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Monoclonal antibodies Two prospective, randomized phase III trials of the combination of cetuximab with cytotoxic drugs are published.
Although, PFS was identical between the two arms 4. Furthermore, a new analysis demonstrated that OS for patients receiving cetuximab, who experienced any grade of rash acne-like rash within three weeks of treatment initiation was The magnitude of benefit while statistically significant was modest 1.
A possible explanation for the discrepancy between the FLEX and the BMS study might be related to the relatively low number of patients participating in the latter trial.
Published results are conflicting and both positive and negative correlations have been reported However, it should be underlined that these differences could be attributed to differences regarding the methodologies used in all these studies Most common of these are in-frame deletions in exon 19 codons and a missense mutation leading to a substitution of arginine for leucine at codon LR.
This study failed to show survival improvement, although time-to-progression was significantly longer for either dose of the drug Squamous histology, metastases to central nervous system, history of hemoptysis, and history of documented hemorrhagic diathesis were reported as exclusion criteria in both studies, limiting the potential use of bevacizumab to selected NSCLC patients.
The ECOG study reported significantly higher toxicity for patients receiving bevacizumab. Importantly, there were only two treatment related deaths in the chemotherapy arm and 15 in the bevacizumab arm Jemal A.
Cancer J. Carney D. To Move On From Chemotherapy. Franklin W. Sedlacek H. Drugs 5. Ciardiello F. Cappuzzo F. Takeda K.
Thatcher N. Lancet 9. Shepherd F. Mok T. Engl J. Mitsudomi T. Lancet Oncol. Kim E. Lancet : Pirker R. Gatzemeier U. Langer C.
Lung Cancer 9: Lynch T. Pallis A. Cancer Sandler A. Reck M. Pitychoutis, Christina Dalla and Zeta PapadopoulouDaifoti Department of Pharmacology, Medical School, University of Athens, Athens, Greece Key words: In situ hybridization; antidepressant, serotonin 5-HT , major depression, psychopharmacology S u m m a r y: Chronic mild stress CMS was developed in the late s and is one of the most extensively investigated animal models of depression to-date.
Research from our lab has underlined the importance of serotonin in the manifestation of sexually dimorphic neurochemical, behavioural and immune responses.
This sexdependent differentiation has been largely attributed to the pronounced sex differences that predominate in both the anatomy and function of the human brain, as well as to the sexually dimorphic hormonal milieu.
Chronic mild stress CMS was developed in the late s and is one of the most extensively investigated animal models of depression to-date.
In our initial studies in male rats exposed to a CMS regimen, we observed a decrease in the prefrontocortical serotonergic activity accompanied by an increase in hippocampal serotonergic activity; all alterations were reversed by chronic imipramine treatment .
In further comparative studies between male and female rats, we used a milder CMS protocol, which did not induce neurochemical alterations in male rats, but resulted in a significant decrease in hippocampal serotonergic activity in females .
Accordingly, exposure to CMS induces a wide spectrum of relevant neurobiological alterations in specific brain regions implicated in the pathophysiology of major depression.
Given the prominent role of the hippocampus in the sex-dependent processing of stressful stimuli, in the present study we investigated whether sex differences exist in the expression of hippocampal 5-HT1A receptor upon CMS application and chronic antidepressant treatment.
Bekris S. Brain Res. Dalla C. Neuroscience 3. Papp M. Psychopharmacology Berl 4. Pitychoutis P. The endocannabinoid system ECS modulates many neurotransmitter systems and is implicated in reward, addiction and the effects of psychostimulants.
The psychostimulant d-amphetamine damp is well known to modulate locomotor activity as well as dopamine and glutamate function; however, it is yet unclear how the ECS is able to intervene in these effects of d-amp.
Thus, the aim of the present study was to investigate the effects of CB1 antagonism on damp-induced behavioural and neurochemical effects.
Sprague- Dawley rats were either observed for locomotor activity after administration of vehicle, d-amp, SR or SR and d-amp or underwent surgery for probe implantation and administered the same treatments in microdialysis experiments measuring dopamine and glutamate in the nucleus accumbens.
Our results showed that d-amp on its own induced hyperlocomotion and increased dopamine and glutamate.
When coadministered with SR, these effects on locomotor activity and neurotransmitter levels were modulated. This study provides further evidence for the role of the ECS in damp- induced behavioural and neurochemical effects in vivo, and furthermore, emphasizes the importance of this modulatory neurotransmitter system in psychostimulant addiction.
The effects of drugs of abuse such as cannabinoids and the psychostimulant d-amp on the brain and on behaviour are not only mediated by the mesolimbic dopaminergic system but also by the excitatory glutamatergic neurotransmitter system.
Amphetamine, an indirect dopamine agonist, is universally known to modulate locomotor activity and extracellular dopamine and glutamate.
Evidence demonstrates that cannabinoids also modify locomotor activity as well as the neurotransmitters dopamine and glutamate, mainly via their action on the CB1 receptor in the brain.
In the present study, we chose to investigate the effects of SR, a CB1 receptor antagonist, coadministered with the psychostimulant, d-amp on locomotor activity, in vivo extracellular dopamine levels and glutamate levels in the nucleus acccumbens, the epicentre of reward.
This interaction can also be extended to pathological states such as drug dependence and addiction. Interestingly, the ECS has been impli- Male Sprague-Dawley rats were divided into two groups; the first group was intraperitoneally i.
Sample collection began 24 h later. Once baseline samples were collected, the rats were injected i. All samples were then measured for dopamine and glutamate using High Performance Liquid Chromatography with electrochemical detection.
Likewise, increased extracellular dopamine and glutamate observed after d-amp administration in the nucleus accumbens, were also modified by SR.
Our results show that SR was indeed able to modulate both locomotor activity and neurotransmitter release induced by d-amp, thus providing us with further evidence for a role of the ECS in the effects of d-amp.
On a larger scale, these results contribute to the expansively growing literature on the significance of the ECS in reward and addiction.
Corbille A. J Neurosci 2. Gardner E. Parolaro D. Drug News Perspect. Polissidis A. Neuropsychopharmacol: 5. Wiskerke J. Margioris2, Katia P.
The latter is further supported by that, CRH and its receptors are expressed in human and murine skin.
In the process of wounded skin repair, fibroblasts from the wound edges migrate into the wound and proliferate in order to fill the site of the wound.
IL-6 is a pro-inflammatory cytokine critically involved in cutaneous wound healing. We have previously shown that CRH regulates IL-6 expression during inflammation and that Crh deficient mice have accelerated wound healing in vivo and suppressed tissue IL-6 expression.
Based on the above, the aim of our study was to clarify the role of endogenous CRH on the function of primary dermal fibroblasts, in vitro.
Evaluation of the proliferation rate of all cells was performed using the MTT and the thymidine incorporation methods.
