Total knee arthroplasty (TKA) is often associated with a severe local inflammatory reaction which, unless controlled, leads to persistent pain up to one year after surgery. Standard and accelerated rehabilitation protocols are currently being implemented after TKA, but no consensus exists regarding the long-term effects. Biophysical stimulation with pulsed electromagnetic fields (PEMFs) has been demonstrated to exert an anti-inflammatory effect, to promote early functional recovery and to maintain a positive long-term effect in patients undergoing joint arthroscopy. The aim of this study was to evaluate whether PEMFs can be used to limit the pain and enhance patient recovery after TKA.A prospective, randomized, controlled study in 30 patients undergoing TKA was conducted. Patients were randomized into experimental PEMFs or a control group. Patients in the experimental group were instructed to use I-ONE stimulator 4hours/day for 60days. Postoperatively, all patients received the same rehabilitation program. Treatment outcome was assessed using the Knee Society Score, SF-36 Health-Survey and VAS. Patients were evaluated pre-operatively and one, two, six and 12 months after TKA. Joint swelling and Non Steroidal Anti Inflammatory Drug (NSAID) consumption were recorded. Comparisons between the two groups were carried out using a two-tail heteroschedastic Student’s t-test. Analysis of variance for each individual subject during the study was performed using ANOVA for multiple comparisons, applied on each group, and a Dunnet post hoc test. A p value < 0.05 was considered statistically significant.Pre-operatively, no differences were observed between groups in terms of age, sex, weight, height, Knee-Score, VAS, SF-36 and joint swelling, with the exception of the Functional Score. The Knee-Score, SF-36 and VAS demonstrated significantly positive outcomes in the I-ONE stimulated group compared with the controls at follow-ups. In the I-ONE group, NSAID use was reduced and joint swelling resolution was more rapid than in controls. The effect of I-ONE therapy was maintained after use of the device was discontinued.The results of the study show early functional recovery in the I-ONE group. I-ONE therapy should be considered after TKA to prevent the inflammatory reaction elicited by surgery, for pain relief and to speed functional recovery.Current Controlled Trials ISRCTN10526056 Osteoarthritis (OA) is a degenerative joint disease that affects approximately 10% of adults over the age of 50 . SatisfaOral Non Steroidal Anti Inflammatory Drugs (NSAIDs) are used to control pain and inflammation in the operated knee. However, their use for periods exceeding 72 hours in an aged population must take into account the possible negative side effects, such as reduction in renal perfusion and gastric mucosa damage.2A adenosine receptors demonstrating the highest anti-inflammatory activity [2A adenosine receptor in neutrophils, chondrocytes and synoviocytes, and this explains the anti-inflammatory effect of PEMFs observed in the knee joint [Recent studies have indicated that the physiological pathway leading to resolution of inflammatory processes can be mediated by the activation of adenosine receptors, with the Aactivity ,7. It haee joint ,9. Levelee joint ,11.The aim of this study was to test whether treatment with PEMFs, as an adjuvant to standard rehabilitation, could limit pain and joint swelling immediately after TKA and shorten the time to functional recovery.In the period between 2008 and 2010, at the Orthopedic and Traumatology Operative Unit of University of Bari in Italy, a prospective, randomized, controlled study was performed to test whether treatment with PEMFs could favor functional recovery in patients undergoing TKA. The study was designed without placebo devices, following Local Ethical Committee indications that did not consider appropriate to ask patients to devote four hours per day for 60 days to using a placebo device, knowing the anti-inflammatory activity of the treatment. The study was approved by the Local Ethical Committee, and patients signed informed consent for recruitment.2) >30, rheumatoid arthritis, autoimmune diseases, systemic diseases, cancer and the use of steroids.The inclusion criteria were the following: patients aged between 60 and 85 years, presenting with an advanced state of knee OA and scheduled for TKA, with varus or valgus deformity not exceeding 20° or 15°, respectively, and with a flexion contracture of less than 15°. Exclusion criteria were: previous surgery to the same knee, omolateral hip prosthesis, Body Mass Index  built on the randomization criteria: sex (M/F), age  and smoking status (yes/no).Thirty patients were randomly assigned to the experimental and control groups. At selection, the clinician informed the patient regarding the chance to be recruited in a trial with two arms. At enrollment, the patient accepted to be addressed to one of the two groups for the entire duration of the study and the patient signed informed consent for recruitment. The assignment of the patient to experimental or control group was performed using a web-based computer program  four hours per day for 60 days by an independent, unblinded research assistant, who will not be involved in patient care or assessment. Physicians, as well as medical assessors, were blinded to the allocation of patients in the study groups.All devices were provided by the manufacturer at no cost. Treatment began within seven days from TKA, and continued at the rehabilitation centre or at the patient’s home. The battery-operated device  generated a peak magnetic field of 1.5 mT at a frequency of 75 Hz  was implanted following a standard procedure.Kinesitherapy began on the same day of surgery, with passive mobilization on Kinetec  from 60° to 90° bending for 90 minutes. On subsequent days, this was continued with bending from 0° to 90° for 90 min per day using the Kinetec in the afternoon; from day three, patients began cautious passive and active assisted mobilization of hip, knee and ankle, exercises for muscular reinforcement of lower limbs, assisted walking with two crutches and partial weight bearing on the operated limb and isometric exercises for the lower limbs.Patients were required to complete subjective assessment forms and the physician to complete the objective ones. Assessments were performed pre-operatively and at one, two, six and 12 months post-operatively and included:the Visual Analogue Scale (VAS), a 10 cm horizontal line, where the left end represents no pain, and the right end maximum possible pain or unbearable pain;a) Knee Score to assess pain, range of motion, stability, contracture in bending, active extension deficit and alignment); (b) Functional Score to evaluate autonomy in walking, stair climbing, use of a stick or frame. Both score values ranged from 0 to 100 [The Knee Society Score including: .At the baseline, no statistically significant differences were observed between the two groups with the exception of the Functional Score, Table In both groups, follow-up Knee scores were greater than the pre-operative baseline values, and the changes were statistically significant at two, six and 12 months (p < 0.05) in the experimental group, but only at six and 12 months in the control group (p < 0.05). Intergroup analysis demonstrated that the Knee score in the I-ONE group was significantly higher after two months  and six months  than in controls. At 12 months, no difference was observed between groups (p = 0.097),  in the experimental group, whilst in the control group the increase became significant at six months. There was no statistically significant difference between the two groups one month after surgery (p = 0.124), but there were highly significant differences between the groups at two months , six months  and 12 months   and the baseline (p < 0.05). The difference between groups was maintained at all follow-up visits: two months , six months  and 12 months  . Figure Swelling was resolved in both groups and was significantly reduced at the follow-up visits with respect to baseline (p < 0.05). The percentage of subjects with mild to moderate swelling was significantly higher in the I-ONE group with respect to control group at 1 and 2 months after surgery . No difference between groups was observed at 6 and 12 months . At two and six months, the percentages of patients using NSAIDs in the experimental and control group were 7% and 86% , and 7% and 46% , respectively. At 12 months, no difference was observed between groups.st post-operative month and then accelerates at six and 12 months, when local inflammation and pain have been resolved [TKA is the most common and effective surgical procedure for the treatment of OA, leading to satisfactory functional recovery in patients. However, it can be associated with moderate or severe post-operative pain and an intense inflammatory reaction. Pain stems from the onset of loco-regional inflammation, and the presence of pro-inflammatory cytokines , tumor necrosis factor-α, histamine, bradykinin, prostaglandin, serotonin, substance P and acetylcholine, which stimulate nociceptors and induce hyperalgesia and allodynia -18. It hresolved ,20. InflInnovative therapeutic strategies are required to locally control the inflammatory reaction following TKA.2A adenosine receptors, and this explains the anti-inflammatory effects observed in experimental [In vitro, PEMFs exposure prevents the release of PGE2 by synoviocytes cultured in the presence of pro-inflammatory cytokines  [It has been demonstrated that PEMFs have an agonist effect on Arimental ,9,21 andrimental ,11 studirimental . In vitr, TNF-α) .These results support the rational basis for the use of PEMFs to control the inflammatory reaction that follows surgical procedures. Two randomized, prospective and double-blind studies have been conducted in patients undergoing arthroscopic procedure on the knee. The first study included patients with cartilage lesions undergoing microfractures, while the second concerned patients undergoing anterior cruciate ligament reconstruction. In both studies, early functional recovery of the joint and diminished consumption of NSAIDs were reported ,11.In patients undergoing hip revision surgery, PEMFs treatment resulted in early pain control and enhanced functional recovery . StraburOn the basis of the above evidence, this prospective, randomized and controlled trial was conducted to verify whether the treatment with I-ONE therapy, in addition to standard rehabilitation, could control pain, reduce swelling and improve functional recovery in patients undergoing TKA.The Knee Score, based on objective examination of joint, was significantly better for the I-ONE group at two and six months after TKA, indicating that the positive effect is maintained even after the end of the treatment. Furthermore, the values of the Knee Score in the control group at 12 months were comparable with those observed in the experimental group two months post TKA.The Functional Score, which measures the subjective evaluation of functional recovery, does not demonstrate statistically significant differences between the treated and control groups. These results are in