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Ovarian cancer is the major cause of death from gynecological malignancy, and there is an urgent need for new therapeutic targets. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been strongly implicated in the genesis of ovarian cancer. However, to identify and evaluate potential targets for therapeutic intervention, it is critical to understand the mechanism by which the PI3K/AKT pathway facilitates ovarian carcinogenesis. Here, we show that AKT3 is highly expressed in 19 of 92 primary ovarian tumors. Strikingly, purified AKT3 exhibited up to 10-fold higher specific activity than AKT1, potentially amplifying the effects of AKT3 overexpression. Consistent with this finding, AKT3 levels in a range of ovarian cancer cell lines correlated with total AKT activity and proliferation rates, implicating AKT3 as a key mediator of ovarian oncogenesis. Specific silencing of AKT3 using short hairpin RNA markedly inhibited proliferation of the two cell lines with highest AKT3 expression and total AKT activity, OVCA429 and DOV13, by slowing G2-M phase transition. These findings are consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers. (Cancer Res 2006; 66(24): 11718-25)

Supplementary Figure S5 from A Specific Role for AKT3 in the Genesis of Ovarian Cancer through Modulation of G2-M Phase Transition

People with cystic fibrosis (CF) are at increased risk of fractures. Our study found that low trabecular bone score (TBS) (a measure of bone strength) may help identify people with CF at risk of fractures especially when combined with bone density measured by DXA, age, hemoglobin A1c, and transplant status.People with cystic fibrosis (CF) are at increased risk of fractures. This study aims to evaluate the association of trabecular bone score (TBS) with fractures in CF.A cross-sectional study of adults with CF who completed bone density between 2009 and 2019. TBS was applied to lumbar spine studies.A total of 202 people with CF were included. A history of fracture was present in 36 (17.8%) subjects. Patients with history of fractures had higher hemoglobin A1c (A1C) (7.8 ± 2.7% vs. 6.7 ± 1.7%, p = 0.024), lower femoral neck (FN) Z/T-score (- 1.05 ± 1.08 vs. - 0.44 ± 1.08, p = 0.012), and lower TBS (1.36 ± 0.13 vs. 1.40 ± 0.11, p = 0.05) compared to those without. Lung transplant recipients had a higher prevalence of fractures (50% vs. 14.1%, p 0.001). The odds ratio (95%CI) of having a fracture for subjects with TBS (≤ 1.2 vs. 1.2) stratified by FN Z/T-score (≤ - 2.0 or - 2.0) was 3.88 (0.92, 16.35), p = 0.07. ROC analysis showed TBS was significantly associated with fractures (p 0.05); however, FN BMD was superior. A model combining FN BMD, age, A1c, transplant, and TBS improved ROC compared to FN BMD + age (0.837 vs. 0.779, p = 0.031).TBS ≤ 1.2 may identify people with CF at high risk of fractures. A model combining FN BMD, age, A1c, transplant, and TBS was significantly associated with fractures compared to FN BMD + age. Future studies are needed to evaluate the prediction of fractures in people with CF using clinical and bone parameters.

The identification, diagnosis, follow-up, and treatment of patients with secondary progressive multiple sclerosis (SPMS) show significant differences between health care professionals in Argentina.To provide consensus recommendations on the management of patients with SPMS in Argentina to optimize patient care.A panel of expert neurologists from Argentina dedicated to the diagnosis and care of multiple sclerosis patients gathered during 2019 and 2020 to carry out a consensus recommendation on the diagnosis and treatment of SPMS patients in Argentina. To achieve consensus, the methodology of 'formal consensus-RAND/UCLA method' was used. Recommendations were established based on published evidence and the expert opinion. Recommendations focused on how to define SPMS and how to follow SPMS patients.The recommendations of this consensus guidelines attempt to optimize the care of SPMS patients in Argentina.Consenso sobre la identificación y seguimiento de la esclerosis múltiple secundaria progresiva en Argentina.Introducción. Existen diferencias significativas en el diagnóstico, la identificación y el seguimiento de pacientes con esclerosis múltiple secundaria progresiva (EMSP) entre los profesionales de la salud a cargo de su tratamiento. Objetivo. Proveer recomendaciones sobre el tratamiento de los pacientes con EMSP en Argentina con el fin de optimizar su cuidado. Desarrollo. Un grupo de neurólogos expertos en esclerosis múltiple de Argentina elaboró un consenso para el tratamiento de pacientes con EMSP en la región mediante metodología de ronda de encuestas a distancia y reuniones presenciales. Se establecieron 33 recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el diagnóstico y el seguimiento de los pacientes con EMSP. Conclusión. Las recomendaciones establecidas en el presente consenso permitirían optimizar el cuidado y el seguimiento de los pacientes con EMSP en Argentina.

Leucoencefalopatia posterior reversible de afectacion troncoencefalica y medular aislada.

Enrollment of patients aged above 80 years in trials assessing endovenous thrombolysis (rt-PA) was scarce. The goal of this study is to compare safety and efficacy of endovenous rt-PA between patients aged above 80 and those below 80 years.A cohort of patients who received rt-PA was prospectively followed. Length of hospital stay, bleeding incidence, in-hospital mortality and 90 days' clinical outcome was compared between patients aged above 80 and those below 80 years.Of 1996 patients admitted at our hospital with ischemic stroke between October 2005 and January 2016, 180 received rt-PA (9%). Mean age was 77 ± 10 years, being 55% of the women. Comparing patients aged above 80 with those below 80 years, in the latter the length of hospital stay was longer with a median length of 15 days (IQR: 6-19) vs 7 days (IQR: 4-12; p = 0.001) and 90 days' clinical outcome was worse (modified Rankin scale 0-1 of 24% vs 41%; p = 0.001). Admission ASPECTS score, bleeding incidence and in-hospital mortality showed no significant differences between both groups. Patients aged over 80 arrived to the hospital earlier (97 ± 34 vs 113 ± 45 min; p = 0.01), however door-to-needle time was longer.Endovenous thrombolysis in patients aged above 80 years was safe, although its efficacy in assuring a better clinical outcome was not as pronounced as in patients below 80 years.Es comparable la seguridad y eficacia del uso de tromboliticos en el ictus isquemico en mayores y menores de 80 años? Experiencia en una cohorte argentina.Introduccion. La inclusion de mayores de 80 años fue escasa en los estudios que evaluaron la terapia trombolitica. El objetivo de este estudio es comparar la seguridad y eficacia del uso de activador del plasminogeno tisular recombinante en pacientes mayores y menores de 80 años. Pacientes y metodos. Estudio prospectivo de pacientes que recibieron tratamiento trombolitico. Se comparo el tiempo de estancia, la incidencia de sangrado, la mortalidad hospitalaria y la evolucion a 90 dias en pacientes mayores y menores de 80 años. Resultados. De 1.996 pacientes con ictus ingresados entre octubre de 2005 y enero de 2016, 180 recibieron tratamiento trombolitico (9%). La edad media fue de 77 ± 10 años, con un 55% de mujeres. Cuando se compararon los menores y mayores de 80 años, en estos ultimos la estancia hospitalaria fue prolongada, con una mediana de 15 dias (rango intercuartilico: 6-19) frente a siete dias (rango intercuartilico: 4-12; p = 0,001), y la discapacidad a los tres meses fue mayor (escala de Rankin 0-1 del 24% frente al 41%; p = 0,001). La puntuacion ASPECTS de ingreso, la incidencia de sangrado y la mortalidad hospitalaria no mostraron diferencias entre mayores y menores de 80 años. Los pacientes mayores de 80 años tuvieron menor tiempo de demora para llegar al hospital (97 ± 34 frente a 113 ± 45 min; p = 0,01); sin embargo, el tiempo puerta-aguja fue superior en los mayores de 80 años. Conclusion. La terapia trombolitica en los mayores de 80 años fue segura, aunque el grado de beneficio para reducir la discapacidad resulto menor.

The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show thatin vitro, purified AKT3 is ∼47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoformsin vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificityin situ.

In this essay, we try to figure out, based on Wilson Gomes’s filmanalysis methodology and on the musical minimalistic theory, which are the cognitive, sensorial, and emotional elements that are composed in the effect production strategies in the experimental film Koyaanisqatsi (Godfrey Reggio, USA, 1982).

This study aims to validate the Multiple Sclerosis (MS) International Quality of Life (MusiQoL) questionnaire, a multi-dimensional, self-administered questionnaire, available in 14 languages, as a disease-specific quality of life scale that can be applied internationally. A total of 1992 patients with different types and severities of MS from 15 countries were recruited. At baseline and day 21 ± 7, each patient completed the MusiQoL, a symptom checklist and the short-form (SF)-36 QoL questionnaire. Neurologists also collected socio-demographic, MS history and outcome data. The database was randomly divided into two subgroups and analysed according to different patient characteristics. For each model, psychometric properties were tested and the number of items was reduced by various statistical methods. Construct validity, internal consistency, reproducibility and external consistency were also tested. Nine dimensions, explaining 71% of the total variance, were isolated. Internal consistency and reproducibility were satisfactory for all the dimensions. External validity testing revealed that dimension scores correlated significantly with all SF-36 scores, but showed discriminant validity by gender, socio-economic and health status. Significant correlations were found between activity in daily life scores and clinical indices. These results demonstrate the validity and reliability of the MusiQoL as an international scale to evaluate QoL in patients with MS. Multiple Sclerosis 2008; 14: 219—230. http://msj.sagepub.com

Phosphatidylinositol 3′-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.

Understanding the regulation of Akt has been of major interest for elucidating the control of normal cellular physiology as well as malignant transformation. The paradigm for activation of Akt involves phosphatidylinositol 3-kinase-dependent membrane localization followed by activating phosphorylation of Thr-308 and Ser-473. Many of the activating signals for Akt involve the stimulation of receptor and non-receptor tyrosine kinases, and the most potent activator known is the tyrosine phosphatase inhibitor pervanadate, highlighting a possible role for tyrosine phosphorylation in the regulation of the enzyme. In this study we show that activation of Akt by pervanadate or serum is associated with tyrosine phosphorylation of Akt. In addition, in SKOV3 ovarian carcinoma cells that exhibit high basal levels of Akt activity, Akt was tyrosine-phosphorylated in the basal state, and this phosphorylation was further enhanced by both pervanadate and insulin-like growth factor-1. We have used NH(2)-terminal sequencing and phosphate release analysis to directly identify Tyr-474 as the site of tyrosine phosphorylation. Substitution of Tyr-474 with phenylalanine abolished tyrosine phosphorylation of Akt and resulted in up to 55% inhibition of Akt activation, indicating phosphorylation at Tyr-474 is required for full activation of the kinase. Our data identifies a novel regulatory mechanism for this pleiotropic enzyme that may be applicable to the AGC family of protein kinases given the conserved nature of the COOH-terminal hydrophobic motif containing Tyr-474.

INTRODUCTION. Multiple sclerosis (MS) it is not considered any more a rare disease in Latin America. Most of the Latin American countries have reported moderate or lower prevalence data. However only very few countries have developed therapeutic guidelines. LACTRIMS prepared this consensus document with specific recommendations for the treatment of the disease. DEVELOPMENT. Experts on treatment and clinical research on MS were invited by LACTRIMS in order to generate a initial document to be discussed in Quito, Ecuador. Several groups were organized in relation of the different clinical variants. These groups were coordinated by experts leaders and prepared a preliminary document that was discussed in Quito during July 8th and 9th, 2011. Finally the final version was submitted to the members and delegates of LACTRIMS in most of the Latin American countries who were able to make modifications and suggest changes to the final manuscript. CONCLUSIONS. Based on the different evidence levels and the AGREE criteria, the clinical variants were reviewed and recommendations were made for the use of drugs and different modifying disease therapeutic agents.

Previous studies showed gender-associated clinical and MRI differences in multiple sclerosis (MS) evolution. However, only few studies were done with non conventional MRI techniques and no one was done in a South American MS population. The aim of this study was to investigate gender differences according to nonconventional MRI measures in patients with MS from Buenos Aires, Argentina.Relapsing-remitting MS patients (RRMS) with at least 6 years of follow up and an MRI at onset and at 6 years were included. Patients were assessed using nonconventional MRI measures: total brain volume (TBV), neocortical grey brain volume (GBV), white brain volume (WBV), lesion load (LL), % of brain volume change between onset and year 6 (% BVC) and regional brain volume change. Gender-related MRI differences were investigated using general linear model analysis.The 45 patients were included (25 female). Mean follow up time was 7.3 ± 0.2 years. No differences in age, EDSS at onset, DMD treatment, TBV, GBV, WBV neither LL were found between gender at baseline. Six years later, males showed a decrease in TBV (P=.002) and GBV (P ≤ 0.001) and an increase in LL (P=.02) and % BVC (P.001) vs. females. Female patients showed a decrease in the volume of frontal subcortical region.This is the first study showing differences in brain volume changes between gender in MS patients from South America. Future studies will confirm our initial findings.

Epidemiologic studies of incidence and prevalence in Parkinson's Disease (PD) show highly variable results. Despite the large number of studies performed worldwide during the last decades, little is known about its prevalence in South America and no incidence studies have been performed. The goal of this study is to assess the incidence and prevalence of PD in a health maintenance organization from Buenos Aires City, the capital city of Argentina.The population were all members of the 'Plan de Salud, Hospital Italiano de Buenos Aires', a large prepaid health medical organization in Buenos Aires. From 1 January 2003 to 31 December 2008 patients diagnosed with PD according to Brain Bank of London diagnostic criteria were identified retrospectively. Incidence density was calculated with 95% confidence interval.Hundred and forty thousand people were followed for a total of 754,082 person-years. A total of 239 incident cases of PD were identified. Crude incidence density was 31.2/100,000 person-years. Prevalence was 394/100,000 in the population older than 40 years. Male to female ratio was 1.31.This is the first study in South America that estimates the incidence of PD. Our results are consistent with other studies from other regions using similar methodologies.

Previous reports have shown that brain atrophy appears early in the course of multiple sclerosis (MS). The aim of the present study was to evaluate whether brain atrophy already exists in clinically isolated syndrome (CIS) by comparing with a control sample.Patients with CIS were included prospectively from June 2008 to June 2009. A control group of healthy persons, matched by age and gender with CIS, was also included during the same period of time. An automated analysis tool, SIENAX, was used to obtain total brain volume (TBV), gray matter volume (GMV) and white matter volume (WMV). Mann-Whitney U test was used to analyze the data.Twenty CIS patients and 30 healthy controls were included (8 vs. 17 females, p=0.11). Mean age for CIS was 35 ± 6 years vs. 34.4±5 in controls (p=0.61). Mean EDSS in CIS was 1.1 ± 0.5. Eighteen patients with CIS (90%) had abnormal baseline MRI. The TBV in CIS was 1.6.l ± 0.22.l × 106 vs.1.65 ± 0.15 × 106 in controls (p=0.005), the GMV in CIS was 0.58 ± 0.05 × 106 vs. 0.67 ± 0.03 × 106 in controls (p ≤ 0.001) and the WMV in CIS was 1 ± 0.1 × 106 vs. 1.12 ± 0.02 × 106 in controls (p=0.03).This is the first study dealing with brain atrophy in a CIS sample from Latin America in which brain atrophy, mainly grey matter atrophy, was shown in early stages of the disease compared with healthy individuals.

previous reports have shown that in Dementia with Lewy body (DLB) and attention-deficit and hyperactivity disorder (ADHD) a hypodopaminergic and noradrenergic substrate seems to play a central role in developing the diseases. We investigated the hypothesis that attention deficit may precede DLB expressed as adult ADHD symptoms long before the clinical onset of dementia.patients with DLB, Alzheimer disease type (ADT) and controls were recruited from the membership of the Italian Hospital Medical Care Program in Argentina from 2000 to 2005. The DSM-IV criteria adapted for the identification of adult patients with ADHD and validated to Spanish Wender Utah Rating Scale were used to identify individuals with preceding ADHD symptoms during their adult life. Analysis of categorical variables was carried out using chi-square. Mann-Whitney test was used for continuous variables. Statistical significance was P0.05.a total of 109 patients with DLB and 251 patients with ADT were matched by age, sex and year of education with 149 controls. The frequency of preceding ADHD symptoms in DLB cases was 47.8% in ADT 15.2% and 15.1% in the control group. The prevalence of ADHD symptoms in DLB cases was significantly higher compared with the control group (P ≤ 0.001, OR 5.1 95%CI 2.7-9.6) and also higher when compared with ADT (P ≤ 0.001, OR 4.9, 95%CI 2.8-8.4).we found a higher risk of DLB in patients with preceding adult ADHD symptoms. To date, there is no clear explanation for the association found; however, further investigation will widen our understanding about both disorders.

The present study was undertaken to determine the incidence of MS in a health maintenance organization from Buenos Aires, the largest populated area in Argentina.Population was all members of a hospital-based health maintenance organization who were affiliated since January 1992 up to December 2007. Each person was followed contributing time at risk since January 1992 or enrollment date to the final date. Patients with definite diagnosis according to Poser's criteria were included. Incidence density was calculated with 95% confidence intervals.A total of 145,000 patients were followed for a total of 1,021,515 person-years, of whom 18 developed the disease. Incidence density (ID): 1.76 /100 000 person-years (95% CI: 1.1-2.8/100,000 person-years).The incidence density of 1.76 per 100,000 suggests a low-median risk area for MS. This study constitutes the first of its kind to cover data of MS incidence in Argentina.

Lumbar spinal stenosis is defined as a narrowing of the neural canal and foramina that result in compression of the lumbosacral nerve roots or cauda equina. Patients with lumbar spinal stenosis may present a variety of signs and symptoms. One such syndrome is neurogenic intermittent claudication, characterized by radicular symptoms exacerbated by walking or standing and relieved by rest. Infrequently, lumbar spinal stenosis produces a cauda equina compression, characterized by intermittent urinary or fecal incontinence, impotence and in rare cases priapism.A 50 year-aged male, presented with spontaneous intermittent priapism and few months later weakness, numbness and pain of his legs provoked by bipedestation or physical exertion that completely disappeared by sitting or lying down. A computed tomographic scan showed a lumbar canal narrowing of L4 through L5. A diagnosis of neurogenic intermittent claudication with dysfunction of the cauda equina roots secondary to the presence of lumbar spinal stenosis was carried out. The symptoms completely resolved after descompressive lumbar laminectomy of L4 and L5.Causal interpretation of neurogenic intermittent claudication still remains obscure. An inadequate blood supply provoked by increased intra-raquid pressure among the roots may act as a dynamic factor. This mechanism could cause stagnant anoxia during the exercise resulting in clinical symptoms. Lumbar spinal stenosis should be kept in mind when autonomic features appear.

Old age groups have different risk profile and stroke features compared to younger groups. Our aim was to examine the risk factor profile and stroke subtype in patients older than 80 years with ischemic stroke. Data of 535 patients with ischemic stroke or transient ischemic attack (TIA) were prospectively recorded. Cardiovascular risk factors and stroke subtype in individuals aged 80 years or older were compared with patients under 80. Of 535 patients a total of 179 were over 80 years (33.5%). The mean age was 84.4 +/- 4.4 years (61.8%; 111 women). The most common risk factors included hypertension (82.7%) and hyperlipidemia (40.2%). Lacunar stroke was the most frequent subtype of stroke (41.7%). When the groups were compared, we observed the following risk factors more frequently in the group older than 80: female patients (P =0.001), hypertension (OR = 1.62), atrial fibrillation (OR = 2.64); whereas diabetes (OR = 0.54), hyperlipidemia (OR = 0.57), smoking (OR = 0.17) and obesity (OR = 0.58) were more frequent in the group younger than 80. In the old group we found a high incidence of ischemic stroke in women. We also found a higher frequency of hypertension and atrial fibrillation. The available and future epidemiological data will provide a better knowledge about the effect of typical risk factors in old people.

Multiple sclerosis (MS) is the most common primary demyelinating disease affecting the central nervous system. In recent years the development of new drugs that have been shown to modify the natural history of MS have had a substantial impact on the treatment of the disease.To harmonise and integrate the evidence available on optimising the treatment of patients with MS.In order to fulfil our main aim, a group of experts from different Latin American countries drew up a list of statements related to the use of immunomodulatory agents in the different clinical forms of the disease and the strategies that should be considered in cases in which the therapeutic response was suboptimal. Each of the participants used a structured scale to express the extent to which he or she agreed or disagreed, and a consensus was considered to have been reached when acceptance of each of the statements was equal to or higher than 80%.These recommendations will provide neurologists with the tools needed to make decisions that optimise the treatment of MS patients.

Com o objetivo de estudar o manejo adequado das cultivares de algodoeiros Bt (DP 90 B e NuOpal) e suas variedades "near-isogenic" (Acala 90 e Delta Opal), foram plantados no dia 21/12/2006 na Fazenda Canaã, localizada no município de Primavera do Leste-MT, um bloco de um ha de cada cultivar. A eficácia sobre as pragas-alvo e a evolução das pragas não-alvo ou secundárias foram avaliadas. O monitoramento regular das lavouras, a base de observações de 50 plantas duas vezes por semana, e da análise de 400 maçãs verdes por bloco e data na fase final do ciclo, confirmou a eficácia das cultivares transgênicas sobre as pragas-alvo tais como o curuquerê (Alabama argillacea) e a lagarta rosada (Pectinophora gossypiella). Com relação às pragas não-alvo e as pragas secundárias verificou-se injúria das lagartas Pseudoplusia includens ("falsa-medideira") e de Spodoptera, principalmente da espécie eridania, além da presença de manchas decorrentes do ataque do ácaro rajado (Tetranychus urticae), da ocorrência de mosca branca (Bemisia tabac;) e do bicudo do algodoeiro (Anthonomus grandis), sendo necessário o uso de produtos específicos para o controle dessas pragas.

Ovarian cancer is the major cause of death from gynecological malignancy, and there is an urgent need for new therapeutic targets. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been strongly implicated in the genesis of ovarian cancer. However, to identify and evaluate potential targets for therapeutic intervention, it is critical to understand the mechanism by which the PI3K/AKT pathway facilitates ovarian carcinogenesis. Here, we show that AKT3 is highly expressed in 19 of 92 primary ovarian tumors. Strikingly, purified AKT3 exhibited up to 10-fold higher specific activity than AKT1, potentially amplifying the effects of AKT3 overexpression. Consistent with this finding, AKT3 levels in a range of ovarian cancer cell lines correlated with total AKT activity and proliferation rates, implicating AKT3 as a key mediator of ovarian oncogenesis. Specific silencing of AKT3 using short hairpin RNA markedly inhibited proliferation of the two cell lines with highest AKT3 expression and total AKT activity, OVCA429 and DOV13, by slowing G2-M phase transition. These findings are consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers. (Cancer Res 2006; 66(24): 11718-25)

The primary objective in the management of a chronic disease is to maximise therapeutic effectiveness, according to the general consensus among specialists. Recent market research has confirmed that a treatment's effectiveness is the primary consideration for neurologists' choice of therapy for multiple sclerosis (MS). Of the available disease-modifying therapies, interferon (IFN) beta appears to be consistently more efficacious than glatiramer acetate. High doses of therapy, and frequent administration of IFN beta should be used to provide maximal effects. This has been supported by a recent Class I comparative trial of two commercial preparations of IFN beta-1a. Preliminary results indicated significantly greater efficacy for IFN beta-1a (Rebif, Serono) 44 microg administered subcutaneously three times weekly (t.i.w.), over IFN beta-1 (Avonex, Biogen) 30 microg administered intramuscularly once weekly IFN beta-1a, 44 microg t.i.w., provides maximal efficacy for patients with relapsing forms of MS.

The Akt protein kinase is a critical signaling molecule in a range of cellular processes. A key to identifying the role of this pleiotropic kinase in any particular process is the ability to quantitate its activity. In this study we show that the synthetic peptide RPRAATF is a specific substrate for the kinase in crude cell extracts, thus enabling rapid, convenient, and sensitive assay of Akt activity. Peptide kinase activity was confined to a single peak upon sequential ion-exchange chromatography of whole-cell extracts of Balb/c 3T3 fibroblasts. This activity was stimulated by both platelet-derived growth factor and pervanadate, phosphatidyl inositol 3-kinase dependent, and inhibited by specific immunodepletion with anti-Akt antisera. Furthermore, direct assays of crude extracts from a range of cell types using this peptide were consistent with the results obtained using specific immunoprecipitation assays.

Biotechnological research and a better understanding of the immunopathogenesis of multiple sclerosis (MS) have recently led to major breakthroughs in treatment. Different drugs that modify the disease process such as interferon beta 1a, interferon beta 1b and glatiramer acetate are now available. Decisions about initiation of therapy and choice of agent should be individualised based on the severity and activity of the disease, concomitant illnesses, adverse effects of the drugs, lifestyle issues, and patient preferences. These different drugs were tested in different clinical trials that used different designs, patient populations, endpoints and statistical analysis. Therefore, simple comparisons between them are hazardous. In this article, the pivotal clinical trials of beta interferons and glatiramer acetate in the treatment of MS are reviewed, and recommendations for their appropriate use are provided. Several ongoing and planned clinical trials in various stages of disease will help to define further the role of these agents in the treatment of multiple sclerosis.