Knowledge of the advantages, limitations, and clinical role of

Knowledge of the advantages, limitations, and clinical role of MK5108 concentration each equation

will facilitate their safe and effective use in drug dosing.”
“Enterovirus 71 (EV71) infection leading to cardiopulmonary failure (CPF) is rare, but usually fatal. In such cases, intensive cardiorespiratory support is essential for survival. In this study, we report our experience in the treatment of EV71-related CPF with extracorporeal life support (ECLS).\n\nThis was a retrospective study of a total of 13 children, aged 16 +/- A 10 months, with EV71-related hemodynamically unstable CPF, which was refractory to conventional treatments, who were rescued by transsternal ECLS from 2000 to 2008. The clinical manifestations and outcomes of the 13 children (present cohort) were compared with those of 10 children (past cohort) who had EV71-related CPF without ECLS between 1998 and 2000.\n\nAmong these 13 patients, 10 were successfully weaned off ECLS and survived. The myocardial recovery time was 71 +/- A 28 (median, 69) h, and the ECLS duration was 93 +/- A 33 (median, 93) h. Six surviving patients had a good neurological outcome at hospital discharge. All surviving patients had some neurological sequelae but showed improvement at follow-up, including dysphagia in nine, central hypoventilation in seven, limb weakness in six and seizure

in three. The present cohort had better neurological outcomes (46 vs. 0%, P = 0.005) and a higher survival rate (77 vs. 30%, P = 0.024) than the past cohort, respectively.\n\nPatients with EV71-related CPF supported by ECLS had a higher survival rate and fewer neurological

sequelae than those who only www.selleckchem.com/products/3-deazaneplanocin-a-dznep.html received conventional treatments. ECLS is an effective alternative method for treatment of children with refractory EV71-related CPF.”
“Phytoremediation is a plant based, cost effective technology to detoxify or stabilise 11-deoxojervine contaminated soils. Fast growing, high biomass, perennial plants may be used not only in phytoremediation but also in energy production. Szarvasi-1 energy grass (Elymus elongatus subsp. ponticus cv. Szarvasi-1), a good candidate for this combined application, was grown in nutrient solution in order to assess its Cd, Cu, Ni, Pb and Zn accumulation and tolerance. Its shoot metal accumulation showed the order Pb < Ni < Cu similar to Cd < Zn. In parallel with this, Pb and Ni had no or very little influence on the growth, dry matter content, chlorophyll concentration and transpiration of the plants. Cu and Cd treatment resulted in significant decreases in all these parameters that can be attributed to Fe plaque formation in the roots suggested by markedly increased Fe and Cu accumulation. This came together with decreased shoot and root Mn concentrations in both treatments while shoot Cu and Zn concentrations decreased under Cd and Cu exposure, respectively. Zn treatment had no effect or even slightly stimulated the plants.

Measurements and Main Results, Rats were randomly divided int

\n\nMeasurements and Main Results, Rats were randomly divided into ART-123 pretreated group, ART-123 treated group, and LPS group, respectively. After the injection Selonsertib purchase of LPS, the levels of inflammatory cytokines and thrombin-antithrombin III complex, plasma HMGB1 concentrations, liver immunohistochemical and histopathologic

characteristics, liver dysfunction, and survival rate were examined. The increased levels of inflammatory cytokines and plasma HMGB1 induced by LPS in this rat model were improved by the administration of ART-123; additionally, reduced liver dysfunction and increased survival rate were observed.\n\nConclusions. This study demonstrated that ART-123 inhibits the expression of inflammatory

cytokines and decreases the plasma HMGB1 levels in experimental endotoxemia. In addition, ART-123 administration markedly reduced liver dysfunction and mortality even with delayed treatment of ART-123. The use of ART-123 may therefore be a beneficial treatment for septic patients. (Crit Care Med 2009; 37:2181-2186)”
“Background Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and S63845 clinical trial offer the opportunity for disease prevention.\n\nMethods and Results We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify check details novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alstrom syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide

polymorphisms of the ALMS1 promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI.\n\nConclusions The glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.”
“Background\n\nFitzpatrick skin type (FST I-IV) is a subjective expression of ultraviolet (UV) sensitivity based on erythema and tanning reactivity after a single exposure. Pigment protection factor (PPF) is an objective measurement of skin sensitivity in all skin types after a single exposure.