Apoptotic cell death was measured with FACS analysis. Evaluation of the migration rate was performed using the scratch assay.
Treatment with CRH 10 nM had no effect on the proliferation rate of cells of either genotype.
No difference was observed in apoptosis between the two genotypes. These experiments revealed increased proliferation and migration rate and suppressed IL-6 secretion of CRF1 antagonisttreated fibroblasts.
Our findings support the direct effects of CRH in skin biology and provide interesting insights for the potential usefulness of the developing specific agonists and antagonists of the CRH family in dermal injury or other skin diseases.
Extracellular matrix molecules, like hyaluronan, are highly implicated in both processes 1. Proteoglycans are major components of the extracellular matrix of the skin.
However, they have been poorly studied in intrinsic and extrinsic skin ageing. In the present study we have tried to elucidate the involvement of certain important proteoglycans in intrinsic and extrinsic skin ageing in humans.
Gene expression of versican 1, versican 0, biglycan, decorin, perlecan and syndecan-3 was down regulated in intrinsic skin ageing, whereas the exception of aggrecan, was up regulated.
Extrinsic skin aging was associated with decreased expression of perlecan and decorin and increased expression of versican 0, versican 1 and aggrecan.
Biglycan and syndecan-3 remained practically unaltered. Photo-protected skin tissue specimens were also obtained from juvenile mean age 5 years patients.
Gene expression of versican 1, versican 0, biglycan, decorin, aggrecan, perlecan and syndecan-3 was analyzed using RT-PCR.
Tzellos T. One capsule of either formulation was administered with low-carbonate water after 10 h of overnight fasting.
After dosing, serial blood samples were collected during a period of 48 hours. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles.
Gabapentin has been shown to increase -aminobutyric acid concentrations in the brain of epilepsy patients 4.
Gabapentin is well established in the treatment of seizures and also has a demonstrated analgesic effect in patients with chronic neuropathic pain 5.
The absorption of gabapentin is saturable in a dose dependent manner involving an active transport process mechanism by an Lamino acid transporter 6.
In humans, GBP is eliminated exclusively by renal excretion of unchanged drug, and plasma protein binding is negligible.
Renal clearance CL is similar to glomerular filtration rate indicating that no net renal secretion or reabsorption takes place 7. The study was conducted in a randomized, single-dose, two-way, cross-over design with a 10 days washout period between two doses.
During each period, the volunteers were admitted to hospital and after an overnight fasting they received a single reference or tested mg Gabapentin capsule.
Low-carbonate water mL was given immediately after drug administration. All volunteers fasted 2 h after the drug administration.
No other food was permitted during the first 24 h after drug administration. The study was performed in accordance with the guidelines of the revised Declaration of Helsinki on biomedical research involving subjects and the requirements of Good Clinical Practice.
Blood samples were drawn at 0. The blood samples were centrifuged at rpm for 15 min and the separated plasma was collected and stored at o 20 C until drug analysis.
After a wash-out period of 10 days, the study was repeated in the same manner to complete the cross-over design. The mixture was vortex-mixed on a vortex mixer Scientific Industries, Inc.
The mixture was then centrifuged at 17, g for 5. Two hundred fifty microliters of the supernatant was transferred into a 2.
Chromatographic conditions Chromatographic analysis was carried out at 30 o C. Detection was carried out at excitation and emission wavelengths of and nm, respectively.
The mobile phase was filtered by passing through a 0. The plasma standard curves were prepared over the range of 0. Standard curves were analyzed and for each standard curve; determined the variability of the slopes and intercepts.
Pharmacokinetic and statistical analysis For computation and analysis of the drugs plasma concentration versus time data and the graphics, the computer software Microsoft Excel 7.
The area under the plasma concentration-time curve AUC and the area to the infinity AUC0- were calculated by using the linear trapezoidal method.
RESULTS After a single oral administration of Gabapentin mg capsule of test and reference in 20 healthy male subjects, the pharmacokinetic parameters showed in Table 1.
And the mean plasma concentration-time curve of Gabapentin is shown in Figure 1. Table 1 Pharmacokinetic parameters of Gabapentin after a single oral administration of test or reference tablet containing mg Gabapentin in 20 healthy subjects!
Plasma GBP concentrations peaked at h after the dose of mg capsule mean, 3. And the peak plasma levels Cmax of gaba-1 pentin of 2. The elimination half-life of gabapentin is between 4.
The obtained values were in good agreement with reported studies. The main objective of bioequivalence studies is to assure the safety and efficacy of generic formulations.
Two formulations of the same drug are considered to be bioequivalent and therapeutically equivalent if they exhibit a comparable extent and rate of absorption, when they are administered in the same molar dose and under similar experimental conditions 9.
Hengy H. Goa K. Drugs 3. Upton N. Patsalos P. Rowbotham M. JAMA 6. Stewart B. Vollmer K. Chow S. Marcel Dekker, New York, Boyd R.
A, Turck D. Recent studies have shown that microglia also expresses the necessary biosynthetic enzymes for the production of neurosteroids, such as Dehy-droepiandrosterone DHEA , Pregnanolone and Allopregnanolone Allo.
DHEA is a multi-functional neurohormone exerting both neuroprotective effects as well as possible modulatory actions on the immune system.
Although there are several studies on the role of DHEA on peripheral macrophages, the impact of neurosteroids on the production of inflammatory mediators from microglia cells has not been yet elucidated.
Based on the above, the aim of our study was to characterize in details the role of DHEA and its synthetic analog BNN27 a 17 spironeurosteroid which is recently developed in our laboratory, deprived of endocrine properties , on the inflammatory response of activated microglia cells.
BV2 cells have been shown to maintain many microglia responses. However, DHEA did not have a similar effect, due to its possible metabolic conversion, by specific steroid converting enzymes that BV2 cells produce.
In addition, the synthetic analog also reduced the proliferation rate of BV2 cells after LPS stimulation, thus further indicating its anti-inflammatory role, since increased rates of proliferation characterize activated microglia.
In summary, our findings provide evidence for the possible pharmacological use of the synthetic analog BNN27 in the inhibition of inflammatory responses of activated microglia and thus ultimately, in the combined treatment of various neurodegenerative disorders.
Balgkouranidou1,2, ES. Lianidou3, D. Mathaios1, N. Xenidis1, K. Amarantidis1, A. Karayiannakis4, G. Kolios2, E. Chatzaki2, and S.
The serum of cancer patients often contains increased free DNA levels, which could potentially offer material for early cancer detection or even information for the development of new therapeutic interventions.
Genetic and epigenetic alterations of the adenomatous polyposis coli APC gene are common events in gastrointestinal tumor development.
Methylation was strongly correlated with metastasis. The secretion of inflammatory mediators was analysed in vivo immunohistochemistry and in vitro Luminex technology 48 h after induction of ischemia.
