bluuebunny/crossref_metadata_2025 huggingface dataset:
Human teratogens: Update 2010
Authors: Holmes Lewis B.
Published: January 2011

A wide variety of human teratogens have been identified. The characteristics of human teratogens can be used in the assessment of apparent “new” teratogens, when postulated. Information is available through online databases, such as TERIS and Reprotox, telephone‐based counseling resources (e.g., Organization of Teratogen Information Systems [OTIS] and European Network Teratology Information Services [ENTIS]), reference books, annual meetings of the Teratology Society, and published articles. There are significant deficiencies in the information available: (1) lack of knowledge about the molecular and cellular basis for most teratogenic effects; (2) the inability to genetically identify more susceptible women before pregnancy; (3) little information is available on dermal and airborne exposures during pregnancy; and (4) most clinicians receive little, if any, training in the identification of or counseling for exposure to potential teratogens. There are many current dilemmas in counseling about exposures in pregnancy, including: (1) Is exposure to specific drugs, such as selected serotonin re‐uptake inhibitors (SSRIs) and the inhibitors of tumor necrosis factor‐alpha, teratogenic in the first trimester of pregnancy? (2) Are the increased risks of birth defects associated with assisted reproductive technology due, in part, to epigenetic effects? (3) What are the “safe” levels of exposure to the plasticizers phthalates during pregnancy? (4) How do we convince busy physicians, nurses, and pharmacists not to use the drug categories A, B, C, D, and X in counseling and to use more accurate sources? There is a need for a national advisory center for pregnancy registries to provide guidance when new registries are being developed. Birth Defects Research (Part A), 2011. © 2011 Wiley‐Liss, Inc.
Liquid crystal phases of DNA: Evaluation of DNA organization by two‐photon fluorescence microscopy and polarization analysis
Authors: Olesiak‐Banska Joanna , Mojzisova Halina , Chauvat Dominique , Zielinski Marcin , Matczyszyn Katarzyna , Tauc Patrick , Zyss Joseph
Published: January 2011

We report on the investigation of the structure of DNA liquid crystal (LC) phases by means of polarization sensitive two‐photon microscopy (PSTPM). DNA was stained with fluorescent dyes, an intercalator propidium iodide, or a groove binder Hoechst 3342, and the angular dependence of the intensity of two‐photon excited fluorescence emitted by the dye was collected. The local orientation of DNA molecules in cholesteric and columnar LC phases was established on the basis of the relative angle between the transition dipole of the dye and the long axis of DNA helix. Three‐dimensional images of the cholesteric phase were obtained making use of the intrinsic 3D resolving ability of two‐photon microscopy. We also discuss the influence of dyes on the parameters of DNA LC phases and comment on advantages and limitations of the PSTPM technique in comparison with other LC characterization techniques. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 365–375, 2011
Use of antibiotics in uncomplicated diverticulitis
Authors: de Korte N , Ünlü Ç , Boermeester M A , Cuesta M A , Vrouenreats B C , Stockmann H B A C
Published: January 2011

Background

The value of antibiotics in the treatment of acute uncomplicated left-sided diverticulitis is not well established. The aim of this review was to assess whether or not antibiotics contribute to the (uneventful) recovery from acute uncomplicated left-sided diverticulitis, and which types of antibiotic and route of administration are most effective.

Methods

Medline, the Cochrane Library and Embase databases were searched. Randomized controlled trials (RCTs), prospective or retrospective cohort studies addressing conservative treatment of mild uncomplicated left-sided diverticulitis and use of antibiotics were included.

Results

No randomized or prospective studies were found on the topic of effect on outcome. One retrospective cohort study was retrieved that compared a group treated with antibiotics with observation alone. This study showed no difference in success rate between groups. Only one RCT of moderate quality compared intravenous and oral administration of antibiotics, and found no differences. One other RCT of very poor quality compared two different kinds of intravenous antibiotic and also found no difference. A small retrospective cohort study comparing antibiotics with and without anaerobe coverage showed no difference in group outcomes.

Conclusion

Evidence on the use of antibiotics in mild or uncomplicated diverticulitis is sparse and of low quality. There is no evidence mandating the routine use of antibiotics in uncomplicated diverticulitis, although several guidelines recommend this.
Improved NADPH supply for xylitol production by engineered Escherichia coli with glycolytic mutations
Authors: Chin Jonathan W. , Cirino Patrick C.
Published: January 2011

