The results indicated that the earliest iron chelation starts in

The results indicated that the earliest iron chelation starts in liver in patients receiving deferasirox. Additionally, by the 6th month of deferasirox, the status of cardiac and renal iron in chronically transfused patients with beta-TM were preserved. This may indicate that the serum creatinine increases may not be attributed to iron decompartmantalization from other organs to kidneys.</.”

drinks have many potential health problems. The inherent acids and sugars have both acidogenic and cariogenic potential, resulting in dental caries and potential enamel erosion. In this report we present a 25-year-old man complaining with the severe worn-out BEZ235 of the front teeth during the past 3 years. He had a history of drinking cola for more than 7 years and had a poor oral hygiene. Severe decays were present in the incisors

and the canines, while less severe lesions were noted on the premolars and the molars. The review is to show the relationship between dental erosion and caries and soft drinks. Some efforts have been taken to reduce the harmful effect of soft drinks.”
“A simple profile-fitting method is applied to determine the concentrations Geneticin cost of metastable and resonant species in a cold atmospheric pressure argon plasma jet. This method is based on the analysis of the effect of self-absorption broadening on the profiles of spectral lines emitted from plasma. The Argon lines which correspond to transitions to metastable and resonant lower states were measured with high resolution optical emission spectroscopy. Fitting the measured line contours yields line-integrated densities (N(l) x L) of metastable Ar(1s(5)) and Ar(1s(3)) of 1.2 x 10(5) m(-2) and 5.0 x 10(14) m(-2), respectively. For Selleck Blebbistatin resonant species, it is difficult to perform a good density-estimation by fitting measured line contours because of the broad intrinsic resonant line shape and the low resonant

densities in the plasma. Top-limits of 4.8 x 10(15) m(-2) and 7.2 x 10(14) m(-2) are estimated for resonant states Ar(1s(2)) and Ar(1s(4)), respectively. By comparing the fittings of metastable and resonant lines, it is found that the applicability of the profile-fitting routine is sensitive to the line-center optical thickness of emission lines (mainly determined by the lower states densities) and the sharpness of intrinsic line profiles of corresponding transitions. (C) 2011 American Institute of Physics. [doi:10.1063/1.3643004]“
“Nanocomposite polymer electrolytes (NCPEs) composed of poly(ethylene oxide), calcium phosphate [Ca3(PO4)2], and lithium perchlorate (LiClO4)/lithium bis(trifluoromethane sulfonyl)imide [LiN(CF3SO2)2 or LiTFSI] in various proportions were prepared by a hot-press method. The membranes were characterized by scanning electron microscopy, differential scanning calorimetry, thermogravimetrydifferential thermal analysis, ionic conductivity testing, and transference number studies.

Protein analysis via SDS-PAGE and identification of Tandem MS/MS

Protein analysis via SDS-PAGE and identification of Tandem MS/MS afterwards showed that outer membrane protein (Omp) primarily deals with decolorization as a channeling regulation. Moreover, molecular modeling and bioinformatics data also provided ACY-738 supplier detailed evidences to confirm the biological significance of Omp.”
“The beta-thalassemias are characterized by a quantitative deficiency of beta-globin chains under-laid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural beta gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most beta-thalassemias

are inherited in a Mendelian recessive fashion but there is a subgroup of beta-thalassemia GM6001 supplier alleles that behave as dominant negatives. Unraveling the molecular

basis of beta-thalassemia has provided a paradigm for understanding of much of human genetics.”
“Polycystic ovary syndrome (PCOS) presents with a range of clinical complications including hyperandrogenism, polycystic ovaries, chronic oligo/anovulation, infertility, and metabolic alterations related to insulin resistance. Because the mechanism by which this disorder develops is poorly understood, information from experimental models of human disease phenotypes may help to define the mechanisms for the initiation and development of PCOS-related pathological events. The establishment of animal models compatible with human PCOS is challenging, and applying the lessons learned from these models to human PCOS is often complicated. In this mini-review we provide examples of currently available genetic mouse models, their ovarian phenotypes,