agreement with those reported by other authors concerning the lack of correlation between the parameters of the subjective evaluation scales and those of the clinical-functional scales ,25.SF-36 Health Survey score demonstrates that patients treated with I-ONE therapy after TKA had significantly higher values than the control group until month twelve. Furthermore, at 12 months the SF-36 value of the control group equated with that of the I-ONE group at one month.The values observed for the control group were compared with information available in the literature for Knee Score, Functional Score and SF-36 Health Survey. Breugem et al.  reportedPain, monitored on the VAS scale, at all follow-ups was significantly lower in treated group with respect to control one. Swelling was resolved earlier in the treated group; no significant difference between groups was observed at 6 and 12 months. Other authors have reported that limitation due to swelling was important during the acute period (one month after TKA) and the improvement continued until 12 months after surgery ,30. At oThe lack of a placebo group is a limitation of this study, but it must be acknowledged that all clinical evaluations were carried out by physicians unaware whether the patient belonged to the control or experimental group. The small population size did not allow to reliably apply the group x time interaction effect test in the analysis of the results. Furthermore, the limited number of patients may explain the difference in Functional Scores observed at the baseline between the two groups. Patients’ compliance was a concern, as the use of I-ONE for four hours per day for 60 days requires significant commitment. However, the treatment was well accepted, and patient compliance was high (3.9 hours per day average use) as the device is portable, battery operated and can be worn while walking or at rest.This study shows that I-ONE therapy can be started soon after TKA. The treatment has been well tolerated and no negative side effects have been reported. The lack of the placebo group prevents to precisely quantify the contribution of the treatment to the observed pain relief and shortening of functional recovery. Nevertheless, I-ONE therapy may represent an important adjunct to postoperative treatment by preventing the detrimental effect of inflammation elicited by TKA on joint tissues, with short and long term positive benefits for patients.SS, FDT are employees of IGEA SpA – Clinical BiophysicsThe authors BM, AN, LM, VPA and VPE declare that they have no competing interests.BM, AN and SS participated in the study design. AN and SS designed the protocol and helped with data interpretation. BM, AN, LM, VPA and VPE carried out the study. SS, FTD and AN interpreted the results and drafted the manuscript. FDT performed the statistical analysis. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/88/prepub


The differentiation of infected diabetic foot ulcers (IDFU) from non infected diabetic foot ulcers (NIDFU) is a challenging issue for clinicians.Recently, procalcitonin (PCT) was introduced as a remarkable inflammatory marker. We aimed to evaluate the accuracy of PCT in comparison to other inflammatory markers for distinguishing IDFU from NIDFU.We evaluated PCT serum level as a marker of bacterial infection in patients with diabetic foot ulcers. Sixty patients with diabetic foot ulcers were consecutively enrolled in the study. A total of 30 patients were clinically identified as IDFU by an expert clinician, taking as criteria for purulent discharges or at least two of manifestations of inflammation including warmth, redness, swelling and pain.9/L, 66% and 67% for WBCs, respectively. The area under the receiver operating characteristic curve for ESR was the greatest , followed by CRP , PCT , and finally WBCs .Procalcitonin, white blood cells (WBCs), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), were found significantly higher in the IDFU group compared to the NIDFU group. The best cut-off value, sensitivity and specificity were 40.5 mm/h, 90% and 94% for ESR, 7.1 mg/dL, 80% and 74% for CRP, 0.21, 70% and 74% for PCT, and 7.7×10These results suggest that PCT can be a diagnostic marker in combination with other markers like ESR and CRP to distinguish infected from non-infected foot ulcers, when clinical manifestations are un specific. Additional research is needed before the routine usage of PCT to better define the role of PCT in IDFU. Diabetic foot ulcer (DFU) is one of the most common causes of mortality and morbidity, accounting for nearly two-thirds of all non-traumatic amputations perfumed in the US , 2. The Infection diagnosis in a DFU is not always simple and explicit. For the moment, most DFU infections are diagnosed clinically  or/and based on laboratory findings , 7. BecaRecently, procalcitonin (PCT) has been introduced as an inflammatory marker and acute phase reactant, which may be especially useful in distinguishing bacterial infections -17. HoweIn this study, the diagnostic accuracy of PCT was evaluated in comparison with other inflammatory markers as an indicator to make the distinction between infected and non-infected DFU, as the addition of antibiotics, costly medications, is justified only in the presence of bacterial infection.Sixty consecutive patients with diabetic foot ulcers hospitalized in the infectious diseases ward of Baqiyatallah Hospital, Baqiyatallah University of Medical Sciences, Tehran, IR Iran, between September 2009 and October 2010, were orderly registered. An extra group of healthy individuals (n = 30) was determined too. Patients with other infectious diseases like sepsis, urinary tract infection, pneumonia, meningitis, patients admitted due to surgery in the previous six weeks, with malignancy, with inflammatory diseases such as inflammatory bowel syndrome, rheumatoid arthritis or other rheumatologic disorders, patients receiving immunosuppressive treatment and with previous use of antibiotics were excluded from the study. The study had approval of Baqiyatallah University of Medical Sciences Ethics Committee, and all participants gave their informed consents.Patients were assessed for diabetic foot infection by an infectious diseases expert, and a general physician was responsible for supervision on data collection. The guidelines of the Infectious Diseases Society of America (IDSA) and the IWGDF were used for clinical classification of IDFU by a specialist of infectious diseases. Localization  and production of pus were recorded. Clinicians diagnosed infected diabetic foot ulcer (IDFU) according to the IDSA guidelines . ClinicaThe blood taken for the analysis of PCT levels was centrifuged for 20 min after being protected at room temperature for 30 min. A BRAHMS PCT kit  was used for detection of PCT serum levels with a functional detection limit of 0.05 ng/mL. Levels of CRP, WBCs and ESR were assessed by the hospital biochemistry laboratory. The investigation was performed in a blind manner.Data were shown as mean ± standard deviation (SD). One-way ANOVA was used for the comparison among groups. T-test was used for the comparison of quantities. The receiver operating characteristic (ROC) curve has been drawn and the are aunder the ROC curve has been shown. With Youden’s J formulation (J = specificity+sensitivity-1), the best cut-off value was calculated. Specificity, sensitivity, and the negative and positive predictive values of the biochemical parameters were determined using the best cut-off value. A P value < 0.05 was considered as statistically significant. Statistical analysis was performed using SPSS software version 17 .In this study, 30 patients with IDFU and 30 patients with NIDFU were enrolled. Patients treated with oral or intravenous (IV) antibiotic during the previous 6 months because of diabetic foot ulcers were excluded from the study. The demographic data of the three groups  have been summarized in With respect to age and gender, there was no statistically significant difference between the three groups (P > 0.05). Fasting blood sugar and HbA1c levels in the IDFU group were significantly higher than in the NIDFU group. Wound characteristics of the NIDFU and IDFU groups have been summarized in The levels of inflammatory markers have been shown in Diabetic foot infection was diagnosed clinically by the presence of suppurative discharge or at least two of the features of inflammation such as redness, warmth, swelling or induration and pain or tenderness .9/L for WBCs. Maximal sensitivity, specificity, and positive and negative predictive values have been displayed in We calculated the area under the ROC curve to estimate the presence of bacterial infection in patients with diabetic foot ulcer . The areThe area under the curve was 0.967 for ESR, 0.871 for CRP, 0.729 for PCT and 0.721 for WBCs.The DFU is one of the most important complications of diabetes, which has a long and difficult healing process. These wounds can become infected and progress and could cause osteomyelitis and sepsis. Therefore, prevention and treatment of infected DFUs with antibiotics are very important. Different methods have been proposed for distinguishing between IDFU and NIDFU, but clinical findings are the most valid criterion yet. However, this method relies on individual expertise . ConsideIn the study of Uzun et al., ESR, WBC and PCT had a decisive role in identifying diabetic foot wound infection, but CRP did not have a significant role, a finding inconsistent with the results of the present study . Also, tJeandrot et al. reported that PCT sensitivity and specificity, compared to other inflammatory markers  are not superior in distinguishing infected from non-infected diabetic foot wounds. In the aforementioned investigation, CRP was the most useful marker, having the highest sensitivity and specificity according to the DFU classification. Although, In the study of Jeandrot et al. CRP was introduced as the most sensitive and specific marker, in our study, specificity and sensitivity of CRP were, on one hand, less significant than ESR and, on the other hand, more than PCT or WBC .The higher efficiency of ESR in denoting infection, compared with PCT, could be rationalized by the mild nature of infection in low grade diabetic foot wounds. Our study results confirmed that a higher level of PCT is presents in higher grades of IDFU. PCT level is usually higher in patients with severe and systemic infection .Sensitivity is more important in differentiating these patients, and the highest sensitivity was obtained when the two markers  were considered together, a finding previously reported in both the studies of Jeandrot et al. and Uzun et al. , 17. SinThe normal level of PCT is very low (< 0.5 ng/mL). In bacterial infections, the amount of PCT may be observed to reach values a hundred times higher . In the Procalcitonin levels, before the study of Uzun et al.  and JeanThere were some limitations in this study, which hinder a definite conclusion. In most hospital laboratories, PCT analysis is not routinely available. Also, controversy exists about the reliability of PCT level in the aforementioned studies because of the variability in outcome by age, pathogen and type of infection , 19-22.


