bluuebunny/crossref_metadata_2025 huggingface dataset:
Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia
Authors: Herishanu Yair , Rogowski Ori , Polliack Aaron , Marilus Rafael
Published: March 2006

Abstract:  Background: Recently, it was shown that fat tissue produces and releases inflammatory cytokines, and that obesity may be regarded as a state of low‐grade inflammation. In this regard, we aimed to establish an association between obesity and persistent leukocytosis. Patients and methods: We present clinical observations of obese subjects primarily referred for further evaluation of leukocytosis without a cause and validated the link between leukocytosis and elevated body mass index (BMI) in a cross‐sectional study. Results: During 1999–2005, 327 patients were referred for further investigation because of persistent leukocytosis. Of these, 15.3% were asymptomatic obese, mostly females, with mild persistent neutrophilia accompanied by elevated acute‐phase reactants. After careful evaluation, no recognized cause for leukocytosis was found other than the fact that the patients were obese. During a mean follow‐up of 45.6 months, the leukocytosis and the elevated acute‐phase reactants persisted and no new causes for leukocytosis were evident. Furthermore, in a cross‐sectional analysis of 3716 non‐smoker subjects, 62 were found to have leukocytosis. Compared with the population with a normal white blood count range, these subjects with leukocytosis had higher BMI, serum C‐reactive protein (CRP) levels, waist circumference, and neutrophil and platelet count (all P < 0.0005). After logistic regression analysis, only BMI was shown to be associated with leukocytosis (P < 0.0005). Conclusions: Obesity is recognized as a possible cause for reactive leukocytosis. Awareness of this ‘obesity‐associated leukocytosis’ may help the clinician to avoid more extensive and unnecessary diagnostic work‐up, particularly in similar obese subjects.
Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations
Authors: Bao Liming , Wang Xiaoqin , Ryder John , Ji Meirong , Chen Yan , Chen Hui , Sun Hengjuan , Yang Yongchen , Du Xinyu , Kerzic Patrick , Gross Sherilyn A. , Yao Lihong , Lv Ling , Fu Hua , Lin Guowei , Irons Richard D.
Published: March 2006

Abstract:  We report a prospective study of 174 unselected adult de novo acute myeloid leukemia (AML) cases diagnosed using the WHO classification. Of those, 57 (33%) were AML with recurrent cytogenetic abnormalities, 41 were (24%) AML with multilineage dysplasia, 74 (42%) were AML not otherwise categorized, and two were acute leukemias of ambiguous lineage. Clonal cytogenetic abnormalities were detected in 64% of the WHO AML cases with t(15;17) (15%), t(8;21) (12%), +8 (11%), −7/del7q (8%) and del9q (5%) being the most common ones. The FLT3/ITD mutations (FMS‐like tyrosine kinase 3/internal tandem duplication) were observed in 12% of the WHO AML cases, which is much lower than ones in the literature, while the 6% incidence of the FLT3‐activating loop mutations (either FLT3/D835 or FLT3/I836) was comparable with others. Both mutations were associated with leukocytosis. Our study also suggests that the FLT3 mutations are biomarkers independent of cytogenetic characteristics.
Response to splenectomy is durable after a certain point in time in adult patients with chronic immune thrombocytopenic purpura
Authors: Johansson Eva , Engervall Per , Landgren Ola , Grimfors Gunnar , Widell Susanne , Rezai Shahideh , Björkholm Magnus
Published: March 2006

Abstract:  Splenectomy may lead to a good response in 60–80% of adult patients with corticosteroid refractory idiopathic thrombocytopenic purpura (ITP) but, the long‐term response to splenectomy still remains less well defined. We assessed the long‐term efficacy and safety of splenectomy in adult patients with chronic ITP. A cohort of 59 splenectomised ITP patients (M/F = 25/34; median age 39 yr; range 14–75) were followed up for a median of 18 yr (range 2–32). No life‐threatening surgical complications were observed. The overall response rate was 78% with 59% complete remission (CR) and 19% partial remission (PR). CR and PR patients were younger than non‐responding patients at time of diagnosis (median age: 36 yr vs 48 yr, P = 0.03) and at splenectomy (median age: 38 yr vs 51 yr, P = 0.02). Among the 46 responding patients, eventually 17 had relapse. No disease progression occurred after 12.1 and 7.3 yr for patients in CR or PR, respectively. One case of fatal septicaemia was recorded. We conclude that splenctomy is an effective and safe treatment in adult patients with chronic ITP failing to respond to corticosteroid treatment and importantly, our findings support the view that response to splenectomy is durable after a certain point in time.
World dental research production: an ISI database approach (1999–2003)
Authors: Gil‐Montoya Jose Antonio , Navarrete‐Cortes Jose , Pulgar Rosa , Santa Samaly , Moya‐Anegón Felix
Published: March 2006

The objective of this study was to obtain a geographic world map of scientific production in dentistry by analysing published papers. Articles and reviews in the Dentistry, Oral Surgery & Medicine category published from 1999 to 2003 were accessed through the ISI database. The data were analyzed quantitatively (number of documents, number of researchers, productivity, interannual variation rate and relative specialization index), qualitatively (weighted impact factor, relative impact factor, citation rate per document and top 5 publications) and socioeconomically (number of documents per inhabitant and per dentist and in relation to the country's GDP). The USA, UK, Japan and Scandinavian countries were found to be the most productive countries (number of publications). Publications from Scandinavian countries were also of high quality as measured by Impact Factor and Citation Rate, while the UK had one of the highest productivity rates (number of documents per researcher).
No effect of experimental occlusal interferences on pressure pain thresholds of the masseter and temporalis muscles in healthy women
Authors: Michelotti A. , Farella M. , Steenks M. H. , Gallo L. M. , Palla S.
Published: March 2006