Escherichia coli engineered to uptake xylose while metabolizing glucose was previously shown to produce high levels of xylitol from a mixture of glucose and xylose when expressing NADPH‐dependent xylose reductase from Candida boidinii (CbXR) (Cirino et al., Biotechnol Bioeng. 2006;95:1167‐1176). We then described the effects of deletions of key metabolic pathways (e.g., Embden–Meyerhof–Parnas and pentose phosphate pathway) and reactions (e.g., transhydrogenase and NADH dehydrogenase) on resting‐cell xylitol yield (YRPG: moles of xylitol produced per mole of glucose consumed) (Chin et al., Biotechnol Bioeng. 2009;102:209‐220). These prior results demonstrated the importance of direct NADPH supply by NADP+‐utilizing enzymes in central metabolism for driving heterologous NADPH‐dependent reactions. This study describes strain modifications that improve coupling between glucose catabolism (oxidation) and xylose reduction using two fundamentally different strategies. We first examined the effects of deleting the phosphofructokinase (pfk) gene(s) on growth‐uncoupled xylitol production and found that deleting both pfkA and sthA (encoding the E. coli‐soluble transhydrogenase) improved the xylitol YRPG from 3.4 ± 0.6 to 5.4 ± 0.4. The second strategy focused on coupling aerobic growth on glucose to xylitol production by deleting pgi (encoding phosphoglucose isomerase) and sthA. Impaired growth due to imbalanced NADPH metabolism (Sauer et al., J Biol Chem. 2004;279:6613‐6619) was alleviated upon expressing CbXR, resulting in xylitol production similar to that of the growth‐uncoupled precursor strains but with much less acetate secretion and more efficient utilization of glucose. Intracellular nicotinamide cofactor levels were also quantified, and the magnitude of the change in the NADPH/NADP+ ratio measured from cells consuming glucose in the absence vs. presence of xylose showed a strong correlation to the resulting YRPG. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011
Primary percutaneous coronary intervention of an unprotected left main using mini‐crush drug‐eluting stents facilitated by intracoronary reteplase
Authors: Triantafyllou Konstantinos , Metaxopoulos Panagiotis , Babalis Dimitrios
Published: January 2011

Patients suffering from acute myocardial infarction with involvement of unprotected left main (LM) coronary artery disease represent a very high‐risk subgroup. A 37‐year‐old male patient was admitted with posterolateral acute myocardial infarction and in borderline hemodynamic condition. His left ventricular ejection fraction was 30% with posterior, lateral wall, and apical akinesis along with mild mitral regurgitation. Emergency coronary angiography demonstrated ostial occlusion of the left circumflex artery (without stump, flow Thrombolysis in Myocardial Infarction 0/Rentrop 0) and severe distal LM disease with superimposed thrombus. The primary percutaneous coronary intervention procedure combined intracoronary reteplase plus thrombus aspiration to restore flow in the left circumflex and deployment of two everolimus‐eluting stents with mini‐crush technique to successfully reconstruct the LM bifurcation. The patient recovered without complications and had a favorable outcome at mid‐term.© 2011 Wiley‐Liss, Inc.
Pediatric catheterization laboratory anticoagulation with bivalirudin
Authors: Forbes Thomas J. , Hijazi Ziyad M. , Young Guy , Ringewald Jeremy M , Aquino Paolo M. , Vincent Robert N. , Qureshi Athar M. , Rome Jonathan J. , Rhodes John F. , Jones Thomas K. , Moskowitz William B. , Holzer Ralf J. , Zamora Rolando
Published: January 2011

Background: Pediatric physicians regularly face the problem of uncertain procedural anticoagulation in children, especially in neonates. We sought to evaluate the safety, plasma concentration (pharmacokinetics, PK), pharmacodynamics (PD), and dosing guidelines of bivalirudin when used as a procedural anticoagulant in pediatric percutaneous intravascular procedures. Methods and Results: Pediatric subjects undergoing percutaneous intravascular procedures for congenital heart disease were enrolled and received the current weight‐based dose used in percutaneous coronary interventions (0.75 mg/kg bolus, 1.75 mg/kg/hr infusion). Blood samples for PK/PD analyses were drawn, and safety was evaluated by monitoring bleeding and thrombosis events. A total of 110 patients (11 neonates, 33 infants, 32 young children, and 34 older children) were enrolled; 106 patients received the protocol dose. The PK/PD response of bivalirudin was predictable and behaved in a manner similar to that in adults. Weight‐normalized bivalirudin clearance rates were more rapid in neonates and decreased with increasing age. Bivalirudin concentrations were slightly lower in neonates, with a trend to an increase with age. Activating clotting time response was consistent with adult studies and prolonged in all age groups, and there was reasonable correlation between activating clotting time and bivalirudin plasma concentrations across all age groups. There were few major bleeding (2 of 110, 1.8%) or thrombotic events (9 of 110, 8.2%) reported. Conclusions: PK/PD response of bivalirudin in the pediatric population is predictable and behaves in a manner similar to that in adults. Using adult dosing, bivalirudin safely provided the expected anticoagulant effect in the pediatric population undergoing intravascular procedures for congenital heart disease. © 2010 Wiley‐Liss, Inc.
Comparison of single‐ versus two‐stent techniques in treatment of unprotected left main coronary bifurcation disease
Authors: Kim Won‐Jang , Kim Young‐Hak , Park Duk‐Woo , Yun Sung‐Cheol , Lee Jong‐Young , Kang Soo‐Jin , Lee Seung‐Whan , Lee Cheol Whan , Park Seong‐Wook , Park Seung‐Jung
Published: January 2011

