JOURNAL OF MEDICAL VIROLOGY, Issue 6 2008
Dianne J. Marais
Abstract This study tested cervical and oral human papillomavirus (HPV) infection in HIV-1 seropositive (HIV+) and seronegative (HIV,) women to determine any association between infections at both sites and the difference in prevalence of the HPV types infecting these women. Participants were 115 women referred to a colposcopy clinic after diagnosis of abnormal cervical cytology. The women showed low grade cervical intraepithelial neoplasia (CIN1) or high grade disease (CIN2/3) or no CIN based on colposcopy and histology. Typing of HPV in cervical and oral cells was by Roche linear array and included direct sequencing on selected oral samples. Cervical HPV prevalence was 86.5% and 97.1% in HIV, and HIV+ women respectively. With the exception of HPV-45, prominent in HIV+ women, the hierarchy of predominant types were similar in HIV, and HIV+ women. HPV-16 was most prevalent in both HIV+ (41.7%) and HIV, women (38.5%) with CIN2/3. Significantly more HIV+ women had multiple cervical (>1) infections than HIV, women (36.1% vs. 88.2%, P,<,0.001) and more oral HPV infections (45.5% and 25% respectively; P,=,0.04). The most prevalent oral HPV types were HPV-33, -11, and -72. The majority of women did not have concordant oral and cervical HPV types, reflecting possible independence of infection at the two sites. HIV immune suppression did not impact significantly on the predominant types of cervical HPV infection (except for HPV-45). HIV+ women had more multiple HPV infections and those with severe cervical disease a similar prevalence of HIV-16 but a lower HPV-18 prevalence than HIV, women. J. Med. Virol. 80:953,959, 2008. © 2008 Wiley-Liss, Inc. [source]

Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women

JOURNAL OF MEDICAL VIROLOGY, Issue 6 2007
D.B. Blossom
Abstract Human papillomavirus (HPV) infection is associated with almost all cases of cervical cancer, and cervical cancer is a common malignancy in women living in developing countries. A cross-sectional study was conducted to determine the prevalence of HPV infection, human immunodeficiency virus (HIV) infection, and cervical cytologic abnormalities in women presenting to a sexually transmitted infections clinic in Kampala, Uganda. In June and July, 2002, 135 women underwent complete physical exams including Papanicolaou (Pap) smears. HIV status was evaluated by serology. Cervical and vaginal swabs were obtained by clinicians and tested for HPV genotypes by PCR/reverse blot strip assay. Of the 106 women with cervical swabs adequate for HPV testing, the HPV prevalence was 46.2% (49/106). HIV prevalence was 34.9% (37/106). High risk genotypes 52, 58, and 16 were the genotypes detected most commonly. Eighteen percent (9/49) of women infected with HPV were found to have genotypes 16 and/or 18. Seventy-three percent (27/37) of HIV-positive women versus 16% (10/63) of HIV-negative women had abnormal Pap smears (P,<,0.0001). Among HIV-positive women, abnormal Pap smears were associated with the presence of high risk HPV genotypes (P,<,0.001). The majority of women infected with HPV attending this sexually transmitted infections clinic in Uganda were infected with high risk HPV genotypes other than 16 and 18. Future studies should focus on whether current HPV vaccine formulations, that are limited to high risk genotypes 16 and 18, would be effective at decreasing the burden of cervical cancer in this population. J. Med. Virol. 79: 758,765, 2007. © 2007 Wiley-Liss, Inc. [source]

Comparison of microscopy, culture and in-house PCR and NASBA assays for diagnosis of Neisseria gonorrhoeae in Russia,

APMIS, Issue 2 2008
ELENA SHIPITSYNA
This study aimed to assess the laboratory diagnosis of Neisseria gonorrhoeae in St. Petersburg, Russia. In total, 334 consecutive symptomatic patients were enrolled. Cervical and urethral specimens from women (n=286) and urethral specimens from men (n=48) were analyzed by microscopy, culture and two in-house NAATs, i.e. polymerase chain reaction (PCR) and nucleic acid sequence-based amplification (NASBA), developed in Russia. All N. gonorrhoeae- positive samples were confirmed using porA pseudogene and 16S rRNA gene sequencing. All methods displayed 100% specificity, i.e. positive predictive values of 100%. Compared to the PCR (most sensitive method in the present study), in women the sensitivity of both microscopy and culture was 31.8%, and that of NASBA was 90.9%. In men, microscopy, culture and NASBA displayed a sensitivity of 75%, 50% and 100%, respectively. The negative predictive values of microscopy, culture, and NASBA were 97.3%, 97.3%, and 99.6% in women, and 97.8%, 95.7%, and 100% in men, respectively. According to the PCR, the prevalences of N. gonorrhoeae were 4.5% (women) and 8.3% (men). In conclusion, both the investigated Russian NAATs displayed a high sensitivity and specificity. However, in general the diagnosis of gonorrhoea in Russia is suboptimal and crucially requires validation, improvements and quality assurance. [source]

Comparative study: conventional cervical and ThinPrep® Pap tests in a routine clinical setting

CYTOPATHOLOGY, Issue 4 2002
A. Grace
The conventional Papanicolaou smear is associated with variable false positive and false negative rates, difficulties with interpretation and high unsatisfactory and suboptimal rates. Newer fluid-based methods such as the ThinPrep® 2000 system (Cytyc Corp., Boxborough, MA) are said to overcome these difficulties. The aim of this study was to compare the conventional smear with the ThinPrep® method in a busy, routine cytology screening laboratory setting. One thousand split samples were evaluated. Using ThinPrep®, the results showed an increased sensitivity and a dramatic improvement in specimen adequacy, with a combined 17.2% reduction in ,unsatisfactory' and ,suboptimal' reports. Screening time per slide was also reduced to 3,4 min. In conclusion, we report an increase in sensitivity, a reduction in screening time and a dramatic improvement in specimen adequacy with the ThinPrep® method. [source]

Healing and prognosis of teeth with intra-alveolar fractures involving the cervical part of the root

