Materials and

Methods. We conducted a retrospective analysis of the patients who underwent CXL between 2010 and 2013 at the Beirut Eye Specialist Hospital, Lebanon. Progression of keratectasia was based on the presence of an increase in maximum keratometry of 1.00 D, a change in the map difference between two consecutive topographies of 1.00 D, a deterioration of visual acuity, or any change in the refraction. Primary and redo CXL were done using the same protocol. Results. Among the 221 eyes of 130 patients who underwent CXL, 7 eyes (3.17%) of five patients met the criteria of progression. All patients reported a history of allergic conjunctivitis and eye rubbing selleck screening library and progressed within 9 to 48 months. No complications were noted and all patients were stable 1 year after CXL redo. Conclusion. Allergic conjunctivitis and eye rubbing were the only risk factors associated with keratoconus progression after CXL. A close followup is thus mandatory, even years after the procedure. CXL redo seems to be a safe and efficient technique to halt the progression after a primary CXL.”
“Filamentous microorganisms of the bacterial genus Streptomyces have a complex life cycle that includes physiological and morphological differentiations.

It is now fairly well accepted that lysis of Streptomyces vegetative mycelium induced by programmed cell death (PCD) provides the required nutritive sources for the

bacterium to erect spore-forming VX-680 aerial hyphae. However, little is known regarding cellular compounds released during PCD and the contribution of these molecules to the feeding of surviving cells in order to allow them to reach the late stages of the developmental program. In this work we assessed the effect of extracellular sugar phosphates (that are likely to be released in the environment upon cell lysis) GSK1210151A on the differentiation processes. We demonstrated that the supply of phosphorylated sugars, under inorganic phosphate limitation, delays the occurrence of the second round of PCD, blocks streptomycetes life cycle at the vegetative state and inhibits antibiotic production. The mechanism by which sugar phosphates affect development was shown to involve genes of the Pho regulon that are under the positive control of the two component system PhoR/PhoP. Indeed, the inactivation of the response regulator phoP of Streptomyces lividans prevented the ‘sugar phosphate effect’ whereas the S. lividans ppk (polyphosphate kinase) deletion mutant, known to overexpress the Pho regulon, presented an enhanced response to phosphorylated sugars.”
“Cyt1Aa is the major and most active component of the parasporal crystal of the Gram-positive soil entomopathogenic bacterium Bacillus thuringiensis subsp. israelensis. The Cyt1Aa protoxin exhibits some hemolytic and cytolytic activity.

We tested the effect of this cytokine family on the angiopoietin (Ang)-Tie system, which is

involved in blood vessel maturation, stabilization, P5091 mouse and regression. Results: Oncostatin M (OSM) increased Ang2 expression in human umbilical vein endothelial cells via Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase activation. Furthermore, OSM induced Ang2 expression in macrovascular endothelial cells isolated from the human aorta and in microvascular endothelial cells isolated from human heart. Our in vivo experiments revealed that mRNA expression of Ang2 in hearts of mice injected with OSM increased significantly, and levels of OSM mRNA significantly correlated with mRNA levels of Ang2 in human hearts. In addition, OSM increased the expression of its own receptors, gp130 and OSM receptor, in endothelial cells in vitro and in mice in vivo, and levels of OSM mRNA significantly correlated with mRNA levels of gp130 and OSM receptor in human hearts. Conclusion:

Our data, showing the effects of OSM on the Ang-Tie system in endothelial cells, in hearts of mice, and in human heart tissue, provide yet another link between inflammation and angiogenesis.”
“Background\n\nGastrointestinal (GI)-specific anxiety (GSA) has been proposed to influence symptom severity and quality of life (QOL) in patients with irritable bowel syndrome (IBS). The Visceral Sensitivity Index (VSI) is a this website recently developed, reliable and valid measure of GSA. Our aim was to evaluate the association between GSA, GI symptom severity, and QOL in IBS patients.\n\nMethods\n\nSixty healthy subjects and 306 patients fulfilling the Rome II criteria for IBS were studied. Demographic and disease-related factors were assessed. Patients completed VSI and GI Symptom Rating Scale (GSRS) and questionnaires to determine psychological symptom severity (Hospital Anxiety and Depression