Preliminary results suggest a decrease in interleukinbeta ILbeta and monocyte chemoattractant protein-1 MCP-1 after treatment, respectively.
Lesion size at 48 h was significantly reduced in the treated group. We quantified microglial cells CD11b by measuring the average intensity of CD11b labelling infra-red emission within the ischemic tissue.
No significant difference was found between groups. In contrast, in vitro data show a modulation of microglial activation after treatment.
Further experiments will show whether D-JNKI1 reduces inflammatory mediators in the brain and in peripheral tissue or systemic circulation.
Borsello et al. Hirt et al. Wiegler et al. Bonovolias, Lefkothea C. Asterios S. Although IM is a designed molecular inhibitor of Bcr-Abl tyrosine kinase, additional mechanisms perhaps are involved leading to IM-induced drug resistance and cardiovascular toxicity.
Our most recent observations that hemin the oxidized form of heme can counteract the cytotoxic effect of IM, prompted us to investigate the question whether IM dismantles the mitochondrial cell respiration pathway by blocking the expression of several genes encoding vital hemoproteins and other related proteins involved in the biosynthesis of cytochrome c oxidase.
These results indicate that IM selectively represses the expression of key-genes and provide novel mechanism s of IM that may explain its cardiovascular toxicity.
Furthermore, it is also known that mutations in SCO2 gene, encoding a cytochrome c oxidase COX assembly protein, lead to fatal infantile cardioencephalomyopathy and COX deficiency 5.
In this study, we further explored the question whether IM represses the transcription of various genes involved in the biosynthesis of heme, hemoproteins and COX assembly genes.
IM at concentrations as low as 1 M inhibited cell growth and caused cell cycle arrest after 24 to 96h. Moreover, IM was found to repress the expression of Bcl-2a, Bcl-2b as well as Nrf2 genes, which are involved in cell survival However, despite these beneficial antineoplastic effects, a portion of patients undergoing IM treatment relapse by exhibiting acquired resistance to IM 2 , while some of them exhibit cardiovascular toxicity 3, 4.
This is an interesting, although unexplored, aspect of IM action. Capdeville R. Drug Discov. Melo J. Cancer Lett. Kerkela R. Will Y. Bonovolias I.
Blood 8. Mayerhofer M. Blood Bonovolias, I. Foltopoulou P. Acta: Lozzio B. Leuk Res. Chomczynski P.
The aim of the present study was to clarify the exact role of L-NAME on memory using different testing procedures. In a last experiment aiming to evaluate the effects of the treatment conditions acute vs.
For this pur- pose, the novel object recognition task was selected. Kenchappa2,8, Anastasia Simi A. Bastiaens4, Peter J. Verveer4, Wilma J.
Friedman5, Giampietro Schiavo6, Bruce D. Carter2, Carlos F. Equal first authors Ligand-mediated receptor dimerization has emerged as a universal mechanism of growth factor receptor activation.
Neurotrophins interact with dimers of the p75 neurotrophin receptor NTR p75 , but the mechanism of receptor activation has remained elusive.
Here, we show that NTR p75 forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys in its transmembrane domain.
In addition, we also show that cross-linking of NTR p75 dimers by cysteine-scanning mutagenesis results in constitutive, ligand-independent activity in several pathways that are normally engaged upon neurotrophin stimulation of native receptors.
The activity profiles of different disulfideNTR crosslinked p75 mutants were similar but not identical, suggesting that different configurations NTR of p75 dimers might be endowed with different functions.
Together, these results indicate that dimeric NTR mutants of p75 functionally resemble neurotrophin bound, not neurotrophin-free, receptors, support formation or stabilization of receptor dimers and oligomers as the mechanism by NTR which neurotrophins activate p75 , and reveal a genetic approach to generate gain-of-function receptor variants with distinct functional profiles.
The use of dietary supplements, including herbals, vitamins and minerals, is extensive. The majority of patients have little or no information about the possible risks and adverse effects from interactions with prescribed medicines.
Concerns about herbal medications include their actual pharmacological properties. Among the more common herbs used for weight loss are Ephedra sinica ephedra , Hoodia gordonii hoodia , Citrus aurantium bitter orange and Larrea tridentate chaparral , and are mostly used in an effort to enhance metabolism.
Receiving ephedra with various medications may lead to interactions, i. Hoodia has been found to suppress appetite, however it has a potential hepatoxicity and therefore safety and efficacy have to be validated.
Bitter orange acts similarly to ephedra and when received together with MAOIs can lead to tachycardia and hypertension.
Chaparral acts similarly to caffeine and also has a mild diuretic effect. Patients should be extremely cautious when receiving herbal medicines especially when are on any prescribed medication.
In general, herbals are less potent than drugs and thus pose a lesser threat to the person taking them. Herbal-drug interactions depend on the active s ingredient s of the herb or herbs in case of a multi-herbal mixture.
Both herbals and drugs are metabolized by the cytochrome P enzyme system of the liver, thus increasing the potential for interactions.
Different herbs are used for weight loss and these include ephedra, hoodia, bitter orange and chaparral, which are mostly used in an effort to enhance metabolism.
They are thought to act as thermogenics and mild diuretics. Most herbal products have not been scientifically evaluated, and therefore information regarding pharmacokinetics, pharmacodynamics, efficacy and safety is in most cases limited.
It can be found in traditional Chinese herbal medications, herbal teas and also other products available via the web Ephedra contains among others the alkaloids ephedrine, pseudoephedrine isoephedrine , and norpseudoephedrine cathine and other constituents, including quinoline.
The stem contains approximately 0. Ephedrine and pseudoephedrine are found in the leaves and stems of ephedra and are structurally related to amphetamines and therefore ephedra is considered a herbal amphetamine 1.
It has been shown to increase the availability and action of the endogenous neurotransmitters norepinephrine and epinephrine and stimulates catecholamine receptors in the brain, heart, and blood vessels both directly and indirectly 2.
There is strong evidence that ephedra is associated with an increased risk of side effects, possibly even fatal ones, and therefore it was banned by the US FDA in 3.
Ephedra or ephedrine alkaloids are considered toxic to the cardiovascular system, and potentially toxic to the neurological, gastrointestinal and endocrine systems.
Another possible effect worth mentioning is the reduced effect of certain drugs antihypertensives, antiseizures, benzodiazepines, antiglycemics when received together with ephedra 4.
Hoodia gordonii hoodia Also known as Kalahari cactus and xhoba. Hoodia gordonii is widely distributed through the arid areas of South Africa and Namibia.
The active appetite suppressant component of Hoodia gordonii was identified as a triglycoside of 12 tigloyloxy -hydroxypregnenone, a minor component in the plant extract 5.