DENTAL TRAUMATOLOGY, Issue 2 2002
Miomir Cvek
Abstract Healing and long-term prognosis of 94 cervical root fractures were evaluated. The teeth were divided into two groups according to type of fracture: transverse fractures limited to the cervical third of the root (51 incisors) and oblique fractures involving both the cervical and middle parts of the root (43 incisors). Neither the frequency nor the type of fracture healing differed significantly between the two groups. In the material as a whole, healing of the fracture with hard tissue formation was observed in 17 teeth (18%), and healing with interposition of periodontal ligament (PDL) and, in some cases, hard tissue between the fragments in 62 teeth (66%). Fifteen teeth (16%) showed no healing and a radiolucency adjacent to the fracture. Statistical analyses revealed that incomplete root formation and a positive sensibility test at the time of injury were significantly related to both healing and hard tissue repair. The same applied to concussion or subluxation compared with dislocation of coronal fragment, as well as optimal compared with suboptimal reposition of displaced coronal fragments. The type and duration of splinting (or no splinting) appeared to be of no significance for frequency or type of healing of cervical root fractures. During the observation time (mean = 75 months), 19 (44%) of the teeth with transverse fractures and 3 (8%) of those with oblique fractures were lost after healing. In conclusion, fractures in the cervical part of the root had a healing potential and the predictive parameters identified for fractures in other parts of the root seemed to be valid for the healing of cervical root fractures. Transverse fractures appeared to have a significantly poorer long-term prognosis compared to oblique fractures, apparently due to a marked post-treatment mobility, which often led to new luxation caused by even minor impacts. [source]

Human Papillomavirus and Overexpression of P16INK4a in Nonmelanoma Skin Cancer

DERMATOLOGIC SURGERY, Issue 3 2004
Ingo Nindl PhD
Background. P16INK4a overexpression has been identified as a specific biomarker in high-risk human papillomavirus (HPV),infected cervical (pre)cancer lesions. Objective. To evaluate the overexpression of this cyclin-dependent kinase inhibitor in skin tumors depending on HPV infections, we analyzed normal skin, benign skin disease, and skin cancer specimens. Methods. Biopsies of 23 patients with normal histology (3), psoriasis (2), verrucae vulgaris (2), actinic keratoses (5), squamous cell carcinoma (SCC) in situ (3), Bowen's carcinoma (1), and SCC (7) were analyzed. Specimens of 23 patients were immunostained using the monoclonal antibody E6H4 specific for p16INK4a. HPV status was assessed by a polymerase chain reaction (PCR) system to detect all currently known HPV types. MY (MY09/MY11 and MYN9/MYN10)-, CP (CP65/CP70 and CP66/CP69)-nested PCR, and three single PCR methods CN1, CN3, and CN4 were used in a first step, and HPV typing was performed by restriction fragment length polymorphism analysis. Only ,-globin,positive patients were included in this study. Results. HPV DNA was detected in all actinic keratoses, SCC in situ, Bowen's carcinoma, and SCC, in 50% (one of two) of verrucae vulgaris, in 66% (two of three) of normal skin, and in none of two psoriasis. P16INK4a expression was not detected in normal skin, psoriasis, and verrucae vulgares. Overexpression of p16INK4a was detected in a subset of dysplastic cells (10% to 80%) of all skin (pre)cancer lesions such as actinic keratoses, SCC in situ, Bowen's carcinoma, and SCC infected with HPV independent of sun exposure. Conclusion. P16INK4a appears to be overexpressed in a portion of dysplastic cells from actinic keratoses and SCC. Further studies to examine the association of HPV infection and the overexpression of p16INK4a are warranted. [source]

An overview of human papillomavirus infection for the dermatologist: disease, diagnosis, management, and prevention

DERMATOLOGIC THERAPY, Issue 5 2010
Michelle Forcier
ABSTRACT Genital human papillomavirus (HPV) is a common, usually transient, dermatologic infection transmitted by genital contact that can cause a variety of anogenital diseases, including warts (condyloma), dysplasia (cervical, vaginal, vulvar, anal), and squamous cell carcinoma. A number of treatment modalities are available to treat anogenital warts, both patient- and provider-applied. Treatment is efficacious, but lesions can recur. Bivalent and quadrivalent vaccines are approved to prevent HPV infection. Both are indicated to prevent cervical cancer, while the quadrivalent vaccine is also approved to prevent vaginal/vulvar cancers as well as genital warts in males and females. Providers should clearly explain the natural history and potential sequelae of HPV disease, counsel patients on prevention strategies, and recommend vaccination as an effective method of prevention to their patients. [source]

Developmental changes in neurite outgrowth responses of dorsal root and sympathetic ganglia to GDNF, neurturin, and artemin

DEVELOPMENTAL DYNAMICS, Issue 3 2003
H. Yan
Abstract The ability of glial cell line,derived neurotrophic factor (GDNF), neurturin, and artemin to induce neurite outgrowth from dorsal root, superior cervical, and lumbar sympathetic ganglia from mice at a variety of development stages between embryonic day (E) 11.5 and postnatal day (P) 7 was examined by explanting ganglia onto collagen gels and growing them in the presence of agarose beads impregnated with the different GDNF family ligands. Artemin, GDNF, and neurturin were all capable of influencing neurite outgrowth from dorsal root and sympathetic ganglia, but the responses of each neuron type to the different ligands varied during development. Neurites from dorsal root ganglia responded to artemin at P0 and P7, to GDNF at E15.5 and P0, and to neurturin at E15.5, P0, and P6/7; thus, artemin, GDNF, and neurturin are all capable of influencing neurite outgrowth from dorsal root ganglion neurons. Neurites from superior cervical sympathetic ganglia responded significantly to artemin at E15.5, to GDNF at E15.5 and P0, and to neurturin at E15.5. Neurites from lumbar sympathetic ganglia responded to artemin at all stages from E11.5 to P7, to GDNF at P0 and P7 and to neurturin at E11.5 to P6/7. Combined with the data from previous studies that have examined the expression of GDNF family members, our data suggest that artemin plays a role in inducing neurite outgrowth from young sympathetic neurons in the early stages of sympathetic axon pathfinding, whereas GDNF and neurturin are likely to be important at later stages of sympathetic neuron development in inducing axons to enter particular target tissues once they are in the vicinity or to induce branching within target tissues. Superior cervical and lumbar sympathetic ganglia showed temporal differences in their responsiveness to artemin, GDNF, and neurturin, which probably partly reflects the rostrocaudal development of sympathetic ganglia and the tissues they innervate. Developmental Dynamics 227:395,401, 2003. © 2003 Wiley-Liss, Inc. [source]