Scale), QOL (Short BIX 01294 price form 36), and presence of functional GI disorders (Rome II Modular Questionnaire).\n\nKey Results\n\nCompared with healthy subjects, patients with IBS had more severe GSA (34.7 +/- 16.9 vs. 2.2 +/- 4.4 [mean +/- standard deviation]; P < 0.0001). In the IBS group, more severe GSA was seen in patients with more severe GI symptoms (P < 0.0001), general anxiety (P < 0.0001) and depression (P < 0.0001), and with lower socioeconomic status (P < 0.05). In a regression analysis, GSA was the strongest predictor for GI symptom severity (GSRS total score), followed by number of Rome II diagnoses, presence of meal-related IBS symptoms, and gender (R2 = 0.34). Gastrointestinal-specific anxiety was also, together with general anxiety, depression, socioeconomic status, and gender, found to be independently associated with mental QOL (R2 = 0.62).

No patients with a history of secondary hyperparathyroidism sustained a fracture while receiving teriparatide therapy versus 6 of 88 patients without a history of secondary hyperparathyroidism (P = .624).\n\nConclusion: Patients with a history of resolved secondary hyperparathyroidism attributable to vitamin D deficiency

responded to teriparatide therapy in a fashion similar to patients without such a history. (Endocr Pract. 2011;17:568-573)”
“Tourette syndrome (TS) and stereotypy in autism spectrum disorders (ASDs) are 2 common movement disorders in childhood. The objective of this review was to summarize randomized controlled trials published over the past 5 years as an update of the current pharmacotherapeutic HDAC inhibitor options for the treatment of tics, TS, and motor stereotypies in children with ASD. We searched MEDLINE (2005-May 2010)

for randomized controlled trials of medications used for the treatment of these disorders. For the treatment of tics in TS, 2 trials suggest that levetiracetam is not effective, whereas 1 trial found that topiramate was effective. Single clinical trials of metoclopramide, atomoxetine, and ondansetron were of limited quality, preventing conclusions to be made regarding the usefulness of these treatments for tic disorders. For the treatment of stereotypy in children with ASD, this website risperidone has been shown in both a Cochrane review in 2006 and 2 subsequent randomized control trials to be effective. The addition of pentoxifylline to risperidone may have added benefit. Haloperidol did not improve stereotypy and was poorly tolerated. There is good evidence SCH727965 order that aripiprazole is effective in the treatment of sterotypies in children with ASD. A large randomized trial of citalopram did not show any improvement in stereotypy. Single trials of levetiracetam, guanfacine, and atomoxetine suggest they are not useful in the reduction of stereotypy in children with ASD. Semin Pediatr Neurol 17:254-260 (C) 2010 Published by

Elsevier Inc.”
“Rice is one of the most important global food crops and a primary source of calories for more than half of the world’s population. Rice production increased steadily during the green revolution era primarily as a result of introducing high-yielding rice varieties. World rice production increased at a rate of 2.3-2.5% per year during 1970s and 1980s, but this rate of growth was only 1.5% per year during the 1990s. The yield growth rate for rice has further declined during the first decade of this century. However, the populations in the major rice-consuming countries continue to grow at a rate of more than 1.5% per year. According to various estimates, world rice production must increase at the rate of 2 million tons per year.

paratuberculosis (MAP). Salubrinal Total 134 samples illustrating gross pathological lesions were collected, only 11.19% (cattle: 6.67%, buffaloes: 12.5%) showed acid fast bacilli through smear staining and were taken as confirmed cases. Thickening of intestines alone was not a reliable indicator of Johne’s disease. Tissue sections

from intestines and mesenteric lymph nodes from these acid fast positive animals were stained with hematoxylin & eosin (H&E) and Ziehl Neelsen (ZN) methods. Sum of (15/134) impression smear staining as well as (15/15) tissue sections of the intestines were found ZN positive, and only 6.7% of impression smears and 100% of tissue sections of mesenteric lymph nodes showed acid fast bacilli. Through ELISA, two cattle and five buffaloes (07/134)

