Adverse events such as dizziness, diarrhea, fatigue, nausea, head

Adverse events such as dizziness, diarrhea, fatigue, nausea, headache and somnolence occur quite frequently with Sativex, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual ‘uptitration’. In summary, initial well-controlled studies with Sativex oromucosal spray administered as an add-on to usual therapy have produced promising results and highlight encouraging

avenues for future research.”
“The intensification of modern agriculture may impact amphibian populations through habitat loss and the AC220 direct and indirect effects of the pesticides upon which it relies. The increased homogeneity of modern agricultural landscapes may be detrimental in times of extreme low and high temperatures associated with climate change, as refuge abundance and habitat connectivity decrease. In this study, we evaluated the impacts of the herbicide glyphosate and subsequent intense drought on the Common Tree Frog, Hypsiboas pulchellus, inhabiting an agricultural landscape. We examined a series of organismic indices (stomach content index,

hepatosomatic index, body fat index, gonadosomatic index, condition factor) as well as biomarkers of oxidative stress (hepatic catalase activity and reduced glutathione [GSH] content), exposure to contaminants (hepatic gluthatione-S-transferase activity), and genotoxicity (frequency of micronuclei). No significant differences were observed in the parameters measured when comparing frogs sampled before, 2, and 15 days after glyphosate exposure. However, anurans sampled in the same site two months later, Rigosertib when a drought was at its peak, presented a decrease in stomach content and hepatosomatic index, as well as an increase in hepatic catalase activity, hepatic GSH content and micronuclei frequency in peripheral circulating erythrocytes. Our findings demonstrate that drought is challenging to these anurans in this environment as evidenced selleck kinase inhibitor by an apparent reduction in food

intake and oxidative stress.”
“P>Aim.\n\nThis paper is a report of a study of the relationship between nurses’ clinical experience and calibration of their self-confidence and judgement accuracy for critical event risk assessment judgements.\n\nBackground.\n\nMiscalibration (i.e. under-confidence or over-confidence of confidence levels) has an important impact on the quality of nursing care. Despite this, little is known about how nurses’ subjective confidence is calibrated with the accuracy of their judgments.\n\nMethods.\n\nA sample of 103 nursing students and 34 experienced nurses were exposed to 25 risk assessment vignettes. For each vignette they made dichotomous judgements of whether the patient in each scenario was at risk of a critical event, and assigned confidence ratings (0-100) to their judgement calls. The clinical vignettes and judgement criteria were generated from real patient cases.

The science of medical decision making seeks to explain how medic

The science of medical decision making seeks to explain how medical judgments and decisions ought ideally to be made, how they are actually made in practice, NVP-LDE225 manufacturer and how they can be improved, given the constraints of medical practice. The field considers both clinical decisions by or for individual patients and societal decisions designed to benefit the public. Despite the relevance of decision making to medical practice, it currently receives little formal attention in the U.S. medical school curriculum. This article suggests three roles for medical decision making

in medical education. First, basic decision science would be a valuable prerequisite to medical training. Second, several decision-related competencies would be important outcomes of medical education; these include the physician’s own decision skills, the ability to guide patients in shared decisions, and knowledge of health policy decisions at the societal level. Finally, decision making could serve as a unifying principle

in the design of the medical curriculum, integrating other curricular content around Bioactive Compound Library screening the need to create physicians who are competent and caring decision makers.”
“Background: Engineered nanomaterials display unique properties that may have impact on human health, and thus require a reliable evaluation of their potential toxicity. Here, we performed a standardized in vitro screening of 23 engineered nanomaterials. We thoroughly characterized the physicochemical properties of the nanomaterials and adapted three classical in vitro toxicity assays to eliminate nanomaterial interference. Nanomaterial toxicity was assessed in ten representative cell lines.\n\nResults: Six nanomaterials induced oxidative cell stress while only a single nanomaterial reduced cellular metabolic activity and none of the particles affected Ricolinostat in vivo cell viability. Results from heterogeneous and chemically identical particles suggested that surface chemistry, surface