Enzymes play important roles in most of the biological processes. Although only a small fraction of residues are directly involved in catalytic reactions, these catalytic residues are the most crucial parts in enzymes. The study of the fundamental and unique features of catalytic residues benefits the understanding of enzyme functions and catalytic mechanisms. In this work, we analyze the structural context of catalytic residues based on theoretical and experimental structure flexibility. The results show that catalytic residues have distinct structural features and context. Their neighboring residues, whether sequence or structure neighbors within specific range, are usually structurally more rigid than those of noncatalytic residues. The structural context feature is combined with support vector machine to identify catalytic residues from enzyme structure. The prediction results are better or comparable to those of recent structure-based prediction methods. Understanding the molecular mechanisms of enzyme catalysis is important in studies of various complicated biological processes. The number of protein structures deposited to the Protein Data Bank  has incrMany methods have been developed to predict protein catalytic sites based on information extracted from protein seqence and structure. One of the most direct strategies is based on finding homologous enzymes whose function and catalytic residues are already known –6. CatalTo directly identify catalytic sites from single protein structure without needing homology information, it is important to study the fundamental differences between catalytic residues and noncatalytic residues. Sacquin-Mora et al.  used theIn this study, we first analyzed the structural context of catalytic and noncatalytic residues based on their sequence and structure neighbors. We show that catalytic residues are usually located in structurally more rigid environment than noncatalytic residues. The sequence or structural neighboring residues within specific range of catalytic residues have distinct structural features. We further combined the structural context features and support vector machine to identify catalytic residues from protein structure.ith residue is based on the distances between the ith residue and all the other residues in the enzyme, as inN is total number of residues in the enzyme, and rij is the distance between ith andjth residues. The coordinate of Cα atom is used to represent the position of the residue.The weighted-contact number model (WCN) , 16 is uith residue is defined as the average structural flexibility of the ith residue and its flanking residues on sequence as ini − n to i + n are the nearest n neighbors of the ith residue on sequence. WCN is inverted for an easy comparison with B-factor. If x is out of the range of the sequence, it is simply ignored in the calculation. The STR of the ith residue is defined as the average structural flexibility of the ith residue and residues whose distance to the ith residue are smaller than a cut-off value as inM is a subset of residues whose distance to the ith residue is smaller than the cut-off distance and m is the number of residues in the subset. The concept of SEQ and STR is extended from our previous work [There are two types of structural context: sequence neighbor flexibility (SEQ) and structure neighbor flexibility (STR). The SEQ of the ous work , which oz-scores:σx are the mean and standard deviations of x of a given protein. In this work, x is SEQ, STR, or B-factor from X-ray crystallographic structures. For a given protein, the mean and standard deviations are calculated based on the scores of the protein. The scores of the protein are then normalized according to its mean and standard deviations. The normalized SEQ, STR, and B-factor are referred to as ZSEQ, ZSTR, and ZB, respectively. For convenience, the normalized SEQ, STR, and normalized B-factor profiles are simply called SEQ profile, STR profile and B-factor profile.The SEQ, STR, and B-factor are normalized to their corresponding SVM finds the separating hyperplane with the largest distance between two classes. However, the data being classified may not always be linearly separable in the space. It was proposed that the original space be mapped into a higher-dimensional space, making the separation easier in that space. The support vector machine method (SVM) has been widely applied to many bioinformatics studies: protein-fold assignment , 19, subZSEQ, ZSTR, ZB, or binary coding of amino acid type. The common problem encountered in enzyme catalytic site prediction using SVM is the extremely unbalanced ratio of catalytic residues and noncatalytic residues. A well-used strategy is to randomly select subsets which have a balanced ratio between catalytic and noncatalytic residues when training [cost and gamma are parameters used in model training and kernel function of LIBSVM and need to be to tuned for optimal prediction results. These parameters are tuned independently using 5-fold cross-validation for each training dataset. In addition to cost and gamma parameters, other settings used in the SVM include the type of SVM: C-SVC; the type of kernel function: radial basis function. Other parameters not mentioned here are set as their default value in the LIBSVM software.Here we used SVM to predict catalytic residues using the structural context features, SEQ and STR, as input features. The feature vector for a residue is one of these features or their combinations: training . Here, aE-value threshold of 5 × 10−3. The sequence conservation score is directly taken from the “information per position” column in the PSSM profile.For comparison with the POOL method, sequence conservation which includes evolutionary information is used as training feature in some predictions reported here. Sequence conservation is from position-specific substitution matrix (PSSM) generated by PSI-Blast  for eachThe dataset used in this work is collected from Catalytic Site Atlas (CSA)  version Sensitivity, specificity, and Matthew's correlation coefficient (MCC) were used for performance measure as follows: used in .ZSEQ, ZSTR, and ZB of catalytic residues and noncatalytic residues for the E760 dataset. Then we show the prediction results based on ZSEQ profile, ZB profile, and amino acid type. Finally, we compared the prediction results based on ZSEQ with those of the methods using other structure-based features.First, we discuss the distributions of ZSEQ when n = 1  for catalytic residues and noncatalytic residues for the E760 dataset. For comparison, the distributions of ZB are also shown in ZSEQ for catalytic and noncatalytic residues show that catalytic residues are much less flexible and located in a more rigid context than noncatalytic residues. The phenomenon is much more significant using ZSEQ than using ZB as shown in ZSEQ ≤ 0 and 40% of noncatalytic residues having ZSEQ ≤ 0. Only 81% of catalytic residues have ZB ≤ 0 and 54% of noncatalytic residues have ZB ≤ 0. SEQ and crystallographic B-factor are both based on the number and distances of neighbors around a given residue and are related to structural flexibility. The SEQ profile is a better and more reliable characteristic to identify catalytic residues than the B-factor profile. B-factor is easily affected by experimental conditions, crystal packing, existence of ligands, or temperature. Two structures of the same enzyme under different experimental conditions may have very different B-factor profiles but have almost identical crystal structures.In this section, we compare the distributions of SEQ (sequence neighbor flexibility) for catalytic residues and noncatalytic residues. ZSEQ of n = 1 (solid lines) and ZB (dashed lines) profiles of two enzymes, diaminopimelate epimerase (PDB id: 1BWZ) and levansucrase (PDB id: 1OYG). The catalytic residues and noncatalytic residues are labeled as triangle and circle on ZSEQ profiles and on ZB profiles, respectively. It is obvious that the catalytic residues are located in the most structurally stable regions for the ZSEQ profiles in both examples. The four catalytic residues  of diaminopimelate epimerase are located near the centroid of the enzyme, forming a rigid catalytic spot. Cys73 and Cys217 are close to each other and connected by a disulfide bond. However, they have unusually high ZB  but reasonable low ZSEQ values (−1.08 and −1.22). His159 is partially buried by surrounding neighbors and has a quite low solvent accessible surface (SAS) of 3 Å2, calculated by the DSSP program [ZB (−0.29) and an extremely low ZSEQ (−1.16) comparing to other residues in the enzyme. Glu208 is relatively more exposed to solvent (SAS = 19 Å2) than His159. It has a high ZB (0.23) but a very low ZSEQ (−0.91). In the protein, the four catalytic residues are structurally rigid, having very low ZSEQ and SAS values. However, their ZB are high, especially for Cys73 that forms a disulfide bond with another catalytic residue, Cys217. program . It has 2, 8 Å2, and 24 Å2, resp.) but are surrounded and thus strongly stabilized by a large number of residues because of their location. The ZSEQ for these three catalytic residues, Asp86, Asp247, and Glu342, are −1.18, −1.46, and −1.36, respectively. Their ZB values are surprisingly not low . SEQ is a better estimation of structural flexibility than B-factor whether the location of residue is exposed to solvent or buried inside the protein.The catalytic site of the second example, levansucrase, is constituted of three catalytic residues, Asp86, Asp247, and Glu342, which are inside a cleft near the geometrical center of the protein. They are moderately accessible to solvent , STR (cutoff = 3 Å), B-factor profile, and their combinations. The prediction sensitivity, specificity, and MCC using different feature sets are listed in In this section, we discuss the prediction results using SVM with several different features, including amino acid type, SEQ (n = 1) and STR (cutoff = 3 Å) are also listed in The prediction results show that SEQ and STR are much better features than B-factor  for identification of catalytic residues. The prediction performances of STR and SEQ are quite similar . We selected SEQ for further-detailed analysis and comparison. Due to the fact that about 95% catalytic residues are polar or charged amino acids, prediction purely based on amino acid type have a MCC of 0.40, which is much higher than that of B-factor. However, the results also show that there are many false positives (specificity = 0.70), which means that catalytic residues have other unique features. SEQ provides information of structural flexibility of residues and their neighbors, which is complementary to amino acid type information. The prediction results that include SEQ and amino acid type show that catalytic residues can be more accurately identified using both features. The MCC is 0.51 and the sensitivity and specificity are 0.74 and 0.76, respectively. The prediction results based on combining SEQ  , which cWe also compared the results of SEQ and those of POOL(T + G) (residue electrostatic combined with structure geometry) on a dataset of 79 enzymes .  Figuren = 1) for each catalytic residue in several example proteins. The rank of our prediction is based on the probability of a residue predicted to be catalytic residue based on the function provided by the LIBSVM software. The results show that our prediction results are in general better than or comparable to those of POOL in these examples.To further compare the results of SEQ and POOL, we have submitted two enzyme structures, diaminopimelate epimerase (PDB code: 1BWZ) and levansucrase (PDB code: 1OYG), to the POOL webserver. For diaminopimelate epimerase, the four catalytic residues, Cys73, His159, Glu208, and Cys217, are ranked 18, 3, 6, and 59, respectively, by POOL . In Here we discuss related catalytic residue prediction methods, including their features, datasets, and prediction performance. Petrova and Wu  used 24 A more recent study by Cilia and Passerini  models sAmitai et al.  applied Wie et al.  used a cIn this work, we calculated theoretical structural flexibility for catalytic residues and their sequence or structure neighboring residues. We found that catalytic residues are in general located in structurally less flexible context. We show that the theoretical structure flexibility (SEQ and STR) we used is better than B-factor for identification of catalytic residues. For a dataset of 760 enzymes of low pairwise sequence identity, the difference of SEQ distributions between catalytic and noncatalytic residues are more obvious than that of B-factor. The prediction results of SEQ are much better then those of B-factor. The MCC, sensitivity, and specificity of prediction are 0.74, 0.76, and 0.51, respectively, using SEQ combined with amino acid type information. The prediction results using SEQ are comparable to or better than those of other structure-based features. Most current prediction methods need homology information, for example, sequence conservation from PSI-Blast, and require the existence of sequence or structure similar proteins. SEQ and STR are calculated from single-protein structure and do not require any homology information. They may be further applied to the detection of enzyme function-related sites, like protein ligand binding site, metal binding site, or protein-protein interaction hotspot residues.


