Here we examine the effects of favorable selection, gene flow, ge

Here we examine the effects of favorable selection, gene flow, genetic drift, and positive-assortative mating in an effort to understand the establishment and maintenance of this polymorphism and the observed heterozygote deficiency for mc1r but not for microsatellite loci. It appears that genetic drift was important in the establishment of the w allele and that the selective advantage was important to counteract immigration from populations without the w allele. Positive-assortative mating can result in a deficiency of heterozygotes but needs to be quite high to result in the large deficiency of heterozygotes observed, suggesting that other factors

must also be contributing. Examination of population genetic factors, singly and jointly, provides insight into the establishment and maintenance of this unusual polymorphism.”
“Recently, the standard of care for metastatic Castration find more Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result

in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. PF-00299804 manufacturer Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within

and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK-700), Epoxomicin ic50 ARN-509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.”
“Prenylated tryptophan-containing cyclic dipeptides are found in different fungi and serve as precursors for the biosynthesis of diverse biologically active secondary metabolites. They show distinct and usually higher biological and pharmacological activities than the respective non-prenylated dipeptides.

Consequently, a detailed procedure for successive regioselective

Consequently, a detailed procedure for successive regioselective lithiations/electrophilic

trapping of furo[3,2-b]pyridines is described and afforded several polyfunctionalized derivatives in good overall yields. A Pd-catalyzed cross-coupling reaction is also described and easily yielded the 7,7′-bifuro[3,2-b]pyridine.”
“Background and Objectives: Peritoneal dialysis catheter (PDC) complications are an important barrier to peritoneal dialysis (PD) utilization. Practice guidelines for PDC placement exist, but it is unknown if these recommendations are followed. We performed a quality improvement study to investigate this issue.\n\nMethods: A prospective observational study involving 46 new patients at a regional US PD center was performed in collaboration with a nephrology fellowship program. Patients completed a questionnaire derived from the International Society for Peritoneal IPI-145 datasheet Dialysis (ISPD) catheter guidelines and were followed for early complications.\n\nResults: Approximately 30% of patients reported not APR-246 manufacturer being evaluated for hernias, not being asked to visualize their exit site, or not receiving catheter location marking before placement. After insertion, 20% of patients reported not being given instructions for follow-up care, and 46% reported not being taught the warning

signs of PDC infection. Directions to manage constipation (57%), immobilize the PDC (68%), or leave the dressing undisturbed (61%) after insertion were not consistently reported. Nearly 40% of patients reported that their PDC education was inadequate. In 41% of patients, a complication developed, with 30% of patients experiencing a catheter or exit-site problem, 11% developing infection, 13% needing

check details PDC revision, and 11% requiring unplanned transfer to hemodialysis because of catheter-related problems.\n\nConclusions: There were numerous deviations from the ISPD guidelines for PDC placement in the community. Patient satisfaction with education was suboptimal, and complications were frequent. Improving patient education and care coordination for PDC placement were identified as specific quality improvement needs.”
“Eucalyptus bleached kraft pulp fibers were modified by adsorption of novel bio-based multifunctional cellulose derivatives in order to generate light responsive surfaces. The cellulose derivatives used were decorated with both cationic groups (degree of substitution, DS of 0.34) and photoactive groups (DS of 0.11 and 0.37). The adsorption was studied by UV-vis spectroscopy, surface plasmon resonance (SPR) and time-of-flight secondary ion mass spectroscopy (ToF-SIMS). The adsorption isotherms followed the Freundlich model and it turned out that the main driving force for the adsorption was electrostatic interaction. Moreover, strong indications for hydrophobic interactions between the fibers and the derivatives and the derivatives themselves were found.