It has been suggested that occlusal interferences may lead to pain and tenderness of the masticatory muscles. Tender jaw muscles are more sensitive to pressure pain, as assessed by means of pressure algometry. We tested the effects of occlusal interferences on the pressure pain threshold of the jaw muscles by means of a double‐blind randomized crossover experiment carried out on 11 young healthy females. Golden strips were glued either to an occlusal contact area (active interference) or to the vestibular surface of the same tooth (dummy interference) and left for 8 d each. Pressure pain thresholds of the masseter and anterior temporalis muscles were assessed under interference‐free, dummy‐interference and active‐interference conditions. The results indicated that the application of an active occlusal interference, as used in this study, did not influence significantly the pressure pain thresholds of these muscles in healthy individuals.
Role of mitogen‐activated protein kinase kinase in Porphyromonas gingivalis‐induced myocardial cell hypertrophy and apoptosis
Authors: Lee Shin‐Da , Chang Sheng‐Huang , Kuo Wu‐Hsien , Ying Tsung‐Ho , Kuo Wei‐Wen , Li Ping‐Chun , Hsu Hsi‐Hsien , Lu Min‐Chi , Ting Hua , Huang Chih‐Yang
Published: March 2006

Secreted factors present in the medium following growth of the periodontal pathogen Porphyromonas gingivalis cause increased cardiomyocyte hypertrophy and apoptosis, whereas secreted factors from Actinobacillus actinomycetemcomitans and Prevotella intermedia have no such effects. The purpose of this study was to clarify the role of mitogen‐activated protein kinase (MAPK)/extracellular‐regulated protein kinase (ERK) pathways in P. gingivalis medium‐induced H9c2 myocardial cell hypertrophy and apoptosis. Cellular morphology, DNA fragmentation, nuclear condensation, total mitogen‐activated protein kinase/extracellular‐regulated protein kinase‐1 (ERK‐1), total ERK‐1 protein, and phosphorylated ERK‐1 protein products in cultured H9c2 myocardial cells were measured by actin immunofluorescence, agarose gel electrophoresis, nuclear condensation, and western blotting following stimulation with P. gingivalis spent growth medium or pre‐administration of U0126, a potent MEK‐1/2 inhibitor. Components of P. gingivalis spent culture medium not only resulted in increased total MEK‐1 and ERK‐1 protein products, but also caused increased cellular size, DNA fragmentation, and nuclear condensation in H9c2 cells. These three parameters, and the phosphorylated ERK‐1 protein products of H9c2 cells treated with P. gingivalis medium, were all significantly reduced after pre‐administration of U0126. The results suggest that P. gingivalis‐secreted factors may initiate MEK/ERK signal pathways and lead to myocardial cell hypertrophy and apoptosis.
Human pulp‐derived cells immortalized with Simian Virus 40 T‐antigen
Authors: Galler Kerstin M. , Schweikl Helmut , Thonemann Birger , D'Souza Rena N. , Schmalz Gottfried
Published: March 2006

Primary cells in culture have a limited capacity to divide and soon reach a non‐proliferative state. This cellular senescence limits the investigation of cells derived from human pulp concerning cellular pathways, gene regulation, mechanisms of dentin formation, or responses to material exposure. To overcome this problem, primary human pulp‐derived cells were established and transfected with a plasmid containing coding sequences of Simian Virus 40 (SV40) large T‐antigen. This resulted in the establishment of several cell clones showing an extension of life span. Expression of T‐antigen transcripts and protein was verified by reverse transcription–polymerase chain reaction (RT–PCR) and immunohistochemistry. Primary human pulp cells were cultured until senescence (i.e. up to passage 7) and transfected cells could be cultured to passage 18 after transfection, when a cellular crisis with massive cell death occurred. One clone escaped from crisis and has been maintained in culture for 55 wk. Experiments were performed to characterize transfected cells in comparison to primary cells. Cell morphology and proliferation were analyzed, and expression of cell‐specific gene transcripts and proteins (including collagen types I and III, alkaline phosphatase, bone sialoprotein, osteocalcin, and dentin sialophosphoprotein and dentin matrix protein I) was detected by RT–PCR and immunohistochemistry. Transfection of human pulp‐derived cells resulted in an immortalized cell line retaining many of the phenotypic characteristics observed in primary cells.
Two‐dimensional electrophoresis study of in vitro pellicle formation and dental caries susceptibility
Authors: Vitorino Rui , De Morais Guedes Sofia , Ferreira Rita , Lobo Maria João C. , Duarte José , Ferrer‐Correia António J. , Tomer Kenneth B. , Domingues Pedro M. , Amado Francisco M. L.
Published: March 2006