Distributions of estrogen receptors alpha and beta in sympathetic neurons of female rats: Enriched expression by uterine innervation

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2002
Elena V. Zoubina
Abstract Estrogen modulates many features of the sympathetic nervous system, including cell numbers and ganglion synapses, and can induce uterine sympathetic nerve degeneration. However, distributions of estrogen receptors , and , within sympathetic neurons have not been described, and their regulation by target tissue or estrogen levels has not been explored. We used immunofluorescence and retrograde tracing to define estrogen receptor expression in sympathetic neurons at large in pre- and paravertebral ganglia and in those projecting to the uterine horns. Estrogen receptor , immunoreactivity was present in 29 ± 1%, while estrogen receptor , was expressed by 92 ± 1% of sympathetic neurons at large. The proportions of neurons expressing these receptors were comparable in the superior cervical and thoraco-lumbar paravertebral ganglia from T11 through L5, and in the suprarenal, celiac, and superior mesenteric prevertebral ganglia. Injections of FluoroGold into the uterine horns resulted in labeled neurons, with peak occurrences in T13, L1, and the suprarenal ganglion. Uterine-projecting neurons showed small but significantly greater incidence of estrogen receptor , expression relative to the neuronal population at large, whereas the proportion of uterine-projecting neurons with estrogen receptor ,-immunoreactivity was nearly threefold greater. Numbers of estrogen receptor-expressing neurons were not altered by acute estrogen administration. We conclude that the vast majority of sympathetic neurons express estrogen receptor , immunoreactive protein, whereas a smaller, presumably overlapping subset expresses the estrogen receptor ,. Expression of the latter apparently can be enhanced by target-mediated mechanisms. © 2002 Wiley Periodicals, Inc. J Neurobiol 52: 14,23, 2002 [source]

[Tris(pyrazolyl)methane]ruthenium Complexes Capable of Inhibiting Cancer Cell Growth

EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 31 2009
Jesse M. Walker
Abstract The [tris(pyrazolyl)methane]ruthenium complexes [(,3 -tpm)RuCl(solv)2]PF6 [tpm = tris(pyrazolyl)methane; solv = MeCN, dmso] and [(,3 -tpm)RuCl(LL)]PF6 [LL = ,2 -dppe, ,2 -dppp, ,2 -dppb, (PMePh2)2] have been prepared, characterized and screened in vitro for their antiproliferative properties against the MCF-7 (breast) and HeLa (cervical) cancer cell lines by using the MTT assay. Although the MeCN and dmso complexes showed no activity under the conditions used, the phosphane complexes exhibited remarkable cytotoxic behaviour. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source]

Descending respiratory polysynaptic inputs to cervical and thoracic motoneurons diminish during early postnatal maturation in rat spinal cord

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005
Laurent Juvin
Abstract Isolated brainstem-spinal cord preparations were used to explore the coexistence of a direct and an indirect descending drive from the brainstem respiratory centre to cervical and thoracic respiratory motoneurons in the neonatal Sprague,Dawley rat. Polysynaptic spinal relay pathways from the respiratory centre were suppressed by selectively perfusing the cord with mephenesin (1 mm) or a solution enriched with Ca2+ and Mg2+. At birth, both direct and spinally relayed pathways are functional and contribute equally to the global descending respiratory drive. However, during the first postnatal week, significant maturational changes appear in the way the respiratory centre controls its target respiratory motoneurons in the cervical and thoracic spinal cord, with the direct respiratory drive becoming progressively predominant with maturation (from 50% to around 75% of the global descending command). The relative contributions of the monosynaptic and the polysynaptic spinal pathways may therefore have important implications for effective respiratory control during early postnatal development. [source]

Cadherin 13 in cancer

GENES, CHROMOSOMES AND CANCER, Issue 9 2010
Alexandra V. Andreeva
We review the evidence suggesting the involvement of Cadherin 13 (CDH13, T-cadherin, H-cadherin) in various cancers. CDH13 is an atypical member of the cadherin family, devoid of a transmembrane domain and anchored to the exterior surface of the plasma membrane via a glycosylphosphatidylinositol anchor. CDH13 is thought to affect cellular behavior largely through its signaling properties. It is often down-regulated in cancerous cells. CDH13 down-regulation has been associated with poorer prognosis in various carcinomas, such as lung, ovarian, cervical and prostate cancer. CDH13 re-expression in most cancer cell lines inhibits cell proliferation and invasiveness, increases susceptibility to apoptosis, and reduces tumor growth in in vivo models. These properties suggest that CDH13 may represent a possible target for therapy in some cancers. At the same time, CDH13 is up-regulated in blood vessels growing through tumors and promotes tumor neovascularization. In contrast to most cancer cell lines, CDH13 overexpression in endothelial cells promotes their proliferation and migration, and has a pro-survival effect. We also discuss molecular mechanisms that may regulate CDH13 expression and underlie its roles in cancer. © 2010 Wiley-Liss, Inc. [source]

Preventive medicine beyond 65

GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2006
Lionel S. Lim
Preventive health care in adults aged 65 and older is essential to ensure that quality of life is maintained with longevity. The first half of this article will focus on the two major causes of mortality in the US adult population: cancer and cardiovascular disease. We will address current screening and chemoprevention issues pertaining to breast, cervical, colorectal, prostate and skin cancer. For cardiovascular disease prevention, we will discuss the importance of screening for and treating hypertension, hyperlipidemia, diabetes mellitus, and the use of aspirin chemoprophylaxis and angiotensin-converting enzyme inhibition. In the latter half, we will discuss other aspects of preventive health care including fall prevention, motor vehicle safety, immunizations and screening issues. Health screening can help detect conditions like osteoporosis, subclinical thyroid disease, hearing impairment, nutritional status, and oral and dental problems. Finally, we will also address psychosocial health issues that affect older people including dementia, depression, elder abuse, lifestyle habits and advanced directives. Our recommendations are based on the latest available evidence and include the US Preventive Services Task Force and other leading health professional organizations. [source]