Earlier diagnosis and management are needed to attain

Earlier diagnosis and management are needed to attain find more a better outcome. (C) 2009 Elsevier Ltd and ISBI. All rights reserved.”
“Background: In vivo animal studies indicate that the developing brain is vulnerable to the neurotoxic effects of anesthetic

agents. There is corresponding concern about the long-term neurological effects of early-in-life exposure in children at both the individual and population levels. Accurate national estimates of the number of children undergoing surgical procedures are required to understand the scope of this potential problem.\n\nMethods: We estimated annual frequencies of in-hospital surgical procedures performed on children in the United States using the 2003, 2006, and 2009 Kids’ Inpatient Database (KID). The KID is produced as part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality and contains a representative national sample of pediatric discharges. Demographic variables and procedure categories were assessed in this cohort to determine rates and types of surgery.\n\nResults:

Over the 3 years evaluated, surgical diagnoses accounted for 12.7% of all discharges, with an average of 450,000 pediatric inpatient surgical admissions each AZD8055 cell line year and 115,000 admissions annually in children under the age of 3. Elective admissions made up 40% of surgical hospitalizations with 55% of surgical admissions classified as gastrointestinal, orthopedic, or urological.\n\nConclusions: In the United States, approximately 450,000 children under 18 years of age are admitted for surgery

as inpatients annually. One quarter of these children are under 3 years of age and the majority for gastrointestinal, orthopedic, or urological surgery. When examined together with data on ambulatory surgery, these results are useful in considering the scope of anesthesia exposure in young children.”
“Lung transplantation Citarinostat is a therapeutic option for patients with end-stage lung diseases. Selection of candidates requires careful consideration of the disease-specific indications and contraindications for transplantation. Advances have been made in candidate selection via the ability to prognosticate outcomes of various lung diseases and through the implementation of the lung allocation score (LAS) with specific consideration of the degree of urgency and good postoperative survival rate, after neglecting the waiting time. This system has resulted in decreased mortality on the waiting list for lung transplantation. The availability of donor organs can possibly be increased by implementation of ex vivo lung perfusion as an alternative to conventional organ preservation. Risk factors for poor outcomes post-lung transplantation have been identified and understanding of the physiological, cellular and molecular mechanisms responsible for lung and airway damage has been extensively expanded.

Odds ratio indicated that heterozygosity of genotypes -819 CT and

Odds ratio indicated that heterozygosity of genotypes -819 CT and -592 AC was more strongly associated with liver chronicity. Significantly, AA homozygous genotype was dominant in chronic hepatitis B cases in IFN-gamma + 874 and IL-10 (-1082 and -592) and is

associated with increased risk of persistent infection.”
“Hippocampal theta rhythm arises from a combination of recently described intrinsic theta oscillators and inputs from multiple brain areas. Interneurons expressing the markers parvalbumin (PV) and somatostatin (SOM) are leading candidates to participate in intrinsic rhythm generation and principal cell (PC) coordination in distal CA1 and subiculum. We tested their involvement by optogenetically activating and silencing PV or SOM interneurons in an intact hippocampus preparation that preserves intrinsic Fludarabine JAK/STAT inhibitor connections and oscillates spontaneously at theta frequencies. Despite evidence suggesting that SOM interneurons are crucial for theta, optogenetic manipulation of these interneurons modestly influenced theta rhythm. However, SOM

interneurons were able to strongly modulate temporoammonic inputs. In contrast, activation of PV interneurons powerfully controlled PC network and rhythm generation optimally at 8 Hz, while continuously silencing them disrupted theta. Our results thus demonstrate a pivotal role of PV but not SOM interneurons for PC synchronization and the emergence of intrinsic hippocampal theta.”
“Bacterial populations frequently act as a collective by secreting a wide LY411575 ic50 range of compounds necessary for cell-cell communication, host colonization and virulence. How such behaviours avoid exploitation by spontaneous ‘cheater’ mutants that use but do not contribute to secretions