gave positive optical densities, while one cattle and seven buffaloes (08/134) were judged as doubtful. It is concluded that infection of MAP can be identified by histopathology and ELISA. The present study was the first record of paratuberculosis among the dairy animals slaughtered at Jhang abattoirs. The objective was to compare different methods for the diagnosis of Johne’s disease. (C) 2012 PVJ. All rights reserved”
“The dental care of oncology patients is an important component of general dental practice. Oncology patients have additional requirements for their outpatient care in the dental office. Intense involvement of the general dental practitioner in the patient’s overall plan of care is essential so that appropriate preventive GSK2879552 and therapeutic strategies are followed selleck screening library prior to chemotherapy, radiation and other medical treatments. This paper provides an overview of the role of the dental practitioner in the pre-treatment workup and post-treatment maintenance of oncology patients, and discusses the complications which occur during the intensive and in-hospital phases of care, in the context of approaches that show promise for reducing or preventing these. The role of the general dental practitioner in the maintenance

of oral health for the remainder of the patient’s life is stressed, with evidence-based recommendations given for optimal use of home care products which support oral health and improve quality-of-life.”
“Fibrin sealant (FS) and tranexamic acid (TXA) have been used in total knee arthroplasty (TKA) to minimize perioperative blood loss. The efficacy of FS has been debated, and few studies have looked into the effects of FS and TXA on perioperative coagulability. The current study retrospectively reviewed 100 cases of unilateral primary TKA. Twenty-five cases served as blank controls, FS was used without TXA in 23, TXA was used without FS in 20, and both FS and TXA (FS + TXA) were used in 32. FS was sprayed before wound closure whereas 1 g of TXA was intravenously administered before incision and 1 g was administered 15 min before tourniquet release.

Overall, there were 71.3% CRT responders as assessed by 6-month echocardiography, and 66% improved at least 1 New York Heart Association class.\n\nCONCLUSION selleck chemical Over the longer term, CRT with the quadripolar LV lead is associated with

excellent pacing thresholds, low rates of dislocations, and PNS.”
“Transistors based on Ill-V semiconductor materials have been used for a variety of analog and high frequency applications driven by the high electron mobilities in materials. On the other hand, the hole mobility in materials has always lagged compared to group-IV semiconductors such as germanium. In this paper, we explore the use of strain and heterostructure design guided by bandstructure modeling to enhance the hole mobility in III-V materials. Parameters such as strain, valence band offset, effective masses, and splitting between the light and heavy hole bands that are important for optimizing hole transport are measured quantitatively using various experimental techniques. A peak Hall mobility for the holes of 960 cm(2)/Vs is demonstrated and the high hole mobility is maintained even at high sheet charge. (C) 2012 American Institute of Physics. [http://0-dx.doi.org.brum.beds.ac.uk/10.1063/1.4718381]“
“Five

PFTα in vivo new diterpenoids named excocarinols A-E (1-5) including three pimaranes, one cleistanthane, and one nor-beyerane, together with nine known compounds, were isolated from the EtOAc extract of the Chinese ethnodrug Gua-jing-ban (Excoecaria acerifolia Didr.). Their

structures were elucidated by the analysis of spectroscopic data including 1D, 2D NMR and HR-MS. The anti-HIV-1 bioassay on the diterpenoids showed that excocarinol A (1) exhibited moderate anti-HIV-1 activity with EC50 5.58 mu M and SI (Selection Index) over 112.71. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved.”
“Although the round ligament, including the umbilical vein, could be used as a venous graft in living donor liver transplantation (LDLT), no studies have determined its appropriate use on the basis of pathological JQ-EZ-05 in vivo findings. We prospectively examined 19 LDLT cases in which the donor’s round ligament was procured and used as a venous graft. The round ligaments were categorized into 3 types based on the CD31 immunohistochemistry of tissue cross-sections: (I) canalized umbilical veins (n = 7 or 36.8%), (II) capillary umbilical vessels (n = 4 or 21.1%), and (III) occluded umbilical veins (n = 8 or 42.1%). After dilatation and incision, the round ligaments provided patch grafts that were 5.8 +/- 0.4 cm long and 1.8 +/- 1.2 cm wide. However, histological studies showed the absence of fine intimal layers on the dilated round ligaments after mechanical maneuvers. The ligaments were used to cuff the venous orifices in 15 patients (left lobe, n = 8; right lobe, n = 7) and were used as venous bridges in 4 patients (left lobe, n = 2; right lobe, n = 2). We detected no thrombosis at the implant sites after LDLT.