coating and chemical composition are likely determinants of nanomaterial toxicity. Individual cell lines differed significantly in their response, dependent on the particle type and the toxicity endpoint measured.\n\nConclusion: In vitro toxicity of the analyzed engineered nanomaterials cannot be attributed to a defined physicochemical property. Therefore, the accurate identification of nanomaterial cytotoxicity requires a matrix based on a set of sensitive cell lines and in vitro assays measuring different cytotoxicity endpoints.”
“Herpesviruses cause chronic lifelong infections in humans and may cause life-threatening diseases in immunosuppressed patients. Antiviral drugs targeted to viral DNA polymerase, such as acyclovir, penciclovir, ganciclovir, foscarnet and cidofovir, are currently available and have been proven to be efficient against clinical symptoms of herpesvirus infections.

Blood samples were obtained at 0 and 6 hours postdose for the mea

Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), Androgen Receptor Antagonist analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms

were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.”
“Since the start of cardiac surgery in the 1950s, multiple techniques have been used to protect the heart during the surgical requirement for elective global ischemia (and the still, relaxed, bloodless field that this provides the surgeon for repair

of the lesion). Most of these techniques have been discarded. The current gold standard, established click here over 30 years ago, is hyperkalemic (moderately increased extracellular potassium) cardioplegia; this technique revolutionized cardiac surgery, allowing significant surgical advancement with relative safety. Hyperkalemic QNZ ic50 cardioplegia induces a rapid depolarized arrest that is readily reversible. Recent patient demographic changes, with surgeons operating on older, sicker patients who have more severe and diffuse disease, potentially

requires a more prolonged elective ischemia: hence, an improved myocardial protection would be of benefit. Several areas of study have demonstrated that a new concept of myocardial protection ‘polarized’ arrest may provide this additional protection. Many pharmacological agents have been shown (in experimental studies), to have the ability to induce a polarized arrest and to provide improved protection. However, the often-overlooked requirements of effect reversibility and systemic safety have meant that these agents usually remain experimental in nature. This review attempts to highlight the cellular components that can be targeted, within the excitation-contraction coupling cascade, to induce cardiac arrest, and to provide an explanation for the mechanism of action of these agents. In this context, the agents are discussed in terms of their clinical potential for use during cardiac surgery, with particular reference to the safety aspects of the agents. (C) 2010 Elsevier Inc.

Critical twinning stress of cadmium zinc telluride (CdZnTe or CZT

Critical twinning stress of cadmium zinc telluride (CdZnTe or CZT) calculated is 1.38 GPa. All the twin boundaries are along the (11-1) orientation, except the one with the (-111) plane that supports

the indentation, interpreting the unidirectional and boundary-free characteristics, confirmed in the experiment. Three twin thicknesses after unloading are 3.2, 3.5, and 16 nm, which is consistent with the experimentally repeated click here pattern of a lamellar twin with thickness larger than 12.7 nm, followed by one or several twins with thicknesses smaller than 12.7 nm. An inverse triangle of a twin combining with three twins generate a synergistic strengthening effect through the hardening and softening functions, illuminating the ultrahigh hardness demonstrated in the experiment. Twinning takes place in loading, and detwinning occurs in unloading, which expounds the high ductility observed in the experiment.”
“Phosphatidylethanolamine (PE) is an important inner membrane phospholipid

mostly synthesized de novo via the PE-Kennedy pathway and by the decarboxylation of phosphatidylserine. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) catalyzes HDAC inhibitor the formation of CDP-ethanolamine, which is often the rate regulatory step in the PE-Kennedy pathway. In the current investigation, we show that the reduced CDP-ethanolamine formation in Pcyt2(+/-) mice limits the rate of PE synthesis and increases the availability of diacylglycerol. This results in the increased formation of triglycerides, which is facilitated by stimulated de novo fatty acid synthesis and increased uptake of pre-existing fatty acids. Pcyt2(+/-) mice progressively accumulate more diacylglycerol and triglycerides with age and have modified fatty acid composition, predominantly in PE and triglycerides. Pcyt2(+/-) additionally