This has been found to suppress appetite for several hours, by signaling satiety on hypothalamic cells far more intensely than glucose 6. There are not any known herb-drug interactions of hoodia; however it has a potential hepatoxicity and therefore its safety and efficacy have to be validated 6.
Citrus aurantium bitter orange Other common names include Seville orange, zhi zhi or sour orange. Bitter orange contains several compounds including synephrine alkaloids 7.
It is commonly used as a substitute for ephedra in dietary supplements 8 and has a mechanism of action which is similar to ephedra and may therefore also lead to cardiovascular and neurologic toxicity when received together with other stimulants e.
When received together with MAOIs can lead to tachycardia and hypertension 9. Larger clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of Citrus aurantium and synephrine alkaloids for promoting weight loss 7.
Larrea divaricata chaparral It is synonymous with for Larrea tridentate and can also be found as creosote bush, hediondilla and greasewood.
Chaparral grows in deserts and is used as a herbal remedy among Native Americans in the Southwestern United States and Northern Mexico It is thought to act as an energy booster and a possible appetite suppressant, having a mechanism of action similar to caffeine and also a mild diuretic effect Chaparral use has been associated with severe hepatotoxicity 10 and is also considered to be a carcinogenic substance 9.
There are not any known herb-drug interactions of chaparral. Many patients think that receiving a dietary supplement herbals are thought to be dietary supplements and not medicines, and therefore their purity, efficacy and safety do not have to be tested or proven is not going to lead to any adverse effects or interfere with prescribed medication Physicians should always ask their patients about possible use of any dietary supplement or herbal product in order to counsel them in the most proper way.
Since there are numerous possible adverse effects and herbdrug interactions of herbs used for weight loss, patients should be able to receive all the needed information from their physician or pharmacist in order to avoid them.
Herbs at a Glance Kalix P. Consumer Advisory ! Tachjian A. Phytochemistry 6. Bent S. Haaz S. Kuhn M. Rodriguez-Fragoso L.
Holcomb S. Nurse Pract. Bishop F. Nitric oxide NO , produced by endothelial nitric oxide synthase eNOS , plays a key role in the regulation of vascular tone.
The study population consisted of patients with a history of MI and control subjects. All subjects were of Greek origin.
The risk for the T allele was estimated at 1. Moreover, strong evidence was found for an increased risk for MI among carriers of the TT genotype who were smokers, hypertensive and had a family history of CAD.
It is possible that TT genotype is closely linked to the etiology of MI even after adjusting for known MI risk factors. Nitric oxide, produced by eNOS, diffuses from the endothelium to vascular smooth muscle cells, where it increases the concentration of cyclic guanosine monophosphate cGMP by stimulating soluble guanylate cyclase, leading to vascular relaxation 1.
The gene encoding eNOS is located on chromosome 7q and contains 26 exons that span 21 kb 2. This is the only known polymorphism changing the eNOS protein sequence, leading to speculation that genetic variation at this site may alter e-NOS activity or regulation and possibly leads to endothelial dysfunction and to pathogenesis of several cardiovascular diseases 3.
The D variant has been associated with myocardial infarction MI in Japanese 4 , English 5 , German 6 and American 7 populations, whereas other studies do not support these findings in Koreans 8 and in Caucasians, i.
Austrian 9 , French-Nothern Irish 10 and Dutch 11 populations. In Greece studies of the ED polymorphism had controversial results Thus, it was the aim of the present study to investigate in a subgroup of the Greek population whether the ED gene variation was related to the risk of myocardial infarction in the total population and among subjects who were at lower or higher risk to this disease.
The control group consisted of volunteers who were selected from the general population of the greater Athens area. Controls were not eligible to participate if they had a history of MI or angina, clinical evidence of coronary artery disease CAD , stroke, or any atherosclerotic disease in the past, based on a detailed medical history and a physical examination followed by a normal electrocardiogram.
From each participant genomic DNA was extracted from peripheral blood leukocytes. The prevalence of atherogenic risk factors such as smoking, family history of CAD, hypertension, diabetes mellitus and hypercholesterolemia was significantly higher in the patient group.
Concerning the allele frequencies of the E to D transition in the MI and control group were calculated at Similarly to recent studies [, ], we found a significant association between homozygous carriers of the T allele and the occurrence of MI in the Greek population.
This finding confirms previous presumptions of a recessive gene effect. MI is a multifactorial disease. Further genetic and environmental risk factors, such as age, gender, BMI, smoking habits and family history as well as accompanying disorders like high blood pressure and hyperholesterolemia contribute significantly to the susceptibility of MI.
The homozygous T allele carriers, as suggested by the univariate analysis of the present study, have an increased risk to develop MI.
These data, possibly suggest, that presence of established underlying endothelial dysfunction, as observed among cigarette smokers, may be necessary for this polymorphism to attenuate endothelial function and predispose patients to increased cardiovascular risk.
This study suggests that an alteration in the activity of the vascular NO system and the decreased amount of endothelial NO, due to the ED mutation, may promote atherosclerosis and thrombosis that lead to MI.
However, the relation of the ED mutation to the severity of coronary atherosclerosis has not been proven yet .
We found evidence that homozygous TT is positively related to the risk of MI and this association is independent of possible effects of other known MI risk factors.
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Get rid of your headache and let us help you improve your grades. Health Promotion in Nursing Practice A BitTorrent file distribution consists of these entities: There are ideally many end users for a single file.
Start running a tracker or, more likely, have one running already. Start running an ordinary web server, such as apache, or have one already.
Associate the extension. Generate a metainfo. Put the metainfo file on the web server. Link to the metainfo. Start a downloader which already has the complete file the 'origin'.
Install BitTorrent or have done so already. Surf the web. Click on a link to a. Select where to save the file locally, or select a partial download to resume.
Wait for download to complete. Tell downloader to exit it keeps uploading until this happens. Metainfo files also known as.
All strings in a. The name key maps to a UTF-8 encoded string which is the suggested name to save the file or directory as.
It is purely advisory. For the purposes of transfer, files are split into fixed-size pieces which are all the same length except for possibly the last one which may be truncated.
It is to be subdivided into strings of length 20, each of which is the SHA1 hash of the piece at the corresponding index. There is also a key length or a key files , but not both or neither.
If length is present then the download represents a single file, otherwise it represents a set of files which go in a directory structure.
In the single file case, length maps to the length of the file in bytes. For the purposes of the other keys, the multi-file case is treated as only having a single file by concatenating the files in the order they appear in the files list.
The files list is the value files maps to, and is a list of dictionaries containing the following keys: length - The length of the file, in bytes.
In the single file case, the name key is the name of a file, in the muliple file case, it's the name of a directory.
Tracker GET requests have the following keys: The 20 byte sha1 hash of the bencoded form of the info value from the metainfo file.
This value will almost certainly have to be escaped. Note that this is a substring of the metainfo file. The info-hash must be the hash of the encoded form as found in the.