remains unclear. We investigate this question using Pseudomonas aeruginosa swarming, a collective surface motility requiring massive secretions of rhamnolipid biosurfactants. We first show that swarming is immune to the evolution of S63845 in vitro rhlA-’cheaters’. We then demonstrate that P. aeruginosa resists cheating through metabolic prudence: wild-type cells secrete biosurfactants only when the cost of their production and impact on individual fitness is low, therefore preventing non-secreting strains from gaining an evolutionary advantage. Metabolic prudence works because the carbon-rich biosurfactants are only produced when growth is limited by another growth limiting nutrient, the nitrogen source. By genetically manipulating a strain to produce the biosurfactants constitutively we show that swarming becomes cheatable: a non-producing strain rapidly outcompetes and replaces this obligate cooperator. We argue that metabolic prudence, which may first evolve as a direct response to cheating or simply to optimize growth, can explain the maintenance of massive secretions in many bacteria. More generally, prudent regulation is a mechanism to stabilize cooperation.

A pulse of both pesticides affected antipredator traits involved

A pulse of both pesticides affected antipredator traits involved in avoiding detection by predators as well as traits involved in escape after detection. After a pesticide pulse, larvae increased activity levels and even further selleck increased the number of walks when predation risk was present. Further, an endosulfan pulse tended to reduce escape swimming speed. In contrast, previous exposure to Roundup caused the larvae to swim faster, yet less often when attacked. Importantly, although both studied pesticides induced maladaptive changes in overall activity,

only for endosulfan this resulted in an increased mortality by predation. Our study highlights that considering changed predator-prey interactions may improve ecological risk evaluations of short pesticide pulses, yet also underscores the need (1) to consider effects on all important antipredator traits of the prey as trait compensation may occur BIX 01294 molecular weight and (2) to effectively score the outcome of predator-prey interactions in staged encounters. (C) 2012 Elsevier B.V. All rights reserved.”
“The objective of this study was to determine the cytotoxicity,

antiproliferative activity, and apoptosis induction activity of two modified glycosides – digoxin and proscillaridin A – conjugated to a generation 3 polyamidoamine dendrimer (G3 PAMAM-NH2) in human breast cancer find more cells. The results suggest that conjugation with the G3 PAMAM-NH2, dendrimer enhances the cytotoxicity of modified digoxin and proscillaridin A both in MCF-7 and in MDA-MB-231 breast cancer cells. Additionally, the conjugate-induced

apoptosis was significantly greater than apoptosis evoked by free modified digoxin and proscillaridin A.”
“Chemical facial cellulitis, while commonly seen in domestic accidents or attempted suicide, is uncommon in the dental office and hence rarely addressed in the dental literature. We present an unusual case of chemical facial cellulitis caused by inadvertent injection of formalin into the soft tissues of the oral cavity, which was mistaken for local anesthesia solution. This report comprises the immediate symptoms, possible root cause, and management of the difficult situation. We also provide some guidelines to avoid such unfortunate events. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:581-582)”
“Despite evidence of persistent methylmercury (MeHg) contamination in the South River (Virginia, USA) ecosystem, there is little information concerning MeHg-associated neurological impacts in resident wildlife.

Bulk heterojunction polymer solar cells (PSCs) were fabricated ba

Bulk heterojunction polymer solar cells (PSCs) were fabricated based on the blend of the as-synthesized polymers and the fullerene derivative Selleck Citarinostat [6,6]-phenyl-C-61-butyric acid methyl ester (PC61BM) in a 1:2 weight ratio. The maximum power conversion efficiency of 2.06% was obtained for PL5-based PSC under the illumination of AM 1.5, 100 mW/cm(2). (C) 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 49: 3604-3614, 2011″
“In the first part of this paper the authors describe an innovative sandwich

panel that comprises Glass Fibre Reinforced Polymer (GFRP) connectors and two thin layers of Steel Fibre Reinforced Self-Compacting Concrete (SFRSCC). This second part of the paper reports the investigation performed by the authors based on the numerical simulation of these sandwich panels. The simulations use the Finite Element Method (FEM) software implemented by the second author (FEMIX). Through linear static analyses and consideration of Ultimate Limit State