Chemokine expression in the white matter spinal cord precursor niche after force-defined spinal cord contusion injuries in adult rats

GLIA, Issue 8 2010
Friederike Knerlich-Lukoschus
Abstract Inflammatory cascades induced by spinal cord injuries (SCI) are localized in the white matter, a recognized neural stem- and progenitor-cell (NSPC) niche of the adult spinal cord. Chemokines, as integrators of these processes, might also be important determinants of this NSPC niche. CCL3/CCR1, CCL2/CCR2, and SDF-1,/CXCR4 were analyzed in the ventrolateral white matter after force defined thoracic SCI: Immunoreactivity (IR) density levels were measured 2 d, 7 d, 14 d, and 42 d on cervical (C 5), thoracic (T 5), and lumbar (L 5) levels. On day post operation (DPO) 42, chemokine inductions were further evaluated by real-time RT-PCR and Western blot analyses. Cellular phenotypes were confirmed by double labeling with markers for major cell types and NSPCs (nestin, Musashi-1, NG2, 3CB2, BLBP). Mitotic profiles were investigated in parallel by BrdU labeling. After lesion, chemokines were induced in the ventrolateral white matter on IR-, mRNA-, and protein-level. IR was generally more pronounced after severe lesions, with soaring increases of CCL2/CCR2 and continuous elevations of CCL3/CCR1. SDF-1, and CXCR4 IR induction was focused on thoracic levels. Chemokines/-receptors were co-expressed with astroglial, oligodendroglial markers, nestin, 3CB2 and BLBP by cells morphologically resembling radial glia on DPO 7 to DPO 42, and NG2 or Musashi-1 on DPO 2 and 7. In the white matter BrdU positive cells were significantly elevated after lesion compared with sham controls on all investigated time points peaking in the early time course on thoracic level: Here, chemokines were co-expressed by subsets of BrdU-labeled cells. These findings suggest an important role of chemokines/-receptors in the subpial white matter NSPC niche after SCI. © 2010 Wiley-Liss, Inc. [source]

Simplifying head and neck microvascular reconstruction

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 11 2004
Eben Rosenthal MD
Abstract Background. Free-tissue transfer has become the preferred method of head and neck reconstruction but is a technique that is considered to use excessive hospital resources. Methods. This study is a retrospective review of 125 consecutive free flaps in 117 patients over a 16-month period at a tertiary care university hospital. Results. Defects of the oral cavity/oropharynx (60%), midface (9%), hypopharynx (15%), or cervical and facial skin (16%) were reconstructed from three donor sites: forearm (70%), rectus (11%), and fibula (19%). Microvascular anastomoses were performed with a continuous suture technique or an anastomotic coupling device for end-to-end venous anastomoses. A single vein was anastomosed in 97% of tissue transfers. There were five flaps (4%) requiring exploration for vascular compromise, and the overall success rate was 97.6%. The major complication rate was 13%. Mean hospital stay was 7 days for all patients and 5 days for those with cutaneous defects. Combined ablative and reconstructive operative times were 6 hours 42 minutes, 7 hours 40 minutes, and 8 hours 32 minutes for forearm, rectus, and fibular free grafts, respectively. A subset of this patient series with oral cavity and oropharynx defects (76 patients; 58%) available for follow-up (74 patients) was assessed for deglutition. Forty-three patients (58%) had a regular diet, 22 patients (30%) had a limited diet or required supplemental tube feedings, and nine patients (12%) were dependent on tube feedings with a severely limited diet. Conclusions. This series suggests that most head and neck defects can be reconstructed by use of a simplified microvascular technique and a limited number of donor sites. Analysis of operative times and length of stay suggest improved efficiency with this approach to microvascular reconstruction. Complications and functional results are comparable to previously published results. © 2004 Wiley Periodicals, Inc. Head Neck26: 930,936, 2004 [source]

Trigger Points in the Suboccipital Muscles and Forward Head Posture in Tension-Type Headache

HEADACHE, Issue 3 2006
César Fernández-de-las-Peñas PT
Objective.,To assess the presence of trigger points (TrPs) in the suboccipital muscles and forward head posture (FHP) in subjects with chronic tension-type headache (CTTH) and in healthy subjects, and to evaluate the relationship of TrPs and FHP with headache intensity, duration, and frequency. Background.,Tension-type headache (TTH) is a prototypical headache in which myofascial TrPs in the cervical and pericranial musculature can play an important role. Design.,A blinded, controlled pilot study. Methods.,Twenty CTTH subjects and 20 matched controls without headache participated. TrPs were identified by eliciting referred pain with palpation, and increased referred pain with muscle contraction. Side-view pictures of each subject were taken in sitting and standing positions, in order to assess FHP by measuring the craniovertebral angle. Both measures were taken by a blinded assessor. A headache diary was kept for 4 weeks in order to assess headache intensity, frequency, and duration. Results.,Sixty-five percent (13/20) CTTH subjects showed active TrPs and 35% (7/20) had latent TrPs in the suboccipital muscles. Six (30%) controls also had latent TrPs. Differences in the presence of suboccipital muscle TrPs between both the groups were significant for active TrPs (P < .001) but not for latent TrPs (P > .5). CTTH subjects with active TrPs reported a greater headache intensity and frequency than those with latent TrPs (P < .05). The degree of FHP was greater in CTTH subjects than in controls in both sitting and standing positions (P < .01). Within the CTTH group, there was a negative correlation between the craniovertebral angle and the frequency of headache (rs=,0.6, P < .01, in sitting position; rs=,0.5, P < .05, in standing position). CTTH subjects with active TrPs had a greater FHP than those with latent TrPs, though this difference was not significant. Conclusions.,Suboccipital active TrPs and FHP were associated with CTTH. CCTH subjects with active TrPs reported a greater headache intensity and frequency than those with latent TrPs. The degree of FHP correlated positively with headache duration, headache frequency, and the presence of suboccipital active TrPs. [source]

Biomarker-assisted diagnosis of ovarian, cervical and pulmonary small cell carcinomas: the role of TTF-1, WT-1 and HPV analysis

