Hierarchy of simulation models in predicting structure and energetics of the Src SH2 domain binding to tyrosyl phosphopeptides.

Structure and energetics of the Src Src Homology 2 (SH2) domain binding with the recognition phosphopeptide pYEEI and its mutants are studied by a hierarchical computational approach. The proposed structure prediction strategy includes equilibrium sampling of the peptide conformational space by simulated tempering dynamics with the simplified, knowledge-based energy function, followed by structural clustering of the resulting conformations and binding free energy evaluation of a single representative from each cluster, a cluster center. This protocol is robust in rapid screening of low-energy conformations and recovers the crystal structure of the pYEEI peptide. Thermodynamics of the peptide-SH2 domain binding is analyzed by computing the average energy contributions over conformations from the clusters, structurally similar to the predicted peptide bound structure. Using this approach, the binding thermodynamics for a panel of studied peptides is predicted in a better agreement with the experiment than previously suggested models. However, the overall correlation between computed and experimental binding affinity remains rather modest. The results of this study show that small differences in binding free energies between the Ala and Gly mutants of the pYEEI peptide are considerably more difficult to predict than the structure of the bound peptides, indicating that accurate computational prediction of binding affinities still remains a major methodological and technical challenge.     

The conceptualization, formative evaluation, and design of a process for student professional development.

This article describes a process for student professional development and the efforts of faculty over almost 2 decades to conceptualize, formatively evaluate, and refine it. Initiated in 1987, the process underwent numerous changes to address both conceptual and pragmatic concerns derived from faculty and student ad hoc feedback. Currently in place is a process that addresses these concerns while lending itself to effective use among master's level students. The development and iteration of the process is offered as a case for consideration by other educators engaged in similar efforts.     

Therapeutic efficacy of three silver dressings in an infected animal model

The organic salt AgNO3 has been available as a topical armamentarium to the medical arena for centuries and for burns for the past 60 years. Thirty-five (1968) years later, Charles Fox introduced and popularized a new topical agent known as silver sulfadiazine. More recently, several new slow-release silver dressings came to the forefront. Acticoat (Smith & Nephew, Largo, FL) Silverlon (Argentum, Lakemont, GA) & Silvasorb (Medline Industries, Inc, Mundelein, IL). Because the standard of care is to change dressings daily, our study focused in on weekly dressing changes as a cost-containment issue. Sprague-Dawley rats received a standard contact burn (20% TBSA). On day 3, the wound was excised and infected with Pseudomonas aeruginosa and Staphylococcus aureus at 5.0 x 10 cfu/ml. The animals were divided into four groups (n = 5 each group): untreated control, Acticoat group, Silvasorb group, and Silverlon group. The dressings remained on the wounds for 10 days when the wounds were quantitatively assessed. Mean wound counts of the control ranged from 1.2 x 10(5) to 6.5 x 10(5) for P. aeruginosa and S. aureus, respectively. Acticoat dressing counts for both organisms were 0 and 1.8 x 10(3) (median alpha); Silvasorb was 0 and 6.3 x 10(3) and Silverlon was 1.5 x 10(4) x 7.4 x 10(4) (median), Acticoat and Silvasorb were both significantly lower (P < .05) than the control for P. aeruginosa, and Acticoat was significantly lower (P < .05) than the control for S. aureus. Although counts for Silvasorb (M) appear significantly lower than the controls for S. aureus, the numbers were not sufficient to be significant. However, Silverlon did achieve a slight significance. These preliminary data suggest that weekly dressing changes with these new silver dressings are feasible and economically and medically congruous.     