loading scenarios, parametric studies were performed in order to optimise the arrangement of the GFRP connectors and the thickness of the SFRSCC layers. Moreover, models considering a specific nonlinear behaviour of SFRSCC were also constructed in order to simulate the progressive damage of the panel induced by cracking. In the scope of the nonlinear analyses, emphasis is given to parameter estimation of fracture modelling parameters for the fibre reinforced concrete based on both inverse analysis and the fib Model Code. (C) 2013 Elsevier Ltd. Lonafarnib mouse All rights reserved.”
“Bio-oil is a promising alternative source of energy produced from fast pyrolysis of biomass. Increasing the viscosity of bio-oil during storage is a major problem that can be controlled by the addition of methanol or other alcohols. This paper reports the results of our investigation of the reactions of short chain

alcohols with aldehydes and acids in bio-oil. The reaction of methanol with hydroxyacetaldehyde (HA) to form the acetal was catalyzed by the addition of 7 x 10(-4) M strong acids such as sulfuric, hydrochloric, p-toluene sulfonic acid, and methanesulfonic acid. HA formed 2,2-dimethoxyethanol (DME), and at 60 degrees C the equilibrium was reached in less than one hour. Smaller amounts of DME were formed in the absence of strong acid. HA, acetaldehyde, and propanal formed their corresponding acetals when reacted with methanol, ethanol, 1-propanol or 1-butanol. Esters of acetic acid and hydroxyacetic acid were observed from reactions with these same four alcohols. Other acetals and esters were observed by GC/MS analysis of the reaction products. The results from accelerated aging experiments at 90 degrees C suggest that the presence of methanol slows polymerization by formation of acetals and esters from low molecular weight aldehydes and organic acids.


Conclusions. A-1331852 L-MSCs can secrete various neurotrophic factors stimulating neurite outgrowth and protecting neurons against brain ischemic injury through paracrine mechanism.”
“Background: In schizophrenia, brain morphometric changes may be associated with antipsychotic medication. Only limited data is available concerning individuals with schizophrenia without antipsychotic medication. We aimed to study the associations of: use versus

no use of antipsychotic medication; length of continuous time without antipsychotic medication; cumulative dose of lifetime antipsychotic medication; and type of antipsychotic medication; with brain morphometry in schizophrenia after an average of 10 years of illness. Methods: Data of 63 individuals with schizophrenia (mean duration of illness 10.4 years) from the Northern Finland Birth Cohort 1966 were gathered by interview and from hospital and outpatient records. Structural MRI data at age CT99021 solubility dmso 34 years were acquired and grey matter volume maps with voxel-based morphometry were analyzed using FSL tools. Results: Of the individuals studied, 15 (24%) had taken no antipsychotic medication during the previous year. Individuals with antipsychotic medication had lower total grey matter (TGM)

volume compared with non-medicated subjects, although this association was not statistically significant (Cohen’s d = -0.51, P = 0.078). Time without antipsychotic medication associated with increased TGM (P = 0.028). Longer time without antipsychotic medication associated with increased regional volume in right precentral gyrus and right middle frontal gyrus. There were no associations between cumulative dose of lifetime antipsychotic medication or type of antipsychotic medication and brain morphometry.

Conclusions: Unlike some previous investigators, we found no association between cumulative dose of lifetime antipsychotic medication and brain morphological changes in this population-based selleck chemicals sample. However, longer continuous time without antipsychotic medication preceding the MRI scan associated with increased gray matter volume. (c) 2015 Elsevier Masson SAS. All rights reserved.”
“AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR.