HISTOPATHOLOGY, Issue 3 2007
J W Carlson
Aims:, Small cell carcinoma of the ovary, hypercalcaemic-type (SCCOH) is morphologically similar to small cell carcinomas from other sites. The aims of this study were to (i) determine if a biomarker panel would distinguish small cell carcinomas of the ovary, cervix (SCCCx) and lung (SCCLu) and (ii) potentially determine the histogenesis of SCCOH. Methods and results:, Nine ovarian small cell carcinomas (seven hypercalcaemic type; two pulmonary type), eight SCCCx and 22 SCCLu were immunostained for thyroid transcription factor (TTF)-1, WT-1, p16, cKIT and OCT3/4; a subset of cases were tested for human papillomavirus (HPV). WT-1 was diffusely positive in 6/7 SSCOH versus two of 33 other small cell carcinomas (P , 0.001). TTF-1 was diffusely positive in 20/22 SCCLu and 1/8 SCCCx, and negative in all SCCOH. p16 and cKIT demonstrated variable patterns of immunoreactivity in all cases. HPV was identified in 5/6 SCCCx; SCCOH and SCCLu were negative for HPV. Conclusions:, Combined staining with WT-1 and TTF-1 will distinguish SCCOH from SCCLu and SCCCx with a sensitivity of 86% and specificity of 97%. HPV is specific for tumours of cervical origin, but p16 immunohistochemistry is not useful for this purpose. The presence of diffuse WT-1 supports a Müllerian origin for SCCOH, whereas the absence of cKIT and OCT3/4 argues against a germ cell origin. [source]

Influence of endodontic sealer cement on fibreglass post bond strength to root dentine

INTERNATIONAL ENDODONTIC JOURNAL, Issue 6 2008
M. S. Menezes
Abstract Aim, To test the hypothesis that the composition of endodontic sealer cements and the time elapsed between root filling and fibreglass post fixation interferes with adhesion to root canal dentine. Methodology, Sixty bovine incisor roots were divided into five groups (n = 12): CI, unfilled; SI, filled with a calcium hydroxide-based cement-Sealer 26, and immediate post fixation; S7, Sealer 26 and post fixation after 7 days; EI, filled with a zinc oxide and eugenol-based cement-Endofill and immediate fixation; and E7 Endofill and post fixation after 7 days. The posts were cemented with adhesive system and dual resin cement. Ten roots were cross-sectioned to obtain two 1-mm-thick discs for each cervical (TC), middle (TM) and apical (TA) third of the prepared root portion. The posts were submitted to a micropush-out test. The other two teeth were evaluated using scanning electron microscopy to analyse the bond interface. Data were analysed using anova, Tukey and Dunnett tests (P < 0.05). Results, Group EI was associated with a significant reduction in bond strength values irrespective of the root region; TC = 3.50 MPa (P = 0.0001); TM = 2.22 MPa (P = 0.0043) and TA = 1.45 MPa (P = 0.003). Region of canal had an influence on the values for the cement used in group E7, in which only the TA presented differences from the CI. Conclusions, Endofill interfered negatively with the bond to root dentine along its full length and in the TA when post fixation was delayed for 7 days. Bond strength decreased from crown to apex in all groups. [source]

Influence of cervical preflaring on apical file size determination

INTERNATIONAL ENDODONTIC JOURNAL, Issue 7 2005
J. D. Pecora
Abstract Aim, To investigate the influence of cervical preflaring with different instruments (Gates-Glidden drills, Quantec Flare series instruments and LA Axxess burs) on the first file that binds at working length (WL) in maxillary central incisors. Methodology, Forty human maxillary central incisors with complete root formation were used. After standard access cavities, a size 06 K-file was inserted into each canal until the apical foramen was reached. The WL was set 1 mm short of the apical foramen. Group 1 received the initial apical instrument without previous preflaring of the cervical and middle thirds of the root canal. Group 2 had the cervical and middle portion of the root canals enlarged with Gates-Glidden drills sizes 90, 110 and 130. Group 3 had the cervical and middle thirds of the root canals enlarged with nickel-titanium Quantec Flare series instruments. Titanium-nitrite treated, stainless steel LA Axxess burs were used for preflaring the cervical and middle portions of root canals from group 4. Each canal was sized using manual K-files, starting with size 08 files with passive movements until the WL was reached. File sizes were increased until a binding sensation was felt at the WL, and the instrument size was recorded for each tooth. The apical region was then observed under a stereoscopic magnifier, images were recorded digitally and the differences between root canal and maximum file diameters were evaluated for each sample. Results, Significant differences were found between experimental groups regarding anatomical diameter at the WL and the first file to bind in the canal (P < 0.01, 95% confidence interval). The major discrepancy was found when no preflaring was performed (0.151 mm average). The LA Axxess burs produced the smallest differences between anatomical diameter and first file to bind (0.016 mm average). Gates-Glidden drills and Flare instruments were ranked in an intermediary position, with no statistically significant differences between them (0.093 mm average). Conclusions, The instrument binding technique for determining anatomical diameter at WL is not precise. Preflaring of the cervical and middle thirds of the root canal improved anatomical diameter determination; the instrument used for preflaring played a major role in determining the anatomical diameter at the WL. Canals preflared with LA Axxess burs created a more accurate relationship between file size and anatomical diameter. [source]

The effect of application time of EDTA and NaOCl on intracanal smear layer removal: an SEM analysis

INTERNATIONAL ENDODONTIC JOURNAL, Issue 5 2005
C. S. Teixeira
Abstract Aim, To verify, under the scanning electron microscope (SEM), the influence of irrigation time with ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite (NaOCl) on intracanal smear layer removal. Methodology, Twenty-one extracted human permanent teeth with single straight root canals were included. The root canals of the teeth were instrumented and, at the end of preparation, were irrigated with 3 mL of 15% EDTA, followed by 3 mL of 1% NaOCl for 1 min (group 1), for 3 min (group 2), and for 5 min (group 3). The canals of teeth in group 4 (control) did not receive the final irrigation. The teeth were sectioned longitudinally and prepared for an SEM. The dentinal wall of cervical, middle and apical thirds was graded according to the amount of debris and smear layer remaining on the walls. The results were analysed using the Kruskal,Wallis and Conover,Inman tests. Results, In all the canals of experimental groups irrigation with EDTA and NaOCl completely removed the smear layer from the cervical and middle thirds. In the apical third, the dentine surface were partially covered, particularly in the teeth of group 1, where there was significantly more smear layer when compared with the other thirds in the same group (P < 0.007). However, the Kruskal,Wallis test showed overall that there were no significant differences between groups 1, 2 and 3 (P > 0.05). Conclusion, In this limited laboratory study, canal irrigation with EDTA and NaOCl for 1, 3 and 5 min were equally effective in removing the smear layer from the canal walls of straight roots. [source]