A dog and a "happy person" visit nursing home residents

Recent recognition of the importance of the human-animal bond has led to the proliferation of programs designed to improve the lives of nursing home residents through the use of animals. Because human-human interaction in the nursing home setting is often of an obligatory nature, we wondered if a visit from a nonjudgmental, outgoing, enthusiastic young adult ("a happy person") could elicit the same positive influence as a visit from a nonjudgmental dog. The purpose of this study was to determine if elderly residents of a midwestern nursing home had a preference for the type of visitor (dog vs. person) when both visits were nonobligatory and nonjudgmental. Behaviors were evaluated to determine if one visitor was more likely to influence prosocial behaviors (moving closer, patting, smiling). Six residents were visited by both the dog and the happy person: 5 of 6 completed the final interview. Residents were equally likely to smile at and move closer to both visitors. Residents were more likely to pat the dog. Three residents liked both visits equally: 1 preferred the dog, and 1 preferred the happy person. These data suggest that nonobligatory visits to nursing home residents from a happy person may be as beneficial to the resident as visits from a dog.     

Approach to decreasing emergency department ambulance diversion hours

Analysis between two local Emergency Departments (EDs) suggested an oscillatory phenomenon for ambulance diversion: When one hospital went on diversion it led to a disproportionate flow of ambulance traffic to a neighboring facility that subsequently was forced to go on divert. We hypothesized if one hospital could avoid diversion status, the need for diversion could be averted in the neighboring facility. ED A secured additional resources and made a commitment to no diversion for 1 week. No changes in operations occurred in hospital B. We found no differences in ambulance runs or ED census at either facility comparing the week before, during, and after the trial. There was a dramatic decline in diversion hours from 19.7 to 1.4 and 27.7 to 0 at hospitals A and B, respectively, during the trial period (p < 0.05) compared to the weeks before and after. We conclude that reciprocating effects can be decreased with one institution's commitment to avoid diversion, thus decreasing the need for diversion at a neighboring facility.     

Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes

The clinical and pathological features, including karyotype data and BCL2 protein expression pattern, of follicular lymphoma without a t(14;18)(q32;q21) have not been well defined. We have identified and conducted a detailed analysis of 50 cases with follicular lymphoma who lack the t(14;18). Fluorescent in situ hybridization (FISH) analysis was used to exclude cases with a cryptic IGH/BCL2 rearrangement. BCL2 protein expression level was assessed by immunohistochemistry. The karyotypes were assessed for recurrent sites of structural rearrangement, duplications and deletions on a band-by-band basis, and compared with a large cohort of cases with t(14;18). A distinct pattern of chromosomal alterations was identified in the cases without t(14;18). BCL2 protein overexpression was detected in 33% of 49 tested cases. In this minority, the karyotypes frequently showed increased copies of chromosome 18. The majority of cases (67%) did not show BCL2 overexpression and were characterized prominently by the presence of t(3;14)(q27;q32), implying a role for BCL6. Follicular lymphomas that lack a t(14;18) were segregated into two subgroups with distinct cytogenetic, phenotypic and possibly clinical features: one with BCL2 protein overexpression not related to an IGH/BCL2 rearrangement and a second without BCL2 overexpression. Objective identification of BCL2 expression level as well as BCL2 and BCL6 status by cytogenetic or FISH analysis has potential clinical utility and may yield insights into alternative genetic mechanisms associated with B-cell lymphomas with a follicular growth pattern.     

The BCR-ABL1 kinase bypasses selection for the expression of a pre-B cell receptor in pre-B acute lymphoblastic leukemia cells

The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre-B cells. Comparing genome-wide gene expression profiles of BCR-ABL1+ pre-B ALL and normal bone marrow pre-B cells by serial analysis of gene expression, many genes involved in pre-B cell receptor signaling are silenced in the leukemia cells. Although normal pre-B cells are selected for the expression of a functional pre-B cell receptor, BCR-ABL1+ ALL cells mostly do not harbor a productively rearranged IGH allele. In these cases, we identified traces of secondary VH gene rearrangements, which may have rendered an initially productive VH region gene nonfunctional. Even BCR-ABL1+ ALL cells harboring a functional VH region gene are unresponsive to pre-B cell receptor engagement and exhibit autonomous oscillatory Ca2+ signaling activity. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains. BCR-ABL1 kinase activity is linked to defective pre-B cell receptor signaling and the expression of a truncated isoform of the pre-B cell receptor-associated linker molecule SLP65. Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571. We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre-) B cell receptor.     