In the present study, a proteomic approach was applied to evaluate the influence of salivary protein composition on in vitro dental pellicle formation and its possible correlation with dental caries. Whole saliva, collected from caries‐free and caries‐susceptible subjects, was analyzed by two‐dimensional electrophoresis, and protein spots were identified by mass spectrometry. Data analysis of salivary protein composition showed a statistically significant correlation between the quantity of acidic proline‐rich proteins (PRPs), lipocalin, cystatin SN and cystatin S, and samples from the caries‐free group of subjects [decayed, missing or filled teeth (DMFT) = 0]. Samples from subjects with a high DMFT index appear to be correlated with high levels of amylase, immunoglobulin A, and lactoferrin. In vitro pellicle‐composition experiments showed the same correlations found for whole saliva. As cystatins are known physiological inhibitors of cathepsins, the higher quantities of lipocalin, and cystatins S and SN found in the samples from the caries‐free subjects suggest that inhibition of proteolytic events on other salivary proteins may indirectly provide tooth protection. The correlation between higher levels of the phosphorylated acidic PRPs 1/2 with samples from the caries‐free group also suggests a protective role for these proteins.
Symptoms of depression and anxiety in relation to dental health behavior and self‐perceived dental treatment need
Authors: Anttila Sirpa , Knuuttila Matti , Ylöstalo Pekka , Joukamaa Matti
Published: March 2006

The purpose of this study was to investigate the dental health behavior and self‐perceived dental treatment need, in relation to depressive symptoms and symptoms of anxiety, among a general population drawn from a sample of 31‐yr‐old‐men and women born in Northern Finland in 1966 (n = 8463). The dental health behavior included toothbrushing frequency and the frequency of dental check‐ups. Depressive symptoms, as well as symptoms of anxiety, were determined on the basis of the Symptom Checklist‐25 (SCL‐25). The participants were also asked about their education and family income. Subjects with a high number of depressive symptoms had lower toothbrushing frequency as well as a lower frequency of dental visits than subjects with no or only a few depressive symptoms. Morover, the self‐perceived dental treatment need was more common among those with a high number of depressive symptoms. Symptoms of anxiety were significantly associated with lower toothbrushing frequency. The results support the view that there is an increased risk for impaired dental health among subjects with depressive symptoms or symptoms of anxiety.
A numeric code for identifying patterns of human tooth agenesis: a new approach
Authors: Van Wijk Arjen J. , Tan Stephan P. K.
Published: March 2006

Human tooth agenesis involves the absence of one or more teeth and often refers to a genetic or a developmental disorder. Identifying whether certain patterns of tooth agenesis are more prevalent than others may prove valuable for treatment planning, as well as for genetic research into its etiology and development. In the present article a method is described where unique values are assigned to patterns of tooth agenesis. Using the idea of binary arithmetic, the absence or presence of teeth are represented by 1 and 0, and translated into corresponding unique values, the Tooth Agenesis Code (TAC). This procedure has an advantage over existing methods in that it allows for easier data analysis. The method described in this article can advance genetic research towards the etiology of tooth agenesis, allows researchers to communicate unequivocally the phenotypes of their studied cases and it can be used in other areas of oral pathology that also require pattern recognition.
Caries‐induced changes in the expression of pulpal neuropeptide Y
Authors: El Karim Ikhlas A. , Lamey Philip‐John , Linden Gerard J. , Awawdeh Lama A. , Lundy Fionnuala T.
Published: March 2006

Recent evidence suggests that the sympathetic nervous system may have a role in modulating neurogenic inflammation and bone remodelling. Neuropeptide Y (NPY) is a well‐characterized neuropeptide transmitter in the peripheral sympathetic nervous system. NPY is known to be present in human dental pulp; however, quantitative data on NPY levels in pulpal health and disease in an adult population remain to be determined. The aims of the current study were to assess, quantitatively, NPY levels by radioimmunoassay and confirm the distribution of NPY fibres by immunocytochemistry in carious and non‐carious adult human pulp tissue. Our results suggest changes in the levels and distribution of NPY in human dental pulp during the caries process, with significantly higher levels of NPY in carious compared with non‐carious adult human teeth. Within the carious samples studied, our finding, that NPY levels were significantly elevated in mild/moderate caries, concurs with the hypothesis that NPY could have a modulatory role in pulpal inflammation and in reparative dentine formation.
Comparison of Clinpro Cario L‐Pop estimates with CIA lactic acid estimates of the oral microflora
Authors: Gerardu Véronique , Heijnsbroek Muriel , Buijs Mark , Van Der Weijden Fridus , Ten Cate Bob , Van Loveren Cor
Published: March 2006

Clinpro Cario L‐Pop (CCLP) is a semiquantitive test claimed to determine the general potential for caries development and to monitor the individual caries risk. This test translates the capacity of the tongue microflora to produce lactic acid into a score of 1–9, indicating a low, medium or high risk for caries development. The aim of this randomized crossover, clinical trial was to evaluate the CCLP on its variation over time and its capacity to monitor the effect of three different oral hygiene procedures. The CCLP readings were compared with measurements of lactic acid in tongue biofilm and plaque samples by capillary ion electrophoresis (CIA). After four washout periods, the distribution of scores in the low‐, medium‐, and high‐risk categories was 10%, 16%, and 74%, respectively. Out of 30 subjects, 11 scored consistently in the same category. The coefficients of variance of lactic acid concentrations were 31% for tongue samples and 25% for plaque samples. After using antimicrobial toothpaste and mouthwash, the number of high‐risk scores was reduced to 33%; reduced acidogenicity was also found in tongue and plaque samples. We conclude that CCLP can be used to monitor and stimulate compliance to an antimicrobial oral hygiene protocol.
Microarray analysis of transcription factor gene expression in melatonin‐treated human peripheral blood mononuclear cells
Authors: Ha Eunyoung , Han Earl , Park Hae Jeong , Kim Hak‐Jae , Hong Mee Suk , Hong Seung‐Jae , Yoon Kyung Sik , Kang Insug , Cho Yong Hoo , Chung Joo‐Ho , Yim Sung‐Vin , Baik Hyung Hwan
Published: March 2006

