapy throughout the country since 2004. The vast majority of patients, however, remain without access to free medicines.

Methods

A retrospective chart review was performed on data obtained from a registry of ninety-three (93) patients attending a self-pay clinic at the All India Institute of Medical Sciences in Delhi, India. Multivariable Cox proportional hazard and logistic regression models were explored to assess the relationship between lost-to-follow-up status and the predictor variables: age, sex, household income, baseline CD4 count, and distance from clinic.

Results

Lost-to-follow-up rates were very high; 68% (63/93) were lost-to-follow-up till the time of chart review, including 59% (55/93) who were lost within one year. In both regression models, younger age, low baseline CD4 counts, and low income level were significantly associated with increased risk of lost-to-follow-up. Additionally, there was a significant interaction between income and CD4 counts. The patients with both low CD4 counts and low income level were more likely to be lost-to-follow-up than would be predicted by each covariable alone.

Conclusion

In this small cohort of AIDS patients attending a self-pay antiretroviral clinic at a large tertiary care center in Delhi, India, follow-up rates were quite poor. Poorer patients tended to present to clinic with more depressed CD4 counts and were less likely to be retained in care. These findings indicate that greater strides must be taken to improve the recruitment and retention of poor patients. The expansion of free antiretrovirals is one step among many necessary to achieve this objective.
Hepatitis B virus and hepatitis C virus in pregnant Sudanese women
Authors: Elsheikh Rasha M , Daak Ahmed A , Elsheikh Mohamed A , Karsany Mubarak S , Adam Ishag
Published: October 2007

Background

The epidemiology of viral hepatitis during pregnancy is essential for health planners and programme managers. While much data exist concerning viral hepatitis during pregnancy in many African countries, no proper published data are available in Sudan.

Aim

The study aimed to investigate the sero-prevalance and the possible risk factors for hepatitis B virus (HBV) and hepatitis C virus (HCV) among antenatal care attendants in central Sudan.

Methods

During 3 months from March–June 2006, sera were collected from pregnant women at Umdurman Maternity Hospital in Sudan, and they were tested for markers of hepatitis B virus (HBVsAg) and HCV.

Results

HBVsAg was detected in 41 (5.6%) out 728 women, Anti-HCV was detected in 3 (0.6%) out of 423 women, all of them were not aware of their condition. Age, parity, gestational age, residence, history of blood transfusion, dental manipulations, tattooing and circumcision did not contribute significantly to increased HBVsAg sero-positivity.

Conclusion

Thus 5.6% of pregnant women were positive for HBVsAg irrespective of their age, parity and socio-demographic characteristics. There was low prevalence of Anti-HCV.
Nucleocapsid formation and RNA synthesis of Marburg virus is dependent on two coiled coil motifs in the nucleoprotein
Authors: DiCarlo Andrea , Möller Peggy , Lander Angelika , Kolesnikova Larissa , Becker Stephan
Published: October 2007

The nucleoprotein (NP) of Marburg virus (MARV) is responsible for the encapsidation of viral genomic RNA and the formation of the helical nucleocapsid precursors that accumulate in intracellular inclusions in infected cells. To form the large helical MARV nucleocapsid, NP needs to interact with itself and the viral proteins VP30, VP35 and L, which are also part of the MARV nucleocapsid. In the present study, a conserved coiled coil motif in the central part of MARV NP was shown to be an important element for the interactions of NP with itself and VP35, the viral polymerase cofactor. Additionally, the coiled coil motif was essential for the formation of NP-induced intracellular inclusions and for the function of NP in the process of transcription and replication of viral RNA in a minigenome system. Transfer of the coiled coil motif to a reporter protein was sufficient to mediate interaction of the constructed fusion protein with the N-terminus of NP. The coiled coil motif is bipartite, constituted by two coiled coils which are separated by a flexible linker.
Phylogenetic simulation of promoter evolution: estimation and modeling of binding site turnover events and assessment of their impact on alignment tools
Authors: Huang Weichun , Nevins Joseph R , Ohler Uwe
Published: October 2007

Background

The phenomenon of functional site turnover has important implications for the study of regulatory region evolution, such as for promoter sequence alignments and transcription factor binding site (TFBS) identification. At present, it remains difficult to estimate TFBS turnover rates on real genomic sequences, as reliable mappings of functional sites across related species are often not available. As an alternative, we introduce a flexible new simulation system, Phylogenetic Simulation of Promoter Evolution (PSPE), designed to study functional site turnovers in regulatory sequences.