Bax redistributed from cytosol to mitochondria from 12 to 48 h af

Bax redistributed from cytosol to mitochondria from 12 to 48 h after bufalin treatment in living cells expressed with green fluorescent protein Bax. Treatment with the antioxidant N-acetyl-cysteine (NAC), a ROS scavenger, inhibited ROS generation and PD173074 Bax translocation and led to a significant protection against bufalin-induced apoptosis. Our results also revealed that bufalin induced

a prominent increase of caspase-3 activation blocked potently by NAC. Taken together, bufalin induced ROS-mediated Bax translocation, mitochondrial permeability transition and caspase-3 activation, implying that bufalin induced apoptosis via ROS-dependent mitochondrial death pathway in ASTC-a-1 cells.”
“Purpose: To report the histological and immunohistochemical findings in a cornea

removed from a patient who had undergone collagen cross-linking (CXL) with riboflavin and ultraviolet-A for progressive keratoconus. CXL was performed following the Siena protocol. Two years post-CXL, a visual acuity impairment in the treated eye secondary Prexasertib to corneal stromal opacity had occurred, together with corneal thinning and flattening.\n\nMethods: The excised cornea was formalin-fixed, paraffin-embedded, and examined microscopically. Deparaffinized 4-mu m sections were stained with hematoxylin-eosin and Masson trichrome. Further tissue sections were subjected to immunohistochemical evaluation of CD34 and Ki-67 antigens.\n\nResults: Histologically, there was no scar tissue in the failed cornea. The biomicroscopic stromal opacity corresponded microscopically to an acellular area, devoid of keratocytes, and to compaction of the lamellar collagen. Amorphous, weakly eosinophilic interlamellar deposits, extending from the anterior to the posterior two thirds of the stroma, were noted.\n\nConclusions: CXL is a promising procedure for the treatment of progressive keratoconus with minimal reported side effects. In the present case,

we speculate that the short corneal soaking time (15 minutes according VEGFR inhibitor to the Siena protocol) may have resulted in inefficient ultraviolet-A blocking, thermal injury, and deeper keratocyte death. Inadequate keratocyte stem cells reservoir could also play a role in individual cases.”
“The robustness of commercial power metal-oxide semiconductor field-effect transistors to combined gamma-heavy ion irradiation has been investigated, evidence that the degradation of the gate oxide caused by the gamma irradiation can severely corrupt the robustness to single-event effects and drastically modify the physical behavior of the device under test after the impact of a heavy ion. A decrease of the critical voltages at which destructive burnouts and gate ruptures for heavy ion impact appear, has been detected in the devices under test, which were previously irradiated with gamma rays.

In addition, several groups have contributed to other new cathete

In addition, several groups have contributed to other new catheter-improving properties of this spectroscopic device. However, a relatively small number of studies has been published in the literature, due to industrial interest in this interdisciplinary and multidisciplinary area. To our knowledge, no review that has focused on the applications of catheters to several modes of spectroscopy has been published. In this work we revised this topic, analyzing

the advancements and limitations of the recent biomedical catheters.”
“Objectives: Low participation rates ill the selection of population controls are an increasing concern for the validity of case-control studies worldwide.\n\nMethods: We conducted GSK1904529A inhibitor a pilot

study to assess two approaches to recruiting population controls in a study of colorectal cancer, including a face-to-face interview and www.selleckchem.com/products/BMS-777607.html blood sample collection. In the first approach, persons identified through a population roster were invited to participate through a telephone call by an interviewer telephoning on behalf of our research center. In the second approach, individuals were identified from the lists of selected family practitioners and were telephoned on behalf of the family practitioner.\n\nResults: When the second method was used, participation rates increased from 42% to 57% and the percentage of refusals decreased from 47% to 13%. The reasons for refusing to participate did not differ significantly between the two methods. Conclusions: Contact through the family practitioner yielded higher response rates in population controls ill the study area. (C) 2010 SESPAS. Published by Elsevier Espana,