and their possible relationship to different aspects of human PCOS. Because of the practical and ethical limitations of studying PCOS-related events in humans, our understanding of the mechanisms that contribute to the etiology of human PCOS may be enhanced through further study of these transgenic and knockout mouse models.”
“Ulcerated diabetic foot is a complex problem. Ischaemia, neuropathy and infection are the three pathological components that lead to diabetic foot complications, and they frequently occur GSK923295 mouse together as an aetiologic triad. Neuropathy and ischaemia are the initiating factors, most often together as neuroischaemia, whereas infection is mostly a consequence. The role of peripheral arterial disease in diabetic foot has long been underestimated as typical ischaemic symptoms are less frequent in diabetics with ischaemia than in non-diabetics. Furthermore, the healing of a neuroischaemic ulcer is hampered by microvascular dysfunction. Therefore, the threshold for revascularising neuroischaemic ulcers should be lower than that for purely ischaemic ulcers. Previous guidelines have largely ignored these specific demands related to ulcerated neuroischaemic diabetic feet.

Biological approaches such as anti-Nogo and cell replacement ther

Biological approaches such as anti-Nogo and cell replacement therapy have shown efficacy in preclinical models but have yet to reach proof of concept in the clinic. Finally, selleck chemical noninvasive cortical stimulation techniques have been used in a few small trials and have shown promising results. It appears that the efficacy of all these platforms can be potentiated through coupling with concomitant behavioral intervention. Given this array of potential mechanisms that exist to augment and/or stimulate neural reorganization

after stroke, we are optimistic that approaches to aphasia therapy will transition from compensatory models to models in which brain reorganization is the goal.”
“In this article, partial oxidation of sodium alginate with potassium permanganate (KMnO(4)) was researched successfully. The

effects of KMnO(4) on the properties of partially oxidized sodium alginate were discussed. It was found that the degree of oxidation and degradation rate of sodium alginate could be controlled by oxidation conditions, as monitored by the reduction of viscosity and decrease of molecular FK228 ic50 weight. This work provides a new method to obtain partially oxidized alginate and to improve degradability of alginate for biomedical applications, (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 113:3585-3589, 2009″
“Background: Diagnostic provocation tests (ICD Z01.5) have a low cost weight in the German DRG system. We aimed at investigating a possible economic Proton Pump inhibitor impact on the number of provocation tests in German university medical centers (UMC) for dermatology.

Methods: We review quality records of 35 German UMC for 2008 and 2010 (ICD Z01.5, total number of patients as well as priority ranking).


33/35 hospitals gave full data for both years including the ten most frequent diagnoses. Between 2008 and 2010, total number of patients treated increased in 23/33 (70 %) UMC, those with ICD Z01.5 only in 11/24 (46 %) UMC with full data. In 2008, the ICD Z01.5 was in the top ten list of main diagnoses in 29/33 (88 %) hospitals, in 2010 in 25/33 (76 %); also, priority ranking tended to decrease. In contrast, total number of ICD Z01.5 in Germany tended to increase slightly.

Conclusions: We noticed a tendency for decreasing numbers of provocation tests being performed in dermatological UMC in Germany. As there is no evidence for a decreasing number of patients suffering from allergies, one may speculate about a shift to non-university departments due to an economic impact.”
“Repetitive transcranial magnetic stimulation (rTMS) has been used to improve language behavior, including naming, in stroke patients with chronic, nonfluent aphasia. Part 1 of this article reviews functional imaging studies related to language recovery in aphasia.

The auditory brainstem response was absent on the

The auditory brainstem response was absent on the EPZ5676 research buy right; however, distortion product otoacoustic emissions were detected on both sides. The right cochlear nerve at the level of the fundus was absent on 3-dimensional constructive interference in steady state magnetic resonance imaging.

Conclusion: Most cases of CND show deafness or profound hearing loss, but the patient in this case had only moderate hearing loss. This finding provides evidence that auditory thresholds are variable in patients with CND. Therefore, careful evaluation is needed in diagnosis of patients with hearing loss.”
“Objective: Transforming

growth factor-beta (TGF-beta) plays a critical role in cartilage homeostasis and deregulation of its signalling is implicated in osteoarthritis (OA). TGF-beta isoforms signal through a pair of transmembrane serine/threonine kinases known as the type I and type II TGF-beta receptors. Endoglin is a TGF-beta co-receptor that binds TGF-beta with high affinity in the presence of the type II TGF-beta CH5424802 receptor. We have previously shown that endoglin is expressed in human chondrocytes and that it forms a complex with the TGF-beta signalling receptors. However,

the functional significance of endoglin expression in chondrocytes is unknown. Our objective was to determine whether endoglin regulates TGF-beta/Smad signalling and extracellular matrix (ECM) production in human chondrocytes and whether its expression varies with chondrocyte differentiation state.