Effectiveness of different techniques for removing gutta-percha during retreatment

INTERNATIONAL ENDODONTIC JOURNAL, Issue 1 2005
A. V. Masiero
Abstract Aim, To evaluate the effectiveness of various techniques for removing filling material from root canals in vitro. Methodology, Eighty extracted mandibular premolar teeth were selected for the study. The teeth were root filled using thermomechanical compaction of gutta-percha. After 8 months, the filling material was removed and canals were reinstrumented using the following techniques: group I , hand instrumentation with K-type files (SybronEndo, Orange, CA, USA); group II , K3 Endo System (SybronEndo); group III , M4 system (SybronEndo) with K-type files (SybronEndo); and group IV , Endo-gripper system (Moyco Union Broach, York, PA, USA) with K-type files (SybronEndo). The amount of filling debris remaining on root canal walls was assessed radiographically; the images were digitized and analysed using AutoCAD 2000 software. Total canal area, area of the cervical, middle and apical thirds, and area of remaining filling material were outlined by one operator. The ratios between these areas were calculated as percentages of remaining debris. Thereafter, data were analysed by means of one-way anova and the post-hoc Duncan test to identify differences between the four techniques. Results, Multiple comparisons of the percentages of remaining filling material in the entire canal did not reveal any significant differences between the methods of removal. However, when each third was analysed separately, significant differences for remaining debris were present between groups. The apical third had the most remaining material, whilst the cervical and middle thirds were significantly cleaner (P = 0.002). Comparison of the techniques revealed that teeth instrumented with K3 rotary instruments had a lower ratio of remaining filling material in the apical third (P = 0.012). Conclusion, In the apical third, K3 rotary instruments were more efficient in removing gutta-percha filling material than the other techniques, which were equally effective for the other thirds. [source]

Evaluation of smear layer removal by EDTAC and sodium hypochlorite with ultrasonic agitation

INTERNATIONAL ENDODONTIC JOURNAL, Issue 5 2002
D. M. Z. Guerisoli
Abstract Aim To evaluate smear layer removal by different irrigating solutions under ultrasonic agitation. Methodology Twenty recently extracted mandibular incisors with a single root canal were divided into four equal groups. Three groups were instrumented using the modified double-flared technique, the fourth remained unprepared. Each group was irrigated with either distilled water, 1.0% sodium hypochlorite alone or associated with 15% EDTAC between each file size. The final group was not instrumented but irrigated with 1.0% sodium hypochlorite and 15% EDTAC. A size 15 file energised by ultrasound was used with small amplitude filing movements against the canal walls in all groups. The teeth were split longitudinally and the roots measured to provide three sections of the same size (cervical, middle and apical). Samples were examined under the scanning electron microscope and assessed for the amount of smear layer by three independent and calibrated examiners. The scoring system ranged from 1 (no smear layer) to 4 (all areas covered by smear layer). Due to the non-parametric nature of the data, Friedman's test was used for statistical analysis. Results Canal walls were covered with smear layer in the group irrigated with 1% sodium hypochlorite alone and the group irrigated with distilled water. Canals irrigated with 1.0% sodium hypochlorite associated with 15% EDTAC had less smear layer throughout the canal (P < 0.001). There were no statistical differences for the amount of smear layer found on the cervical, middle and apical thirds when each group was analysed separately. Conclusions Under ultrasonic agitation, sodium hypochlorite associated with EDTAC removed the smear layer from root canal walls, whereas irrigation with distilled water or 1.0% sodium hypochlorite alone did not remove smear layer. [source]

Breast cancer and microbial cancer incidence in female populations around the world: A surprising hyperbolic association

INTERNATIONAL JOURNAL OF CANCER, Issue 5 2008
Anamaria Savu
Abstract Current literature on cancer epidemiology typically discusses etiology of cancer by cancer type. Risks of different cancer types are, however, correlated at population level and may provide etiological clues. We showed previously an unexpected very high positive correlation between breast cancer (BC) and young-adult Hodgkin disease incidence rates. In a population-based case,control study of BC, older ages at the first Epstein,Barr virus exposure, indicated by older ages at onset of infectious mononucleosis, were associated with elevated BC risk. Here we examine BC risk in association with microbial cancer (MC) risk in female populations across the world. MC cancers are cervical, liver and stomach cancers with established causal associations with human papillomaviruses, hepatitis viruses, and helicobacter pylori, respectively. We examined age-adjusted BC and MC incidence rates in 74 female populations around the world with cancer registries. Our analysis suggests that BC and MC rates are inversely associated in a special mathematical form such that the product of BC rate and MC rate is approximately constant across world female populations. A differential equation model with solutions consistent to the observed inverse association was derived. BC and MC rates were modeled as functions of an exposure level to unspecified common factors that influence the 2 rates. In conjunction with previously reported evidence, we submit a hypothesis that BC etiology may have an appreciable link with microbial exposures (and/or immunological responses to them), the lack of which, especially in early life, may elevate BC risk. © 2008 Wiley-Liss, Inc. [source]

Cancer survival in Germany and the United States at the beginning of the 21st century: An up-to-date comparison by period analysis