Results

Using PSPE, we study replacement turnover rates of different individual TFBSs and simple modules of two sites under neutral evolutionary functional constraints. We find that TFBS replacement turnover can happen rapidly in promoters, and turnover rates vary significantly among different TFBSs and modules. We assess the influence of different constraints such as insertion/deletion rate and translocation distances. Complementing the simulations, we give simple but effective mathematical models for TFBS turnover rate prediction. As one important application of PSPE, we also present a first systematic evaluation of multiple sequence aligners regarding their capability of detecting TFBSs in promoters with site turnovers.

Conclusion

PSPE allows researchers for the first time to investigate TFBS replacement turnovers in promoters systematically. The assessment of alignment tools points out the limitations of current approaches to identify TFBSs in non-coding sequences, where turnover events of functional sites may happen frequently, and where we are interested in assessing the similarity on the functional level. PSPE is freely available at the authors' website.
Quality of Life in Cured Patients with Differentiated Thyroid Carcinoma
Authors: Hoftijzer Hendrieke C. , Heemstra Karen A. , Corssmit Eleonora P. M. , van der Klaauw Agatha A. , Romijn Johannes A. , Smit Johannes W. A.
Published: October 2007

Objective: This study was performed to evaluate the impact of cured differentiated thyroid carcinoma (DTC) on quality of life. Previous studies on quality of life in patients with DTC were hampered by small patient numbers or limited quality-of-life parameters or were uncontrolled.

Design: This was a cross-sectional case-control study.

Method: We assessed quality of life in 153 cured DTC patients with a median duration of cure of 6.34 yr (range 0.3–41.8) and studied the contribution of disease-specific, biochemical, and social variables, focusing on the degree of TSH suppression. Four validated health-related questionnaires were used (Short Form-36, Multidimensional Fatigue Index-20, Hospital Anxiety and Depression Scale, and Somatoform Disorder Questionnaire), including multiple aspects of physical, psychological, and social functioning. Patients were compared with 113 controls selected by patients themselves (control group I) and 336 pooled age- and gender-matched controls from other Leiden quality-of-life studies (control group II).

Results: Patients had significantly decreased quality of life in 11 of 16 subscales when compared with control group I. In comparison with control group II, decreased scores in 13 of 16 items were observed. An important independent predictor for quality of life was duration of cure. Quality-of-life parameters were not influenced by serum TSH levels both measured at the time of quality-of-life assessment and measured over time since initial therapy.

Conclusions: Patients cured for DTC have impaired quality of life, independently of TSH level. Quality-of-life parameters were inversely affected by duration of cure and consequently may be restored after prolonged follow-up.
Differences in Free Estradiol and Sex Hormone-Binding Globulin in Women with and without Premenstrual Dysphoric Disorder
Authors: Thys-Jacobs Susan , McMahon Don , Bilezikian John P.
Published: October 2007

Context: Over the years, different hypotheses involving the ovarian steroid hormones have been proposed to explain the luteal phase occurrence of severe premenstrual syndrome symptoms. Although it had been strongly suspected that differences in the concentrations of the ovarian steroids may underlie the mood and psychological imbalance of this disorder, the evidence for this hypothesis has been inconsistent and remains controversial.

Objective: Our objective was to measure the ovarian steroid hormones across the menstrual cycle in women with and without luteal phase symptoms consistent with premenstrual dysphoric disorder (PMDD).