The attractiveness of plants to pea aphids (Acyrthosiphon

pisum Harris) was positively affected by AM fungi and correlated with the extent of root colonization; however, attractiveness was neither affected by P treatment nor correlated with leaf P concentration. These findings suggest that increased P uptake is not the main mechanism by which mycorrhiza increase the attractiveness of plants to aphids. Instead, the mechanism is likely to operate via AM fungi-induced plant systemic signalling.”
“Pediatric surgeons provide care for infants and children with a wide variety of conditions throughout the body. Many of these conditions are congenital or occur very early in life, and for this reason, providing continuity of care for these patients into adulthood is an emerging challenge. In the gastrointestinal tract, congenital and GW-572016 nmr acquired conditions are now associated with excellent long-term prognosis; however, little guidance on long-term care exists. The aim of this article is to discuss aspects that are important to transitioning

care of pediatric surgical patients with complex gastrointestinal disorders from pediatric to adult practitioners. Transitional care of patients with short bowel syndrome, Hirschsprung Disease, and anorectal malformations will be the focus of this discussion, but the concepts

introduced here may translate KPT-8602 nmr to other diagnoses as well. (C) 2015 Elsevier Inc. All rights reserved.”
“Zhang JJ, Wu M, Schoene NW, Cheng WH, Wang TT, Alshatwi AA, Alsaif M, Lei KY. Effect of resveratrol and zinc on intracellular zinc status in normal human prostate epithelial cells. Am J Physiol Cell Physiol 297: C632-C644, 2009. First published June 24, 2009; doi:10.1152/ajpcell.00139.2009.-To evaluate the influence of resveratrol on cellular zinc status, normal human Selleck LBH589 prostate epithelial (NHPrE) cells were treated with resveratrol (0, 0.5, 1, 2.5, 5, and 10 mu M) and zinc [0, 4, 16, and 32 mu M, representing zincdeficient (ZD), zinc-normal (ZN), zinc-adequate (ZA), and zinc-supplemented (ZS) conditions, respectively]. A progressive reduction in cell growth was observed in cells treated with increasing amounts of resveratrol (2.5-10 mu M). Resveratrol at 5 and 10 mu M resulted in a dramatic increase in cellular total zinc concentration, especially in ZS cells. Flow cytometry indicated that 10 mu M resveratrol induced arrest of the cell cycle at the G(2)/M phase in association with the observed cell growth inhibition. Data from an in vitro experiment using zinquin as an indicator of intracellular free Zn(II) status demonstrated complex interactions between resveratrol and Zn(II).

The anatomical structures of Meckel cave and the related zones adjacent to Meckel cave were observed and measured with endoscopic endonasal approach. Results: Endoscopic endonasal, endo-maxillary sinus, and endo-pterygoid GSK461364 purchase process approaches were successfully applied in observation of the anatomical structures of meckel cave and the rerated zones adjacent to Meckel cave and in measurement of distances between related anatomical structures for each case of samples. The

relevant data were obtained. The distance between the front mouth of palatovaginal canal and vidian canal was 21.4 +/- 7 mm, the distance between opening of sphenoid sinus to the upper margin of the choana was 22.3 +/- 2.8 mm, the distance between the opening of vidian and foramen Protein Tyrosine Kinase inhibitor rotundum was 7.57 +/- 0.7 mm and the length of the pterygoid canal was 13.3 +/- 1.2 mm. Based on these data, the positions of the related important structures can be roughly located during surgical operation and various important structures in Meckel cave and its adjacent zones can be found out in a convenient and safe way. Conclusion: 1) It is feasible to use endonasal endoscopic approach to perform surgical operation in Meckel cave; 2) Use of endonasal endoscopic approach can protect and fully take the advantage of the vidian nerve to locate the position of foramina lacerum

of the internal carotid artery during surgical operation; and 3) the observational and experimental data obtained with this approach can provide the rational basis for clinical operation procedures.”
“Objective-Hepatocyte nuclear factor-4 alpha (HNF4A) is a transcription factor that influences plasma triglyceride metabolism via an as of yet unknown mechanism. In this study, we searched for the critical protein that mediates this effect using different human model systems.\n\nMethods and Results-Up-and downregulation of HNF4A in human hepatoma Huh7 and HepG2 cells was associated with marked changes in the secretion of triglyceride-rich lipoproteins (TRLs). Short interfering RNA (siRNA) inhibition