Conversely that means clients must either reject invalid metainfo files or extract the substring directly. They must not perform a decode-encode roundtrip on invalid data.
Each downloader generates its own id at random at the start of a new download. This value will also almost certainly have to be escaped.
Generally used for the origin if it's on the same machine as the tracker. Common behavior is for a downloader to try to listen on port and if that port is taken try , then , etc.
Note that this can't be computed from downloaded and the file length since it might be a resume, and there's a chance that some of the downloaded data failed an integrity check and had to be re-downloaded.
If not present, this is one of the announcements done at regular intervals. An announcement using started is sent when a download first begins, and one using completed is sent when the download is complete.
No completed is sent if the file was complete when started. Downloaders send an announcement using stopped when they cease downloading.
Tracker responses are bencoded dictionaries. If a tracker response has a key failure reason , then that maps to a human readable string which explains why the query failed, and no other keys are required.
Otherwise, it must have two keys: interval , which maps to the number of seconds the downloader should wait between regular rerequests, and peers.
Note that downloaders may rerequest on nonscheduled times if an event happens or they need more peers. More commonly is that trackers return a compact representation of the peer list, see BEP If you want to make any extensions to metainfo files or tracker queries, please coordinate with Bram Cohen to make sure that all extensions are done compatibly.
It is common to announce over a UDP tracker protocol as well. Peer connections are symmetrical. Messages sent in both directions look the same, and data can flow in either direction.
The peer protocol refers to pieces of the file by index as described in the metainfo file, starting at zero.
When a peer finishes downloading a piece and checks that the hash matches, it announces that it has that piece to all of its peers.
Connections contain two bits of state on either end: choked or not, and interested or not. Choking is a notification that no data will be sent until unchoking happens.
The reasoning and common techniques behind choking are explained later in this document. Data transfer takes place whenever one side is interested and the other side is not choking.
Interest state must be kept up to date at all times - whenever a downloader doesn't have something they currently would ask a peer for in unchoked, they must express lack of interest, despite being choked.
Implementing this properly is tricky, but makes it possible for downloaders to know which peers will start downloading immediately if unchoked.
Connections start out choked and not interested. When data is being transferred, downloaders should keep several piece requests queued up at once in order to get good TCP performance this is called 'pipelining'.
On the other side, requests which can't be written out to the TCP buffer immediately should be queued up in memory rather than kept in an application-level network buffer, so they can all be thrown out when a choke happens.
The peer wire protocol consists of a handshake followed by a never-ending stream of length-prefixed messages. The handshake starts with character ninteen decimal followed by the string 'BitTorrent protocol'.
The leading character is a length prefix, put there in the hope that other new protocols may do the same and thus be trivially distinguishable from each other.
All later integers sent in the protocol are encoded as four bytes big-endian. After the fixed headers come eight reserved bytes, which are all zero in all current implementations.
If you wish to extend the protocol using these bytes, please coordinate with Bram Cohen to make sure all extensions are done compatibly.
Next comes the 20 byte sha1 hash of the bencoded form of the info value from the metainfo file. If both sides don't send the same value, they sever the connection.
The one possible exception is if a downloader wants to do multiple downloads over a single port, they may wait for incoming connections to give a download hash first, and respond with the same one if it's in their list.
After the download hash comes the byte peer id which is reported in tracker requests and contained in peer lists in tracker responses.
If the receiving side's peer id doesn't match the one the initiating side expects, it severs the connection. That's it for handshaking, next comes an alternating stream of length prefixes and messages.
Messages of length zero are keepalives, and ignored. Keepalives are generally sent once every two minutes, but note that timeouts can be done much more quickly when data is expected.
All non-keepalive messages start with a single byte which gives their type. The possible values are: 'choke', 'unchoke', 'interested', and 'not interested' have no payload.
Its payload is a bitfield with each index that downloader has sent set to one and the rest set to zero.
Downloaders which don't have anything yet may skip the 'bitfield' message. The first byte of the bitfield corresponds to indices 0 - 7 from high bit to low bit, respectively.
The next one , etc. Spare bits at the end are set to zero. The 'have' message's payload is a single number, the index which that downloader just completed and checked the hash of.
The last two are byte offsets. Length is generally a power of two unless it gets truncated by the end of the file.
They are generally only sent towards the end of a download, during what's called 'endgame mode'. When a download is almost complete, there's a tendency for the last few pieces to all be downloaded off a single hosed modem line, taking a very long time.
To make sure the last few pieces come in quickly, once requests for all pieces a given downloader doesn't have yet are currently pending, it sends requests for everything to everyone it's downloading from.
To keep this from becoming horribly inefficient, it sends cancels to everyone else every time a piece arrives.
Note that they are correlated with request messages implicitly. Downloaders generally download pieces in random order, which does a reasonably good job of keeping them from having a strict subset or superset of the pieces of any of their peers.
Choking is done for several reasons. TCP congestion control behaves very poorly when sending over many connections at once. Also, choking lets each peer use a tit-for-tat-ish algorithm to ensure that they get a consistent download rate.
The choking algorithm described below is the currently deployed one. It is very important that all new algorithms work well both in a network consisting entirely of themselves and in a network consisting mostly of this one.
There are several criteria a good choking algorithm should meet. It should cap the number of simultaneous uploads for good TCP performance.
It should avoid choking and unchoking quickly, known as 'fibrillation'. It should reciprocate to peers who let it download.
Finally, it should try out unused connections once in a while to find out if they might be better than the currently used ones, known as optimistic unchoking.
The currently deployed choking algorithm avoids fibrillation by only changing who's choked once every ten seconds.
It does reciprocation and number of uploads capping by unchoking the four peers which it has the best download rates from and are interested.
Peers which have a better upload rate but aren't interested get unchoked and if they become interested the worst uploader gets choked.
If a downloader has a complete file, it uses its upload rate rather than its download rate to decide who to unchoke.
For optimistic unchoking, at any one time there is a single peer which is unchoked regardless of its upload rate if interested, it counts as one of the four allowed downloaders.
Which peer is optimistically unchoked rotates every 30 seconds. To give them a decent chance of getting a complete piece to upload, new connections are three times as likely to start as the current optimistic unchoke as anywhere else in the rotation.
The BitTorrent Economics Paper outlines some request and choking algorithms clients should implement for optimal performance When developing a new implementation the Wireshark protocol analyzer and its dissectors for bittorrent can be useful to debug and compare with existing ones.
This document has been placed in the public domain. Singkat, Padat, dan Jelas Ingat bahwa perusahaan membutuhkan resume untuk mempercepat waktu mereka melakukan seleksi sebelum interview.
Oleh karena itu, waktu untuk melihat tiap resume juga sangat singkat menit sehingga resume yang kita buat harus benar benar padat dan jelas.