Exposure to NM (3 2 mg) caused a more profound increase in epider

Exposure to NM (3.2 mg) caused a more profound increase in epidermal thickness and apoptotic cell death in WT relative to p53+/- mice at 24 h. However, by 72 h after exposure, there was a comparable increase in NM-induced epidermal cell death in both WT and p53+/- mice. Myeloperoxidase activity data showed that neutrophil SBE-β-CD order infiltration was strongly enhanced in NM-exposed WT mice at 24 h persisting through 72 h of exposure. Conversely, robust NM-induced neutrophil infiltration (comparable to WT mice) was seen only at 72 h after exposure in p53+/- mice. Similarly, NM-exposure strongly induced macrophage and mast cell infiltration in WT, but not p53+/- mice. Together, these data

indicate that early apoptosis and inflammation induced by NM in mouse skin are p53-dependent. Thus, targeting this pathway

could be a novel strategy for developing countermeasures against vesicants-induced skin injury. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Objective. Fibromyalgia (FM) comprises many symptoms and features. Consequently, click here studies on the condition have used a wide variety of outcome measures and assessment instruments. We investigated those Outcome measures and instruments in association with the OMERACT (Outcome measures in Rheumatoid Arthritis Clinical Trials) FM Workshop initiative to define core outcome measures that should be used to assess FM.\n\nMethods. A systematic literature review Lip to December 2007 was carried out using the keywords “fibromyalgia,” AS1842856 purchase “treatment” or “management,” and “trial.” Data were extracted on Outcome measures and assessment instruments used and the pre and post mean and standard deviation to calculate effect sizes (ES). Further sensitivity analysis was carried out according to treatment type, blinding status, and Study Outcome.\n\nResults. The outcome domains identified fell largely within those defined by OMERACT. Morning stiffness was frequently assessed and therefore has been included here. The number of assessment instruments used was wide-ranging, so sensitivity analysis was only carried out on the top 5 within each domain. ES ranged from 0.54 to 3.77 for the key OMERACT domains.

Health-related quality of life (HRQOL) was the only exception that had no instrument with moderate sensitivity. Of the secondary domains, dyscognition was lacking any sensitive instrument. Lis were fatigue and anxiety in pharmacological trials.\n\nConclusion. Each of the key OMERACT domains has an instrument that appears to be sensitive to change, with the exception of HRQOL, which requires, further research. Dyscognition, fatigue, and anxiety Would all benefit from more research into their assessment instruments. (First Release Sept 15 2008: J Rheumatol 2008;35:2094-105 doi: 10.3899/jrheum.080077)”
“A fraction of FVIII:Ag in commercial recombinant FVIII (rFVIII) cannot bind VWF whereas all the FVIII:Ag in plasma-derived FVIII (pd-FVIII) concentrates does.

Lactate dehydrogenase assays, FITC Annexin V staining assay were

Lactate dehydrogenase assays, FITC Annexin V staining assay were performed to evaluate cellular cytotoxicity and apoptosis activity. The results showed that pretreatment with these polyphenols induced apoptosis in A549 cells. Liquiritin, isoliquiritin and isoliquirigenin

significantly increased cytotoxicity of, and upregulated p53 and p21 and downregulated the apoptotic pathways. Furthermore, it inhibited cell cycle at the G2/M phase. Western blot analysis showed it significantly decreased the protein expression of PCNA, MDM2, p-GSK-3, p-Akt, p-c-Raf, p-PTEN, caspase-3, pro-caspase-8, pro-caspase-9 and PARP, Bcl-2 in a concentration-dependent AZD9291 molecular weight manner while the protein expression of p53, p21 and Bax was increased. In addition, Akt pathway was downregulated. These findings suggest that liquiritin, isoliquiritin and isoliquirigenin inhibited the p53-dependent pathway and showed crosstalk SBC-115076 between Akt activities.