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2007
Adam Gondos
Abstract Transatlantic cancer survival comparisons are scarce and involve mostly aggregate European data from the late 1980s. We compare the levels of cancer patient survival achieved in Germany and the United States (US) by the beginning of the 21st century, using data from the Cancer Registry of Saarland/Germany and the SEER Program of the US. Age-adjusted 5- and 10-year relative survival for 23 common forms of cancer derived by period analysis for the 2000,2002 period were calculated, with additional detailed age- and stage-specific analyses for cancers with the highest incidence. Among the 23 cancer sites, 5 (10) year relative survival was significantly higher for 1 (2) and 8 (5) cancers in Germany and the US, respectively. In Germany, survival was significantly higher for patients with stomach cancer, whereas survival was higher in the US for patients with breast, cervical, prostate, colorectal and oral cavity cancer. Among the most common cancers, age-specific survival differences were particularly pronounced for older patients with breast, colorectal and prostate cancer. Survival advantages of breast cancer patients in the US were mainly due to more favorable stage distributions. This comprehensive survival comparison between Germany and the US suggests that although survival was similar for the majority of the compared cancer sites, long-term prognosis of patients continues to be better in the US for many of the most common forms of cancer. Among these, differences between patients with breast and prostate cancer are probably due to more intensive screening activities. © 2007 Wiley-Liss, Inc. [source]

HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation

INTERNATIONAL JOURNAL OF CANCER, Issue 7 2007
Se-Heon Kim
Abstract The prevalence of human papillomavirus (HPV) infection is high in the oropharyngeal mucosal regions, of which the tonsil is the most commonly affected. There may be a link between HPV and the pathogenesis of tonsillar cancer (TC), because of common anatomical characteristics between cervical and tonsillar cancer. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of TC by making a comparison between infection prevalence, physical status and viral loading numbers, and clinicopathologic prognostic factors. To compare HPV-related molecules between TC and tonsillitis (CFT), p16, survivin, HIF-1,, skp-1, cyclin A, cyclin B1, c-myc and EGFR were investigated. We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated. Compared with HPV-negative TC, HPV-positive TC showed a strong association with p16 overexpression (p < 0.0001), and an inverse association with EGFR amplification (p = 0.0478). HPV-16 integration status was strongly associated with c-myc amplification (p = 0.034) and HIF-1, overexpression (p = 0.022). HPV-16 integration could be directly related to tonsillar carcinogenesis initially in tonsillar crypts, followed by cell cycle aberration such as p16 overexpression related to the G1-S phase. © 2006 Wiley-Liss, Inc. [source]

Giardia lamblia intestinalis: a new pathogen with possible link to Kikuchi,Fujimoto disease.

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 12 2004
An additional element in the disease jigsaw
Summary A 16-year-old Caucasian girl of Albanian origin was admitted to the hospital complaining of intermittent fever (38 °C) for a week, nausea, vomiting, and abnormal laboratory findings (elevated serum aminotransferases levels AST/ALT 77/40 U/l and erythrocyte sedimentation rate 80 mm/first hour, as well as leukopenia 2.5 × 103/mm3), which were found in a blood examination. Physical examination revealed slight hepatomegaly and splenomegaly, as well as cervical and axillary lymphadenopathy. A diagnostic open lymph node biopsy was performed and Kikuchi,Fujimoto disease (KFD) was established based on the characteristic histological pattern. Other abnormal laboratory findings were C-reactive protein 6.8 mg/dl and serum lactate dehydrogenase 900 U/l. Her history included a diarrhoea syndrome 2 months before the present admission, during the summer holidays, for which she was treated with metronidazole. At that time, characteristic cysts of giardia lamblia intestinalis were observed in the stools. Herein, we present this case hypothesising that the protozoal infection caused by the giardia lamblia intestinalis was probably triggering an immune response leading to KFD. The patient's age in combination with this firstly reported protozoal pathogen, as a triggering agent leading to KFD, consist a very interesting originality. Additionally, some review data is also given. [source]

Chronic lymphocytic leukemia presenting as cutaneous and bone involvement

INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2001
Maria P. Stefanidou MD
An 84-year-old man had a 3-year history of a progressive, painless, papulonodular eruption, that was particularly prominent on the face and extremities. Physical examination revealed firm, bluish-red nodules and plaques, located on the tip of the nose, the cheeks, ears, and distal digits. Skin lesions produced a leonine facies (Fig. 1), deformities of the fingers and toes, finger clubbing, and onyxis. An identical lesion was seen on a postoperational scar on the left cheek. The mucous membranes were spared. The patient had anterior and posterior cervical and bilateral axillary lymphadenopathy and splenomegaly. Figure 1. Leonine facies On admission, the peripheral blood count revealed 260,000/mm3 leukocytes (lymphocytes 97%, neutrophils 2%, and monocytes 1%), a hemoglobin level of 9.5 g/dL, and platelet count of 100,000/mm3. Hypogammaglobulinemia with reduction of immunoglobulin G (IgG) and IgM was found. Radiography of the fingers showed multiple osteolytic lesions of the phalanges and phalangette destruction of the left median finger (Fig. 2a,b). Computed tomography of the chest and abdomen revealed bilateral axillary, mediastinal, and para-aortic lymphadenopathy and spleen enlargement. Figure 2. X-Ray of the hands: (a) ,multiple osteolytic lesions of the phalanges and (b) ,partial destruction of the left median phalangette Skin biopsy specimens from the ear and finger lesions showed a massive nonepidermal leukemic infiltration in the papillary and reticular dermis, with a grenz zone consisting of small lymphocytes (Fig. 3). Figure 3. Skin biopsy (hematoxylin and eosin, ×,250). Massive leukemic infiltration consisting of small lymphocytes. Subepidermally, a grenz zone of connective tissue is noted Biopsy of the enlarged cervical lymph node showed a diffuse infiltration with lymphocytes. Tissue biopsy from a finger lytic lesion revealed infiltration of bone trabecular and fibrous tissue with a dense population of small- and medium-sized lymphocytes. Immunohistochemical study of cutaneous and bone lesions showed that the infiltrate in both biopsies consisted mainly of B lymphocytes (CD20+, CD45R+, CD45Ro,, OPD4,). Peripheral blood smear had a B-cell phenotype (CD19 98%, CD20 97%, CD23 99%, CD25 40%, CD5 90%, HLA-DR 100%). Bone marrow smear and immunophenotyping surface marker analysis found a diffuse pattern of B-lymphocytic infiltration. A diagnosis of B-cell chronic lymphocytic leukemia stage C (Binet staging system), with specific cutaneous and bone lesions, was established. The patient received chemotherapy with chlorambucil and methylprednisolone, which resulted in improvement of the hematologic profile. Two years later, the cutaneous lesions showed partial remission. [source]