Method: Endoglin function was determined by overexpression or antisense morpholino/siRNA knockdown of endoglin in human chondrocytes and measuring TGF-beta-induced Smad learn more phosphorylation, transcriptional activity and ECM production. Alterations in endoglin expression levels were determined during subculture-induced dedifferentiation of human chondrocytes and in normal vs OA cartilage samples.

Results: Endoglin enhances TGF-beta

1-induced Smad1/5 phosphorylation and inhibits TGF-beta 1-induced Smad2 phosphorylation, Smad3-driven transcriptional activity and ECM production in human chondrocytes. In addition, the enhancing effect of endoglin siRNA knockdown on TGF-beta 1-induced Smad3-driven transcription is reversed by ALK1 overexpression. Furthermore, endoglin levels are increased in chondrocytes following subculture-induced dedifferentiation and in OA cartilage as compared to normal cartilage.

Conclusion: Together, our results suggest that endoglin regulates the balance between TGF-beta/ALK1/Smad1/5 and ALK5/Smad2/3 signalling and ECM production in human chondrocytes and that endoglin may represent a marker for chondrocyte phenotype. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.”
“Background: Adult-onset primary dystonia is thought to be a purely motor disorder.

Immunohistochemical studies showed the cells to stain positively

Immunohistochemical studies showed the cells to stain positively for pan cytokeratin and smooth muscle actin, indicating myoepithelial differentiation (MED). Foci of conventional basal cell carcinoma were present, and cells with MED were also admixed within some of the aggregations of basal cell carcinoma. On the basis of these findings, we interpreted this lesion to represent basal cell carcinoma

with MED. A review Crenolanib in vitro of the existing literature of basal cell carcinomas with similar morphologic features is also presented.”
“The anatomy of dental compensation curve in the frontal plane described by George H. Wilson is one of the occlusal determinants of orthodontic treatment. However, there is few published comparing malocclusion and normocclusion individuals.

Objectives: The aim of this study is to compare the curve of Wilson at first and second maxillary molars, normocclusion pattern and malocclusion pattern, with and without bilateral posterior crossbite, using angular references in CBCT studies.

Material and Methods: INCB018424 datasheet We analyzed

10 cases of malocclusion with bilateral posterior crossbite, 10 cases of malocclusion without bilateral posterior crossbite and 10 cases with non orthodontic normocclusion (patients who underwent cone beam study for other reasons than orthodontic). All of them were adults, more than 19 years. Angular variables from left and right axis (line connecting the occlusal and furcation groove) of first and second molars towards a perpendicular to the frontal palate were measured. There was carried out an Anova test, Bonferroni analysis and Levene’s statistics.


The descriptive analysis of the results shows an average values of total maxillary curve of Wilson for first molars (sum of left and right angle) of 8.1 degrees for normocclusion group, 0.4 degrees for the malocclusion pattern with bilateral posterior learn more crossbite and 16.9 degrees for the malocclusion pattern without this alteration. The mean differences was statistical significant (P<0,042) between between malocclusion pattern groups with and without crossbite.

Conclusion: The curve of Wilson, measured at maxillary first molars in patients with bilateral posterior crossbite is more concave than the other groups, suggesting no dentoalveolar compensations.”
“Accumulation of amyloid-beta (A beta) peptides (predominantly A beta(40, 42)) and their aggregation into plaques in the brain are thought to be the one of the major causes of Alzheimer’s disease (AD). Originally discovered in our Chinese hamster ovary (CHO) cell line stably expressing human wild-type amyloid precursor protein (APP) (CHO/APPwt) cultures devoid of A beta production, we found that Mycoplasma selectively degrades soluble A beta in a time and dose (colony forming unit) dependent manner.

After informed consent, subjects were interviewed using EQ-5D, EQ

After informed consent, subjects were interviewed using EQ-5D, EQ-VAS and SF-6D, and their socio-demographic and medical information was solicited.