Design: We measured estradiol (E2), progesterone, and SHBG in women with and without PMDD using a cross-sectional and prospective experimental design. Participating women underwent 2-month self-assessment symptom screening and 1-month hormonal evaluation.

Results: Overall means for LH, progesterone, E2, peak E2, and free E2 were not different between groups. Across the menstrual cycle, overall percent free E2 was significantly lower and SHBG significantly greater in the PMDD group compared with controls (1.39 ± 0.26 vs. 1.50 ± 0.28, P = 0.03; 61.4 ± 25.1 vs. 52.4 ± 21.3 nmol/liter, P = 0.046, respectively). During the luteal phase, free E2 was significantly lower in the PMDD group compared with controls (PMDD 7.6 ± 7.0 vs. controls 8.9 ± 8.4 pmol/liter; P = 0.032). For both follicular and luteal phases, SHBG was significantly higher in the PMDD group (follicular phase 60.5 ± 31.7 vs. 51.4 ± 38.2 nmol/liter, P = 0.047; luteal phase 65.1 ± 32.3 vs. 55.1 ± 38.9 nmol/liter, P =0.03). In both groups, SHBG significantly increased from the follicular to luteal phase.

Conclusion: Luteal phase concentrations of free E2, percent free E2, and SHBG differ significantly between women with and without PMDD.
PITX2 controls asymmetric gonadal development in both sexes of the chick and can rescue the degeneration of the right ovary
Authors: Guioli Silvana , Lovell-Badge Robin
Published: October 2007

The gonads arise on the ventromedial surface of each mesonephros. In most birds, female gonadal development is unusual in that only the left ovary becomes functional, whereas that on the right degenerates during embryogenesis. Males develop a pair of equally functional testes. We show that the chick gonads already have distinct morphological and molecular left-right(L-R) characteristics in both sexes at indifferent (genital ridge) stages and that these persist, becoming more elaborate during sex determination and differentiation, but have no consequences for testis differentiation. We find that these L-R differences depend on the L-R asymmetry pathway that controls the situs of organs such as the heart and gut. Moreover, a key determinant of this, Pitx2, is expressed asymmetrically, such that it is found only in the left gonad in both sexes from the start of their development. Misexpression of Pitx2 on the right side before and during gonadogenesis is sufficient to transform the right gonad into a left-like gonad. In ZW embryos, this transformation rescues the degenerative fate of the right ovary, allowing for the differentiation of left-like cortex containing meiotic germ cells. There is therefore a mechanism in females that actively promotes the underlying L-R asymmetry initiated by Pitx2 and the degeneration of the right gonad, and a mechanism in males that allows it to be ignored or overridden.
Functional analyses of genetic pathways controlling petal specification in poppy
Authors: Drea Sinéad , Hileman Lena C. , de Martino Gemma , Irish Vivian F.
Published: October 2007

MADS-box genes are crucial regulators of floral development, yet how their functions have evolved to control different aspects of floral patterning is unclear. To understand the extent to which MADS-box gene functions are conserved or have diversified in different angiosperm lineages, we have exploited the capability for functional analyses in a new model system, Papaver somniferum (opium poppy). P. somniferum is a member of the order Ranunculales, and so represents a clade that is evolutionarily distant from those containing traditional model systems such as Arabidopsis, Petunia, maize or rice. We have identified and characterized the roles of several candidate MADS-box genes in petal specification in poppy. In Arabidopsis, the APETALA3(AP3) MADS-box gene is required for both petal and stamen identity specification. By contrast, we show that the AP3 lineage has undergone gene duplication and subfunctionalization in poppy, with one gene copy required for petal development and the other responsible for stamen development. These differences in gene function are due to differences both in expression patterns and co-factor interactions. Furthermore, the genetic hierarchy controlling petal development in poppy has diverged as compared with that of Arabidopsis. As these are the first functional analyses of AP3 genes in this evolutionarily divergent clade, our results provide new information on the similarities and differences in petal developmental programs across angiosperms. Based on these observations, we discuss a model for how the petal developmental program has evolved.
Dissecting the role of the ARF guanine nucleotide exchange factor GBF1 in Golgi biogenesis and protein trafficking
Authors: Szul Tomasz , Grabski Robert , Lyons Susan , Morohashi Yuichi , Shestopal Svetlana , Lowe Martin , Sztul Elizabeth
Published: October 2007