Fibromuscular dysplasia of cervical and intracranial arteries

INTERNATIONAL JOURNAL OF STROKE, Issue 4 2010
Emmanuel Touzé
Fibromuscular dysplasia is an uncommon, segmental, nonatherosclerotic arterial disease of unknown aetiology. The disease primarily affects women and involves intermediate-sized arteries in many areas of the body, including cervical and intracranial arteries. Although often asymptomatic, fibromuscular dysplasia can also be associated with spontaneous dissection, severe stenosis that compromises the distal circulation, or intracranial aneurysm, and is therefore responsible for cerebral ischaemia or subarachnoid haemorrhage. Fibromuscular dysplasia affects middle and distal portions of the internal carotid and vertebral arteries, and occasionally, intracranial arteries. Several pathological and angiographic patterns exist. The most frequent pathological type is medial fibromuscular dysplasia, which is associated with the ,string of beads' angiographic pattern. Unifocal lesions are less common and can be associated with several pathological subtypes. The pathophysiology of the disease is widely unknown. Fibromuscular dysplasia may in fact result from various causes and reflect a non-specific response to different insults. The poor knowledge of the natural history and the lack of randomised trials that compared the different treatment options do not allow any satisfactory judgement to be made regarding the need for or the efficacy of any treatment. [source]

Clinical Characteristics of Flexed Posture in Elderly Women

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 10 2003
Lara Balzini PT
Objectives: To investigate the relationships between the severity of flexed posture (FP), skeletal fragility, and functional status level in elderly women. Design: Cross-sectional study. Setting: Geriatric rehabilitation research hospital. Participants: Sixty elderly women (aged 70,93) with FP referred to a geriatric rehabilitation department for chronic back pain without apparent comorbid conditions. Measurements: Multidimensional clinical assessment included the severity of FP (standing occiput-to-wall distance) demographic (age) and anthropometric (height, weight) data, clinical profile (number of falls, pain assessment, Mini-Mental State Examination, Comorbidity Severity Index, Geriatric Depression Scale, Multidimensional Fatigue Inventory), measures of skeletal fragility (number of vertebral fractures by spine radiograph, bone mineral density (BMD), and T-score of lumbar spine and proximal femur), muscular impairment assessment (muscle strength and length), motor performance (Short Physical Performance Battery, Performance Oriented Mobility Assessment, instrumented gait analysis), and evaluation of disability (Barthel Index, Nottingham Extended Activities of Daily Living Index). Results: The severity of FP was classified as mild in 11, moderate in 28, and severe in 21 patients. Although there were no differences between FP groups on the skeletal fragility measurements, the moderate and severe FP groups were significantly different from the mild FP group for greater pain at the level of the cervical and lumbar spine. The severe FP group was also significantly different from the mild but not the moderate FP group in the following categories: clinical profile (greater depression, reduced motivation), muscle impairment (weaker spine extensor, ankle plantarflexor, and dorsiflexor muscles; shorter pectoralis and hip flexor muscles), the motor function performance-based tests (lower scores in the balance and gait subsets of the Performance Oriented Mobility Assessment), the instrumented gait analysis (slower and wider base of support), and disability (lower score on the Nottingham Extended Activities of Daily Living Index). The total number of vertebral fractures was not associated with differences in severity of FP, demographic and anthropometric characteristics, clinical profile, muscular function, performance-based and instrumental measures of motor function, and disability, but it was associated with reduced proximal femur and lumbar spine BMD. Conclusion: The severity of FP in elderly female patients (without apparent comorbid conditions) is related to the severity of vertebral pain, emotional status, muscular impairments, and motor function but not to osteoporosis, and FP has a measurable effect on disability. In contrast, the presence of vertebral fractures in patients with FP is associated with lower BMD but not patients' clinical and functional status. Therefore, FP, back pain, and mobility problems can occur without osteoporosis. Older women with FP and vertebral pain may be candidates for rehabilitation interventions that address muscular impairments, posture, and behavior modification. Randomized controlled trials are needed to support these conclusions. [source]

Association of Geometric Factors and Failure Load Level With the Distribution of Cervical vs.

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2006
Trochanteric Hip Fractures
Abstract We experimentally studied the distribution of hip fracture types at different structural mechanical strength. Femoral neck fractures were dominant at the lowest structural strength levels, whereas trochanteric fractures were more common at high failure loads. The best predictor of fracture type across all failure loads and in both sexes was the neck-shaft angle. Introduction: Bone geometry has been shown to be a potential risk factor for osteoporotic fractures. Risk factors have been shown to differ between cervical and trochanteric hip fractures. However, the determinants of cervical and trochanteric fractures at different levels of structural mechanical strength are currently unknown. In addition, it is not known if the distribution of fracture types differs between sexes. The aim of this experimental study on excised femora was to investigate whether there exist differences in the distribution of cervical and trochanteric fractures between different structural mechanical strength levels and different sexes and to identify the geometric determinants that predict a fracture type. Materials and Methods: The sample was comprised of 140 cadavers (77 females: mean age, 81.7 years; 63 males: mean age, 79.1 years) from whom the left femora were excised for analysis. The bones were radiographed, and geometrical parameters were determined from the digitized X-rays. The femora were mechanically tested in a side impact configuration, simulating a sideways fall. After the mechanical test, the fracture patterns were classified into cervical and trochanteric. Results: The overall proportion of cervical fractures was higher in females (74%) than in males (49%) (p = 0.002). The fracture type distribution differed significantly across load quartiles in females (p = 0.025), but not in males (p = 0.205). At the lowest load quartiles, 94.7% of fractures in female and 62.5% in males were femoral neck fractures. At the highest quartiles, in contrast, only 52.6% of fractures in females and 33.3% in males were cervical fractures. Among geometric variables, the neck-shaft angle was the best predictor of fracture type, with higher values in subjects with cervical fractures. This finding was made in females (p < 0.001) and males (p = 0.02) and was consistent across all failure load quartiles. Conclusions: Femoral neck fractures predominate at the lowest structural mechanical strength levels, whereas trochanteric fractures are more common at high failure loads. Females are more susceptible to femoral neck fractures than males. The best predictor of fracture type across all structural strength levels and both sexes was the neck-shaft angle. [source]