Abstract:  The existence of specific melatonin‐binding sites in lymphoid cells led to the discovery of signal transduction pathway for melatonin in human lymphocytes and immunomodulatory role of melatonin in immune cells. In recent years, transcriptional regulation of melatonin on various transcription factors has been demonstrated. Therefore, this study was designed to assess by cDNA microarray analysis the regulatory effects of melatonin on transcription factors in human peripheral blood mononuclear cells (PBMCs). Forty‐six genes were upregulated and 23 were downregulated more than twofold in melatonin‐treated PBMCs. Of the more than twofold upregulated transcription factor genes, homeo box A4 (HOXA4), forkhead box O1A (FOXO1A), transcription elongation factor B (SIII), polypeptide 3 (TCEB3), and peroxisome proliferative activated receptor delta (PPARD) were identified. Of the more than twofold downregulated genes, PHD finger protein 15 (PHF15) and zinc finger protein 33a (ZNF33A) were identified. In summary, identification of these genes by cDNA microarray analysis in response to melatonin administration may provide a foundation for further studies on the function of melatonin in human PBMCs.
Effect of melatonin and diazepam on the dissociated circadian rhythm in rats
Authors: Carpentieri Agata Rita , Pujolràs Montserrat Anglès , Chiesa Juan José , Noguera Antoni Diez , Cambras Trinitat
Published: March 2006

Abstract:  The main structures involved in the circadian system in mammals are the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN contain multiple autonomous single‐cell circadian oscillators that are coupled among themselves, generating a single rhythm. However, under determined circumstances, the oscillators may uncouple and generate several rhythmic patterns. Rats exposed to an artificially established 22‐h light–dark cycle (T22) express two stable circadian rhythms in their motor activity that reflect the separate activities of two groups of oscillators in the morphologically well‐defined ventrolateral and dorsomedial SCN subdivisions. In the experiments described in this paper, we studied the effect of melatonin and diazepam (DZP) administration in drinking water on the dissociated components of rat motor activity exposed to T22, to deduce the possible mechanism of these drugs on the circadian system. In order to suppress the endogenous circadian rhythm of melatonin, in some of the rats the pineal gland or the superior cervical ganglia were removed. The results show that melatonin or DZP treatment increased the manifestation of the light‐dependent component to the detriment of the manifestation of the non‐light‐dependent component and that melatonin, but not DZP, shortens the period of the non‐light‐dependent component. These findings suggest that both DZP and melatonin favor entrainment to external light, and that melatonin could also act on the SCN, producing changes in the period of the circadian cycle.
Customer‐oriented counseling for physical activity in older people: study protocol and selected baseline results of a randomized‐controlled trial (ISRCTN 07330512)
Authors: Leinonen R. , Heikkinen E. , Hirvensalo M. , Lintunen T. , Rasinaho M. , Sakari‐Rantala R. , Kallinen M. , Koski J. , Möttönen S. , Kannas S. , Huovinen P. , Rantanen T.
Published: March 2006

The objective of this study is to describe the rationale, design and selected baseline results of a 2‐year randomized‐controlled trial (RCT) on the effects of physical activity counseling in community‐living older people.

After a four‐phase screening and data‐collection process targeting all independently living people in the city center of Jyväskylä, Finland, six hundred and thirty‐two 75–81‐year‐old cognitively intact, sedentary persons who were able to move independently outdoors at least minimally and willing to take part in the RCT were randomized into intervention and control groups. At baseline, over half of the subjects exercised less than two to three times a month and two‐thirds were willing to increase their physical activity level. The desire to increase physical activity was more common (86%) among subjects with mobility limitation compared with those without (60%,P=0.004).

The intervention group received an individualized face‐to‐face counseling session, followed by phone contacts every 3 months throughout the intervention. The study outcomes include physical activity level, mobility limitation, functional impairments, disability, mood, quality of life, use of services, institutionalization and mortality.

The screening and recruitment process was feasible and succeeded well, and showed that unmet physical activity needs are common in older people.
Src Triggers Circular Ruffling and Macropinocytosis at the Apical Surface of Polarized MDCK Cells
Authors: Mettlen Marcel , Platek Anna , Van Der Smissen Patrick , Carpentier Sarah , Amyere Mustapha , Lanzetti Letizia , de Diesbach Philippe , Tyteca Donatienne , Courtoy Pierre J.
Published: March 2006