COPI recruitment to membranes appears to be essential for the biogenesis of the Golgi and for secretory trafficking. Preventing COPI recruitment by expressing inactive forms of the ADP-ribosylation factor (ARF) or the ARF-activating guanine nucleotide exchange factor GBF1, or by treating cells with brefeldin A (BFA), causes the collapse of the Golgi into the endoplasmic reticulum (ER) and arrests trafficking of soluble and transmembrane proteins at the ER. Here, we assess COPI function in Golgi biogenesis and protein trafficking by preventing COPI recruitment to membranes by removing GBF1. We report that siRNA-mediated depletion of GBF1 causes COPI dispersal but does not lead to collapse of the Golgi. Instead, it causes extensive tubulation of the cis-Golgi. The Golgi-derived tubules target to peripheral ER-Golgi intermediate compartment (ERGIC) sites and create dynamic continuities between the ERGIC and the cis-Golgi compartment. COPI dispersal in GBF1-depleted cells causes dramatic inhibition of the trafficking of transmembrane proteins. Unexpectedly, soluble proteins continue to be secreted from GBF1-depleted cells. Our findings suggest that a secretory pathway capable of trafficking soluble proteins can be maintained in cells in which COPI recruitment is compromised by GBF1 depletion. However, the trafficking of transmembrane proteins through the existing pathway requires GBF1-mediated ARF activation and COPI recruitment.
High throughput microscopy: from raw images to discoveries
Authors: Wollman Roy , Stuurman Nico
Published: October 2007

Technological advances in automated microscopy now allow rapid acquisition of many images without human intervention, images that can be used for large-scale screens. The main challenge in such screens is the conversion of the raw images into interpretable information and hence discoveries. This post-acquisition component of image-based screens requires computational steps to identify cells, choose the cells of interest, assess their phenotype, and identify statistically significant `hits'. Designing such an analysis pipeline requires careful consideration of the necessary hardware and software components, image analysis, statistical analysis and data presentation tools. Given the increasing availability of such hardware and software, these types of experiments have come within the reach of individual labs, heralding many interesting new ways of acquiring biological knowledge.
LAR, liprin α and the regulation of active zone morphogenesis
Authors: Stryker Emily , Johnson Karl G.
Published: October 2007

Active zones are protein-rich regions of neurons that act as sites of synaptic vesicle fusion and neurotransmitter release at the pre-synaptic terminus. Although the discovery that the receptor protein tyrosine phosphatase LAR and its cytoplasmic binding partner liprin α are essential for proper active zone formation is nearly a decade old, the underlying mechanisms are still poorly understood. Recent studies have identified a number of binding partners for both LAR and liprin α, several of which play key roles in active zone assembly. These include nidogen, dallylike and syndecan – extracellular ligands for LAR that regulate synapse morphogenesis. In addition, liprin-α-interacting proteins such as ERC2, RIM and the MALS/Veli-Cask-Mint1 complex cooperate to form a dense molecular scaffold at the active zone that is crucial for proper synaptic function. These studies allow us to propose testable models of LAR and liprin α function, and provide insights into the fundamental molecular mechanisms of synapse formation and stabilization.
Fuzzy modelling of an agent oriented manufacturing enterprise
Authors: Choudhary A K , Tiwari M K , Shankar R
Published: October 2007