Untuk orang yang sudah mempunyai pengalaman kerja cukup lama, halaman masih bisa ditoleransi tetapi tetap usahakan dalam 1 halaman kecuali anda benar2 memiliki hal khusus yang perlu ditulis sebanyak itu.
Context Action Result CAR framework Ketika saya melihat resume dari beberapa orang dalam menulis pengalaman kerja, biasanya mereka hanya menulis judul dari pekerjaannya dan waktunya.
Contoh: - Sales Representative PT. Grosir Baju Indonesia - Dengan teknik penulisan seperti itu, apa yang bisa dilihat oleh perusahaan. Perusahaan hanya tahu bahwa kita punya pengalaman menjadi sales representative selama 4 tahun dan sales supervisor selama 2 tahun di PT.
Grosir Baju Indonesia. Tetapi Perusahaan tidak akan pernah bisa melihat nilai lebih yang anda tawarkan. Ketika mereka melihat resume dari kandidat lain mereka akan melihat hal yang sama.
Bandingkan jika anda menulis seperti ini. Contoh Lain pengalaman sebagai programmer : - Membuat program akuntasi dengan cepat. Telp, E-mail.
Untuk Tempat tanggal lahir, biasanya tidak perlu dimasukkan karena orang akan sudah bisa mengetahui dari waktu anda menempuh pendidikan terakhir.
Tidak perlu mencantumkan daftar pendidikan mulai SD. Orang hanya tertarik untuk mengetahui pendidikan terakhir anda.
Untuk mengetahui contoh aplikasi teknik cara membuat resume bisa anda lihat di. Artikelnya sangat bermanfaat, terima kasih Admin untuk sharingnya.
Terima kasih infonya bro, sangat membatu saya.. Terimakasih untuk informasinya. Setidaknya dapat membantu dalam menambah wawasan kita.
Be Careful. Urus Pendirian PT. Urus Pendirian CV. Urus Ijin Prinsip dan perubahan. Urus Rekomendasi Departemen Perindustrian.
Urus Merk Dagang. Urus Ijin ISO Urus Pernikahan di Luar Negeri Beda Agama Dan masih banyak lagi perijinan lainnya untuk informasi lebih lanjut silahkan hubungi kami: atau.
How long did you walk your child to the door for school? Context : Macbeth is talking to the earth, in a soliloquy. Significance : There are several possible meanings to this quote.
If Macbeth is saying that sound will spoil the mood, then that is an example of metatheatre, which in a way, takes away from the gruesome details of the murder, as it somewhat breaks the forth wall and remind the listeners that Macbeth is only a character in a play.
This quote contains apostrophe, as Macbeth is talking to an inanimate object, and personification. Context : This quote is said by Macbeth to Lady Macbeth.
Macbeth had just killed Duncan, and he and Lady Macbeth are discussing what he had done. Macbeth is horrified and imagines voices that speak of his evildoings.
Macbeth will not sleep anymore. Later, Macbeth refers to himself using his three names, which could symbolize the three stages of his prophesy and his development.
Therefore, Glamis could symbolize his past self, which he was before he killed Duncan, Cawdor could symbolize his current self, which is who killed Duncan, and Macbeth could refer to his future self.
This follows the motif of three, as there were three witches and Hecate was commonly portrayed with three faces.
He feels very guilty, worried, and paranoid, so much as that he believes he will never be able to sleep again. His sleep will disappear along with his innocence, as sleep is depicted as innocent and good.
The witches punish people with lack of sleep, such as when they punished the sailor whose wife was mean with a lack of sleep. This quote contains many metaphors.
Context : This quote is said by Ross to an old man. They exchanging accounts of recent unnatural happenings.
It is the morning after Macbeth killed Duncan. Meaning : According to the clock, it is day, but darkness blocks the sun. Is it dark because night has become more powerful than day, or because day is hiding its face in shame?
People at this time believed that social standing was determined by God, so trying to usurp someone to put yourself in their place goes against the natural order of things.
Kings were believed to also have been chosen by divine powers, so killing and usurping Duncan was especially heinous.
The falcon could be representing King Duncan, while the owl, a bird often attributed to death, could represent witchcraft; therefore, this could be saying that witchcraft has killed Duncan.
Also, night, which can represent evil, is taking over day, which is good and supposed to be predominate.
This quote contains personification and metaphors. Context : Macbeth is talking to himself, in a soliloquy. I have ruined my peace for their benefit and given my soul to the devil to make them, the sons on Banquo, kings.
Instead of letting that happen, let fate come to the arena and fight me to the death. Macbeth, who committed evil deeds, will be punished, while Banquo, who has been good and loyal to the king, will be rewarded.
This quote also contains personification and metaphors. Context : Macbeth is speaking to Lady Macbeth. Meaning : We have hurt the snake, but have not killed it.
It is better to be with the dead, whom we have killed and put to rest in order to secure our peace, than to lie with tortured minds in a frenzy of sleeplessness.
He decides that he rather destroy the world than continue to live in fear, which indicates the reign of terror that Scotland will fall under.
Simply choose your favorite and get started. Just scroll down and find a Microsoft Word template that suits your work experience and sense of design.
Save time and effort — it does all of the writing and formatting for you. Click the button below and get started! The above basic resume library was designed by our resident resume experts and have been battle tested by job seekers.
As this set performed the best, we included them in our resume builder software— and now we are offering them to you for free to download in Microsoft Word format.
Each professional template comes in five colors. Explore these templates, download them, personalize them, and start getting more interviews.
Resume Template Library 2: Advanced Layouts. Professional Brick Red. Timeless Dark Blue. Elegant 2.
Modern Brick Red. Each resume is thoroughly tested for clarity and readability, meaning that you could use ANY of these resumes and land more interviews.
So have fun, and pick one that suits your sense of design. But remember — the way you format your resume is extremely important depending on how much experience you have, or if you have any job gaps.
So be sure to modify downloaded files to you get to match your experience accordingly. Template Library 3: Professional Profile Layouts.
Washington Brick Red. Murray Dark Blue. Trump Brick Red. Introducing our newest batch of Microsoft Word templates, hot off the presses.
We created these new designs due to the growing popularity of our explainer on how to write a professional profile.
People interested in a layout featuring a PP introduction skyrocketed, so we toiled to create 8 brand new HR-approved documents for you to download for free.
Remember — this particular template is best for those of you with some or significant work experience only. Template Library 4: Creative Layouts.
Brooklyn Bridge Black. Taj Mahal Dark Blue. White House Brick Red. Empire State Gray. Mount Rushmore Dark Blue. Are you having trouble separating yourself from your competitors?
Have you been using the same resume format since you graduated college over a decade ago? Then it might be time to add some style to your resume!
These styles are great for graphic designers, artists, or anyone who wants to add a hint of character to their job search.