We addressed the role of Src on cortical actin dynamics and polarized endocytosis in MDCK cells harboring a thermosensitive v‐src mutant. Shifting monolayers established at 40 °C (non‐permissive temperature) to 34 °C (permissive temperature) rapidly reactivated v‐Src kinase, but tight junctions and cell polarity resisted for >6 h. At this interval, activated v‐src was recruited on apical vesicles, induced cortactin‐associated apical circular ruffles productive of macropinosomes, thereby accelerating apical pinocytosis by approximately fivefold. Ruffling and macropinosome formation were selectively abrogated by inhibitors of actin polymerization, phosphoinositide 3‐kinase, phospholipase C, and phospholipase D, which all returned apical pinocytosis to the level observed at 40 °C, underscoring the distinct control of apical micropinocytosis and macropinocytosis. Src promoted microtubule‐dependent fusion of macropinosomes to the apical recycling endosome (ARE), causing its strong vacuolation. However, preservation of tubulation and apical polarity indicated that its function was not affected. The ARE was labeled for v‐src, Rab11, and rabankyrin‐5 but not early endosome antigen 1, thus distinguishing two separate Rab5‐dependent apical pathways. The mechanisms of Src‐induced apical ruffling and macropinocytosis could shed light on the triggered apical enteroinvasive pathogens entry and on the apical differentiation of osteoclasts.
Oral health in renal transplant recipients administered cyclosporin A or tacrolimus
Authors: Spolidorio LC , Spolidorio DMP , Massucato EMS , Neppelenbroek KH , Campanha NH , Sanches MH
Published: March 2006

Objective:  The aim of this study was to determine the oral status of renal transplant recipients receiving cyclosporin A (CsA) or tacrolimus (FK‐506) as immunosuppressant.

Subjects and methods:  A total of 88 renal transplant recipients receiving CsA (63 men and 25 women, mean age 51.4 years) and 67 receiving FK‐506 (57 men and 10 women, mean age 33.5 years) were included in the study. Donor type, histocompatibility, cold ischemia time and prior delayed graft function were similar between the two groups. Demographics and pharmacological data were recorded for all subjects.

Results:  The results demonstrated that CsA caused a greater number of oral diseases. A greater number of gingival overgrowth was present in patients treated with CsA. However, the combined use with calcium channel blockers increased the gingival overgrowth number. The occurrence of candida in saliva was observed in 80 renal recipients treated with CsA and 20 treated with FK‐506. The presence of squamous oral carcinoma (n = 3) and herpes simplex (n = 10) was observed in patients treated with CsA. These alterations were not observed in renal recipients treated with FK‐506.

Conclusions:  Renal recipients constitute a high‐risk group for oral diseases, as they are immunocompromised. However, the FK‐506 regime appears to ameliorate this effect, compared with CsA. Adequate pre‐ and post‐transplant oral health care is recommended for these subjects, irrespective of the time interval for which the drug is administered.
Platelet‐derived growth factor (PDGF) isoform and PDGF receptor expression in drug‐induced gingival overgrowth and hereditary gingival fibrosis
Authors: Wright HJ , Chapple ILC , Cooper P , Matthews JB
Published: March 2006

Objective:  To investigate possible associations between platelet‐derived growth factor (PDGF), PDGF receptor expression and macrophages in drug‐induced and hereditary gingival overgrowth.

Materials and Methods:  Tissues from patients with drug‐induced gingival overgrowth (DIGO) (n = 10) and hereditary gingival fibrosis (n = 10) were studied and compared with ‘control’ gingiva (n = 10). Expression of PDGF and its α and β receptors was investigated immunohistochemically and by RT‐PCR. Macrophages were identified by immunostaining for CD68.

Results:  PDGF isoforms and receptors were detected in most cells within all specimens. There were no differences in the numbers of macrophages, or fibroblasts expressing PDGF or receptors, between groups. The level of PDGF expression by fibroblasts, determined by absorbance measurements, was similar between groups for PDGF A. Significantly lower levels of total PDGF and the receptors were detected in drug‐induced overgrowth compared to those in hereditary fibrosis (P < 0.004) and control specimens (P < 0.034). All specimens expressed mRNA for PDGF A, PDGF B and α and β receptors.

Conclusions:  These data do not support a pivotal role for macrophage‐derived PDGF B in the pathogenesis of DIGO. They suggest that fibroblasts in drug‐induced lesions have a lowered capacity to produce, and respond to, PDGF, a property not shared by fibroblasts associated with hereditary fibrosis.
Comparison of renal function markers in Kuwaiti patients with sickle cell disease
Authors: Marouf R , Mojiminiyi O , Abdella N , Kortom M , Al Wazzan H
Published: March 2006

Background:Proteinuria is a common manifestation of renal disease which is a significant cause of morbidity in patients with sickle cell disease (SCD).

Objective:To evaluate and compare cystatin C, β2-microglobulin, and creatinine as markers of renal disease in relation to the degree of proteinuria and other complications of SCD.

Methods:24 h urine collections were used for estimation of urine protein and creatinine clearance in 59 patients with SCD. Results were correlated with plasma cystatin C, β2-microglobulin, creatinine, glomerular filtration rate (GFR; derived from plasma creatinine by Cockcroft-Gault, MDRD formulae, and calculated cystatin C clearance), and clinical and haematological variables.

Results:Comparing the different methods of GFR, the proportion of patients with hyperfiltration (GFR >140 ml/min) were 30.5% (MDRD), 44.1% (Cockcroft-Gault), and 10.2 % (calculated cystatin C clearance). Cystatin C was the most consistent marker of hyperfiltration. The endogenous markers of GFR showed an increasing trend with increasing proteinuria, but haematological variables were not correlated with cystatin C, β2-microglobulin, or plasma creatinine. Urine protein excretion was correlated with age (r = 0.33) and significant proteinuria was present in 13.6% of patients. Patients with proteinuria had lower haemoglobin concentration (p = 0.027) than those without proteinuria but HbF was not related to the degree of proteinuria or to markers of GFR.