Background: This study sought to compare 3‐year outcomes of single‐ versus two‐stent techniques in patients with distal unprotected left main coronary artery (LMCA) disease treated with drug‐eluting stents (DES). Methods and Results: A total of 392 patients with distal unprotected LMCA disease who underwent DES implantation with single‐ (n = 234) or two‐ (n = 158) stent techniques were evaluated. The primary end point was major adverse cardiac events (MACE), defined as the composite of death, myocardial infarction (MI), and target lesion revascularization (TLR). The two‐stent group was more likely to have extensive coronary artery stenosis. After adjustment with weighted Cox model using the inverse probability of treatment weighting, the 3‐year risk of death was similar in the single‐ and two‐stent groups (hazard ratio [HR], 0.77, 95% confidence interval [CI], 0.28–2.13, P = 0.62). However, the 3‐year risks of MI (HR, 0.38, 95% CI, 0.19–0.78, P = 0.008), TLR (HR, 0.16, 95% CI, 0.05–0.57, P = 0.005), and MACE (HR, 0.89, 95% CI, 0.22–0.67, P = 0.0007) were significantly lower in the single‐stent group. Conclusion: Compared with the two‐stent technique, the single‐stent technique showed more favorable long‐term clinical outcomes in patients with distal unprotected LMCA disease who received DES. © 2011 Wiley‐Liss, Inc.
Early Maladaptive Schema Factors, Chronic Pain and Depressiveness: a Study with 271 Chronic Pain Patients and 331 Control Participants
Authors: Saariaho Tom , Saariaho Anita , Karila Irma , Joukamaa Matti
Published: January 2011

Chronic pain and depression are coexisting entities with high simultaneous prevalence. Both are linked with early adversities. Early maladaptive schemas (EMS) can be seen as a reflection of these adversities. EMSs extensively indicate underlying psychic patterns and provide a good opportunity to detect covert processes and psychic shapes (latent factors), which create the basis of how people rate their schemas. The purpose of this study was to explore these latent, higher order schema factors (SF) and to find out how they are associated with pain intensity or depression in chronic pain patients and a control sample. The study subjects consisted of 271 first‐visit pain patients and 331 control participants. Sociodemographic and pain data were gathered by questionnaire; 18 EMSs were measured with the Young Schema Questionnaire (short form) and depressiveness was measured with the Beck Depression Inventory, Version II. Exploratory factor and regression analyses were used. The chronic pain patient group showed two SFs. The first SF showed a shameful, defective, socially isolated, failure, emotionally inhibited, deprived, submissive and resigned pattern. The second SF showed a demanding, approval seeking, self‐sacrificing and punitive pattern. SF1 predicted more than half of the depressiveness in the pain patient sample. A three‐factor structure was found in the control sample, and SFs 1 and 3 together predicted almost one‐third of depressiveness. The pain patient and the control groups had a different, higher order factor structure. We assume that SF1 in the pain patients reflected a rather serious, undefined early psychic trauma and was also associated with their depressiveness. Copyright © 2011 John Wiley & Sons, Ltd.

Key Practitioner Message

Chronic pain patients showed a two‐factor higher order schema factor (SF) structure, which we labelled Loser and Encumbered.

The control participants showed a three‐factor structure with many similarities to earlier studies.

The first SF (Loser) was strongly associated with depression in the chronic pain patients.

The data support the view that early adversities predispose chronic pain patients to depression.

From the therapeutic point of view, we should be able to support the ashamed, failure, dependent, incompetent, negative and vulnerable ones (Loser) to feel dignity and calm down the ‘Encumbered’ ones to get them relaxed and their suffering bodies to heal.
Attachment security representations in institutionalized children and children living with their families: links to problem behaviour
Authors: Torres Nuno , Maia Joana , Veríssimo Manuela , Fernandes Marilia , Silva Filipa
Published: January 2011

The present work analyses differences in the attachment representations of institutionalized children as compared with children from low and high educational level living with their natural families. Participants were 91 Portuguese children, 52% girls, aged 48–96 months. There were three different groups: 19 institutionalized children, 16 low educational level families' children and 56 from high educational level families'. Attachment representations were assessed for Security of the narratives of the Attachment Story Completion Task (ASCT). Psychopathological symptoms were assessed using the Child Behaviour Checklist for parents and caretakers. Verbal skills were assessed using the Wechsler Preschool and Primary Scale of Intelligence—Revised. Results show that institutionalized children have significantly lower security of attachment representations, less verbal skills and higher aggressive behaviour than the other two groups. Attachment representations were associated with social/withdrawal and aggression, independently of age, verbal skills and parents' education. The main effect of institutionalization on externalizing aggressive behaviour was completely mediated by the security of attachment representations. Copyright © 2010 John Wiley & Sons, Ltd.