In order to remain in contention in the world market, it is necessary for manufacturing enterprises to design and produce new products with the shortest possible lead time as well as in an effective and competitive way. This includes features of a distributed control paradigm, to adjust to dynamic situations such as frequent process disturbances. Feasibility of a manufacturing enterprise can be enhanced by forming an efficient, flexible, and responsive network of autonomous agents, which can be termed an ‘agent networks’. The flexibility and responsiveness of an agent network can be implemented only when there is proper interaction and communication facility between its various entities. The goal of this paper is to streamline the structural intricacies related to the agent network so that the system as a whole can be more flexible and responsive. In this context, a fuzzy c-means-based clustering algorithm is proposed to group the agents in order to capture effectively the uncertainty and imprecision associated with them. This leads to clustering of the pertinent agents and thus reduces the number of discrete entities of the manufacturing system, thereby simplifying the function of the system. A test problem has been solved to show the effectiveness of the proposed approach.
Numerical simulation of the filling stage for plastic injection moulding based on the Petrov-Galerkin methods
Authors: Yan B , Zhou H , Li D
Published: October 2007

Simulation of plastic injection moulding is carried out essentially to solve non-isothermal, viscous, incompressible, and non-Newtonian convection-diffusion flow equations. However, finite element methods present spurious numerical oscillations, which give a failure result associated with the classical Galerkin formulations of viscous incompressible Navier-Stokes equations. The streamline-upwind/Petrov-Galerkin (SUPG) and pressure-stabilizing/Petrov-Galerkin (PSPG) formulations were employed to prevent these potential numerical instabilities by adding to the weighting functions with their derivatives, thus resulting in stabilized finite element formulations using equal-order interpolation functions for velocity and pressure. Numerical experiments showed that the numerical algorithms developed perform in a stable way and give accurate results compared with the well-known commercial software Moldflow.
Stopped-flow-optical and -ESR Study on Oxidative Reaction of Quercetin by Nitrosodisulfonate Radical as a Model of Reactive Oxygen Species
Authors: Hodaka Sanuki , Komatsu-Watanabe Rushiru , Ideguchi Tomoko , Sakamoto Shunji , Ichimori Kohji , Kanaori Kenji , Tajima Kunihiko
Published: October 2007

By means of the stopped-flow-ESR and -optical methods, oxidation of quercetin by nitrsodisulfonate (NDS) radical anion was studied. The results of optical measurements demonstrated that NDS readily oxidize quercetin to the quinone form. The rapid field-sweep ESR spectrum revealed the formation of short-lived quercetin-derived o-semiquinone anion radical. The radical was confirmed to be a transient intermediate species for generation of the quinone of form.
Stability of Partial Doses of Omeprazole–Sodium Bicarbonate Oral Suspension
Authors: Johnson Cary E , Cober Mary Petrea , Ludwig Jennifer L
Published: October 2007

Background:

Omeprazole-sodium bicarbonate powder for oral suspension has recently been marketed. The manu facturer provides no information regarding the acceptability of using partial doses and recommends that the reconstituted suspension be administered immediately after preparation.

Objectives:

To determine the stability of the powder for oral suspension over 45 days, evaluate the stability of a partial dose (<20 mg) following exposure to Simulated Gastric Fluid USP (SGF) over 2 hours, and determine the feasibility of administering the suspension through neonatal and pediatric nasogastric feeding tubes compared with lansoprazole.

Methods:

Three identical samples of omeprazole–sodium bicarbonate suspension 2 mg/mL were stored in the refrigerator (3–5°C) and assayed by high-performance liquid chromatography immediately after preparation and at 7, 15, 30, and 45 days. Stability of a 1 mg/kg dose with an estimated volume of SGF for a simulated 12.7 kg pediatric patient was determined In triplicate over 2 hours at 37°C. The ability to administer a typical dose of omeprazole suspension and lansoprazole suspension (microgranules and water compounded from lansoprazole oral disintegrating tablets) was assessed in triplicate using 3 different sizes of neonatal/pediatric nasogastric feeding tubes.

Results:

At least 98% of the initial concentration of omeprazole remained throughout the 45 day study period in all suspensions. The suspension maintained at least 93% of the initial concentration following exposure to SGF for 2 hours. The lansoprazole bead mixture partially clogged the 6 French feeding tube and completely clogged the 5 French feeding tube. The omeprazole-sodium bicarbonate suspension was easily administered through all 3 sizes of neonatal/pediatric feeding tubes.