Conclusions:Markers of GFR show variable ability to identify hyperfiltration in patients with SCD, but cystatin C is the best endogenous marker. Proteinuria is associated with age, haemoglobin, and abnormalities of GFR. Routine screening is recommended to allow for early detection and intervention.
High grade prostatic intraepithelial neoplasia with squamous differentiation: Figure 1
Authors: Melissari M , Lopez Beltran A , Mazzucchelli R , Froio E , Bostwick D G , Montironi R
Published: March 2006

An unusual variant of prostatic intraepithelial neoplasia with prominent and extensive squamous differentiation is described. The lesion was identified in the transition zone of a 79 year old man with a three year history of increasing urinary obstructive symptoms and a clinical diagnosis of benign prostatic hyperplasia who underwent simple prostatectomy. Two years after surgery, prostatic biopsies showed atrophy and mild chronic inflammation, with no evidence of malignancy. This unusual intraepithelial lesion seems not to have been described before and may represent a new variant of high grade prostatic intraepithelial neoplasia (HGPIN) with squamous differentiation.
Increased expression of connexins 26 and 43 in lymph node metastases of breast cancer
Authors: Kanczuga-Koda L , Sulkowski S , Lenczewski A , Koda M , Wincewicz A , Baltaziak M , Sulkowska M
Published: March 2006

Background:Gap junctions are intercellular channels composed of connexins, which mediate the direct passage of small molecules between neighbouring cells. They are involved in regulation of cell cycle, cell signalling, and differentiation, and probably invasion and metastasis. The role of connexins in the metastatic process is controversial, because some studies indicate that connexin expression is inversely correlated with metastatic capacity. In contrast, others demonstrate that connexins may be involved in metastasis. In addition, connexin status in breast cancer metastasis has not been widely studied.

Methods:We evaluated by immunohistochemistry the expression of connexin 26 (Cx26) and connexin 43 (Cx43) in primary breast tumours (PTs) and matched paired metastases to lymph nodes (MLNs).

Results:In PTs, we observed predominantly cytoplasmic localisation of evaluated connexins, indicating alterations in connexin expression in breast cancer cells. We demonstrated that expression of Cx26 and Cx43 was increased in MLNs compared with PTs (p<0.00001 and p<0.001, for CX26 and Cx43, respectively). In addition, Cx26 and Cx43 negative PTs developed Cx26 and Cx43 positive MLNs. Furthermore, besides increased cytoplasmic staining, enhanced membranous localisation of Cx43, typical of normal cells, was found in MLNs. Additionally, membranous Cx26 expression appeared only in metastatic breast cancer cells.

Conclusions:These findings suggest that connexins may contribute to the efficient metastasising of breast cancer to the lymph nodes.
SINGULARITIES OF IMPROPER AFFINE SPHERES AND SURFACES OF CONSTANT GAUSSIAN CURVATURE
Authors: ISHIKAWA GO-O , MACHIDA YOSHINORI
Published: March 2006

We study the equation for improper (parabolic) affine spheres from the view point of contact geometry and provide the generic classification of singularities appearing in geometric solutions to the equation as well as their duals. We also show the results for surfaces of constant Gaussian curvature and for developable surfaces. In particular we confirm that generic singularities appearing in such a surface are just cuspidal edges and swallowtails.
Posttraumatic Stress Disorder: Etiology, Epidemiology, and Treatment Outcome
Authors: Keane Terence M. , Marshall Amy D. , Taft Casey T.
Published: March 2006

Posttraumatic stress disorder (PTSD) results from exposure to a traumatic event that poses actual or threatened death or injury and produces intense fear, helplessness, or horror. U.S. population surveys reveal lifetime PTSD prevalence rates of 7% to 8%. Potential reasons for varying prevalence rates across gender, cultures, and samples exposed to different traumas are discussed. Drawing upon a conditioning model of PTSD, we review risk factors for PTSD, including pre-existing individual-based factors, features of the traumatic event, and posttrauma social support. Characteristics of the trauma, particularly peritraumatic response and related cognitions, and posttrauma social support appear to confer the greatest risk for PTSD. Further work is needed to disentangle the interrelationships among these factors and elucidate the underlying mechanisms. Based upon existing treatment outcome studies, we recommend use of exposure therapies and anxiety management training as first-line treatment for PTSD. Among psychopharmacological treatments, selective serotonin reuptake inhibitors evidence the strongest treatment effects, yet these effects are modest compared with psychological treatments.
Interactions between imprinting effects: summary and review
Authors: Cattanach B.M. , Beechey C.V. , Peters J.
Published: March 2006

Mice with uniparental disomies (uniparental duplications) for defined regions of certain chromosomes, or certain disomies, show a range of developmental abnormalities most of which affect growth. These defects can be attributed to incorrect dosages of maternal or paternal copies of imprinted genes lying within the regions involved. Combinations of certain partial disomies result in interactions between the imprinting effects that seemingly independently affect foetal and/or placental growth in different ways or modify neonatal and postnatal development. The findings are generally in accord with the ‘conflict hypothesis’ for the evolution of genomic imprinting but do not demonstrate common growth axes within which imprinted genes may interact. Instead, it would seem that any gene that favours embryonic/foetal development, at consequent cost to the mother, will have been subject to evolutionary selection for only paternal allele expression. Reciprocally, any gene that reduces embryonic/foetal growth to limit disadvantage to the mother will have been selected for only maternal allele expression. It is concluded that survival of the placenta is core to the evolution of imprinting.
Complementation hypothesis: the necessity of a monoallelic gene expression mechanism in mammalian development
Authors: Kaneko-Ishino T. , Kohda T. , Ono R. , Ishino F.
Published: March 2006