Key Practitioner Message:

• Behavior problems, Attachment, Institution.
Fine needle aspiration of salivary gland masses in HIV‐infected patients
Authors: Michelow Pam , Dezube Bruce J. , Pantanowitz Liron
Published: January 2011

Salivary gland disease is an important manifestation of HIV‐infection. The aim of this study was to evaluate the cytologic findings of salivary gland fine needle aspiration (FNA) in South African human immunodeficiency virus (HIV)‐infected patients. A retrospective review was performed on confirmed HIV‐positive patients who underwent FNA of various body sites, including salivary glands, over a 5‐year period. There were 495 (14.1%) salivary gland FNAs out of a total of 3,501 HIV‐positive patients. This included 260 (52.5%) parotid, 226 (45.7%) submandibular, 2 (0.4%) sublingual, and 7 (1.4%) specimens labeled as a salivary gland aspirate, exact site not provided. Patients were of average age 34 years (range 9 months to 63 years) with a female: male ratio of 1:0.6. There were 37 (7.5%) inadequate FNAs and 22 (4.4%) that contained normal gland constituents only. Most diagnoses were benign and comprised 168 (33.9%) reactive lymphadenopathy, 115 (23.2%) benign lymphoepithelial cysts, 62 (12.5%) mycobacterial infections, and 52 (10.5%) abscesses, of which 10 had associated mycobacterial infections. Neoplasms accounted for 31 (6.7%) diagnoses including 11 pleomorphic adenomas, 13 lymphoma, 3 Kaposi sarcoma, 1 squamous cell carcinoma, 1 metastatic carcinoma, and 1 rhabdomyosarcoma. There were four epidermoid inclusion cysts, three non‐specific sialadenitis, one mucocele, and one spindle cell lesion not able to be further characterized. FNA is a useful procedure to evaluate salivary gland lesions in an HIV‐infected population, allowing prompt management to be undertaken and obviating the need for surgery in many instances, an important consideration in an underfunded public health care system. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.
Malignant effusion of chromophobe renal‐cell carcinoma: Cytological and immunohistochemical findings
Authors: Teresa Pusiol , Maria Grazia Zorzi , Doriana Morichetti , Irene Piscioli , Michele, Scialpi
Published: January 2011

Malignant effusions because of renal‐cell carcinoma (RCC) are an unusual event and occur in patients with papillary and clear cell tumors. We have studied a 65‐year‐old man who underwent right renal tumorectomy, diagnosed as chromophobe RCC (pT1). After 16 months, the patient presented cough and fever. Positron emission computed tomography demonstrated extensive mediastinal lymphadenopathy. Chest radiograph showed right pleural effusion. The cytological examination of the fluid showed malignant cells. Immunohistochemistry had been performed on primary renal tumor and on cell block of pleural effusion. The renal tumor showed positivity for parvalbumin, cytokeratin (CK) 7, C‐kit (CD117), E‐cadherin, and RCC marker. The neoplastic cells of pleural effusion showed positive immunohistochemical staining for parvalbumin, RCC marker, pancytokeratin, epithelial membrane antigen, CK7, C‐kit (CD117), E‐cadherin, and CD10. They were negative for thyroid transcription factor‐1, CK20, calretinin, CK5, D2‐40 podoplanin, CDX2, and Wilms' tumor suppressor gene. Malignant effusion secondary to RCC is rare. In several studies, RCC had been the cause of 1–2.2% of malignant pleural fluids. Chromophobe RCC tends to be localized into the kidney and to be of nuclear grade 2 at presentation, factors that probably explain its more favorable outlook. In our case, the chromophobe RCC was asymptomatic and was discovered because abdominal pain due to stone in the gallbladder. The tumor had an unusual aggressive clinical behavior. Immunohistochemistry performed on the cell block let to establish the renal origin and the chromophobe histotype of malignant cells found in the pleural fluid. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.
A multivariate statistical study to obtain effective criteria to detect well‐differentiated adenocarcinoma in endometrial cytology
Authors: Nambu Masami , Matsumoto Shinji , Takeshita Morishige , Nabeshima Kazuki , Iwashita, Akinori
Published: January 2011

Consistency in endometrial cytology is relatively poor. This can be partly attributed to generally accepted criteria based on cellular features. The cytological distinction between grade‐1 adenocarcinoma and endometrial hyperplasia is more reliant on architectural features than cellular features. We examined statistical criteria based on cytoarchitecture for detecting grade‐1 adenocarcinoma in endometrial cytology.

Histologically, the study population consisted of 11 cases of grade‐1 adenocarcinoma, 6 of atypical endometrial hyperplasia, 16 of endometrial hyperplasia without atypia, and 74 of a normal proliferative endometrium. In each case, all cellclumps were divided into five patterns (tubular; sheet; dilated and/or branched tubular; regular overlapping; atypical). The frequencies of each pattern were submitted to five‐variate cluster analysis. The validity and reproducibility of cluster analysis were tested by canonical discriminant analysis and multigroup linear discriminant analysis, respectively.

All 107 cases were classified into three groups, A (11), B (36), and C (60), by five‐variate cluster analysis. In comparison with this classification and histopathologic diagnosis, group A corresponded to adenocarcinoma, and groups B and C correlated with non‐carcinoma. Most cases of atypical endometrial hyperplasia were included in group B.