Professionalism is defined as the conceptualization of obligations, attributes, interactions, attitudes, and role behaviors required of professionals in relationship to individual clients and to society as a whole. Professionalism attributes include knowledge, spirit of inquiry, accountability, autonomy, advocacy, innovation and visionary, collaboration and collegiality, and ethics. The study assessed level and attributes of professionalism in nursing in Mekelle, Tigray, Ethiopia.Institutional based cross sectional study supplemented by qualitative design was employed. Self administered semi structured questionnaire developed from RANO guideline was used. The FGD guideline was developed from different literatures. Data was analyzed using SPSS 16.0. Descriptive statistics and significance was checked at p < 0.05. Professionalism was measured using ANOVA. Qualitative of data were analyzed using coding technique. Written informed consent was obtained from the nurses and confidentiality was assured for all the information provide.The mean scores for the nurses in Mekelle public hospitals on the professionalism were 140.50, knowledge (25.06), followed by ethics (25.00). The attitudes of respondents on professionalism were at high, moderate, low and very low level. Pearson product–moment correlation analysis revealed small yet significant associations among several professionalism attributes and characteristics of nurses in Mekelle Public hospitals. Age of respondents and work experience were significantly correlated with total professionalism. Work setting in Mekelle hospital was significantly associated with professionalism. Depending on FGD, the major factors were workload, had no vision, FMOH did not focused nursing as a profession, Weakness of the Ethiopian Nursing Association, lack of life insurance as well as the Health professionals and society’s views of the profession.Nurses with longer years of experience and the older respondents had significantly related with professionalism. Nurses who join professional organizations had high score on professionalism; and nurses working in Military Hospital had high score of professionalism. Nursing is autonomous and collaborative care of individuals of all ages, families, groups and communities, sick or well and in all settings. Nursing includes the promotion of health, prevention of illness, and the care of ill, disabled and dying people .Professionalism is a multi-dimensional concept; there is no one simple, generalizable definition, or how to assess it. We can, however, assess professionalism by considering its individual , inter-personal  and societal dimensions , and the interactions amongst these dimensions .Professionalism is defined as the conceptualization of obligations, attributes, interactions, attitudes, and role behaviors required of professionals in relationship to individual clients and to society as a whole ,4.Nursing professional practice is a commitment to compassion, caring and strong ethical values; continuous development of self and others; accountability and responsibility for insightful practice; demonstrating a spirit of collaboration and flexibility . Nurses The professional status of nursing often is subjected to both internal and external debate. Historians, sociologists, and nurses themselves struggle to determine whether professionalism is present or absent in the occupation called nursing . For manStudy that assessed the levels of professionalism and examined factors associated with professionalism among Korean American registered nurses (RNs) used Hall’s Professionalism Inventory (HPI) scale. Current position in nursing, current employment status, work setting, total years of nursing experience, total years of nursing experience in the United States, location of final degree attainment, and duration of nursing education in the United States were associated with the level of professionalism among Korean American RNs .The Ethiopian Nursing Association (ENA) was formed in 1952 E.C as a member of the health professional council involved in registration &licensing of health professionals in Ethiopia. However, In Ethiopia, there was no published studies describing on professionalism in nursing designed to measure professionalism among nurse’s working in hospitals. The objectives of this study were to assess the factors that influence professionalism in nursing. The outcomes of this assessment would help ENA and FMOH in drafting policies and guiding principles of nursing professionalism in Ethiopia as well as for nurses to confirm their professional status and to examine demographic, experiential, and educational factors associated with professionalism.Permission was obtained from Addis Ababa University College of Health Science School of medicine Department Of Nursing and Midwifery Institutional Review Board (IRB) for approval. Following the approval by IRB, Official letter of co-operation was written to concerned bodies by the Department of nursing and midwifery AAU. Written informed consent was given to nurses and confidentiality assured for all the information provided.A cross sectional quantitative study design supplemented by qualitative was employed to measure level of professionalism and examine factors associated with professionalism among nurses working in Mekelle public Hospitals. Simple random sampling was used to select sample of 210 nurses. Data were collected using questionnaire adapted from RANO guideline. The sampling frame consisted of 400 clinical nurses via a self administered questioner. The sample size was calculated using single population proportion formula with confidence level of 95% and 5% significance level. Since the total population is less than 10000, using correction formula the final sample size become 210. Simple random sampling technique was used to select the 210 nurses from the four public hospitals.The data were collected by self administered structured questionnaire which had two parts. Part I socio demographic variables and part II, the attributes of professionalism in Nursing.Four focus Group Discussions were conducted among nurses in the four hospitals to help the self administered questionnaire and to provide information on the main factors affecting professionalism. The method for the selection of the nurses for FGD was purposive sampling. In order to get detail information within the group, they were structured by department head and year of working experience: In each FGD the number of participants was 5–10 in number. Each discussion was 30 minutes–1 hour.The questioner was developed from RNAO guideline, which contains likert scale questions prepared in English. The questionnaire was validated by experts on the profession and pre test was done also to assess the reliability of the questionnaire. The Likert scale responses allow subjects to describe how well their opinions and attitudes about nursing agree with the item statements . A 34-item scale was used to measure a total score for professionalism and the eight attributes of professionalism in five subscales . Scores for the entire scale may range from 34 to 170, with higher scores indicative of professionalism. In addition to the RANO, questions were asked to elicit demographic characteristics. The demographic questions included age, gender, marital status, religion, and year of nursing experience, professional organization membership, and work setting. FGD was prepared to supplement the quantitative data which was prepared open ended questions.Data were entered into a database using Epi Info and analyzed through the Statistical Package for the Social Sciences software version 16 (SPSS 16). Bivariate analyses and multiple logistic regression models using enter method and leveling professionalism and its attributes using mean and standard deviation, (above mean high and below mean low);and for continuous variables categorical and quarter method was used to examine factors associated with professionalism in nursing. P-value less than .05 was defined as statistically significant.Descriptive statistics were utilized to describe characteristics of the respondents and to assess the levels of professionalism. Descriptive statistics like frequencies, percentages, means, SDs, and ranges were used to describe study subjects. Inferential analyses including t-tests variance (ANOVA) and Correlation were used to determine differences in professionalism and its attributes, Pearson product–moment correlation to identify factors correlated with professionalism.The FGD was analyzed manually. First the information was transcribed by arranging notes according to forwarded question. Then the data was grouped based on thematic frame works. The themes were workload, had no vision, FMOH did not focused nursing as a profession, Weakness of the Ethiopian Nursing Association, lack of life insurance as well as the Health professionals and society’s views of the profession.Nearly half, 123(58.57%) were females. The mean age of the respondents was 32.4 years (SD = 8.42) and an average work experience was 10.35 years (SD =9.2) in nursing. With their educational status half of the respondents, 108(51.4%) currently possess BSc degree in Nursing, 101(48.1%) diploma, while only one (0.48%) had masters degree . Mean scores for the attributes Knowledge 25.06), ethics (25.0), and Advocacy (16.8) were highest, while for the attributes autonomy (11.98), innovation and visionary (11.75) were lowest  than did nurses working in Ayder Referral Hospital (138.9), Quiha (mean = 141.2) and Mekelle hospitals (mean = 140).Mean scores of professionalism has also shown variation against working experiences. Nurses who worked for 20 or more years had higher scores than those with = <10 years M = 139.46) and 11–20 years of working experience , 41.9% (n = 88), 31.9% (n = 6 7), 13.3% (n = 28) respectively , lack of refreshment courses to upgrade knowledge, work load, lack of ENA, had no respect with HPs and the society, had no life insurance, FMOH not focus on professionalism in nursing, had clear job description and no vision. This all makes the nurses to have low attitude towards professionalism.AAU: Addis Ababa University; ENA: Ethiopian Nursing Association; EB: Ethiopian Birr; FGD: Focus Group Discussion; FMOH: Federal Minister of Health; HO: Health Officer; HPs: Health Practitioners; HPI: Hall’s Professionalism Inventory; IRB: Institutional Review Board; ICN: International Council of Nurse; NP: Nursing Practitioners; PI: Principal Investigator; RNs: Register Nurses; RNAO: Registered Nurses’ Association of Ontario; US: United States.The authors declare that they have no competing interest.AF has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. AD has been involved in drafting the manuscript or revising it critically for important intellectual content. KG has given final approval of the version to be published. AZ has been involving in revising the draft. GY has been contributing in designing and analyzing the data. Finally, all authors read and approved the final manuscript.Atsede Fantahun, Msc in Adult Health Nursing, Lecturer in Mekelle University.Asrat Demessie, Assisstant Professor and President of Nursing Association.Kahsu Gebrekirstos, Msc in Child Health Nursing, Lecturer in Mekelle University.Ayalnesh Zemene, Msc in Maternity and Reproductive Health, Lecturer in Mekelle University.Gebre Yetayeh, Msc in Adult Health Nursing, Lecturer in Mekelle University.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6955/13/10/prepub