Impact of Balance Confidence on Daily Living Activities of Older People with Knee Osteoarthritis with Regard to Balance,Physical Function,Pain, and Quality of Life – A Preliminary Report

Objectives: The objective of this study was to explore the impact of balance confidence on different activities of daily living (ADL) in older people with knee osteoarthritis (OA).

Methods: Forty-seven consecutive participants with knee OA were included in this cross-sectional study. They were divided according to the results of the Activities-specific Balance Confidence (ABC) Scale into a group with a low level of confidence in physical functioning (ABC < 50, n = 22) and a group with moderate and high levels of confidence (ABC ≥ 50, n = 25).

Results: In the ABC < 50 group, the effect of pain on ADL, the physician’s global assessment of the disease, and the Western Ontario and McMaster Universities Osteoarthritis Index scores were significantly higher, while quality of life (Short form-36) was lower compared to the ABC ≥ 50 group. No significant difference was found between the two groups regarding the static and dynamic balance measurements.

Conclusions: Older people with knee OA who were less confident in their daily physical activities had more physical difficulties and a greater effect of pain on ADL, lower quality of life, and a higher physician’s global assessment, but no differences were obtained in balance tests.

Clinical Implications: In people with knee OA, decreased balance confidence is associated with more physical difficulties, an increased effect of pain on ADL, and lower quality of life. An improved awareness of decreased balance confidence may lead to more effective management of older people with knee OA by improving their mobility and QOL through rehabilitation. Furthermore, future research in that direction is warranted.     

Prevalence of mood and anxiety disorder in self reported irritable bowel syndrome (IBS). An epidemiological population based study of women

Background  

Irritable bowel syndrome (IBS) is commonly regarded as a functional disorder, and is hypothesized to be associated with anxiety and depression. This evidence mainly rests on population-based studies utilising self-report screening instruments for psychopathology. Other studies applying structured clinical interviews are generally based on small clinical samples, which are vulnerable to biases. The extant evidence base for an association between IBS and psychopathology is hence not conclusive. The aim of this study was therefore to re-examine the hypothesis using population-based data and psychiatric morbidity established with a structured clinical interview.     

Area-based socioeconomic status and mood disorders: cross-sectional evidence from a cohort of randomly selected adult women

Objective

Data suggest there are established socio-economic disparities associated with mental health although most research has focused on individual-level indicators of socio-economic position. The aim of this study was to investigate the association between mood disorders and area-based socio-economic status (SES), and whether both ends of the SES continuum experienced increased odds for a mood disorder.

Methods

Using a clinical interview (SCID-I/NP), psychiatric history was ascertained in a population-based sample of 1095 women (20–93 years) from the Barwon Statistical Division, south-eastern Australia. SES was determined by cross-referencing residential addresses with Australian Bureau of Statistics 2006 census data for the region and categorised into three groupings of low, mid, and upper SES. The Index of Economic Resources (IER), Index of Education and Occupation (IEO), and Index of Relative Socioeconomic Advantage/Disadvantage (IRSAD) were utilised. Lifestyle factors were self-reported.

Results

For IER, the low SES group had a 2.0-fold increased odds of a current mood disorder compared to the mid group, after adjustment for physical activity and current anxiety (OR = 2.0, 95% CI 1.0–4.1, p = 0.05). This pattern was similarly observed for IEO (OR = 1.8, 95% CI 0.9–3.7, p = 0.1) and IRSAD (OR = 1.6 95% CI 0.8–3.4, p = 0.2). Those within the upper SES group showed a non-significant increase in the odds of a current mood disorder compared to the mid-group; IER (OR = 1.4, 95% CI 0.8–2.5, p = 0.3), IEO (OR = 1.2, 95% CI 0.07–2.3, p = 0.5) and IRSAD (OR = 1.2, 95% CI 0.7–2.1, p = 0.6).

Conclusions

Women in the low SES category were most likely to have a mood disorder. Furthermore, being in an upper SES group may not be protective against mood disorders.