These data suggest that statistical groupings based on cytoarchitecture are useful in the discrimination of grade‐1 adenocarcinoma from endometrial hyperplasia and normal tissue. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.
Fine‐needle aspiration diagnosis of metastatic urothelial carcinoma: A review
Authors: Cantley R. L. , Kapur U. , Truong L. , Cimbaluk D. , Barkan G. A. , Wojcik E. , Gattuso P.
Published: January 2011

Urothelial carcinoma (UC) is the most common malignant neoplasm of the urinary tract. Metastases of UC are most common in the regional lymph nodes, lungs, liver, bone, and adrenal glands. Fine‐needle aspiration cytology diagnosis of such metastases can be difficult, particularly in the setting of incomplete clinical history or when multiple primary neoplasms may be present. This review focuses on the cytologic features helpful in differentiating UC from its potential mimics, as well as ancillary studies that may be helpful in the distinction. Diagn. Cytopathol. 2012;. © 2011 Wiley Periodicals, Inc.
Intraprocedural evaluation of fine‐needle aspiration smears: How good are we?
Authors: Factor Rachel , Layfield Lester J.
Published: January 2011

A significant percentage of fine‐needle aspirations (FNAs) is obtained using radiographic image guidance. Such image‐guided aspirates are associated with increased costs, and it is highly desirable that adequate material for diagnosis is obtained at the time of the initial procedure. Hence, intraoperative evaluation of smear material is frequently performed to evaluate adequacy and to triage the aspirate to specialized tests such as flow cytometry and cytogenetics for appropriate work‐up. Although FNA under radiologic guidance has been shown to be useful, little data exist as to the accuracy of such intraprocedural evaluation. The quality‐assurance records between May 2009 and May 2010 were electronically searched for all FNA cases with intraprocedural evaluation. The reports were obtained and reviewed to compare the intraprocedural diagnosis and the final cytopathologic diagnosis. Percentage of deferred cases and percentage of disagreement were calculated. From May 2009 to May 2010, a total of 775 FNAs were performed with intraprocedural review. These cases were reviewed by seven board‐certified cytopathologists. In 738 cases, the preliminary interpretation agreed with the final diagnosis. In 2.2% (17 of 775) of cases, the interpretation was deferred until‐cell block, and/or cytospin preparations were obtained. In 2.6% (20 of 775) of cases, a disagreement in diagnosis existed between the initial interpretation and the final sign‐out diagnosis. Intraprocedural interpretation of FNA material appears to be highly reliable with disagreements occurring in only 2.6% of cases. This degree of disagreement is slightly higher than that reported in some frozen section studies. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.
Plasma cell tumors with neurologic symptoms: Cytological findings
Authors: Azarpira Negar , Vasei Mohammad , Rasekhi Alireza
Published: January 2011

Plasma cell neoplasms (plasma cell dyscrasias) are a group of entities characterized by the neoplastic proliferation of a single clone of plasma cells, typically producing a monoclonal immunoglobulin. These tumors can manifest as multiple myeloma, monoclonal gammopathy of undetermined significance, plasma cell myeloma, or plasmacytoma.

We report two plasma cell tumors, one of them presented with headache and diplopia, and the second one complained from low back pain. The aspirate exhibited numerous plasma cells in various stage of maturation and was initially diagnosed as extra‐skeletal solitary plasmacytoma on fine‐needle aspiration cytology (FNAC). Immunohistochemistry demonstrated monoclonal expression of light immunoglobulin chains together with demonstration of CD 38 positivity. Systematic approach such as bone marrow examination, serum protein electrophoresis, skeletal imaging, and urine examination for Bence‐Jones proteins were performed for patients. With these investigations, one case was labeled as multiple myeloma with secondary solitary plasmacytoma in pituitary gland and soft tissue and another one as primary extra‐skeletal solitary plasmacytoma.

Although fine‐needle aspiration is a reliable and rapid technique for initial diagnosis, further work‐up and clinical follow‐up of these patients is necessary to rule out multiple myeloma. Because of cytomorphological similarity between plasma cells and endocrine cells, EMP of sellar region may be confused with pituitary adenoma especially at the time of intraoperative consultation. Diagn. Cytopathol., 2012. © 2011 Wiley Periodicals, Inc.
Image cytometry of insular carcinoma
Authors: Dey Pranab , Barwad Adarsh , Gupta Nalini , Saikia Uma Nahar
Published: January 2011

To study the morphometric features of insular carcinoma (IC) of thyroid and follicular carcinoma (FC) in fine needle aspiration cytology (FNAC) smear to evaluate the role of the morphometric features to distinguish these two groups. We performed image morphometry in Hematoxyline and Eosin stained FNAC smears of eight each histopathology proven cases of IC and FC of thyroid. Nuclear area, diameter, perimeter, and standard deviation of nuclear area (SDNA) of these two groups were studied and compared. Nuclear area, diameter, perimeter, and SDNA of IC and FC were 30.43 μ2, 7.31 μ, 23.01 μ, 8.81 and 38.43 μ2, 7.66 μ, 25.63 μ, 10.83, respectively. Student's t‐test analysis did not show any significant difference (P > 0.05) in these two groups. Nuclear morphometry data indicate that the nuclear size and shape of IC and FC are essentially similar and it is not possible to differentiate these two entities with the help of image morphometric data. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.
Decreased variation of inflammatory markers in gestational diabetes
Authors: Pöyhönen‐Alho Maritta , Ebeling P. , Saarinen A. , Kaaja R.
Published: January 2011

Background

Gestational diabetes is a prediabetic state. Sub‐clinical inflammation may play a role in the transition from gestational diabetes to type 2 diabetes; the role of the autonomic nervous system as a mediating system has been raised. We aimed to study the association of the sympathetic nervous system and sub‐clinical inflammation in women with gestational diabetes.