Job Hopper Original. Mid-Level Dark Blue. Career Changer Brick Red. Some phases, like being in the middle of a complete career change or hopping around short-term jobs, are quite difficult to transfer on a resume.
Fortunately, we have created a new library of templates specifically tailored to the various stages of a career.
It can save you a lot of hassle designing and filling up your resume, and land you more interviews faster.
Not Sure Which Template to Choose? The answer is yes — if you want to. Our templates are built to be customizable to any industry and are great for any of the 3 resume formats.
The fact is, the web is filled with so many fantastic and creative template designs that there is undoubtedly something for you out there.
Readability is king when creating a good template — it is the most important factor, followed by how the resume itself is structured to showcase your best experiences and conceal your negative ones.
Creating your own is fine, too. Wrong again. Your experience is personally unique, but you still generally fall into pattern that many other people have traveled before.
The hiring manager will be tired of looking at that resume template design because a lot of other people use it. That hiring manager should be fired.
We hope that clears up any misconceptions you may have had. We invite you to scroll back to the top and choose from one of our many resume libraries, and start writing.
Should i include collegiate sports in my resume? And if so where? It depends how much professional experience you have. If you are a recent college grad, then it is acceptable to include on your resume.
Good luck on the job hunt! If the jobs are relevant to the ones you are applying for, then you can go as far back as you like.
Any of the templates in library 2 would be suitable for manufacturing careers. Best of luck! Multiple employers with jobs lasting two to three years each.
The jobs have been similar, so the experience looks a bit repetitive. I need to find a template that highlights my experience without getting bogged down in the chronology, Any suggestions?
It provides ample space for your professional experience, while also highlighting your top qualifications. How would I write that on my resume?
Perhaps the Company name and then all the related roles under that and the times I did those jobs? I was always the Executive Admin, but I did other jobs during that period.
Yes, your suggestion is correct. Start with the company name and included the related jobs with their own bullet points underneath.
Good luck! Ive never had a job so what should I use? Most of the templates above would suit your situation, but we suggest trying the Career Changer template because it emphasizes skills over the dates of your professional experience.
Good luck with grad school! Hope this helps! Good luck with the internship! Good Day Resume Genius.
The skill I know is more on the medical. What template should I use? Which is good for cabin crew applicant? I have no many work experience in service.
So i want to highlight the other things. Which template would you recommend for a career in education? Best of luck on the promotion!
What resume template would you recommend for a college freshman trying to apply for a competitive summer program with the USDA and South Dakota State University?
Good luck with the summer program. Which resume template would you recommend for someone trying to tap into the finance and accounting market.
Looking for an entry-level position. Good luck with the job hunt. Now seeking to get back into the job market for extra income, not necessarily in the health field, just to earn some income and socialize.
What resume do you suggest? Good luck with your job search! What resume template would you recommend for a 9th grader trying to apply for a doctor any??
Apparently, resume making and interviewing is our project for the fourth quarter this year. Good luck on your project.
Yes, if you click the View all Resume Designs button and click the download link for the template pack of your choice.
Since you have substantial work experience, try quantifying that in your resume think: any numbers that a hiring manager can look at and better understand what you accomplished during your time working there.
Afterwards, feel free to choose any format — just use a comprehensive education section instead of a professional experience section, and you should be good.
Good luck landing that internship! Get awesome job opportunities sent directly to your inbox. Think you can judge the quality of a resume within 6 seconds?
The answer may surprise you. Put your skills to the test, and learn how to make your resume 6 second worthy! There are tons of errors throughout.
See why. How to Modify and Maximize your Resume Template. Need a resume template? Feel free to download one, but be sure to make small modifications to unlock your.
Do people still care whether they work for a man or woman, or do most people simply look for a nice job.
Resume Builder Comparison Resume Genius vs. LinkedIn Labs. What are the differences between the major online resume builders?
Here's an in depth analysis of what. Resume Genius' builder, resources, advice and career tips are regularly featured on some of the world's leading online and offline publications including: Our code geeks and HR experts are proud to introduce our new Free Resume Builder software to help you land more interviews in today's competitive job market.
The rich are the big gainers in America's new prosperity. Add this article to your reading list by clicking this button.
The gap between rich and poor is bigger than in any other advanced country, but most people are unconcerned.
Whereas Europeans fret about the way the economic pie is divided, Americans want to join the rich, not soak them. Eight out of ten, more than anywhere else, believe that though you may start poor, if you work hard, you can make pots of money.
It is a central part of the American Dream. Thanks to a jump in productivity growth after , America's economy has outpaced other rich countries' for a decade.
In the late s everybody shared in this boom. Though incomes were rising fastest at the top, all workers' wages far outpaced inflation.
But after something changed. The pace of productivity growth has been rising again, but now it seems to be lifting fewer boats.
If you take into account the value of employee benefits, such as health care, the contrast is a little less stark. But, whatever the measure, it seems clear that only the most skilled workers have seen their pay packets swell much in the current economic expansion.
The fruits of productivity gains have been skewed towards the highest earners, and towards companies, whose profits have reached record levels as a share of GDP.
Even in a country that tolerates inequality, political consequences follow when the rising tide raises too few boats.
The impact of stagnant wages has been dulled by rising house prices, but still most Americans are unhappy about the economy.
The White House professes to be untroubled. He is right, but his claim is misleading, since the median worker—the one in the middle of the income range—has done less well than the average, whose gains are pulled up by the big increases of those at the top.
Privately, some policymakers admit that the recent trends have them worried, and not just because of the congressional elections in November.
The statistics suggest that the economic boom may fade. Americans still head to the shops with gusto, but it is falling savings rates and rising debts made possible by high house prices , not real income growth, that keep their wallets open.
A bust of some kind could lead to widespread political disaffection. Eventually, the country's social fabric could stretch.
America is nowhere near Brazil yet see chart 1. Despite a quarter century during which incomes have drifted ever farther apart, the distribution of wealth has remained remarkably stable.
The richest Americans now earn as big a share of overall income as they did a century ago see chart 2 , but their share of overall wealth is much lower.
Indeed, it has barely budged in the few past decades. The elites in the early years of the 20th century were living off the income generated by their accumulated fortunes.
Today's rich, by and large, are earning their money. The rise of the working rich reinforces America's self-image as the land of opportunity.
But, by some measures, that image is an illusion. In America about half of the income disparities in one generation are reflected in the next.
In Canada and the Nordic countries that proportion is about a fifth. It is not clear whether this sclerosis is increasing: the evidence is mixed.
Many studies suggest that mobility between generations has stayed roughly the same in recent decades, and some suggest it is decreasing.
Even so, ordinary Americans seem to believe that theirs is still a land of opportunity. The proportion who think you can start poor and end up rich has risen 20 percentage points since That helps explain why voters who grumble about the economy have nonetheless failed to respond to class politics.