Conclusions:

Omeprazole-sodium bicarbonate suspension 2 mg/mL prepared from 20 mg packets was stable for at least 45 days when stored at 3–5°C. A partial dose of 12.7 mg was stable following exposure to SGF for 2 hours at 37°C. This suspension can be easily administered through 5, 6, and 8 French neonatal/pediatric feeding tubes and, when taking time and ease of preparation into account, it is cost competitive with simple omeprazole suspension.
Tobramycin-Induced Hepatotoxicity
Authors: Nisly Sarah A , Ray Shaunta' M , Moye Robert A
Published: October 2007

Objective:

To report a case of tobramycin-induced hepatotoxicity.

Case Summary:

A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3–6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values.

Discussion:

This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive timeline present, lack of specific symptoms, and unnecessary risk to the patient.

Conclusions:

Although no other case reports on this interaction have been published through October 9, 2007, historical data from tertiary sources reveal the possibility of aminoglycoside-induced hepatotoxicity; therefore, tobramycin-induced hepatotoxicity cannot be ruled out in this patient. Clinicians should be aware of this adverse event.
Propofol Associated with a Shorter Duration of Mechanical Ventilation than Scheduled Intermittent Lorazepam: A Database Analysis Using Project Impact
Authors: Fong Jeffrey J , Kanji Salmaan , Dasta Joseph F , Garpestad Erik , Devlin John W
Published: October 2007

Background:

While one prospective controlled study in medical intensive care unit (ICU) patients demonstrated that sedation with propofol leads to a shorter duration of mechanical ventilation compared with scheduled intermittent intravenous lorazepam, its conclusions may not be applicable to surgical ICU patients and institutions not using daily sedation interruption.

Objective:

To compare the duration of mechanical ventilation between medical and surgical ICU patients receiving propofol versus scheduled intermittent lorazepam in routine clinical practice.

Methods:

Retrospective data (January 2001–December 2005) were obtained from the Project IMPACT database for medical and surgical ICU patients at Tufts-New England Medical Center, a 450 bed academic hospital. These patients had been mechanically ventilated for 24 hours or more and had received 24 hours or more of either propofol or scheduled intermittent lorazepam as the sole sedative. Clinically relevant variables were identified a priori, and their influence on duration of mechanical ventilation was evaluated. Differences in these variables between propofol and scheduled intermittent lorazepam groups within the ICU cohorts were then measured.

Results:

Of 4608 database patients, 287 met criteria. Factors associated with a prolonged duration of mechanical ventilation for the medical ICU cohort included sedation use for 5 or more days (OR 13.8; 95% CI 8.3 to 19.4), narcotic use (OR 7.6; 95% CI 2.3 to 13), and scheduled intermittent lorazepam use (OR 7.0; 95% CI 0.4 to 13.7). For the surgical ICU cohort, these factors included sedation use for 5 or more days (OR 15; 95% CI 11.4 to 19.4), APACHE II (Acute Physiology and Chronic Health Evaluation II) score equal to or greater than 18 (OR 4.1; 95% CI 0.4 to 7.8), and scheduled intermittent lorazepam use (OR 4.0; 95% CI 0.2 to 7.7). Duration of mechanical ventilation was the only variable that differed significantly between propofol and scheduled intermittent lorazepam in both the medical ICU, with a median (range) of 6 (3–12) versus 11 (5–25; p = 0.03), and surgical ICU, with a median of 4 (2–15) versus 9 (4–20; p = 0.001), groups.

Conclusions:

Sedation with propofol in the naturalistic setting appears to be associated with a shorter duration of mechanical ventilation compared with scheduled intermittent lorazepam in both medial and surgical ICU patients when only one sedative drug is used. Data from this uncontrolled observational study are consistent with findings from a randomized clinical trial.