Methods

We studied 41 Caucasian women with gestational diabetes and 22 healthy pregnant and 14 non‐pregnant controls. We assayed plasma noradrenaline, insulin, C‐reactive protein, interleukin‐6, insulin growth factor‐1, serum amyloid A, steroid hormone‐binding globulin, α‐1 acid glycoprotein and cortisol at 2400, 0400 and 0700 h.

Results

No differences existed in the concentrations of inflammatory markers between gestational diabetes and normal pregnancy but women with gestational diabetes showed loss of variation in C‐reactive protein and serum amyloid A. Levels of hormone‐binding globulin were lower in hypertensive compared with normotensive women with gestational diabetes at all time points and lowest at midnight when α‐1 acid glycoprotein levels were higher in hypertensive women.

Conclusions

Gestational diabetes is associated with loss of natural variation of C‐reactive protein and serum amyloid A, suggesting altered modulation of inflammation. Hypertension in gestational diabetes seems not to be associated with higher levels of inflammatory markers other than α‐1 acid glycoprotein. Copyright © 2011 John Wiley & Sons, Ltd.
PI3Kγ deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome
Authors: Berod Luciana , Heinemann Christina , Heink Sylvia , Escher Angelika , Stadelmann Christine , Drube Sebastian , Wetzker Reinhard , Norgauer Johannes , Kamradt Thomas
Published: January 2011

PI3Ks control signal transduction triggered by growth factors and G‐protein‐coupled receptors and regulate an array of biological processes, including cellular proliferation, differentiation, survival and migration. Herein, we investigated the role of PI3Kγ in the pathogenesis of EAE. We show that, in the absence of PI3Kγ expression, clinical signs of EAE were delayed and mitigated. PI3Kγ‐deficient myelin oligodendrocyte glycoprotein (MOG)35–55‐specific CD4+ T cells appeared later in the secondary lymphoid organs and in the CNS than their WT counterparts. Transfer of WT CD4+ cells into PI3Kγ−/− mice prior to MOG35–55 immunisation restored EAE severity to WT levels, supporting the relevance of PI3Kγ expression in Th cells for the pathogenesis of EAE; however, PI3Kγ was dispensable for Th1 and Th17 differentiation, thus excluding an altered expression of these pathogenetically relevant cytokines as the cause for ameliorated EAE in PI3Kγ−/− mice. These findings demonstrate that PI3Kγ contributes to the development of autoimmune CNS inflammation.
1,25‐Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis
Authors: Mayne Christopher G. , Spanier Justin A. , Relland Lance M. , Williams Calvin B. , Hayes Colleen E.
Published: January 2011

Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D3 supplies, supporting our hypothesis that the sunlight‐dependent hormone, 1,25‐dihydroxyvitamin D3 (1,25‐(OH)2D3), inhibits autoimmune T‐cell responses in MS. Moreover, 1,25‐(OH)2D3 inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25‐(OH)2D3 inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio‐sensitive hematopoietic cells or radio‐resistant non‐hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25‐(OH)2D3 to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25‐(OH)2D3 nor T‐cell‐specific VDR targeting influenced CD4+Foxp3+ T‐cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25‐(OH)2D3 acts directly on pathogenic CD4+ T cells to inhibit EAE.
CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity
Authors: Mayer Christian T. , Floess Stefan , Baru Abdul Mannan , Lahl Katharina , Huehn Jochen , Sparwasser Tim
Published: January 2011

“Suppressor T cells” were historically defined within the CD8+ T‐cell compartment and recent studies have highlighted several naturally occurring CD8+Foxp3− Treg populations. However, the relevance of CD8+Foxp3+ T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8+Foxp3− T cells is counter‐regulated by DC‐mediated co‐stimulation via CD80/CD86. CD8+Foxp3+ T cells fail to develop in TCR‐transgenic mice with Rag1−/− background, similar to classical CD4+Foxp3+ Tregs. Notably, both naturally occurring and induced CD8+Foxp3+ T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN‐γ production upon restimulation when compared with their CD8+Foxp3− counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3+ cells by eGFP reporter expression, we demonstrate that induced CD8+Foxp3+ T cells similar to activated CD8+Foxp3− T cells only mildly suppress T‐cell proliferation and IFN‐γ production. We therefore categorize CD8+Foxp3+ T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4+Foxp3+ Tregs, but lacking potent suppressive activity.
IL‐22 in antifungal immunity
Authors: Zelante Teresa , Iannitti Rossana , De Luca Antonella , Romani Luigina
Published: January 2011