Compared CHIR-99021 concentration to the general population (n = 364), CP/CPPS patients (n = 268) reported significantly worse HRQoL with median score of the EQ-5D utility index (0.73

vs. 0.85), SF-6D utility index (0.76 vs. 0.81), and EQ-VAS (70.0 vs. 85.0). Multiple linear regression analyses showed pain symptom had the strongest predictive power for HRQoL, compared to symptom duration and urinary symptom. Socio-demographic factors and comorbidities did not significantly contribute to poorer HRQoL.

CP/CPPS patients experienced deteriorated HRQoL with lower health-related utility scores compared to general population, and pain

severity was the main physical symptom predicting decreased GW786034 nmr health-related utility. Further studies are needed to provide the reference utility index for the comparison and better characterizing the influence of geographic and cultural factors on variation of health-related utility of CP/CPPS patients.”
“Background and methods: A double-blind, parallel-group, controlled study was performed to investigate if milnacipran was noninferior to paroxetine in terms of improvement in symptoms of depression in Japanese patients with major depressive disorders in a fixed-dose design. The efficacy and safety of milnacipran GSK621 chemical structure 200 mg/day were also assessed in comparison with those at the standard dose of 100 mg/day.

Results: Changes in 17-item Hamilton depression rating scale (HAM-D) total score (mean +/- standard deviation) for group M1 (milnacipran 100 mg/day), group M2 (milnacipran 200 mg/day), and group PX (paroxetine 30 or 40 mg/day) were -12.9 +/- 5.8, -12.8 +/- 6.1, and -13.1 +/- 6.2, respectively, and the estimated differences in total score for group PX (Dunnett’s 95% simultaneous confidence interval) were 0.1 (-1.1 to 1.3) for group M1 and 0.3 (-0.9 to 1.5) for group M2. The noninferiority

of groups M1 and M2 to group PX was thus confirmed, because the upper confidence limit of differences between groups M1 and PX and between groups M2 and PX was less than 2.0. The estimated mean difference of change in HAM-D total score (95% confidence interval) between groups M2 and M1 was 0.2 (-0.9 to 1.2), indicating a comparable change in total score for both groups. The incidence of treatment-related adverse events was 71.7% for group M1, 68.8% for group M2, and 69.3% for group PX, indicating no significant difference between the three groups.

Conclusion: These results demonstrate that milnacipran 100 mg/day and 200 mg/day is not inferior to paroxetine in terms of efficacy and safety.”
“Ethylene biosynthesis is directed by a family of 1-aminocyclopropane-1-carboxylic acid (ACC) synthases (ACS) that convert S-adenosyl-l-methionine to the immediate precursor ACC.

The parotidectomy specimen showed a 3 cm-sized solid nodular lesi

The parotidectomy specimen showed a 3 cm-sized solid nodular lesion with small cysts. Microscopically, the lesion was an unencapsulated mass of sclerotic fibrous tissue with cystic ducts, multiple calcifications, and lymphoplasma cell infiltration. Sclerosing adenosis and cystic ducts with frequent apocrine-like cells were noted. Familiarity with the cytologic and histological

features of SPA is very important making the correct diagnosis.”
“Many animals exhibit behavioural syndromes-consistent individual differences in behaviour across two or more contexts or situations. Here, we present adaptive, state-dependent mathematical models for analysing issues about behavioural syndromes. We find that asset protection (where individuals with more ‘assets’ tend be more cautious) and starvation avoidance, two state-dependent HSP inhibition mechanisms, can explain short-term behavioural consistency, but not long-term stable behavioural types (BTs). These negative-feedback mechanisms tend to produce convergence in state and behaviour over time. In contrast, a positive-feedback mechanism, state-dependent safety (where individuals with higher energy reserves, size, condition or vigour

are better at coping with predators), can explain stable differences in personality over the long term. The relative importance of negative-and positive-feedback mechanisms in governing behavioural consistency depends on environmental conditions (predation risk and check details Raf inhibitor resource availability). Behavioural syndromes emerge more readily in conditions of intermediate ecological favourability (e. g. medium risk and medium resources, or high risk and resources, or low risk and resources). Under these conditions, individuals with higher initial state maintain a tendency to be bolder than individuals that start with low initial state; i.e. later BT is determined by state during an early ‘developmental window’. In contrast, when conditions are highly favourable (low risk, high resources) or highly unfavourable (high risk, low resources), individuals converge