Americans tend to blame their woes not on rich compatriots but on poor foreigners. More than six out of ten are sceptical of free trade.
A new poll in Foreign Affairs suggests that almost nine out of ten worry about their jobs going offshore. Congressmen reflect their concerns.
Though the economy grows, many have become vociferous protectionists. Other rich countries are watching America's experience closely.
For many Europeans, America's brand of capitalism is already far too unequal. Such sceptics will be sure to make much of any sign that the broad middle-class reaps scant benefit from the current productivity boom, setting back the course of European reform even further.
The conventional tale is that the changes of the past few years are simply more steps along paths that began to diverge for rich and poor in the Reagan era.
During the s and s, the halcyon days for America's middle class, productivity boomed and its benefits were broadly shared. The gap between the lowest and highest earners narrowed.
After the oil shocks, productivity growth suddenly slowed. A few years later, at the start of the s, the gap between rich and poor began to widen.
The exact size of that gap depends on how you measure it. Look at wages, the main source of income for most people, and you understate the importance of health care and other benefits.
Look at household income and you need to take into account that the typical household has fallen in size in recent decades, thanks to the growth in single-parent families.
Look at statistics on spending and you find that the gaps between top and bottom have widened less than for income. But every measure shows that, over the past quarter century, those at the top have done better than those in the middle, who in turn have outpaced those at the bottom.
The gains of productivity growth have become increasingly skewed. If all Americans were set on a ladder with ten rungs, the gap between the wages of those on the ninth rung and those on the first has risen by a third since Economists have long debated why America's income disparities suddenly widened after The consensus is that the main cause was technology, which increased the demand for skilled workers relative to their supply, with freer trade reinforcing the effect.
Some evidence suggests that institutional changes, particularly the weakening of unions, made the going harder for people at the bottom. Whether these shifts were good or bad depends on your political persuasion.
Those on the left lament the gaps, often forgetting that the greater income disparities have created bigger incentives to get an education, which has led to a better trained, more productive workforce.
In their haste to applaud or lament this tale, both sides of the debate tend to overlook some nuances. First, America's rising inequality has not, in fact, been continuous.
The gap between the bottom and the middle—whether in terms of skills, age, job experience or income—did widen sharply in the s.
But during the s, particularly towards the end of the decade, that gap stabilised and, by some measures, even narrowed.
Real wages rose faster for the bottom quarter of workers than for those in the middle. After most people lost ground, but, by many measures, those in the middle of the skills and education ladder have been hit relatively harder than those at the bottom.
People who had some college experience, but no degree, fared worse than high-school dropouts. Some statistics suggest that the annual income of Americans with a college degree has fallen relative to that of high-school graduates for the first time in decades.
So, whereas the s were hardest on the lowest skilled, the s and this decade have squeezed people in the middle. The one truly continuous trend over the past 25 years has been towards greater concentration of income at the very top.
The scale of this shift is not visible from most popular measures of income or wages, as they do not break the distribution down finely enough.
But several recent studies have dissected tax records to investigate what goes on at the very top.
The figures are startling. Put these pieces together and you do not have a picture of ever-widening inequality but of what Lawrence Katz of Harvard University, David Autor of the Massachusetts Institute of Technology and Melissa Kearney of the Brookings Institution call a polarisation of the labour market.
The bottom is no longer falling behind, the top is soaring ahead and the middle is under pressure. Can changes in technology explain this revised picture?
Up to a point. Computers and the internet have reduced the demand for routine jobs that demand only moderate skills, such as the work of bank clerks, while increasing the productivity of the highest-skilled.
Studies in Britain and Germany as well as America show that the pace of job growth since the early s has been slower in occupations that are easy to computerise.
For the most talented and skilled, technology has increased the potential market and thus their productivity. Top entertainers or sportsmen, for instance, now perform for a global audience.
Some economists believe that technology also explains the soaring pay of chief executives. One argument is that information technology has made top managers more mobile, since it no longer takes years to master the intricacies of any one industry.
As a result, the market for chief executives is bigger and their pay is bid up. Global firms plainly do compete globally for talent: Alcoa's boss is a Brazilian, Sony's chief executive is American and Welsh.
But the scale of America's income concentration at the top, and the fact that no other country has seen such extreme shifts, has sent people searching for other causes.
The typical American chief executive now earns times the average wage, up tenfold from the s.
Continental Europe's bosses have seen nothing similar. Whichever explanation you choose for the signs of growing inequality, none of the changes seems transitory.
The middle rungs of America's labour market are likely to become ever more squeezed. And that squeeze feels worse thanks to another change that has hit the middle class most: greater fluctuations in people's incomes.
The overall economy has become more stable over the past quarter century. America has had only two recessions in the past 20 years, in and , both of which were mild by historical standards.
But life has become more turbulent for firms and people's income now fluctuates much more from one year to the next than it did a generation ago.
Some evidence suggests that the trends in short-term income volatility mirror the underlying wage shifts and may now be hitting the middle class most.
What of the future? It is possible that the benign pattern of the late s will return. The disappointing performance of the Bush era may simply reflect a job market that is weaker than it appears.
Although unemployment is low, at 4. More likely, the structural changes in America's job market that began in the s are now being reinforced by big changes in the global economy.
The integration of China's low-skilled millions and the increased offshoring of services to India and other countries has expanded the global supply of workers.
This has reduced the relative price of labour and raised the returns to capital. That reinforces the income concentration at the top, since most stocks and shares are held by richer people.
More important, globalisation may further fracture the traditional link between skills and wages. As Frank Levy of MIT points out, offshoring and technology work in tandem, since both dampen the demand for jobs that can be reduced to a set of rules or scripts, whether those jobs are for book-keepers or call-centre workers.
Alan Blinder of Princeton, by contrast, says that the demand for skills depends on whether they must be used in person: X -rays taken in Boston may be read by Indians in Bangalore, but offices cannot be cleaned at long distance.
So who will be squeezed and who will not is hard to predict. The number of American service jobs that have shifted offshore is small, some 1m at the most.
And most of those demand few skills, such as operating telephones. Mr Levy points out that only 15 radiologists in India are now reading American X -rays.
But nine out of ten Americans worry about offshoring. That fear may be enough to hold down the wages of college graduates in service industries.
All in all, America's income distribution is likely to continue the trends of the recent past. While those at the top will go on drawing huge salaries, those in the broad middle of the middle class will see their incomes churned.
The political consequences will depend on the pace of change and the economy's general health. With luck, the offshoring of services will happen gradually, allowing time for workers to adapt their skills while strong growth will keep employment high.
But if the economy slows, Americans' scepticism of globalisation is sure to rise. And even their famous tolerance of inequality may reach a limit.
Inequality and the American Dream. The world's most impressive economic machine needs a little adjusting.
A hidden industry has changed all our lives; but some companies are operating rather close to the.
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