Deciphering cellular and molecular mechanisms that maintain host immune homeostasis with fungi and the breakdown of this homeostatic tolerance during fungal infections disease is a challenge in medical mycology. In fact, the virulence of fungi may be determined by the interaction between fungi and the host immune status and its classification as a commensal microorganism or a pathogen may shift depending on the balance. In addition to the central role of the IL‐12/IFN‐γ‐dependent Th1 responses in cell‐mediated immune protection against fungi, Th17 cells provide protection and inflammation at mucosal surfaces, and Tregs fine‐tune immune responses to prevent damage to the host. Recent evidence indicates that IL‐22‐producing cells, employing primitive antifungal effector mechanisms, contribute to antifungal resistance at mucosal surfaces under conditions of defective adaptive immunity. The fact that IL‐22 production is driven by commensals points to the need of an integrated, systems biology approach to improve our understanding of the inherent and intimate mechanisms underlying multilevel host–fungus interactions.
Co‐stimulation by dendritic cells maintains the peripheral pool of Tregs
Authors: Garbi Natalio , Hämmerling Günter J.
Published: January 2011

Many aspects of an immune response are regulated by dendritic cells (DCs). DCs play key proinflammatory roles by sensing microbial invaders and promoting the activation of innate immune cells such as NK cells. In addition, DCs are required for the initiation and maintenance of adaptive T‐cell responses against invading pathogens. Moreover, DCs also fulfill important anti‐inflammatory functions: they induce peripheral T‐cell tolerance by silencing self‐reactive T cells and supporting the homeostasis of regulatory T cells (Tregs). A study in this issue of the European Journal of Immunology reveals that CD80/CD86 expression on DCs contributes to the maintenance of the peripheral pool of Tregs. This Commentary discusses current findings on this topic, focusing on the role of DCs in the homeostatic control of Tregs and myeloid cells, and the potential consequences for T‐cell activation.
Antiprion drugs 6‐aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy
Authors: Barbezier Nicolas , Chartier Aymeric , Bidet Yannick , Buttstedt Anja , Voisset Cécile , Galons Hervé , Blondel Marc , Schwarz Elisabeth , Simonelig Martine
Published: January 2011

Oculopharyngeal muscular dystrophy (OPMD) is an adult‐onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6‐aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub‐effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N‐terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti‐aggregation molecules.
GSK3β negatively regulates oligodendrocyte differentiation and myelination in vivo
Authors: Azim Kasum , Butt Arthur M.
Published: January 2011

Glycogen synthase kinase 3β (GSK3β) is an essential integrating molecule for multiple proliferation and differentiation signals that regulate cell fate. Here, we have examined the effects of inhibiting GSK3β on the development of oligodendrocytes (OLs) from their oligodendrocyte precursors (OP) in vivo by injection into the lateral ventricle of postnatal mice and ex vivo in organotypic cultures of isolated intact rodent optic nerve. Our results show that a range of GSK3β inhibitors (ARA‐014418, lithium, indirubin, and L803‐mt) increase OPs and OLs and promote myelination. Inhibition of GSK3β stimulates OP proliferation and is prosurvival and antiapoptotic. The effects of GSK3β inhibition in OPs is via the canonical Wnt signaling pathway by stimulating nuclear translocation of β‐catenin. However, direct comparison of the effects of Wnt3a and GSK3β inhibition in optic nerves shows that they have opposing actions on OLs, whereby GSK3β inhibition strikingly increases OL differentiation, whereas Wnt3a inhibits OL differentiation. Notably, GSK3β inhibition overrides the negative effects of Wnt3a on OLs, indicating novel GSK3β signaling mechanisms that negatively regulate OL differentiation. We identify that two mechanisms of GSK3β inhibition are to stimulate cAMP response element binding (CREB) and decrease Notch1 signaling, which positively and negatively regulate OL differentiation and myelination, respectively. A key finding is that GSK3β inhibition has equivalent effects in the adult and stimulates the regeneration of OLs and remyelination following chemically induced demyelination. This study identifies GSK3β as a profound negative regulator of OL differentiation that contributes to inefficient regeneration of OLs and myelin repair in demyelination. © 2011 Wiley‐Liss, Inc.
Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll‐like receptor 3 activation
Authors: Li Xianwu , Cudaback Eiron , Keene C. Dirk , Breyer Richard M. , Montine Thomas J.
Published: January 2011