to be all relatively bold or all relatively cautious, respectively. In those circumstances, initial differences in BT are not maintained over the long term, and there is no early developmental window where initial state governs later BT. The exact range of ecological conditions favouring behavioural syndromes depends also on the strength of state-dependent safety.”
“Bartonella spp. are intra-erythrocytic pathogens of mammals. In this study, we investigated the role of the spleen, and other tissue and organs in Bartonella infection. Using an in vivo model of mice infection by Bartonella birtlesii, we detected accumulation of bacteria in the spleen, with transient infection of the liver, but failed to detect any bacteria in brain or lymph nodes. We then compared bacteraemia in normal Balb/C mice and in splenectomized mice.

Their demographics and attitudes toward the Pap test were analyze

Their demographics and attitudes toward the Pap test were analyzed.

ResultsThe median age of the participants was 27.5 years and 88.2% were sexually active. Before the first vaccination, 38.5% (57/148) of the screening targets had never had a Pap test. Among the women who completed the third vaccination, Pap test experiences within the recent 2 years increased from 45.3% (63/139) at the first vaccination to 71.2% (99/137) at the third vaccination, and 67.5% (54/80) 2 years later.

In 45.3% of the screening targets who had never had a Pap test at the time of their first HPV vaccination, their first Pap test was followed by their vaccination.

ConclusionsHaving biennial Pap tests

in accordance with the Japanese GANT61 molecular weight national cancer JIB04 screening guideline was shown to be difficult even for the women in the medical community; however, education about the Pap test and the efficacy of HPV vaccination in providing opportunistic screening encouraged them to have their first or suspended Pap test. Our interim data suggest the need for urgently changing the cervical cancer prevention strategy for young adult women who are excluded from the national HPV vaccine program.”
“Case Description-2 spayed female (8 and 9 years old) and 1 sexually intact male (6.5 years old) Boxers were treated because of sustained ventricular tachycardia by electrical cardioversion.

Clinical Findings-Physical examination of the 8-year-old female Boxer revealed tachycardia (heart rate, 250 beats/min), weak femoral pulses, pale mucous membranes, panting, and lethargy. The 6.5-year-old male Boxer had similar physical examination findings, with the addition of a syncopal event. Analysis of the ECG rhythm strips for the 8- and 6.5-year-old dogs indicated a right ventricular origin of the ventricular tachycardia. The 9-year-old female Boxer was being treated with an IV constant rate infusion of lidocaine hydrochloride because of ventricular arrhythmias during the initial examination; physical examination revealed weakness, pale

mucous membranes, prolonged capillary refill time, weak femoral pulses, and tachycardia (heart rate, 265 selleck beats/min). Analysis of the ECG rhythm strip for the 9-year-old Boxer indicated a left ventricular origin of the ventricular tachycardia.

Treatment and Outcome-Pharmacological cardioversion treatment was unsuccessful in all 3 Boxers; however, electrical cardioversion by use of a biphasic defibrillator synchronized to conduct 30 J of energy during the peak of the QRS complex was successful in each dog. The electrical cardioversion procedure was performed 2 times (5-day interval between procedures) in the 9-year-old female as a result of relapse of the ventricular tachycardia condition.

Decrease in creatinine clearance by correction of the fluid imbal

Decrease in creatinine clearance by correction of the fluid imbalance and wound closure by skin graft surgery likely contributed to the restoration of fluid shift, resulting in normal disposition of cefepime and favorable clinical outcome of the patient.”
“The essential oil profile of Baccharis anomala DC was examined. Samples were collected from in the Pro-Mata area (Sao Francisco de Paula, Rio Grande do Sul State, Brazil), and

GC-MS data and retention indices were used to identify 58 oil components. beta-Selinene (40.8%), caryophyllene oxide (9.9%) and spathulenol (6.8%) were the major constituents of the steam-distilled oil. The olfactive profile of the B. anomala oil was described as: sweet, resinous and woody. When the oil was evaluated by gas chromatography-olfactometry (GC-O), the study revealed that the oil has a complex aroma profile formed by 34 odorants Protein Tyrosine Kinase inhibitor with modified frequency above 40,31 of which could be identified. In this way, the odor, was objectively established for this species. (C) 2013 Elsevier B.V. All rights reserved.”
“Objective: To compare temporal aspects of peripheral neural responses and central auditory perception between groups of younger adult and elderly cochlear implant users.