S.L. All rights reserved.”
“Despite the decline in the overall incidence of tuberculosis (TB) in many developed countries, it remains an important problem among the older population. The control of TB in the elderly remains a major challenge because of the limitations of the existing tools for the diagnosis and treatment of latent TB infection and clinically active disease. This article examines the current and possible future status of TB in the elderly, focusing on epidemiology, risk factors, preventive treatment strategies, and clinical disease.”
“An attempt A-1210477 clinical trial was made to optimize the mechanical properties by tailoring the process parameters for two newly developed high-strength carbide-free bainitic steels with the nominal compositions of 0.47 pct C, 1.22 pct Si, 1.07 pct Mn, 0.7 pct Cr (S1), and 0.30 pct C, 1.76 pct Si, 1.57 pct Mn, and 0.144 pct Cr (S2) (wt pct), respectively. Heat treatment was carried out via two different routes: (1) isothermal transformation and (2) quenching followed by isothermal tempering. The results for the two different processes were compared.

This compartment likely contains CSCs since it

is express

This compartment likely contains CSCs since it

is expressing the putative CSC markers CD44, ALDH1 and CK14. This cell layer therefore should be considered a major therapeutic target in the treatment of head and neck cancer. (C) 2009 Elsevier Ltd. All rights reserved.”
“Purpose: To prospectively evaluate the clinical effectiveness of snapshot inversion recovery (SNAPIR), which is a dedicated optimized inversion-recovery-prepared single-shot fast GW3965 datasheet spin-echo T1-weighted sequence, in the delineation of normal fetal brain anatomy compared with that of the currently used T1-weighted gradient-echo protocol, which often yields images of poor quality due to motion artifacts and inadequate contrast.\n\nMaterials and Methods: This study was approved by the hospital research ethics committee,

and informed written consent was obtained from all patients. Forty-one fetuses were examined at 19-37 weeks gestation (mean, 29 weeks gestation) by using both the standard T1-weighted protocol and the optimized T1-weighted SNAPIR protocol with a 1.5-T CT99021 purchase imager. Two independent blinded observers performed qualitative analysis, evaluating overall diagnostic quality, detailed anatomic delineation, and severity of motion artifacts. Quantitative analysis comprised calculation of contrast ratios (CRs) for the cortical gray matter, subplate, white matter, and cerebrospinal fluid. The Wilcoxon signed rank test was used to compare image rating scores, the paired t test was used to compare CRs, and kappa statistics were used to test interobserver agreement.\n\nResults: Both overall diagnostic quality (P < .001) and detailed anatomic delineation (P < .001) were enhanced with SNAPIR compared with the standard T1-weighted acquisition. Also, motion artifacts were

less severe (P = .008) and less extensive (P < .001) with SNAPIR. Corresponding CRs were increased with SNAPIR in seven of eight examined regions.\n\nConclusion: CCI-779 SNAPIR is a promising robust alternative to the current T1-weighted acquisitions; its role in the detection of disease requires further study. (C) RSNA, 2010″
“Background: Guidelines recommend evaluation of cardiac function, valvular and ischemic heart disease, and thyroid, kidney, and liver function on initial diagnosis of atrial fibrillation (AF). Hypothesis: We hypothesized that initial workup of patients with newly identified AF would vary by age, sex, and burden of comorbid illness. Methods: In a retrospective analysis of a large sample of commercially insured patients 18 to 64 years old (n = 40 245) and a nationally representative 5% cohort of Medicare beneficiaries 65 years or older (n = 204 676), we measured claims for guideline-recommended services for initial evaluation of AF among patients with a new diagnosis between 2000 and 2008.