In two experiments, we investigated the impact of spatial attributes on therepresentation acquired during a serial reaction time task. Two sequences wereused, in which structural regularities occurred either in the horizontal or inthe vertical locations of successive stimuli. After training with the dominanthand, participants were required to respond with the non-dominant hand to eitherthe original sequence or to a mirror-ordered version of the original sequencethat required finger movements homologous to those used during training. Weobserved that a difference in reaction times between the two transfer conditionswas smaller in the vertical sequence than in the horizontal sequence. Thispattern of results was independent of whether three fingers (Experiment 1) wereused or only one finger (Experiment 2) was used for responding. This resultsuggests that perceptual and motor learning mechanisms may be weighteddifferently depending on the context in which the stimulus is presented. In serial reaction time (SRT) tasks, participants respond to sequences of stimuliwith sequences of corresponding responses. Reaction times (RTs) typically decreasemore quickly in response to structured sequences than to random sequences , which sDespite much progress in this research area over the past few decades, the questionof what people learn when producing movement sequences remains controversial.According to one view, performance benefits during structured sequences resultbecause people learn the patterns of the stimulus sequences .Other scrowdingeffect, which occurs when a target becomes more difficult to perceive whenit is embedded in adjacent distractors. Feng, Jiang, and He , can be acquired simultaneously cf. . For insAgainst this background, we introduced conditions that selectively affected therelative salience of either the horizontal or the vertical stimulus dimension. Arepetitive subsequence of three elements was embedded in a fixed order of ninetwo-dimensional spatial positions. The subsequence was exclusively related to theposition order of the stimulus either on the horizontal or on the verticaldimension. Thus, we varied the relative amount of regularity along the two dimensions while keeping all other stimulus properties constant. Twoquestions were examined in the present study. First, we sought to determine whetherperceptual advantages of horizontal processing over vertical processing wouldenhance an individual’s ability to learn the perceptual structure of asequence . In particular,we wanted to explore whether the learning of the sequence of two-dimensionalpositions of stimuli and/or of response keys might benefit if the horizontallocation of each stimulus were highly predictable.Perceptual and motor components of learning were accessed by means of intermanualtransfer cf. . We follParticipants performed an SRT task, in which they responded to circular locationsarranged in a 3 × 3 matrix by pressing assigned keys on a numerical keypad withtheir index, middle, and ring fingers. After an initial practice block, a fixedfirst-order conditional sequence of nine elements was repeatedly presented. Thecritical manipulation was related to the redundancies in the stimulus sequence. Onegroup of participants practiced a sequence that could be parsed into threesubsequences, each with three elements presented in the same succession of locationsin the horizontal dimension . That is, the order ofright, left, and middle circle positions was repeated three times in thenine-element sequence. The second group of participants practiced another sequence,which was identical to the horizontal sequence in the statistical and the relationalstructures. However, it contained vertical regularities . After practicing with the dominant hand, participants had to perform theSRT task with their non-dominant hands. In one condition, participants responded tothe original sequence of stimuli (and of response keys) with an unpracticed patternof finger movements . In another condition, the stimulussequence was modified to reverse the left and right targets around the verticalmidline leading to the response sequence, which involved finger movements homologousto those used during training (mirror condition). Accordingly, participants had torely on a sequence of homologous finger movements by responding to a changedstimulus sequence. As a consequence of more effective perceptual learning, weexpected better intermanual transfer of the horizontal sequence, compared with thevertical, in the parallel condition. In the mirror condition, in contrast, thevertical sequence might be better transferred to the untrained hand than thehorizontal sequence due to greater sequential motor knowledge.Mage = 21.25). Twenty-six participants werepredominantly right-handed and the remaining two were predominantlyleft-handed.Twenty-eight undergraduate students of the University of Würzburgparticipated in the study to partially fulfill their course requirements.They gave their informed consent to engage in the procedures. The sample wascomprised of 17 females and 11 males between the ages of 19 to 28 years. In each trial, one of the nine circles was shaded toindicate the current stimulus location, and participants had to respond asquickly and accurately as possible to this stimulus see . ParticiThe experiment consisted of 17 blocks, each consisting of 162 trials.Participants responded in the first 14 blocks using their dominant hand andin the last three intermanual transfer blocks with their nondominant hand.In the first, 12th, and 16th blocks, pseudo-random sequences of stimuli werepresented to establish baseline blocks. These sequences were random with theconstraint that the whole sequence of nine positions was completed before another repetition began. Moreover, immediaterepetitions of stimuli were avoided to ensure high comparability with theregular sequences (see below).Two nine-element first-order conditional sequences were used as the primarystructured sequences in the remaining training blocks and completed usingthe dominant hand. These sequences were also completed in the intermanualtransfer blocks using the nondominant hand. The Sequence Type constituted abetween-subject factor. Fourteen participants were randomly assigned to oneof two experimental groups.horizontaldimension. As shown in The first group responded to the sequence shown in verticalregularities. In this group, the “below-above-middle” serieswas repeated three times, and the location succession in the horizontaldimension was complex . Thus, this manipulation entailed sequences that had exactly thesame statistical structure without differing in the relational structure.The sequences only differed by the introduction of either vertical orhorizontal dimensional redundancies.During the intermanual transfer phase of the experiment, three differentblock types were presented. Participants responded to the same sequence ofstimuli that they had previously practiced , to themirrored version of the original sequence (mirror transfer), and to apseudo-random sequence (see above). To avoid a possible influence of themirrored transfer on the parallel transfer blocks (and vice versa) andpossible serial position effects, the succession of these three blocks wasarranged to ensure the random block always occurred between the other twoblock types. This order of blocks was counterbalanced acrossparticipants.error(“Fehler”) appeared on the monitor. Subjects receivedinformation about the mean RT of the previous responses at the end of eachblock. The RT difference between Blocks 13 and 14 was used as a measure ofoverall sequence learning, while the amount of intermanual transfer wasassessed by comparing the performance in the last training block before thetransfer phase (14) to the performance in the parallel and mirror transferblocks.The latency between the onset of the stimulus presentation and the key strokewas defined as the RT. As soon as the participant pressed a key, the nextstimulus was presented. The refresh rate of the monitor was approximately100 Hz; thus, a response-stimulus interval of ~10 ms was used. When aresponse was incorrect, the German word for To encourage subjects to follow the finger-key alignment, we asked them topress the center key with their middle fingers to start the blocks. Eachregular block began at a randomly determined position in the nine-elementsequence. After completing the SRT task, participants were debriefed aboutthe presence and length of the sequence and were asked to recall thesequence. More specifically, they were asked to fill nine empty circlearrays by beginning at any position in the sequence. This recollection taskwas used as a test of sequence awareness.RTs from error trials (3.55 %) were excluded from the analysis. Moreover,responses that were more than three standard deviations above the mean RT, asdetermined separately for each participant and each block, were consideredoutliers and discarded from further analyses (1.93 % of responses). In theremaining trials, we computed median RTs for each subject and block of trials.The mean median RTs for each sequence and block are shown in SD = 59.48) for the horizontalsequence and 234 ms (SD = 61.60) for the vertical. Thesedifferences were significant, t(13) = 14.92, p< .001, and t(13) = 14.23, p < .001, andindicative of structure-specific learning. The difference between the twoconditions was not significant, t(26) = 0.13,p = .902.The initial levels of performance achieved in the first practice and in the next11 training blocks were comparable in the horizontal and in the verticalconditions. We calculated the individual differences of RTs between Block 13 andBlock 14 as a measure of overall structure-specific learning. The meandifferences were 237 ms  = 94.62, p < .001, partial η2 =.784.More importantly, it revealed a significant Transfer Type × Sequenceinteraction, F = 6.23, p = .019,partial η2 = .193. As shown in To assess the completeness of the intermanual transfer, the RT differencesbetween the intermanual transfer blocks, in which the original sequence or its mirrored version (mirror condition) were presented,and the last training block  were computed. An analysis ofvariance (ANOVA) performed on these transfer costs with the Sequence as thebetween-subjects factor and the Transfer Type as the within-subjects factorrevealed a significant main effect of the transfer type, t(26) = 0.88, p = .387, orthe mirror transfer, t(26) = 1.18, p =.251.Additional analyses computed for each transfer condition, however, did notindicate significant differences between the two sequences for either theparallel transfer, t(26) = 0.53, p =.602. To test whether awareness of the sequence affected the observed results = 0.88,p = .364, partial η2 = .059, but it wassignificant for the explicit group, F = 7.31,p = .022, η2 = .422.We scored participants’ performance in the post-experimental recall taskby determining the maximum number of sequence elements that were reproduced inthe correct order. The horizontal sequence was associated with a mean of 5.4correctly reproduced sequence elements, while 4.9 positions were recalled in thevertical sequence condition, ultscf.  