These active polyphenols can be an alternative agent for the treatment of lung cancer.”
“Purpose: In patients with early-stage breast cancer treated with breast-conserving surgery, randomized trials have found little difference in local control and survival outcomes between patients treated with conventionally fractionated (CF-) whole breast irradiation (WBI) and those receiving hypofractionated (HF)-WBI. However, it remains controversial whether these results apply to all subgroups of patients. We therefore developed an evidence-based guideline to provide direction for clinical practice.\n\nMethods and Materials: A task force authorized by the American Society for Radiation Oncology

weighed evidence from a systematic literature review and produced the recommendations contained herein.\n\nResults: The majority of patients in randomized trials were aged 50 years or older, had disease Stage pT1-2 pN0, did not receive chemotherapy, and were treated with a radiation dose homogeneity within +/- 7% in the central axis plane. Such patients experienced equivalent outcomes with either HF-WBI or CF-WBI. Patients VX-680 in vivo not meeting these criteria were relatively underrepresented, and few of the trials reported subgroup analyses. For patients not receiving a radiation boost, the task force favored a dose schedule of 42.5 Gy in 16 fractions when HF-WBI is planned. The task force also recommended that the heart should be excluded from the primary treatment fields (when HF-WBI is used) due to lingering uncertainty regarding late effects of HF-WBI on cardiac function. The task force could not agree on the appropriateness of a tumor lied boost in patients treated with HF-WBI.\n\nConclusion: Data were sufficient to support the use of HF-WBI for patients with early-stage breast cancer who met all the aforementioned criteria. For other patients.

Materials and Methods: We analyzed 44 pediatric arterial stro

\n\nMaterials and Methods: We analyzed 44 pediatric arterial stroke patients and click here 75 healthy controls. Following DNA isolation, genotyping of the A3 haplotype was determined via PCR and RFLP. Additionally, fasting sEPCR levels were determined via ELISA.\n\nResults: There wasn’t a significant difference in the sEPCR level between the control and patient groups, although the sEPCR level was higher in the patient group. We didn’t observe a difference in the distribution of the CC and CG/GG genotypes between the control and patient groups.\n\nConclusion: Further study on sEPCR levels at the onset of pediatric stroke is needed in order to reach a more definitive conclusion.”

structures of 2-methylmalonic acid, 2-ethylmalonic acid

and 2-phenylmalonic acid, which are derivatives of malonic acid and have found usefulness in diagnostics and biochemical evaluations as markers and organic synthesis, are reported. 2-Methylmalonic acid and 2-ethylmalonic acid both crystallize in triclinic P-1 space group with cell parameters of a = 5.1033(7), b = 5.4231(7), c = 10.0887(14) angstrom, alpha = 88.074(4), beta = 89.999(5) and gamma = 67.955(4)A degrees for 2-methylmalonic acid, and a = 5.2073(4), b = 7.2258(6), c = 8.5655(6) angstrom, alpha = 88.086(2), beta = 75.307(2) and gamma = 85.904(3)degrees for 2-ethylmalonic acid, 2-phenylmalonic acid on the other hand crystallizes in monoclinic P2(1)/c with cell parameters a = 8.6494(4), b = 5.48733(19), c = 17.1706(6)angstrom and beta = 90.1068(17)degrees. The observed topology of the hydrogen bonding network HDAC activation is to a large extent dictated by the symmetrical substitution pattern with an open arrangement of hydrogen bonds. Each of the C=O double bonds in both 2-methylmalonic acid and 2-ethylmalonic acid is translationally offset, forming planar centrosymmetric carboxy-dimers. Molecules related by centre of inversion in spite of the constraints imposed by substituents are linked by O-H center dot see more center dot center dot O hydrogen bonds. This results in the formation of parallel zig-zag chains running along the [101]

direction. In 2-phenylmalonic acid, the zig-zag molecular residue is parallely stacked with successive catemers. These laterally displaced catemers are also coiled in a twofold twist on the screw axis (x, 1/2 + y, 1/2 – z) along the b-glide (x, 1/2 – y, 1/2 + z) when viewed along the (101) plane.”
“Given that RNA is involved in virtually all biological processes, it is perhaps not surprising that several RNA-binding proteins are associated with aging and with different age-related disorders. Other articles in this volume will discuss some specific examples of diseases where RNA plays a role that are also associated with aging, such as cancer and inflammation, so here I will discuss some general aspects of how RNA changes with the aging process.