The current study assessed the effects of acamprosate

The current study assessed the effects of acamprosate HKI-272 molecular weight on alcohol use and mood symptoms in subjects with co-occurring bipolar disorder and active alcohol dependence.\n\nMethods: Thirty-three

adults meeting criteria for bipolar I or bipolar II disorder and current alcohol dependence were randomized to receive add-on acamprosate (1998 mg/day) or placebo while concurrently maintained on mood stabilizing medications. Participants were assessed weekly for frequency and quantity of alcohol consumption and general clinical severity for eight weeks. Depressive symptoms, manic symptoms, and alcohol craving were assessed biweekly. Biomarkers of alcohol use were assessed at study baseline and endpoint.\n\nResults: Of the 33 subjects randomized, 23 (69.7%) completed all active phase visits. Over the trial as a whole, no statistically significant treatment differences were detected in drinking outcomes. Post-hoc analysis revealed lower Clinical Global Impression

scores of substance G418 mw use severity in acamprosate-treated participants in weeks 7-8 of the trial. No significant differences in depressive symptoms, manic symptoms, or adverse events were observed between groups.\n\nConclusions: Acamprosate was well-tolerated, with no worsening of depressive or manic symptoms, and appeared to confer some clinical benefit in study completers in the last two weeks of the trial. Larger studies of longer duration are required to fully explore the utility of acamprosate in this population.”
“Fruit presence often ACY-738 mw positively and seldom negatively affects leaf carbon assimilation rate in fruit-trees. In almond (Prunus dulcis (Mill.) DA Webb) the presence of

fruit often results in the death of the fruit bearing spurs. The mechanism of this effect is unclear, but may be a consequence of diminished carbon assimilation rate in leaves adjacent to fruit and the subsequent depletion of nutrient and carbohydrates reserves. This study evaluated the influence of fruit on leaf carbon assimilation rate and leaf nitrogen throughout the season. Carbon assimilation rate (A(a)), rubisco carboxylation capacity at leaf temperature (V-cmax@Tleaf), maximum rate of RubP regeneration at leaf temperature (J(max@Tleaf)), leaf nitrogen on a mass basis (N%) and area basis (N-a), and specific leaf weight data were recorded. Fruit presence negatively affected leaf nitrogen concentration by a reduction in specific leaf weight and leaf nitrogen content. The impact of fruit presence on carbon assimilation rate was predominantly associated with the negative effect of fruit on N-a and resulted in a significant reduction in J(max@Tleaf) and therefore in A(a), especially after full leaf and fruit expansion.

After 1, 2 and 4weeks, the animals were sacrificed and mRNA expre

After 1, 2 and 4weeks, the animals were sacrificed and mRNA expression

of OPG/RANKL was evaluated by real-time PCR. One rat was sacrificed without any interventions (negative control) to determine the baseline expression of the mediators involved. Data were analysed by one-way anova.\n\nResultsSimvastatin significantly (P<0.05) enhanced the expression of OPG and reduced the mRNA expression of RANKL in the experimental Saracatinib inhibitor group compared with the control group.\n\nConclusionsOral administration of Simvastatin attenuated RANKL expression and accelerated OPG expression in induced rat periapical lesions.”
“Plant nutrient uptake from soil is mainly governed by diffusion and transpirationally induced mass flow, but the current methods for assessing the relative importance of these processes are indirect. We developed a microdialysis LY2606368 chemical structure method using solutions of different osmotic potentials as perfusates to simulate diffusion and mass flow processes, and assessed how induced mass flow affected fluxes of nitrogen (N) compounds in solution and in boreal forest soil. Varying the osmotic potential of perfusates induced vertical fluxes in the direction of the dialysis membranes at rates of between

1 x 10(-8) and 3 x 10(-7) m s(-1), thus covering the estimated range of water velocities perpendicular to root surfaces and induced by transpiration. Mass flow increased N fluxes in solution but even more so in soil. This effect was explained by an indirect effect of mass flow on rates of diffusive fluxes, possibly caused by the formation of steeper gradients in concentrations of N compounds from membrane surfaces out in the soil. Our results suggest that transpiration may be an essential driver of plant N acquisition.”
“The most dramatic shift in the management of abdominal aortic aneurysms (AAAs) occurred in 1991, when the first endovascular AAA repair was reported. Endovascular aneurysm repair has revolutionized the treatment of infrarenal AAAs. In the last few years, the companies have developed renewed models of grafts and have modified delivery systems tending to make