we repeaPerformance was generally better for the parallel transfer than for the mirrortransfer. This result supports findings from several previous reports e.g., and indiSimple effect tests did not reveal significant results, and the observed patternof results proved to be more pronounced in participants who possessedconsiderable explicit knowledge; thus, further research is necessary to betterevaluate possible conclusions. One possible reason for the observed interactionmay be related to the setup used in Experiment 1. Specifically, using threefingers to respond, as well as the applied key-finger assignment, may limit thevalidity and generalizability of the results. For instance, using three fingersmay reinforce the relative salience of the horizontal dimension; this bias maybe strengthened by the horizontal regularities. The assignment of the fingers tothe three columns of the keypad may also differentially impact performance inthe parallel and mirror transfer conditions depending on the sequence type.Because movement trajectories of each finger are more compatible with theregularities of the vertical sequence than with those of the horizontalsequence, the vertical condition may be associated with a stronger bias towardsresponse-based learning. Furthermore, the relation between the introducedredundancies and the finger succession is not equal in both sequence conditions.With the horizontal sequence, the “right-left-middle” successionin the stimulus sequence corresponds to the succession “ring finger-indexfinger-middle finger”. No such relation is evident for the verticalsequence. Finally, Richard and colleagues  recentlyIn Experiment 2, we aimed to replicate and extend the results of Experiment 1. Toevaluate the extent to which the use of multiple fingers and of a respectivekey-finger assignment may account for the pattern of results observed in Experiment1, in Experiment 2 the participants were asked to respond with only their indexfingers. All other manipulations remained the same as in the first experiment. Ifthe difference between the parallel and mirror transfer costs were reduced for thevertical sequence, compared with the horizontal sequence, then this interactionwould not be attributable to such specific factors as the number of effectors andthe key-finger assignment.The methods in Experiment 2 were nearly identical to those of Experiment 1, withthe few differences described below.Mage = 23.32 years; age range of 19-39years). None of these students had previously participated in Experiment 1. Theyprovided their informed consent and received course credit at the end of theexperimental session. Twenty-six participants were predominantly right-handed,and two participants were predominantly left-handed.Twenty-eight students of the University of Würzburg participated  and outliers (2.23%) were excluded from analyses.The mean median RTs for the remaining trials are illustrated in SD =68.11) for the horizontal sequence and 217 ms (SD = 72.79) forthe vertical sequence; t(13) = 10.75, p<.001, for the horizontal condition; t(13) = 11.13,p < .001 for the vertical condition. The differencebetween the two conditions was not significant, t(26) = 0.79,p = .437. Moreover, we conducted an ANOVA to analyze theintermanual transfer costs. The Sequence Type served as the between-subjectsvariable, and Transfer Type served as the within-subjects factor, and the RTdifferences between Block 14 and the parallel and mirror transfer blocks wereused. The results yielded a significant main effect of transfer type,F = 172.37, p < .001, partialη2 = .869, and a significant interaction between TransferType and Sequence Type, F = 10.46, p =.003, partial η2 = .287. As shown in t(26) = 1.56, p = .130, for the paralleltransfer and t(26) = 1.12, p = .273, for themirror transfer.As shown in t(26) = 0.37, p = .711. We alsorepeated the main analysis of the intermanual transfer costs for two subsamplesof participants, which were grouped by the median of elements that werecorrectly reproduced. Similar to the results of Experiment 1, a significantTransfer Type × Sequence interaction was present in participants with ahigh degree of explicit knowledge (> 8 elements), F =16.09, p = .002, and η2 = .594. In contrast,the interaction was not significant in the group with less explicit knowledge (8 elements), F = 0.79, p = .389, andη2 = .057.In the post-experimental recall task, the mean number of correctly reproducedsequence elements was 6.7 for the vertical sequence and 7.1 for the horizontalsequence, The results of Experiment 2 indicate that, as in Experiment 1,participants’ responses were slower in the mirror condition than in theparallel condition. More importantly, a significant Sequence Type ×Transfer Type interaction was observed. The difference between the parallel andmirror transfer costs was smaller for the vertical sequence than for thehorizontal sequence. This interaction pattern was also evident in participantswith a high degree of explicit knowledge. Thus, the main results of Experiment 1were replicated. Therefore, specific factors like the number of fingers or thefinger-key assignment cannot account for the observed interaction between thedimension of spatial redundancies and the type of intermanual transfer.We investigated the influence of visual stimulus characteristics on the nature ofrepresentations acquired during a perceptual-motor task in two experiments. Theprimary question of interest was whether the amount of motor and perceptualknowledge depends on spatial regularities in the horizontal dimension versus thevertical dimension. In one condition, the horizontal positions of stimuli were morepredictable than the vertical positions . In another condition,the vertical stimulus dimension was more redundant . We predicteda better intermanual transfer of the horizontal than of the vertical sequence in theparallel condition and predicted a reversed pattern in the mirror condition. Weobserved a difference in the intermanual transfer costs between the parallel and themirror condition that depended on whether horizontal or vertical regularities werepresent in the stimulus sequence. This difference in transfer costs was smaller forthe vertical sequence than for the horizontal sequence. However, we did not findsignificant differences between the two sequence conditions when the two transferconditions were considered separately, although mean values indicated a trend in theexpected direction. Thus, although the data allow only restricted conclusions, theresults suggest that perceptual learning mechanisms may be more sensitive to thehorizontal dimension of the sequence structure than to the vertical dimension and/orthat motor learning may be more responsive to the vertical structure of asequence.The observed differences between parallel and mirror transfers for the horizontalsequence might be due to more effective processing of the horizontal stimulusfeatures compared with the vertical stimulus features. As mentioned in theIntroduction, there is evidence that perception may benefit more if stimuli arearranged along the horizontal meridian of the visual field than if they are arrangedalong the vertical meridian. Such a benefit for horizontal processing is notimplausible because most of the relevant visual information related to our dailyactivities such as reading, walking, or driving is allocated along the horizontaldimension. Thus, as a result of ecological constraints, the visual system might bemore strongly aligned with the horizontal than with the vertical dimension cf.. StructuThe observed difference between the two sequence conditions is also compatible withthe assumption that in the vertical sequence, where perceptual learning mightrequire more effort, subjects relied more heavily on effector movement sequencesthan in the horizontal condition. Because the overall learning performance wascomparable in both sequence conditions, the results may suggest that subjectscompensated for perceptual learning disadvantages by weighting motor informationmore heavily. This is expected if one assumes that multiple independent learningprocesses operate in parallel to optimize the performance and points to a highadaptivity of learning behavior.The overall results provide evidence supporting the idea that spatial regularitiesaffect the nature of representations acquired during perceptual-motor learning.Moreover, the results seem to align well with a number of previous reports thatsuggested task conditions may modulate learning mechanisms . OurresThese conclusions are tentative and have to be considered with caution due to anumber of factors that may limit functional interpretations. For instance, theperformance in the mirror transfer condition may not necessarily reflect the amountof motor learning. According to the motor hypothesis, which served as our premise,activation of homologous movements may account for the mirror transfer. Suchrepresentations may operate on the level of hand postures cf. ; thus, tMoreover, the observed differences in responding to stimuli with horizontal andvertical regularities may be relative rather than absolute. As suggested in theresearch of the spatial stimulus-response compatibility effects e.g., , many reFurthermore, we relied on a well-established assumption that local associations areformed between successive stimuli, successive responses, and/or successive responselocations. Provided that this assumption is correct, the results of the mirrortransfer condition are unambiguous. However, if more abstract perceptual and/ormotor know-ledge has been acquired during the experiments , then a possible benefit of the vertical sequence over the horizontalsequence in the mirror condition may be related to the differences in the fit ofthis knowledge to the features of the mirrored sequence. While the abstract regularstructure of the vertical sequence is maintained after mirroring , the learned “right-left-middle” successionof the horizontal sequence is not more present after mirroring. Thus, the greaterdifference between the parallel transfer and the mirror transfer for the horizontalsequence may be partially attributed to this loss of learning and, consequently, dueto the impossibility of applying the mentioned type of knowledge on the newsequence.It should also be mentioned that participants did not acquire significantly moreexplicit knowledge in the horizontal condition, which is associated with moreperceptual learning. Perceptual learning is often assumed to be explicit, whilemotor learning is typically seen as implicit cf. . We assuFinally, it is unclear how eye movements may have affected the current results. Asequence of stimuli may be accompanied by a sequence of eye movements. Accordingly,learning may also be based on motor information of the ocular system, instead of, orin addition to, visual information cf. . If so, To conclude, the results of this study suggest that the content of the memory tracegenerated in perceptual-motor tasks may vary depending on the context of thestimuli. Visual stimuli containing redundant information on the horizontal dimensionappear to facilitate perceptual learning mechanisms. Vertical redundancies, incontrast, seem to enhance a motor component of learning. However, given thecomplexity of sensorimotor interactions and the relatively small size of theobserved effects, further studies are needed to evaluate the validity and generalityof these conclusions. Given some weaknesses in the method of intermanual transfer,other paradigms could be applied to replicate and extend the current results. Forinstance, a dissociation between stimulus-based and response location-based learningwith another type of transfer task cf.  may prov


This longitudinal study examined multiple factors that influence survival in a cohort of Alzheimer patients followed over two decades.Time to death after symptom onset was determined in 641 probable AD patients who were evaluated annually until death or loss to follow-up, and information was entered into a longitudinal database. Date of death was available for everyone including those eventually lost. Baseline variables included age, sex, race, disease severity, a calculated index of rate of initial cognitive decline from symptom onset to cohort entry (pre-progression rate or PPR), years of education, and medical comorbidities . Multivariable Cox proportional hazard regression analysis was used to analyze the baseline and/or time dependent association in Mini-mental Status Exam (MMSE) severity, Physical Self Maintenance Scale (PSMS), Persistency Index (PI) of exposure to antipsychotic and antidementia drugs, and psychotic symptoms  with mortality.Baseline covariates significantly associated with increased survival were younger age (p = .0016), female sex (p = .0001), and a slower PPR (p < .0001). Overall disease severity at baseline, medical comorbidities, and education did not influence time to death. Time-dependent changes in antipsychotic drug use, development of psychotic symptoms, antidementia drug use, and observed MMSE change were not predictive. In the final model the only time-dependent covariate that significantly decreased survival was worsening of functional ability on the PSMS .In this large AD cohort survival is influenced by age, sex, and the development of functional disability during follow-up. The most important predictor of mortality was a faster rate of cognitive decline at the initial patient visit (PPR). The currently available antidementia drugs do not prolong survival in Alzheimer patients. Life expectancy in people with Alzheimer's disease (AD) is, overall, shorter than what is expected in age-matched, cognitively normal seniors and may be influenced by age, disease severity, general debility, extrapyramidal signs, gender, and race or ethnicity -4. AntipSince 1993, five drugs have been marketed in the US for the treatment of AD . Antidementia drugs have been proven to mitigate the symptoms of AD but their influence on long-term course and life span is not established. Recent observational studies suggest that cognitive and functional benefits continue over many years for patients who persist in their treatment, beyond the relatively short duration of benefit evident in clinical research trials . AntidemInformed consent was received from all patients involved in the study. The patients were evaluated at the Baylor College of Medicine Alzheimer's Disease and Memory Disorders Center. The study began in 1989 and enrolled 1,833 patients with dementia as of 31 December 2005 (censoring date). All members of this community-based cohort agreed to participate in a database approved by the institutional review board of the Baylor College of Medicine. Six hundred forty-one participants met the established criteria for probable AD as determined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association)  and wereCumulative drug exposure to antidementia drugs (cholinesterase inhibitors or memantine or both) or antipsychotic drugs  was determined from the onset of symptoms. The onset of first symptoms is estimated by a physician using a standardized algorithm to the nearest half-year . Start aBaseline variables were age, sex, race (white versus non-white), disease severity based upon Mini-Mental Status Examination (MMSE) score , years oWe used a time-dependent mechanism to assess the impact of changes in cognition measured by the MMSE, basic activities of daily living measured by the Physical Self-Maintenance Scale (PSMS) , time-deP value of not more than 0.05), and hazard ratios for significant covariates were determined in the final model.Time to death for all-cause mortality was evaluated by multivariable Cox proportional hazard regression analysis with stepwise selection process to evaluate baseline and time-dependent change in covariates or risk factors. All analyses were performed by using SAS version 9.2 . Logistic regression was applied to determine the covariates significantly associated with survival , and there were 352 deaths. The mean (standard deviation) follow-up time after the baseline visit to censoring or death was 3.0 (1.94) years; overall, the patients in this cohort returned to the clinic for an average of 2.4 (1.64) visits. The cohort predominately was female (68%) and white (87%). Many participants were already using antidementia drugs prior to the initial visit (42.6%). The average baseline MMSE score was 19.5 (6.64), and the range was 0 to 30; the average baseline PSMS score was 7.9 (3.05), and the range was 6 to 25 , male gender , and faster rate of cognitive decline at baseline as measured by the PPR category - hazard ratios were 0.45 (slow versus rapid), 0.75 (slow versus intermediate), and 0.59 (intermediate versus rapid), and 95% CIs were 0.30 to 0.66, 0.54 to 1.04, and 0.43 to 0.82, respectively - were significantly associated with increased risk of death , but the mortality between intermediate and fast progressors did not reach significance in that study  [Like the investigators in a large population study that was performed in the UK and that used multivariable adjustment , we foun = 0.24) . The preIt is often presumed that medical comorbidities should also influence survival with AD. Diabetes, hypertension, hyperlipidemia, coronary disease, and cerebrovascular disease at baseline did not influence survival in this cohort. This result was similar to that of another study  and coulAlthough studies suggest that atypical antipsychotic drugs increase risk of death in older patients with dementia  and the The majority of caregivers for patients with AD identify quality of life and preservation of patient cognition and function as being the most important benefits to be derived from therapy . PreviouIn this large AD cohort, survival is influenced by age, sex, and a calculable intrinsic rate of decline. Disease severity at baseline, vascular risk factors, and years of education did not influence time to death. Time-dependent changes in antipsychotic drug use or development of psychotic symptoms, antidementia drug use, and observed MMSE score change were not predictive. The only time-dependent covariate that significantly decreased survival was worsening of functional abilities. Currently available antidementia drugs provide cognitive and functional benefit yet do not prolong overall survival in patients with AD.AD: Alzheimer's disease; CI: confidence interval; MMSE: Mini-Mental Status Examination; PI: Persistency Index; PPR: pre-progression rate; PSMS: Physical Self-Maintenance Scale.In the past five years, SDR has received investigator-initiated grant funding from the Forest Laboratories, Inc.  and honoraria from the Forest Laboratories, Inc, Pfizer Inc , and Novartis  for speaking at non-CME  events. In the past five years, RSD has received honoraria for serving as a consultant to Novartis and Pfizer Inc in regard to general drug development and honorarium from the Forest Laboratories, Inc for attending an advisory meeting; her institution has received payments from Janssen Alzheimer Immunotherapy  and Pfizer Inc for performing clinical trials on unmarketed drugs, for which she is the principal investigator. The other authors declare that they have no competing interests.SDR participated in research design and analysis of data and wrote the manuscript. WC and EJD performed data analysis. VNP participated in revision of the manuscript. RSD participated in obtaining funding, analysis of data, and revision of the manuscript. All authors read and approved the final manuscript.


Primary adrenal lymphoma (PAL) is an extremely rare subtype of extranodal non-Hodgkin’s lymphoma. Some researchers have reported some of the characteristics of PAL and its association with poor prognosis; however, the clinicopathological features of PAL remain to be elucidated.From 2008 to 2011 we experienced seven cases of PAL in our institutions. We retrospectively analyzed the clinical and pathological features of these patients.The patients ranged in age from 50 to 85 years, with a median of 71 years. The overall male:female ratio was 6:1. All seven patients were diagnosed with diffuse large B-cell lymphoma (DLBCL) pathologically. Bilateral adrenal involvement was confirmed in five patients. The median largest tumor diameter at diagnosis was 58 mm. The Ki-67 index was generally high (>70%). All patients were treated with rituximab-containing chemotherapy, and central nervous system (CNS) prophylaxis was conducted for three patients. One patient with CNS involvement at the time of the diagnosis also received whole-brain radiation. The overall survival rate at two years was 57% . It is noteworthy that the three patients who received a full course of the rituximab-containing regimen and CNS prophylaxis are currently alive without disease relapse, and that none of the seven patients died due to progression of lymphoma.Primary adrenal DLBCL can be a clinically aggressive disease entity. Rituximab-containing chemotherapy combined with CNS prophylaxis could be a reasonable option for the treatment of PAL; however, analyses of more PAL cases are needed for the establishment of this strategy. Malignant lymphoma primarily arising in the adrenal gland, i.e., primary adrenal lymphoma (PAL), is an extremely rare disease and accounts for less than 1% of all non-Hodgkin’s lymphoma. Around 100 cases of PAL have been reported in the English literature to date; with the exception of a few investigational reports based on several cases, most have been single case reports and literature reviews . These rWe herein analyzed the clinicopathological features and clinical courses of seven cases of PAL encountered at our institutions in recent years; all were pathologically diagnosed as DLBCL and treated with rituximab-containing chemotherapy.From 2008 to 2011 in our institutions, seven cases were newly diagnosed as primary adrenal DLBCL. We thoroughly reviewed their clinical and pathological findings retrospetctively. The clinical features of the patients are shown in Table The mean maximum diameter of the tumor at diagnosis was 58 mm, with a range from 40 to 80 mm. Two patients with unilateral adrenal involvement underwent surgical resection due to an initial suspicion of adrenal carcinoma. On the other hand, the remaining five patients with bilateral adrenal involvement were diagnosed by needle biopsy. Four bilateral cases  had paraaortic lymph node lesions; all of which were smaller than the adrenal lesions. These patients were stratified to be in a high-risk group by the International Prognosis Index (IPI) [18F] fluoro-2-deoxy-d-glucose (FDG) was performed in all cases. The uptake of FDG in the adrenal tumor was confirmed in all cases, and in four cases, uptake was also detected in adjacent paraaortic lymph nodes. No other lesions with significant FDG uptake were detected in any of the patients. Uptake foci at the adrenal tumors were revealed in all cases, and the maximum standardized uptake values (SUVmax) in each case were generally high . The SUVmax seemed to be higher in the cases with bilateral adrenal infiltration  than in the cases with unilateral infiltration . In addition, the values of the SUVmax in adjacent lymph nodes were all lower than those in the adrenal tumors. Bone marrow infiltration was not detected in any of the patients.Positron emission tomography (PET) with 2-[Apparent CNS infiltration was not confirmed at the time of diagnosis in any of the cases except in Case 4, in which a brain tumor and bilateral adrenal tumors were detected simultaneously. Both the cerebral and adrenal lesions were biopsied and concluded to have the same histology as DLBCL. In Case 5, multiple cerebral infarctions emerged a month before the patient’s presentation to our institutions. This may have been caused by the infiltration of lymphoma cells toward cerebral vessels, although magnetic resonance imaging of the brain and cytology of the cerebrospinal fluid did not detect any infiltration of lymphoma cells.The serum lactic dehydrogenase (LDH) level was above the normal limits in all cases. The serum level of soluble interleukin-2 receptor (sIL-2R) was also elevated in all six cases in which it was measured. The rapid adrenocorticotropic hormone (ACTH) stimulation test, in which a cortisol level less than 18 – 20 μg/dL at 60 minutes after ACTH challenge is regarded to be a poor response , revealeThe pathological and immunohistochemical findings of all seven cases are shown in Table All patients were treated with rituximab-containing chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab (R-CHOP), with a successful clinical outcome Table . The couAfter the completion of chemotherapy, we assessed the response in each case. CT scans were performed in all cases, and FDG-PET was also performed in some cases . In the five patients who received a full course of rituximab-containing chemotherapy and the additional therapy mentioned above, a favorable clinical outcome  was achieved, and there have been no cases of relapse as of the writing of this manuscript. The other two patients died of complications during the course of chemotherapy . In both cases, no signs of lymphoma progression, such as further elevation of the serum LDH level, were detected within their clinical course after the initiation of chemotherapy.The median survival time of all patients from diagnosis until death or the date of the last follow-up was 24.8 months . No patients experienced a relapse of lymphoma, and none died due to the progression of lymphoma. Both the OS and FFS at two years were 57.1%  subtype and the non-GCB subtype (combining the activated B-cell-like subtype and the type 3 subtype) ; the latet al. recently reported that lymphomas showing intense FDG uptake have an increased capacity for proliferation and rapid growth, which was confirmed by the Ki-67 expression [In addition to the pathological factors mentioned above, some clinical factors for predicting the prognosis of DLBCL have recently been reported. For example, a high sIL-2R level was reported to be associated with a poor prognosis among patients with DLBCL who were treated with R-CHOP . It has pression . In the We successfully treated PAL patients in a tolerable general condition with rituximab-containing systemic chemotherapy and CNS prophylaxis. PAL is frequently treated with cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone (CHOP), or a CHOP-like regimen; however, the prognosis is generally poor ,2. In rePAL with DLBCL histology is a clinically aggressive disease. Rituximab-containing chemotherapy combined with CNS prophylaxis could be a reasonable option for the treatment of PAL; however, further accumulation of clinical experiences, as well as additional research, is necessary to establish the optimal therapeutic strategy for PAL.From 2008 to 2011 in our institutions, a total of 563 patients were diagnosed with DLBCL. We reviewed the records of the patients with newly diagnosed primary adrenal DLBCL. Cases with secondary adrenal involvement and those with human immunodeficiency virus infection were excluded. A total of seven cases were included in this study. All had unilateral or bilateral adrenal tumors, which were the predominant tumors considered to be primary lesions (and were biopsied), while some other lesions, such as paraaortic lymph node swelling or central nervous system lesions, were also detected in several cases. The therapeutic strategy was chosen at the discretion of the attending physicians.All available data, including the clinical presentations, laboratory findings, radiological findings, therapeutic regimens and follow-up information, were evaluated. The staging procedures included a complete physical examination, computed tomography (CT) scans of the neck, chest and abdomen, positron emission tomography (PET) scans and bone marrow biopsy and/or aspiration. This study was approved by the Ethics Committee of each hospital. The procedures performed for the present study were done in accordance with the Declaration of Helsinki.Tissue specimens were fixed in 10% formalin solution, routinely processed and embedded in paraffin. The sections were stained with hematoxylin-eosin for microscopic examination. Immunohistochemical studies were performed using antibodies against CD3, CD5, CD10, CD20, CD45RA, CD79a, BCL2, BCL6, MUM1, Ki-67 and Epstein–Barr virus-encoded small RNA (EBER). For two cases with sufficient materials available, flow cytometry was performed using various monoclonal antibodies against CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD13, CD19, CD20, CD22, CD30, CD45, CD56, TCRαβ, TCRγδ, Igκ and Igλ. Markers that were expressed on more than 20% of the cells were judged to be positive.All statistical analyses were performed using the GraphPad Prism software program . The treatment outcomes were measured by the failure-free survival (FFS) and overall survival (OS). The FFS was defined as the time from initial diagnosis to the first occurrence of progression, relapse after a response or death from any cause. The follow-up of patients not experiencing one of these events was censored at the date of last contact. The OS was measured from the time of the initial diagnosis until death from any cause, with surviving patient follow-up censored at the last contact date. Estimates of the FFS and OS were determined using the Kaplan–Meier method.The authors declare no competing interests.SI, the first author, designed the research project, analyzed the data, reviewed the literature, drafted the manuscript and revised the final manuscript. NF, the corresponding author, designed the research project, contributed to discussions and reviewed the manuscript. AI, RO, YK, YO, JY, OS, JN and OF were in charge of the treatment and follow-up of the patients and collected the patient information. HK interpreted the pathological slides. KI contributed to the discussion and review of the manuscript. RI interpreted the pathological slides and contributed to the discussion and review of the manuscript. HH, the last author, supervised the overall project and contributed to the discussion and review of the manuscript. All authors reviewed and approved the final version of the manuscript.