Study Design: Cohort study.

Setting: Academic hospital and cochlear implant center.

Patients: Adult cochlear implant users aged 28 to 57 years in the younger group (n = 5) and 61 to 89 years

(n = 9) in the elderly group. All subjects Selleck Birinapant used Advanced Bionics devices.

Intervention: Diagnostic.

Main Outcome Measures: Time constants of neural (i. e., electrically evoked compound action potentials [ECAPs]) and perceptual recovery from forward masking. Interstimulus intervals Sapanisertib chemical structure (ISIs) were varied in both experiments.

Results: ECAP recovery rates were equivalent between groups, and no correlation was found between ECAP recovery and age. No correlations were found between ECAP recovery and speech perception. Psychophysical recovery was significantly slower in the elderly compared with the younger subjects (p < 0.0005), with a significant effect

of age (R-2 = 0.70, p < 0.0005). At the longest ISI (240 ms), elderly subjects experienced a mean maximum threshold shift of 35.2% (relative to 1 ms ISI) versus 14.8% for younger subjects. There was a significant positive relationship between psychophysical recovery and consonant-nucleus-consonant word scores (R-2 = 0.62, p < 0.001), although no relationship was found with Hearing in Noise Test sentences.

Conclusion: These findings suggest that difficulties observed in speech perception by elderly CI users may be due to age-related changes in the central rather than peripheral auditory system. With further study, these results may provide information to allow clinicians to assess patients’ temporal processing abilities and facilitate setting program parameters that will maximize their auditory perceptual experience with a cochlear implant.

This case report is accompanied by a review of the relevant liter

This case report is accompanied by a review of the relevant literature.”
“Ischemic stroke is the third leading cause of death in the United States and a common reason for hospitalization. The subacute period after a stroke refers to the time when the decision to not employ thrombolytics is made up until two weeks after the stroke occurred. Family physicians are often involved in the subacute management of ischemic stroke. All patients with an ischemic stroke should be admitted to the hospital in the subacute period for cardiac and neurologic monitoring. buy Cilengitide Imaging studies, including

magnetic resonance angiography, carotid artery ultrasonography, and/or echocardiography, may be indicated to determine the cause of the stroke. Evaluation for aspiration risk, including a swallowing assessment, should be performed, and nutritional, physical, occupational, and speech therapy should be initiated. Significant causes of morbidity and mortality following ischemic stroke include venous thromboembolism, pressure sores, infection, and delirium, and measures should be taken to prevent these complications. For secondary prevention of future strokes, antiplatelet therapy with aspirin should be initiated within 24 hours of phosphatase inhibitor library ischemic stroke in all patients without contraindications,

and one of several antiplatelet regimens should be continued long-term. Statin therapy should also be given in most situations. Although permissive hypertension is initially warranted, antihypertensive therapy should begin within 24 hours. Diabetes mellitus should be controlled and patients counseled about lifestyle modifications to reduce stroke risk. Rehabilitative therapy following hospitalization improves outcomes and should be considered. (Am Fam Physician. 2011;84(12):1383-1388. Copyright (C) 2011 American Academy of Family Physicians.)”
“The high prevalence of craniovertebral

junction malformation in Northeastern Brazil is historically associated with brachycephalic BIX 01294 mw biotype (flat head), also common in this region. It has been postulated that this trait was introduced to this region by the Dutch during the colonial period in Brazil’s history. Based, on the confrontation of this paradigm against some historical facts, the authors concluded that the brachycephalic phenotype was inherited from prehistoric ancestors (Amerindians) who were already living in this region when white European men arrived.”
“Some members of the Toll-like receptor (TLR) family, which plays key roles in both innate and adaptive immune responses, are involved in the pathogenesis of autoimmune, chronic inflammatory and infectious diseases. However, the role of TLR in the pathogenesis of oral lichen planus (OLP) has not been investigated. The aim of this study was to understand the roles of TLR in OLP.