them more atraumatic and flexible in order to deal with difficult anatomies and severely atheromatous and tortuous vessels. The aim of the present paper was to analyze learn more the technical characteristics and properties of the new stent-graft system E-vita abdominal XT and to review the current literature. The E-vita abdominal XT stent-graft seems to be safe and reliable; however, long-term results are needed.”
“AimLack of insight is a cardinal feature of psychosis with crucial implications for outcome. Concerns have been raised regarding a link between insight and suicidality. This study aimed to test the relationship between suicidal behaviour preceding first-episode psychosis (FEP) and insight dimensions at treatment onset.

Acosmium is excluded from the Genistoids s l and strongly resolv

Acosmium is excluded from the Genistoids s.l. and strongly resolved within the newly circumscribed tribe Dalbergieae. By providing a better resolved phylogeny of the earliest-branching papilionoids, this study, in combination with other recent evidence, will lead to a more stable phylogenetic classification of the Papilionoideae. (C) 2013 SAAB. Published by Elsevier B.V. All rights reserved.”
“Patients presenting with primary aldosteronism experience more cardiovascular events than patients with essential hypertension independent of blood pressure. Therefore,

the presence of primary HDAC inhibitor aldosteronism should be detected, not only to determine the cause of hypertension, but also to prevent such complications. This review focuses on human data regarding increased end-organ damage and comorbidities in primary aldosteronism. Special emphasis is put on the effects of aldosterone excess on blood vessels, the heart, the kidney, and the brain. The data reviewed in our article demonstrate

that primary aldosteronism is associated with a prevalence of cerebro-, cardiovascular and renal complications selleck that are out of proportion to the blood pressure and benefits substantially from treatment in the long term. In this view, adrenalectomy and aldosterone antagonist treatment seem to be of considerable therapeutic value to control and limit the progression of comorbidities in primary aldosteronism.”
“Three phase partitioning is a process in which mixing t-butanol with ammonium sulphate with a protein

solution leads to the formation of three phases. Generally, the interfacial protein precipitate (formed between upper t-butanol rich and lower aqueous phase) can be easily dissolved back in aqueous buffers. In case of ovalbumin, this led to a precipitate which was insoluble in aqueous buffers. This precipitate when solubilized with 8 M urea and subjected to three phase partitioning under various conditions led to many refolded soluble conformational variants of ovalbumin. One of these showed trypsin selleck products inhibitory activity, had marginally higher beta-sheet content and had higher surface hydrophobicity (both with respect to native ovalbumin). Scanning electron microscopy and Atomic force microscopy of this preparation showed a thread like structure characteristic of amyloid fibrils. The behaviour of ovalbumin during three phase partitioning makes it a valuable system for gaining further understanding of protein aggregation. (C) 2013 Elsevier B.V. All rights reserved.”
“Background and Aim: The prognosis of cryptogenic cirrhosis-associated hepatocellular carcinoma (CC-HCC) was reported to be poor because many of them were discovered at the advanced stage. The aim of this study is to reveal the clinical features of early CC-HCC.

Therefore, a strong stimulation by the psychoactive component of

Therefore, a strong stimulation by the psychoactive component of marijuana, delta-9-tetrahydrocanabinol (THC), might lead to subtle but lasting neurobiological changes that can affect adult brain functions and behaviour.\n\nThe literature here summarized by use of

experimental animal models, puts forward that heavy cannabis consumption in adolescence may induce subtle changes in the adult brain circuits ending in altered emotional and cognitive performance, enhanced vulnerability for the use of more harmful drugs of abuse in selected individuals, and may represent a risk factor for developing schizophrenia in adulthood.\n\nTherefore, the potential problems arising in relation to marijuana consumption in adolescence suggest that selleck inhibitor this developmental phase is a vulnerable period for persistent adverse effects of cannabinoids. (C) 2008 Elsevier Ireland Ltd. All selleck screening library rights reserved.”
“We studied the clinical benefits of radiological imaging, in the follow-up of patients after combined modality treatment for stage I/II classical supradiaphragmatic Hodgkin lymphoma (HL). Imaging data were collected for 78 adults treated during 1996-2008. Median follow-up was 4.6 years. Six of the nine relapses were detected clinically. On average, 31 imaging studies/patient were performed, with an estimated cost of $12 608/patient. Chest computed tomography (CT) scans accounted