Gene expression from both parental alleles (biallelic expression) is beneficial in minimizing the occurrence of recessive genetic disorders in diploid organisms. However, imprinted genes in mammals display parent of origin-specific monoallelic expression. As some imprinted genes play essential roles in mammalian development, the reason why mammals adopted the genomic imprinting mechanism has been a mystery since its discovery. In this review, based on the recent studies on imprinted gene regulation we discuss several advantageous features of a monoallelic expression mechanism and the necessity of genomic imprinting in the current mammalian developmental system. We further speculate how the present genomic imprinting system has been established during mammalian evolution by the mechanism of complementation between paternal and maternal genomes under evolutionary pressure predicted by the genetic conflict hypothesis.
Origins of extreme sexual dimorphism in genomic imprinting
Authors: Bourc’his D. , Bestor T.H.
Published: March 2006

Roughly equal numbers of imprinted genes are subject to repression from alleles of maternal and of paternal origin. This masks the strong sexual dimorphism that underlies major aspects of imprinted gene regulation. First, imprints are established very early in the male germ line and persist for the reproductive life of the organism, while maternal genomic imprints are established shortly prior to ovulation and are erased soon thereafter in the primordial germ cells of the next generation. Second, many CpG island-associated promoters are subject to maternal methylation but no known promoters are subject to paternal-specific germline methylation. The few known paternal methylation marks are kilobases distant from the affected genes and have a low CpG density. Third, Dnmt3L is required for imprint establishment but not transposon methylation in female germ cells, while Dnmt3L is required for transposon methylation and has only a minor role in de novo methylation at imprinted loci in male germ cells. Fourth, maternally expressed genes are commonly repressed on the paternal allele by paternally expressed imprinted genes produced in cis and encoding nontranslated RNAs. It is here suggested that rapid loss of highly mutable methylated CpG sites has led to the depletion of methylation target sites in paternally repressed imprinted genes, and that an imprinting mechanism based on RNAs or local inhibitory influences of ongoing transcription of regulatory loci has evolved to counter the erosion of paternally methylated regulatory regions. This mutability model is based on the fact that paternally methylated sequences are maintained in the methylated state for a much longer time than are maternally methylated sequences, and are therefore lost at a correspondingly faster rate. The difference in timing of imprint establishment is likely to underlie the increasing sexual dimorphism of other aspects of imprinted gene expression.
Genomic imprinting in the mealybugs
Authors: Khosla S. , Mendiratta G. , Brahmachari V.
Published: March 2006

The coccid insects (Hemiptera; Sternorrhyncha; Aphidiformes; Coccoidea; Pseudococcidae) are well suited to study not only the mechanisms of genomic imprinting but also facultative heterochromatization, a phenomenon well exemplified by inactivation of the X chromosome in female mammals. Coccids show sex-specific heterochromatization of an entire set of chromosomes and transcriptional silencing of all the paternally contributed chromosomes in males. Thus, genomic imprinting and the resultant differential regulation operate on 50% of the genome in contrast to the single X chromosome in female mammals. A significant insight into the phenomenon of genomic imprinting has come from very elegant cytological analysis of the coccid system. Recently, efforts have been made to dissect out at the molecular level the phenomenon of genomic imprinting in these insects. The present review summarizes both of these aspects. In light of the accruing experimental evidence for chromatin-based differences in the maternal and paternal genomes, it appears that the mealybug system may provide evidence for stable maintenance of chromatin code not only through mitosis but also through meiosis.
How imprinting centres work
Authors: Lewis A. , Reik W.
Published: March 2006

Imprinted genes tend to be clustered in the genome. Most of these clusters have been found to be under the control of discrete DNA elements called imprinting centres (ICs) which are normally differentially methylated in the germline. ICs can regulate imprinted expression and epigenetic marks at many genes in the region, even those which lie several megabases away. Some of the molecular and cellular mechanisms by which ICs control other genes and regulatory regions in the cluster are becoming clear. One involves the insulation of genes on one side of the IC from enhancers on the other, mediated by the insulator protein CTCF and higher-order chromatin interactions. Another mechanism may involve non-coding RNAs that originate from the IC, targeting histone modifications to the surrounding genes. Given that several imprinting clusters contain CTCF dependent insulators and/or non-coding RNAs, it is likely that one or both of these two mechanisms regulate imprinting at many loci. Both mechanisms involve a variety of epigenetic marks including DNA methylation and histone modifications but the hierarchy of and interactions between these modifications are not yet understood. The challenge now is to establish a chain of developmental events beginning with differential methylation of an IC in the germline and ending with imprinting of many genes, often in a lineage dependent manner.
Genomic imprinting in the placenta
Authors: Wagschal A. , Feil R.
Published: March 2006