have an inherent blockage in fatty acid utilization as energy substrate and develop impaired tolerance to glucose and insulin at an older age. Accordingly, Nepicastat gene expression analyses demonstrated the up-regulation of the main lipogenic genes and down-regulation of mitochondrial fatty acid beta-oxidation genes. These data demonstrate for the first time that to preserve membrane PE phospholipids, Pcyt2 deficiency generates compensatory changes in triglyceride and energy substrate metabolism, resulting in a progressive development of liver steatosis, hypertriglyceridemia, obesity, and insulin resistance, the main features of the metabolic syndrome.”
“In 1999, the American Academy of Pediatrics (AAP) issued a policy statement addressing media use in children. The purpose of that statement was to educate parents about the effects that media-both the amount and the content-may have on children.

1063/1 3074109]”
“Previous caries experience correlates to f

“Previous caries experience correlates to future caries risk; thus, early identification of lesions has importance for risk assessment and management. In this study, we

aimed to determine if Quantitative Light-induced Fluorescence (QLF) parametersarea (A [mm(2)]), fluorescence loss (F [%]), and Q [%xmm(2)]obtained by image analyses can predict lesion progression. We secured consent from 565 children (from 5-13 years old) and their parents/guardians selleck compound and examined them at baseline and regular intervals over 48 months according to the International Caries Detection Assessment System (ICDAS), yearly radiographs, and QLF. QLF images from surfaces with ICDAS 0/1/2/3/4 at baseline that progressed (N = 2,191) to cavitation (ICDAS 5/6) or fillings and surfaces that did not progress to cavitation/fillings (N = 4,141) were analyzed independently for A, F, and Q. Linear mixed-effects models were used to compare means and slopes (changes over time) between surfaces that progressed and those that did not. QLF

A, F, and Q increased at Selleckchem Pinometostat a faster rate for surfaces that progressed than for surfaces that did not progress (p = .0001), regardless of type of surface or baseline ICDAS score. AUC for ICDAS ranged from 0.65 to 0.80, but adding QLF information improved AUC (0.82-0.87, p < .0005). We concluded that faster changes in QLF variables can indicate lesion progression toward cavitation and be more clinically relevant than actual QLF values.”
“Curves which belong to the class of the generalized Sturmian spirals and obey to the Elastica equation are studied. Analytical formulae for their para-metrizations and a few illustrative plots are presented.”
“The mechanism of yeast cell death induced by heat shock was found to be dependent on the intensity of heat exposure. Moderate (45A degrees C) heat shock strongly increased the generation of reactive oxygen species (ROS) and cell death. Pretreatment with cycloheximide (at 30A degrees C) suppressed cell death, but produced no effect on ROS production. The protective effect was absent if cycloheximide was added immediately before heat exposure and the cells were incubated

with the drug during the heat treatment and recovery period. The rate of ROS production and protective PP2 supplier effect of cycloheximide on viability were significantly decreased in the case of severe (50A degrees C) heat shock. Treatment with cycloheximide at 39A degrees C inhibited the induction of Hsp104 synthesis and suppressed the development of induced thermotolerance to severe shock (50A degrees C), but it had no effect on induced thermotolerance to moderate (45A degrees C) heat shock. At the same time, Hsp104 effectively protected cells from death independently of the intensity of heat exposure. These data indicate that moderate heat shock induced programmed cell death in the yeast cells, and cycloheximide suppressed this process by inhibiting general synthesis of proteins.

In addition, N-glycosylation of ZP glycoproteins occurred during

In addition, N-glycosylation of ZP glycoproteins occurred during meiotic maturation and was crucial in spermZP interactions, was responsible for sperm penetration, sperm binding to ZP and induction of

acrosome reaction VX-689 molecular weight in ZP-bound sperm. However, the inhibition of N-glycosylation by tunicamycin during IVM did not influence ZP hardness and male pronuclear formation, indicating that this N-glycosylation was involved in the initial stage of fertilization. We conclude that 2444 h of N-glycosylation of ZP glycoproteins during meiotic maturation was crucial in sperm penetration and sperm binding to ZP and the induction of acrosome reaction in sperm bound to ZP of porcine DOs.”
“Objective: To examine temporal and spatial gait parameters in Mexican healthy pediatric subjects to describe normal values which could LY2835219 ic50 serve as reference data to eventually compare pathological patterns of the Mexican infant gait.\n\nMaterials and methods: Descriptive study that analyzed the gait of 120 children (61 boys and 59 girls) between the ages of 6 and 13 years old. Modifying factors (age, gender,

and footwear) were recorded and its impact over temporal and spatial gait parameters was assessed. The data was stratified according to the modifying factors. A GAITRite (R) System was used for recording the gait data.\n\nResults: Significant differences were noted for the following factors: age and the use of footwear. As the individual advances in age, a decrease in number of steps, normalized velocity, velocity, cadence, normalized cadence, normalized step and stride length was observed. In contrast, step and stride length increased. Use of PCI-32765 nmr footwear increased velocity (normalized and non-normalized), normalized cadence, step and stride length (normalized and non-normalized), and percentage of stance GC phase; cadence and swing GC percentage diminished. Gender stratification showed no significant

differences in any temporal and spatial gait parameters. There were also found significant differences with those reported for normal adult and pediatric gait in the literature.\n\nConclusion: Age and footwear modified gait pattern in the studied sample, while gender apparently did not exert any influence on it. (C) 2010 Elsevier B.V. All rights reserved.”
“This study aimed to investigate the influence of growth rate and onset of boar contact on age at first observed estrus of the replacement gilts raised in Thailand. In total, 766 gilts were measured for body weight and backfat thickness prior to insemination. Body weight was further calculated for growth rate. Estrus detection was performed twice a day by back pressure test with an existence of mature boars with high libido. The first date of boar exposure and that of first observed estrus were individually recorded. Due to growth rate, they were classified into three groups: high ( bigger than 700 g/day), moderate (600-700 g/day), and low ( smaller than 600 g/day).

4 +/- 5 3 kcal/mol and Delta S-double dagger = -45 +/- 15 e u , c

4 +/- 5.3 kcal/mol and Delta S-double dagger = -45 +/- 15 e.u., compared with Delta H-double dagger = 17.3 +/- 2.6 kcal/mol and Delta S-double dagger = -29 +/- 7 e:u. for the C-CN activation

pathway. These parameters indicate that C-H activation Crenolanib datasheet is favored enthalpically, but not entropically, over C-C activation, implying a more ordered transition state for the former.”
“In recent years it has become increasingly evident that MYC rearrangements are not confined to classical Burkitt lymphoma (BL), but also occur in diffuse large B-cell lymphoma (DLBCL) and in the new subtype, “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL” (BCLU), which was recently described in the 2008 revision of the World Health Organization classification. The accurate identification of MYC rearrangements in these three subtypes of high-grade lymphoma is becoming increasingly critical both in terms of diagnosis of classical BL and in light of the prognostic implications in cases of DLBCL and BCLU. We describe three cases of high-grade Dinaciclib nmr lymphoma in which cryptic insertion events, resulting in clinically significant IGH-MYC rearrangements, were detectable using an IGH/MYC three-color, dual-fusion fluorescence in situ hybridization (FISH) probe set, but were not detected using break-apart MYC FISH probes, thus highlighting the limitations of using break-apart

probes as a stand-alone test, particularly with the increased use of interphase FISH analysis of formalin-fixed, paraffin-embedded tissue sections in the diagnostic work-up of these patients. (C) 2010 Elsevier Inc. All rights reserved.”
“A facile carbocation-induced electrophilic cyclization reaction Pinometostat concentration has been developed for the synthesis of 3-alkyl- or 3-allenyl-2-amidobenzofurans from o-anisole-substituted ynamides and diarylmethanol or 1,1-diarylprop-2-yn-1-ol.”
“Case Description-A 9-year-old spayed female mixed-breed dog was evaluated because of a progressively worsening, nonproductive cough and gagging of 1 year’s duration.\n\nClinical Findings-Physical examination results were unremarkable. A cranial mediastinal mass was identified at the heart base with 3-view

thoracic radiography. A CT scan of the thorax revealed an invasive mass surrounding major vessels at the heart base that was not considered surgically resectable. Thoracoscopic biopsy specimens of the cranial mediastinal mass were obtained, and histologic evaluation revealed that the tumor was a chemodectoma.\n\nTreatment and Outcome-On the basis of results of the CT scan, a 3-D conformal radiation therapy plan was generated with computer treatment-planning software. The patient was treated with external beam radiation therapy; a 6-MV linear accelerator was used to deliver a prescribed dose of 57.5 Gy in twenty-three 2.5-Gy fractions. The cough improved following radiation therapy. Prior to treatment, the tumor volume was calculated to be 126.69 cm(3).

Among these variants, we recently identified 21 novel alleles (*3

Among these variants, we recently identified 21 novel alleles (*36-*56) in the Han Chinese

population. The aim of this study was to assess the catalytic activities of 36 CYP2C9 variants found in the Chinese population toward losartan in vitro.\n\n2. Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.5-25 mu M losartan for 30 min at 37 degrees C. Next, the products were extracted, and signal detection was performed using high-performance liquid chromatography.\n\n3. Compared with wild-type CYP2C9.1, the intrinsic clearance (V-max/K-m) values of all variants except for CYP2C9.56 were significantly altered. One variant exhibited markedly increased values (>250%), whereas 33 variants exhibited significantly decreased values (from 20 to 96%) due see more to increased K-m and/or decreased V-max values.\n\n4. These findings suggest that more attention should be paid to subjects carrying these infrequent CYP2C9 alleles when administering losartan in the clinic.”
“Despite recent advances in our understanding of the neural control of breathing, the precise cellular, synaptic, and molecular mechanisms underlying the generation and modulation of

respiratory rhythm remain largely unknown. This lack of fundamental knowledge in the field of neural control of respiration is likely due to the complexity of the mammalian brain where synaptic connectivity between central respiratory neurons, motor neurons and their peripheral counterparts cannot be mapped reliably. We have therefore developed an invertebrate model system wherein the essential elements of the central pattern generator (CPG), the motor neurons and the peripheral chemosensory cells involved in respiratory control have been worked out both in vivo and in vitro. We discuss our recent identification of peripheral, hypoxia sensitive chemoreceptor elements in a sensory organ of the pulmonate freshwater pond snail Lymnaea stagnalis, which provide an excitatory drive to the respiratory CPG neuron RPeD1 via find more direct chemical synaptic connections. Further studies using this unique invertebrate model system may reveal highly conserved principles

of CPG neuromodulation that will remain relevant to more complex mammalian systems.”
“Aim: In this retrospective study, we evaluated the clinical responses to antiepileptic drug (AED) therapy in pediatric epilepsy patients treated at a single center.\n\nMaterials and methods: We identified 28 children with intractable epilepsy and 213 patients with drug-responsive epilepsy.\n\nResults: Univariate analysis showed that age at onset, high (daily) initial seizure frequency, infantile spasm, history of neonatal seizures, abnormal neurodevelopmental status, neurological abnormalities, mental retardation, remote symptomatic etiology, and abnormal brain imaging results were significant risk factors for the development of intractable epilepsy (P < 0.05).