for 25%, abdominopelvic CT scans 41% and positron emission tomography (PET) or PET/CT scans 22% of this expense. Only one patient recurred infradiaphragmatically. The estimated radiation dose from imaging was 399 mSv and 229 mSv per patient, in relapse and non-relapse groups, respectively. CT scans contributed over 80% of the imaging radiation exposure. The routine use of CT scans in the surveillance of patients with HL after curative treatment adds to healthcare costs and total body radiation exposure with a low yield. History and physical examination remain effective tools for the follow-up of patients.”
“Cigarette smoking causes cellular oxidative stress resulting in inflammatory diseases of lung wherein

transcription factor NF-kappa TPCA-1 B plays an important role. It is possible that vitamin C, an antioxidant, may prevent cigarette smoke (CS)-induced NF-kappa B activation that involves degradation of I-kappa B epsilon and nuclear translocation of c-Rel/p50 in alveolar epithelial cells. Therefore, to examine the hypothesis, we verified the effect of vitamin C on CS-induced expression of NF-kappa B driven luciferase reporter and NF-kappa B binding at its target DNA by EMSA in alveolar epithelial A549 cells. We also examined the level of I-kappa B epsilon and sub-cellular distribution of c-Rel by western blotting and immunofluorescence respectively in CSE-treated A549 cells with or without vitamin C pretreatment.

Herein, we examined the potential of HIV-1 negative factor (Nef)

Herein, we examined the potential of HIV-1 negative factor (Nef) to impact KSHV viral interleukin-6 (vIL-6)-induced angiogenesis and tumorigenesis. In vitro experiments showed that exogenous Nef penetrated vIL-6-expressing endothelial cells. Both internalized and ectopic expression of Nef in endothelial cells and fibroblasts synergized with vIL-6 to promote vascular tube formation and cell proliferation. Using a chicken chorioallantoic membrane (CAM) model, we demonstrated that Nef synergistically promotes vIL-6-induced angiogenesis

and tumorigenesis. Animal experiments further showed that Nef facilitates vIL-6-induced angiogenesis and tumor formation in athymic nu/nu mice. Mechanistic studies indicated that Nef synergizes with vIL-6 to enhance angiogenesis check details and tumorigenesis by activating the AKT pathway in the CAM model, as well as nude mice. LY294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), significantly impaired the ability of Nef to promote vIL-6-induced tumorigenesis in an allograft model of nude mice. Our data provide first-line evidence that Nef may contribute to the pathogenesis underlying AIDS-KS in synergy with vIL-6. buy EVP4593 These novel findings also suggest that targeting the PI3K/AKT signal may be a potentially effective

therapeutic approach in AIDS-KS patients.”
“A field trial was conducted in a Lyme disease-endemic area of New Jersey to determine the efficacy of a doxycyline Roscovitine Cell Cycle inhibitor hyclate rodent bait to prophylactically protect and cure small-mammal reservoirs and reduce infection rates in questing Ixodes scapularis ticks for Borrelia burgdorferi and Anaplasma phagocytophilum. The doxycycline-laden bait was formulated at a concentration of 500 mg/kg and delivered during the immature tick feeding season in rodent-targeted bait boxes. The percentage of infected small mammals recovered from

treated areas after 2 years of treatment was reduced by 86.9% for B. burgdorferi and 74% for A. phagocytophilum. Infection rates in questing nymphal ticks for both B. burgdorferi and A. phagocytophilum were reduced by 94.3% and 92%, respectively. Results from this study indicate that doxycycline-impregnated bait is an effective means of reducing infection rates for B. burgdorferi and A. phagocytophilum in both rodent reservoirs and questing I. scapularis ticks.”
“Aristolochic adds are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic add nephropathy (AAN). Aristolochic adds undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic.