Midface hypoplasia in syndromic craniosynostosis: predicting craniofacial growth via a novel regression model from anatomical morphometric analysis.

Midface hypoplasia in syndromic craniosynostosis (SC) may lead to serious respiratory issues. The aim of this study was to analyse the morphometric correlation between midface and cranial base parameters in paediatric SC patients in order to formulate predictive regression models. The computed tomography scans of 18 SC patients and 20 control were imported into Materialise Mimics Medical version 21.0 software for the measurement of multiple craniofacial landmarks and correlation analysis. The results showed a strong correlation of anterior cranial base (SN), posterior cranial base (SBa), and total cranial base (NBa) (r = 0.935) to maxilla length and width (ZMR-ZML) (r = 0.864). The model of NBa = - 1.554 + 1.021(SN) + 0.753(SBa) with R2 = 0.875 is proposed to demonstrate the development of the cranial base that causes a certain degree of midface hypoplasia in SC patients. The formula is supported using a prediction model of ZMR-ZML = 5.762 + 0.920(NBa), with R2 = 0.746. The mean absolute difference and standard deviation between the predicted and true NBa and ZMR-ZML were 2.08 ± 1.50 mm and 3.11 ± 2.32 mm, respectively. The skeletal growth estimation models provide valuable foundation for further analysis and potential clinical application.

Effectiveness of Decision Aid in Men with Localized Prostate Cancer: a Multicenter Randomized Controlled Trial at Tertiary Referral Hospitals in an Asia Pacific Country.

There are several treatment options for localized prostate cancer with very similar outcome but vary in terms of technique and side effect profiles and risks. Considering the potential difficulty in choosing the best treatment, a patient decision aid (PDA) is used to help patients in their decision-making process. However, the use and applicability of PDA in a country in Asia Pacific region like Malaysia is still unknown. This study aims to evaluate the effectiveness of a PDA modified to the local context in improving patients' knowledge, decisional conflict, and preparation for decision making among men with localized prostate cancer. Sixty patients with localized prostate cancer were randomly assigned to control and intervention groups. A self-administered questionnaire, which evaluate the knowledge on prostate cancer (23 items), decisional conflict (10 items) and preparation for decision-making (10 items), was given to all participants at pre- and post-intervention. Data were analyzed using independent T test and paired T test. The intervention group showed significant improvement in knowledge (p = 0.02) and decisional conflict (p = 0.01) from baseline. However, when compared between the control and intervention groups, there were no significant differences at baseline and post-intervention on knowledge, decisional conflict and preparation for decision-making. A PDA on treatment options of localized prostate cancer modified to the local context in an Asia Pacific country improved patients' knowledge and decisional conflict but did not have significant impact on the preparation for decision-making. The study was also registered under the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12614000668606 registered on 25/06/2014.

Relationship between HbA1c and Lipid Profile Seen in Bangladeshi Type 2 Diabetes Mellitus Patients Attending BIRDEM Hospital: A Cross-Sectional Study.

Diabetes mellitus is one of the leading non-communicable diseases all over the world including Bangladesh. Diabetes is characterized by chronic hyperglycemia and disturbances of carbohydrate, lipid and protein metabolism. Glycated hemoglobin (HbA1c) level of ≥6.5% has been included as a criterion for diagnosis of diabetes. Impaired lipid profile is commonly present in type 2 diabetes. Aim of the study was to investigate the association between serum lipid profile and blood glucose. And hypothesizing that early detection of lipid abnormalities and treatment can minimize the risk for atherogenic cardiovascular disorder and cerebrovascular calamity in patients with type 2 diabetes mellitus (T2DM). This observational cross sectional study was carried out in the department of Biochemistry, Bangladesh Institute of Research & Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) hospital, Dhaka, Bangladesh from January 2016 to June 2016. A total 105 patients with T2DM of age within the range of 30-45 years were selected for the purpose. Fasting blood glucose (FBG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and glycated haemoglobin (HbA1c) levels were evaluated. Test of significance was calculated by unpaired Student's 't' test. Correlation studies (Pearson's correlation) were performed between glycated haemoglobin (HbA1c) and serum lipid profile. Significance was set at p<0.05. Significantly higher mean serum levels of TC, TG and LDL-C and significantly lower mean serum levels of HDL-C were noted in patients with diabetes. Significant correlations were observed between HbA1c value and serum levels of TC, TG and HDL-C (p<0.05) but no significant correlation of HbA1c value with LDL-C in-diabetes patient. The study concluded that HbA1c value correlate well with lipid profile in-diabetes patients. So, HbA1c can be used as a predictor of dyslipidemia in type 2 diabetes.

Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment.

DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

Evaluation of HIV testing recommendations in specialty guidelines for the management of HIV indicator conditions.

OBJECTIVES: European guidelines recommend HIV testing for individuals presenting with indicator conditions (ICs) including AIDS-defining conditions (ADCs). The extent to which non-HIV specialty guidelines recommend HIV testing in ICs and ADCs is unknown. Our aim was to pilot a methodology in the UK to review specialty guidelines and ascertain if HIV was discussed and testing recommended. METHODS: UK and European HIV testing guidelines were reviewed to produce a list of 25 ADCs and 49 ICs. UK guidelines for these conditions were identified from searches of the websites of specialist societies, the National Institute of Clinical Excellence (NICE) website, the NICE Clinical Knowledge Summaries (CKS) website, the Scottish Intercollegiate Guidance Network (SIGN) website and the British Medical Journal Best Practice database and from Google searches. RESULTS: We identified guidelines for 12 of 25 ADCs (48%) and 36 of 49 (73%) ICs. In total, 78 guidelines were reviewed (range 0-13 per condition). HIV testing was recommended in six of 17 ADC guidelines (35%) and 24 of 61 IC guidelines (39%). At least one guideline recommended HIV testing for six of 25 ADCs (24%) and 16 of 49 ICs (33%). There was no association between recommendation to test and publication year (P = 0.62). CONCLUSIONS: The majority of guidelines for ICs do not recommend testing. Clinicians managing ICs may be unaware of recommendations produced by HIV societies or the prevalence of undiagnosed HIV infection among these patients. We are piloting methods to engage with guideline development groups to ensure that patients diagnosed with ICs/ADCs are tested for HIV. We then plan to apply our methodology in other European settings as part of the Optimising Testing and Linkage to Care for HIV across Europe (OptTEST) project.

Contribution of transmission in HIV-positive men who have sex with men to evolving epidemics of sexually transmitted infections in England: an analysis using multiple data sources, 2009-2013.

HIV seroadaptive behaviours may have contributed to greater sexually transmitted infection (STI) transmission in HIV-positive men who have sex with men(MSM) and to the global increase in STIs. Using multiple national surveillance data sources and population survey data, we estimated the risk of STIs in HIV-positive MSM and assessed whether transmission in HIV-positive MSM has contributed to recent STI epidemics in England. Since 2009, an increasing proportion of STIs has been diagnosed in HIV-positive MSM, and currently, the population rate of acute bacterial STIs is up to four times that of HIV-negative or undiagnosed MSM. Almost one in five of all diagnosed HIV-positive MSM in England had an acute STI diagnosed in 2013. From 2009 to 2013, the odds of being diagnosed with syphilis increased from 2.71 (95% confidence interval (CI) 2.41­3.05, p<0.001) to 4.05 (95%CI 3.70-4.45, p<0.001) in HIV-positive relative to HIV negative/undiagnosed MSM. Similar trends were seen for gonorrhoea and chlamydia. Bacterial STI re-infection rates were considerably higher in HIV-positive MSM over a five-year follow-up period, indicative of rapid transmission in more dense sexual networks.These findings strongly suggest that the sexual health of HIV-positive MSM in England is worsening, which merits augmented public health interventions and continued monitoring.

Similar glucose control with basal-bolus regimen of insulin detemir plus insulin aspart and thrice-daily biphasic insulin aspart 30 in insulin-naive patients with type 2 diabetes: Results of a 50-week randomized clinical trial of stepwise insulin intensification.

OBJECTIVE: This study aimed to demonstrate the non-inferiority of 50-week treatment with stepwise insulin intensification of basal-bolus insulin analogues [insulin detemir (IDet) and aspart (IAsp)] versus biphasic insulin aspart 30 (BIAsp30) in insulin-naive type 2 diabetes mellitus (T2DM) patients not controlled by oral glucose-lowering drugs (OGLDs). RESEARCH DESIGN AND METHODS: In this open-label multicentre, multinational, randomized, parallel-arm treat-to-target trial, 403 insulin-naive patients with T2DM in four African countries were randomized to either an IDet+IAsp (n = 200) or BIAsp1-2-3 (n = 203) treatment group. Stepwise insulin intensification was performed at the end of 14, 26 and 38 weeks, depending on HbA1c values. The primary endpoint was change in HbA1c after 50 weeks of treatment. Safety variables were hypoglycaemia incidence, occurrence of adverse events and weight gain. RESULTS: Non-inferiority of the IDet+IAsp versus BIAsp1-2-3 treatment regimen was demonstrated by their similar HbA1c levels at the end of trial (IDet+IAsp: baseline 8.6%, 50 weeks 7.4%; BIAsp1-2-3: baseline 8.7%, 50 weeks 7.3%; full analysis set difference: 0.1% [95% CI: -0.1, 0.3]; per protocol: 0.2% [95% CI: -0.1, 0.4]). At week 50, 40.3 and 44.9% of patients achieved HbA1c <7.0% with IDet+IAsp and BIAsp1-2-3, respectively. The rate of overall hypoglycaemia during the trial was also similar in both groups (IDet+IAsp: 9.4 events/patient-year; BIAsp1-2-3: 9.8 events/patient-year). CONCLUSION: Insulin initiation and intensification using IDet+IAsp was not inferior to BIAsp1-2-3 in insulin-naive patients with T2DM not controlled by OGLDs. Both regimens led to similar reductions in HbA1c values after 50 weeks of treatment.

Effects of short-term sitagliptin treatment on immune parameters in healthy individuals, a randomized placebo-controlled study.

Sitagliptin, a dipeptidyl-peptidase 4 (DPP-4) inhibitor, improves blood glucose control in patients with type 2 diabetes by blocking cleavage of glucagon-like peptide 1 (GLP-1). In type 2 diabetes patients sitagliptin use is associated with an increase in minor infections, and in new-onset type 1 diabetes patients the ability of sitagliptin to dampen autoimmunity is currently being tested. DPP-4, also known as CD26, is expressed on leucocytes and can inactivate many chemokines important for leucocyte migration, as well as act as a co-stimulatory molecule on T cells. Therefore, this study was conducted to test whether sitagliptin is immunomodulatory. In this randomized, placebo-controlled trial, healthy volunteers were given sitagliptin or placebo daily for 28 days, and blood was drawn for immune assays. No significant differences were observed in the percentage of leucocyte subsets within peripheral blood mononuclear cells (PBMCs), plasma chemokine/cytokine levels or cytokines released by stimulation of PBMCs with either lipopolysaccharide (LPS) or anti-CD3. Individuals taking sitagliptin displayed increases in the percentage of cells expressing higher levels of CD26 at early time-points compared to placebo controls, but these differences resolved by day 28 of treatment. Therefore, in healthy volunteers, treatment with sitagliptin daily for 28 days does not overtly alter systemic immune function.

Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection.

Arterial dissections account for 2% of strokes in all age groups, and up to 25% in patients aged 45 years or younger. The safety of endovascular intervention in this patient population is not well characterized. We identified all patients in the Merci registry - a prospective, multi-center post-market database enrolling patients treated with the Merci Retriever thrombectomy device - with arterial dissection as the most likely stroke etiology. Stroke presentation and procedural details were obtained prospectively; data regarding procedural complications, intracerebral hemorrhage (ICH), and the use of stenting of the dissected artery were obtained retrospectively. Of 980 patients in the registry, ten were identified with arterial dissection (8/10 ICA; 2/10 vertebrobasilar). The median age was 48 years with a baseline NIH stroke scale score of 16 and median time to treatment of 4.9 h. The procedure resulted in thrombolysis in cerebral ischemia (TICI) scores of 2a or better in eight out of ten and TICI 2b or better in six out of ten patients. Stenting of the dissection was performed in four of nine (44%). The single complication (1/9; 11%) - extension of a dissected carotid artery - was treated effectively with stenting. No symptomatic ICH or stroke in a previously unaffected territory occurred. A favorable functional outcome was observed in eight out of ten patients. Despite severe strokes on presentation, high rates of recanalization (8/10) and favorable functional outcomes (8/10) were observed. These results suggest that mechanical thrombectomy in patients with acute stroke resulting from arterial dissection is feasible, safe, and may be associated with favorable functional outcomes.

Surface Modification of PET Fabric by Graft Copolymerization with Acrylic Acid and Its Antibacterial Properties.

Graft copolymerization of acrylic acid (AA) onto Poly(ethylene terephthalate) (PET) fabrics with the aid of benzoyl peroxide was carried out. The effect of polymerization parameters on the graft yield was studied. Percent grafting was enhanced significantly by increasing benzoyl peroxide (BP) concentrations up to 3.84 g/lit and then decreased upon further increase in initiator concentration. Preswelling of PET leads to changes in its sorption-diffusion properties and favors an increase in the degree of grafting. The antibiotics treated grafted fabrics showed antibacterial properties towards gram-positive and gram-negative microorganisms. FTIR and SEM were used to characterize AA-grafted polyester fabrics.

Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies.

BACKGROUND: Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success. METHODS: We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment. RESULTS: All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events. CONCLUSIONS: In seven patients with type B insulin resistance, standardized treatment with rituximab, cyclophosphamide, and pulse steroids results in remission of the disease. Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.

High dose intensity doxorubicin in aggressive non-Hodgkin's lymphoma: a literature-based meta-analysis.

BACKGROUND: Aggressive non-Hodgkin's lymphoma (NHL) represents approximately 60% of lymphomas in the West and even more in the developing world. cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recognized as the standard chemotherapy regimen and the addition of rituximab to B-cell subtypes has been shown to significantly improve treatment outcomes. Nevertheless, still a significant fraction of patients is not offered rituximab due to economic reasons. Thus, CHOP is still offered to these patients as well as those with T-cell subtypes. Data from the early 1990s have indicated that the dose intensity (DI) of doxorubicin is a key factor in predicting survival. METHODS: A Medline and Cochrane library search was carried out using the search terms 'CHOP', 'lymphoma' and 'randomized trials'. Eligible trials had CHOP as a control arm and any regimen administering doxorubicin at a higher DI (16.6 mg/m(2)/week) as the investigational arm. Pooling of data was carried out using the mixed effect model. RESULTS: Eight trials were eligible. Patients receiving DI doxorubicin-based regimens had a significantly better overall survival [summary hazard ratio (SHR) 0.82; 95% confidence interval (CI) 0.71-0.96], event-free survival (SHR 0.86; 95% CI 0.75-0.99) and higher complete response rate (summary odds ratio 0.91; 95% CI 0.67-0.97). CONCLUSION: High DI doxorubicin based should be considered in patients with aggressive NHL.

Frequency of the 35delG allele causing nonsyndromic recessive deafness in the Algerian patients.

Deafness is a heterogeneous disorder showing different patterns of inheritance and involving a multitude of different genes. Mutations in the GJB2 gene encoding connexin 26 (Cx26) protein are a major cause for non-syndromic autosomal recessive and sporadic deafness. Among these mutations, the c.35delG deletion is the most common mutation for sensorineural deafness. One hundred sixteen persons from fifty-eight families were tested by the method based on the principle of PCR-mediated-site-directed mutagenesis (PSDM), followed by a Bsl1 digestion. Mutation c.35delG was diagnosed in sixteen families (11 homozygotes and 5 heterozygotes). The low allelic frequency (17.24%) and low ratio of individuals homozygous (13.8%) and heterozygous (6.9%) for the c.35delG mutation suggest that there are other mutations in the GJB2 gene or other genes responsible for deafness in the Algerian population. This study reports a significant association (P=0.003) between first cousin consanguinity and non-syndromic prelingual deafness.

Should the presence of congenital para-ureteral diverticulum affect the management of vesicoureteral reflux?

PURPOSE: The presence of congenital para-ureteral diverticulum (PUD) has been presumed to lower the resolution rate of vesicoureteral reflux (VUR). PUD is considered an important cause of distortion of the vesicoureteral junction and persistence of VUR. Early surgery has been recommended based on this assumption. However, the scientific evidence supporting this approach is weak. We have been managing this group of patients more conservatively in the last 7 to 8 years on the premise that the presence of PUD is not per se an indication for surgery. To test this hypothesis, we performed a retrospective cohort study to compare the outcome of VUR in children with and without PUD. MATERIALS AND METHODS: We identified 141 consecutive patients with VUR associated with PUD between 1990 and 2004. Of the patients 57 with duplication, ureterocele, neurogenic bladder or outlet obstruction were excluded from study. Median age of the remaining 84 patients at diagnosis was 2.9 years and 56 (69%) were males. Reflux was bilateral in 4 patients, and low (I to II), intermediate (III) and high (IV to V) grade in 39%, 35% and 26%, respectively. Followup was 3 to 168 months (median 47). The outcome was compared to a control group of 95 patients (150 units) with primary VUR and no PUD. The baseline parameters and followup were comparable in both groups. RESULTS: Overall, VUR resolved in 43%, persisted in 27% and was surgically corrected in 30% of the units with PUD. In the 25 patients (26 units) who underwent surgical intervention breakthrough urinary tract infection or new renal scars were the indication in only 5. The remainder were operated on because of persistent VUR and the presence of PUD, mainly before 1997. The incidence of breakthrough urinary tract infection or new renal scar was similar in the controls (6% in PUD group vs 10% in controls, p = 0.7). The resolution rate was 60% for low grade, 39% for intermediate grade and 22% for high grade VUR. These figures were not significantly different from those of the control group in which the resolution rates were 52%, 28% and 33% for comparable grades (p = 0.9). Kaplan-Meier analysis and log rank test did not show any difference in resolution of VUR in the 2 groups (p = 0.84). Multivariate analysis identified grade as the only variable affecting resolution (p = 0.028). The size of PUD did not affect the likelihood of resolution. CONCLUSIONS: The outcome of VUR is similar in children with or without PUD. Therefore, treatment of these patients should not differ. Surgery should be reserved for patients with breakthrough infection or renal scar progression.

Endovascular embolectomy of acute basilar artery occlusion.

Acute basilar artery occlusion has a mortality rate approaching 90%. The authors describe a case of acute basilar artery occlusion managed successfully with endovascular embolectomy. A 31-year-old man sought treatment for confusion, dysarthria, and right-sided weakness. He soon became unresponsive and was found to have a vertebral artery dissection and an associated basilar artery embolism. The dissection was managed with endovascular stenting, and the basilar artery embolus was removed with a clot retriever at 7 hours. The patient recovered without neurologic deficit.

[Care and management of cleft lip and palate by CLP Department hospital Robert Debre in Paris]. / Prise en charge des fentes labio-palatines par l'équipe de l'hôpital Robert Debré à Paris.

Cleft lip and palate repair must take a place at an early stage and respect physiology. Iatrogenic consequences harming maxillary growth must be avoided. Owing to early and reverse timing, short and long term results have been improved. Correction of the soft palate is performed at 3 months of age, lip and hard palate at 6 months without elevation of mucoperiosteum. A palatal plate is applied before and after each surgical stage. Patients receive phonetic, dental end ENT follow-up on a regular basis till end of growth. Correction of sequelae, especially of nasal tip, can be undertaken around grade school entrance at about 6 years of age. Nasal sequelae such as deviation of the septum must not be corrected before end of puberty. Surgery and follow-up must be conducted by an experienced multi-disciplinary team in which the surgeon plays the part of master of works.

Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation.

To investigate the transcriptional program underlying thyroid hormone (T3)-induced cell proliferation, cDNA microarrays were used to survey the temporal expression profiles of 4,400 genes. Of 358 responsive genes identified, 88% had not previously been reported to be transcriptionally or functionally modulated by T3. Partitioning the genes into functional classes revealed the activation of multiple pathways, including glucose metabolism, biosynthesis, transcriptional regulation, protein degradation, and detoxification in T3-induced cell proliferation. Clustering the genes by temporal expression patterns provided further insight into the dynamics of T3 response pathways. Of particular significance was the finding that T3 rapidly repressed the expression of key regulators of the Wnt signaling pathway and suppressed the transcriptional downstream elements of the beta-catenin-T-cell factor complex. This was confirmed biochemically, as beta-catenin protein levels also decreased, leading to a decrease in the transcriptional activity of a beta-catenin-responsive promoter. These results indicate that T3-induced cell proliferation is accompanied by a complex coordinated transcriptional reprogramming of many genes in different pathways and that early silencing of the Wnt pathway may be critical to this event.

Microarray analysis of the in vivo effects of hypophysectomy and growth hormone treatment on gene expression in the rat.

Complementary DNA microarrays containing 3000 different rat genes were used to study the consequences of severe hormonal deficiency (hypophysectomy) on the gene expression patterns in heart, liver, and kidney. Hybridization signals were seen from a majority of the arrayed complementary DNAs; nonetheless, tissue-specific expression patterns could be delineated. Hypophysectomy affected the expression of genes involved in a variety of cellular functions. Between 16-29% of the detected transcripts from each tissue changed expression level as a reaction to this condition. Chronic treatment of hypophysectomized animals with human GH also caused significant changes in gene expression patterns. The study confirms previous knowledge concerning certain gene expression changes in the above-mentioned situations and provides new information regarding hypophysectomy and chronic human GH effects in the rat. Furthermore, we have identified several new genes that respond to GH treatment. Our results represent a first step toward a more global understanding of gene expression changes in states of hormonal deficiency.

Sampling activated mechanisms in proteins with the activation-relaxation technique.

The activated dynamics of proteins occur on time scales of milliseconds and longer. Standard all-atom molecular dynamics simulations are limited to much shorter times, of the order of tens of nanoseconds. Therefore, many activated mechanisms that are crucial for long-time dynamics will not be observed in such molecular dynamics simulation; different methods are required. Here, we describe in detail the activation-relaxation technique (ART) that generates directly activated mechanisms. The method is defined in the configurational energy landscape and defines moves in a two step fashion: (a) a configuration is first brought from a local minimum to a nearby first-order saddle point (the activation); and (b) the configuration is relaxed to a new metastable state (the relaxation). The method has already been applied to a wide range of problems in condensed matter, including metallic glasses, amorphous semiconductors and silica glass. We review the algorithm in detail, discuss some previously published results and present simulations of activated mechanisms for a two-helix bundle protein using an all-atom energy function.