Activation of innate immunity via toll‐like receptors (TLRs) is associated with neurodegenerative diseases, and some effectors, like tumor necrosis factor alpha (TNFα) and interleukin 6 (IL‐6), directly contribute to neurodegeneration. We tested the hypothesis that prostaglandin (PG) E2 receptor subtype 1 (EP1) was necessary for the induction of microglial cytokines following the activation of innate immunity. Primary murine microglia had cytokine secretion by activators of TLR3 > TLR9 > TLR4 > TLR2. TLR3 activation induced early expression of cyclooxygenase 2 (COX2) and delayed expression of membranous PGE synthase and secretion of PGE2. Nonselective and COX2‐selective inhibitors blocked TLR3 induction of TNFα and IL‐6. Moreover, of the nine of twenty cytokines and chemokines induced by TLR3 activation, only TNFα and IL‐6 were significantly dependent on EP1 signaling as determined using microglia from mice homozygous deficient for EP1 gene or wild‐type microglia coincubated with an EP1 antagonist. These results were confirmed by blocking intracellular Ca2+ release with 2‐aminoethoxy‐diphenyl borate or Xestospongin C, inhibitors of IP3 receptors. Our results show that suppression of microglial EP1 signaling achieves much of the desired effect of COX inhibitors by selectively blocking TLR3‐induced microglial secretion of two major effectors of paracrine neuron damage. In combination with the ability of EP1 suppression to ameliorate excitotoxicity, these data point to blockade of EP1 as an attractive candidate therapeutic for neurodegenerative diseases. © 2011 Wiley‐Liss, Inc.
Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine‐1‐phosphate metabolism/signaling and development
Authors: López‐Juárez Alejandro , Morales‐Lázaro Sara , Sánchez‐Sánchez Roberto , Sunkara Manjula , Lomelí Hilda , Velasco Iván , Morris Andrew J. , Escalante‐Alcalde Diana
Published: January 2011

Bioactive lipids serve as intracellular and extracellular mediators in cell signaling in normal and pathological conditions. Here we describe that an important regulator of some of these lipids, the lipid phosphate phosphatase‐3 (LPP3), is abundantly expressed in specific plasma membrane domains of Bergmann glia (BG), a specialized type of astrocyte with key roles in cerebellum development and physiology. Mice selectively lacking expression of LPP3/Ppap2b in the nervous system are viable and fertile but exhibit defects in postnatal cerebellum development and modifications in the cytoarchitecture and arrangement of BG with a mild non‐progressive motor coordination defect. Lipid and gene profiling studies in combination with pharmacological treatments suggest that most of these effects are associated with alterations in sphingosine‐1‐phosphate (S1P) metabolism and signaling. Altogether our data indicate that LPP3 participates in several aspects of neuron‐glia communication required for proper cerebellum development. © 2011 Wiley‐Liss, Inc.
Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7
Authors: Oosterhuis Koen , Öhlschläger Peter , van den Berg Joost H. , Toebes Mireille , Gomez Raquel , Schumacher Ton N. , Haanen John B.
Published: January 2011

To allow vaccination irrespective of HLA type, DNA vaccines encoding full‐length antigens are required. However, here, we demonstrate that the immunogenicity of DNA vaccines encoding the full‐length human papillomavirus (HPV) type 16 E7 and E6 proteins is highly reduced compared to vaccines encoding only the immunodominant epitope. Furthermore, the low remaining immunogenicity is essentially lost for both E7 and E6 when a nononcogenic “gene‐shuffled” variant is utilized. To address these issues, we tested whether alterations in transgene design can restore the immunogenicity of full‐length and gene‐shuffled DNA vaccines. Remarkably, genetic fusion of E7 with tetanus toxin fragment C (TTFC) resulted in a dramatic increase in immunogenicity both for the full‐length and the gene‐shuffled version of E7. Moreover, the TTFC fusion vaccines were more immunogenic than a vaccine encoding a fusion of E7 and mycobacterial heat shock protein‐70, which has recently been tested in a clinical trial. Interestingly, vaccination with these TTFC fusion vaccines also resulted in extremely persistent T‐cell responses. The E7‐specific CD8+ T cells induced by TTFC fusion vaccines were functional in terms of IFN‐γ production, formation of immunological memory, in vivo cytolytic activity and tumor eradication. Finally, we show that genetic fusion with TTFC also improves the immunogenicity of a gene‐shuffled E6 DNA vaccine. These data demonstrate that genetic fusion with tetanus toxin fragment C can dramatically improve the immunogenicity of full‐length and gene‐shuffled DNA vaccines. The DNA fusion vaccines developed here will be evaluated for the treatment of HPV‐positive carcinomas in future studies.
IGFBP‐4 activates the Wnt/beta‐catenin signaling pathway and induces M‐CAM expression in human renal cell carcinoma
Authors: Ueno Koji , Hirata Hiroshi , Majid Shahana , Tabatabai Z. Laura , Hinoda Yuji , Dahiya Rajvir
Published: January 2011

The Wnt/β‐catenin signaling pathway is inactivated by Wnt antagonists in most cancers and IGFBP‐4 is an antagonist of the Wnt/ β‐catenin signaling pathway. However, the function of IGFBP‐4 is not currently understood in renal cell carcinoma (RCC). We initially found that the expression of IGFBP‐4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP‐4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in primary renal cancer. Tcf transcriptional activity was significantly increased in IGFBP‐4 transfectants compared to mock cells and β‐catenin expression was increased. Also the β‐catenin downstream effector, MT1‐MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M‐CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP‐4 mRNA in a metastatic renal cancer cell lines (ACHN) was knocked‐down using a siRNA technique. The cell growth and motility was decreased in si‐IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA. Tcf activity in ACHN cells was also decreased with si‐IGFBP‐4 transfection. This is a first report documenting that IGFBP‐4 expression in RCC activates cell growth, metastasis, Wnt/beta‐catenin signaling and may be involved in RCC metastasis.