of HNF4A influenced the expression of several genes, including acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1). siRNA knockdown Cyclosporin A concentration of DGAT1 reduced DGAT1 activity and decreased the secretion of TRLs. No additive effects of combined siRNA inhibition of HNF4A and DGAT1 were found on the secretion of TRLs, whereas the increase in TRL secretion induced by HNF4A overexpression was largely abolished by DGAT1 siRNA inhibition. A putative binding site for HNF4A was defined by in silico and in vitro methods. HNF4A and DGAT1 expressions were analyzed in 80 human liver samples, and significant relationships were observed between HNF4A and DGAT1 mRNA levels (r(2) = 0.50, P<0.0001) and between DGAT1 mRNA levels and plasma triglyceride concentration (r(2) = 0.09, P<0.01).

Inactivation of Smug1 when combined with inactivation of the Ung uracil-DNA glycosylase gene leads to a loss of nearly all detectable uracil excision activity. Thus, SMUG1 is the dominant glycosylase responsible for hmU-excision in mice as well as the major UNG-backup for U-excision. Both Smug1-knockout and Smug1/Ung-double knockout mice breed normally and remain apparently healthy beyond 1 year of age. However, combined deficiency in SMUG1 and UNG exacerbates the cancer predisposition of Msh2(-/-) mice suggesting that when both base excision and mismatch repair pathways are defective,

VS-6063 molecular weight the mutagenic effects of spontaneous cytosine deamination are sufficient to increase

cancer incidence but do not preclude mouse development.”
“Although it is well known that silent atrial fibrillation (AF) MK-0518 datasheet is associated with morbidity and mortality rates similar to those of symptomatic AF, no specific strategy for screening and management of this form of AF has been advocated. The purpose of this survey was to identify current practices for the diagnosis and management of silent AF. This survey is based on an electronic questionnaire sent to the European Heart Rhythm Association Research Network partners. Responses were received from 33 centres in 16 countries. The preferred screening methods for silent AF in patients with rhythm control by pharmacological therapy was 12-lead electrocardiogram find more (ECG) at outpatient visits (31.3) and periodical 24 h Holter ECG recordings (34.4), while after pulmonary vein isolation the corresponding figures were 6.3 and 65.6, respectively. No consensus has been

reached concerning the therapeutic approach for such patients. Most responders preferred rate control over rhythm control in patients with silent AF, although some favoured pulmonary vein isolation in young patients. However, oral anticoagulant therapy in patients at high thromboembolic risk was considered mandatory by most, provided that at least one episode of silent AF was documented, without recommending further investigations. The results of this survey have confirmed that there is currently no consensus regarding the screening and management of patients with silent AF and that clinical practice is not always consistent with the few existing evidence-based recommendations.”
“Chemokine CXC ligand 13 (CXCL13) and CXC receptor type 5 (CXCR5) are constitutively expressed in tertiary lymphoid follicles where the CXCL13/CXCR5 system regulates B lymphocytes homing. In this study, we sought to examine CXCL13 expression in the H. pylori-infected and -uninfected gastric mucosa and to elucidate the implication in the pathogenesis of HAG in humans.

“
“Human African trypanosomiasis (HAT, commonly known as MK5108 manufacturer African sleeping sickness) is categorized as a neglected disease, as it afflicts >50,000 people annually in sub-saharan Africa, and there are few formal programs in the world focused on drug discovery approaches for this disease. In this study, we examined the crude extracts

of two fungal strains (Aspergillus fumigatus and Nectria inventa) isolated from deep water sediment which provided >99% growth inhibition at 1 mu g/mL of Trypanosoma brucei, the causative parasite of HAT. A collection of fifteen natural products was supplemented with six semi-synthetic derivatives and one commercially 3-deazaneplanocin A price available compound. Twelve