Genomic imprinting is an epigenetic mechanism that is important for the development and function of the extra-embryonic tissues in the mouse. Remarkably all the autosomal genes which were found to be imprinted in the trophoblast (placenta) only are active on the maternal and repressed on the paternal allele. It was shown for several of these genes that their paternal silencing is not dependent on DNA methylation, at least not in its somatic maintenance. Rather, recent studies in the mouse suggest that placenta-specific imprinting involves repressive histone modifications and non-coding RNAs. This mechanism of autosomal imprinting is similar to imprinted X chromosome inactivation in the placenta. Although the underlying reasons remain to be explored, this suggests that imprinting in the placenta and imprinted X inactivation are evolutionarily related.
Small non-coding RNAs and genomic imprinting
Authors: Royo H. , Bortolin M.-L. , Seitz H. , Cavaillé J.
Published: March 2006

Experimental and computer-assisted approaches have led to the identification of hundreds of imprinted small RNA genes, mainly clustered in two chromosomal domains (human 15q11→q13 and 14q32 loci). The genes are only detected in placental mammals and belong to the C/D RNA and microRNA gene families. These are small non-coding RNAs involved in RNA-guided post-transcriptional RNA modifications and RNA-mediated gene silencing, respectively. Here, we discuss their potential functions and report the identification of novel small RNA genes lying within (or nearby) known imprinted chromosomal domains.
Repetitive elements in imprinted genes
Authors: Walter J. , Hutter B. , Khare T. , Paulsen M.
Published: March 2006

Genomic imprinting in mammals results in mono-allelic expression of about 80 genes depending on the parental origin of the alleles. Though the epigenetic mechanisms underlying imprinting are rather clear, little is known about the genetic basis for these epigenetic mechanisms. It is still rather enigmatic which sequence features discriminate imprinted from non-imprinted genes/regions and why and how certain sequence elements are recognized and differentially marked in the germlines. It seems likely that specific DNA elements serve as signatures that guide the necessary epigenetic modification machineries to the imprinted regions. Inter- and intraspecific comparative genomic studies suggest that the unusual occurrence and distribution of various types of repetitive elements within imprinted regions may represent such genomic imprinting signatures. In this review we summarize the various observations made and discuss them in light of experimental data.
The role of DMDs in the maintenance of epigenetic states
Authors: Paoloni-Giacobino A. , Chaillet J.R.
Published: March 2006

An important aspect of genome reprogramming is the establishment and maintenance of gamete-specific DNA methylation patterns that distinguish the parental alleles of imprinted genes. Disrupting the accurate transmission of genomic imprints by interfering with these methylation patterns causes severe defects in fetal growth and development. The inheritance of sex-specific DNA methylation patterns from both parents is thus a fundamental molecular definition of genomic imprinting. The other cardinal aspect is the regulation of imprinted gene expression over a long genomic distance, spanning a few clustered imprinted genes. There is converging experimental evidence that differentially methylated domains (DMDs), located in non-coding regions of imprinted genes, are involved in both processes. As such, DMDs are the imprinting backbone upon which the fundamental processes of sex-specific methylation and imprinted gene expression are built.
Regulation of imprinted DNA methylation
Authors: Holmes R. , Soloway P.D.
Published: March 2006

DNA methylation is an essential enzymatic modification in mammals. This common epigenetic mark occurs predominantly at the fifth carbon of cytosines within the palindromic dinucleotide 5′-CpG-3′. The majority of methylated CpGs are located within repetitive elements including centromeric repeats, satellite sequences and gene repeats encoding ribosomal RNAs. CpG islands, frequently located at the 5′ end of genes, are typically unmethylated. DNA methylation also occurs at imprinted genes which exhibit parent-of-origin-specific patterns of methylation and expression. Imprinted methylation at differentially methylated domains (DMDs) is one of the regulatory mechanisms controlling the allele-specific expression of imprinted genes. Proper control of DNA methylation is needed for normal development and loss of methylation control can contribute to initiation and progression of tumorigenesis (reviewed in Plass and Soloway, 2002). Because patterns of imprinted DNA methylation are highly reproducible, imprinted loci make useful models for studying regulation of DNA methylation and may provide insights into how this regulation goes awry in cancer. Here, we review what is currently known about the mechanisms regulating imprinted DNA methylation. We will focus on cis-acting DNA sequences, trans-acting protein factors and the possible involvement of RNAs in control of imprinted DNA methylation.
Bisulfite sequencing and dinucleotide content analysis of 15 imprinted mouse differentially methylated regions (DMRs): paternally methylated DMRs contain less CpGs than maternally methylated DMRs
Authors: Kobayashi H. , Suda C. , Abe T. , Kohara Y. , Ikemura T. , Sasaki H.
Published: March 2006

Imprinted genes in mammals show monoallelic expression dependent on parental origin and are often associated with differentially methylated regions (DMRs). There are two classes of DMR: primary DMRs acquire gamete-specific methylation in either spermatogenesis or oogenesis and maintain the allelic methylation differences throughout development; secondary DMRs establish differential methylation patterns after fertilization. Targeted disruption of some primary DMRs showed that they dictate the allelic expression of nearby imprinted genes and the establishment of the allelic methylation of secondary DMRs. However, how primary DMRs are recognized by the imprinting machinery is unknown. As a step toward elucidating the sequence features of the primary DMRs, we have determined the extents and boundaries of 15 primary mouse DMRs (including 12 maternally methylated and three paternally methylated DMRs) in 12.5-dpc embryos by bisulfite sequencing. We found that the average size of the DMRs was 3.2 kb and that their average G+C content was 54%. Dinucleotide content analysis of the DMR sequences revealed that, although they are generally CpG rich, the paternally methylated DMRs contain less CpGs than the maternally methylated DMRs. Our findings provide a basis for the further characterization of DMRs.