Seedlings, saplings and adult trees were all susceptible to inocu

Seedlings, saplings and adult trees were all susceptible to inoculation with P. austrocedrae. Under favourable experimental conditions (flooding), inoculated seedlings suffered massive mortality in less than a month. The importance of diseases caused by Phytophthora spp. in South American forests is discussed.”
“The diversity of 40 strains of Ralstonia solanacearum causing bacterial wilt of potato in the major potato-growing areas of Iran was assessed. Based on rep-PCR genomic fingerprinting, strains fell into two distinct groups. The first group contained 37 of the 40 strains and the second consisted of three

strains from a narrow tropical region in Iran. The three strains from the narrow tropical region were found to be phenotypically and genotypically most Navitoclax mw similar to R. solanacearum biovar 2T strains, whereas all other strains were phenotypically and genotypically identified as being R. solanacearum biovar 2/race 3. Phylogenetic analysis of endoglucanase gene sequence information of two of the strains from

the tropical region revealed that they belonged to phylotype II of the R. solanacearum species complex and had 100% sequence similarity to a biovar 2T strain from potato in Peru. This is the first report of the presence of R. solanacearum phylotype II/biovar 2T in Iran and the first report of the existence of this group of R. solanacearum outside South America.”
“Orbital floor fractures have the potential to cause significant morbidity both in the short and long terms and commonly present to the ED for

initial assessment. Although treatment of the majority of these injuries AZD0530 involves clinic review and possible later surgery, there is a specific subset that present to emergency clinically suggestive of a head injury. This subset, ‘white-eyed blowout’, usually INCB028050 chemical structure occurring under 18 years of age, with a history of trauma and little sign of soft tissue injury, describes a trap door orbital floor fracture with herniation and acute entrapment of orbital muscle and is regarded as a maxillofacial emergency. The injury presents with marked nausea, vomiting, headache and irritability suggestive of a head injury that commonly distracts from the true aetiology. It requires prompt diagnosis and treatment to avoid permanent morbidity. We present three cases and discuss their management.”
“By global standards, the prevalence of community-onset expanded-spectrum-cephalosporin-resistant (ESC-R) Escherichia coli remains low in Australia and New Zealand. Of concern, our countries are in a unique position, with high extramural resistance pressure from close population and trade links to Asia-Pacific neighbors with high ESC-R E. coli rates. We aimed to characterize the risks and dynamics of community-onset ESC-R E. coli infection in our low-prevalence region. A case-control methodology was used. Patients with ESC-R E. coli or ESC-susceptible E.

They were genetically characterized according

They were genetically characterized according Selleckchem Nepicastat to S. aureus protein A (spa) types and important virulence-associated genes. Sixty-five different spa types corresponding to nine different spa clonal complexes were observed. Analysis of different virulence genes showed a frequency of 17% for toxic-shock syndrome toxin and 5% for exfoliative toxin D. In conclusion, spa typing revealed a great genetic diversity without predominant spa type, not providing evidence for clonal spreading.”
“PURPOSE. Bothnia dystrophy ( BD) is an autosomal recessive retinitis pigmentosa ( arRP) associated with the c. 700C > T mutation

in the RLBP1 gene. Testing of patients with BD has revealed the c. 700C > T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.\n\nMETHODS. Patients with BD heterozygous

for the RLBP1 c. 700C > T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism ( RFLP), sequencing, denaturing (d) HLPC and find more allelic discrimination. The ophthalmic examinations were performed in all c. 700C > T heterozygotes.\n\nRESULTS. The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c. 677T > A, corresponding to p. M226K was detected in all 10 cases. Segregation analysis showed that the mutations were allelic, and the patients were compound heterozygotes [ c. 677T > A] +[ c. 700C > T]. One of those patients was also a carrier of the c. 40C > T corresponding to the p. R14W change in carbonic anhydrase IV ( CAIV) associated with autosomal dominant RP, RP17. His mother, BMS-345541 nmr a carrier of the identical change was declared healthy after ophthalmic

examination. This sequence variant was found in 6 of 143 tested blood donors.\n\nConclusions. The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene: c. 677T > A and c. 700C > T. BD is caused by the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p. R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.”
“The activity of mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is severely reduced in human pathologies where oxidative stress is traditionally thought to play an important role, such as familial and sporadic forms of Alzheimer’s disease and other age-related neurodegenerative diseases.