of the compounds, each containing a diketopiperazine core, showed excellent activity against T. brucei (IC(50) = 0.002-40 mu M), with selectivity over mammalian cells as great as 20-fold. The trypanocidal diketopiperazines were also tested against two cysteine protease targets Rhodesain and TbCatB, where five compounds showed inhibition activity at concentrations less than 20 mu M. A preliminary activity pattern is described and analyzed. (C) 2010 Elsevier Ltd. All rights reserved.”
“The standard methods used to diagnose scalp psoriasis vary in sensitivity, reproducibility, and invasiveness. Videodermoscopy can be used to explore Cyclopamine cost microcirculatory modifications in skin diseases. Psoriasis presents three pathognomonic vascular patterns: red dots, hairpin vessels and red globular rings. Our aim was to create a videodermoscopy scalp psoriasis severity index (VSCAPSI) for evaluation of scalp psoriasis, especially mild and moderate forms that often are not clinically appreciable. VSCAPSI takes into account the area of the scalp affected

by psoriasis, the presence and morphology of vascular patterns, the erythema and desquamation. Videodermoscopy images obtained between November 2009 to June 2010 from 900 participants with various scalp and hair disorders were reviewed for distinguishing features. During the 2010 Italian congress on psoriasis, in order to assess the reproducibility and efficacy of the VSCAPSI, 146 dermatologists were asked to evaluate 16 videodermoscopy images of scalp psoriasis using the VSCAPSI. Of the 900 patients, 85 new cases of scalp psoriasis were diagnosed. The other 815 patients were found to be suffering from different scalp and hair diseases. Of 146 dermatologists, 28 did not recognize erythema, 15 desquamation and 7 the vascular patterns. The VSCAPSI provides important evidence for early diagnosis, differential diagnosis, for follow-up and screening.”
“Interleukin-1 beta (IL-1 beta) is a potent negative inotrope implicated in the functional abnormalities of heart failure.

We believe these findings point to YPEL3 being a novel tumor suppressor, which upon induction triggers selleck chemical a permanent growth arrest in human tumor and normal cells. Cancer Res; 70(9); 3566-75. (C) 2010 AACR.”
“Human native milk lactoferrin (LF) and recombinant forms of lactoferrin (rLF) are available

with identical aa sequences, but different glycosylation patterns. Native lactoferrin (NLF) possesses the intrinsic ability to stimulate vigorous IgG and IgE antibody responses in BALB/c mice, whereas recombinant forms (Aspergillus or rice) are 40-fold less immunogenic and 200-fold less allergenic. Such differences are independent of endotoxin or iron content and the glycans do not contribute to epitope formation. A complex glycoprofile is observed for NLF, including sialic acid, fucose, mannose, and Lewis (Le)x structures, whereas both Selleckchem GPCR Compound Library rLF species display a simpler glycoprofile rich in mannose. Although Lex type sugars play a Th2-type adjuvant role, endogenous expression of Lex on NLF did not completely account for

the more vigorous IgE responses it provoked. Furthermore, coadminstration of rLF downregulated IgE and upregulated IgG2a antibody responses provoked by NLF, but was without effect on responses to unrelated peanut and chicken egg allergens. These results suggest glycans on rLF impact the induction phase to selectively inhibit IgE responses and that differential glycosylation patterns may impact on antigen uptake, processing and/or presentation, and the balance between Th1 and Th2 responses.”
“Matrix metalloproteinase-12 (MMP-12), an enzyme responsible for degradation of extracellular matrix, plays an important role in the progression of various diseases, including inflammation and fibrosis. Although most CYT387 purchase of those are pathogenic conditions induced by ethanol ingestion, the effect of ethanol on MMP-12 has not been explored. In the present study, we investigated the effect of ethanol on MMP-12 expression and its potential mechanisms in macrophages. Here, we demonstrated that ethanol treatment increased

MMP-12 expression in primary murine peritoneal macrophages and RAW 264.7 macrophages at both mRNA and protein levels. Ethanol treatment also significantly increased the activity of nicotinamide adenine dinucleotide (NADPH) oxidase and the expression of NADPH oxidase-2 (Nox2). Pretreatment with an anti-oxidant (N-acetyl cysteine) or a selective inhibitor of NADPH oxidase (diphenyleneiodonium chloride (DPI)) prevented ethanol-induced MMP-12 expression. Furthermore, knockdown of Nox2 by small interfering RNA (siRNA) prevented ethanol-induced ROS production and MMP-12 expression in RAW 264.7 macrophages, indicating a critical role for Nox2 in ethanol-induced intracellular ROS production and MMP-12 expression in macrophages.