Canadian Association of Radiologists Musculoskeletal System Diagnostic Imaging Referral Guideline.

The Canadian Association of Radiologists (CAR) Musculoskeletal System Expert Panel consists of musculoskeletal radiologists, a family physician, a sports and exercise medicine physician, emergency medicine physicians, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 25 musculoskeletal clinical/diagnostic scenarios, a systematic rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for 1 or more of these clinical/diagnostic scenarios. Recommendations from 41 guidelines (50 publications) and contextualization criteria in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for guidelines framework were used to develop 124 recommendation statements across the 25 scenarios related to the evaluation of the musculoskeletal system. This guideline presents the methods of development and the recommendations for imaging in the context of musculoskeletal pain, infection, tumors, arthropathies, metabolic bone disease, stress injuries, orthopedic hardware, avascular necrosis/bone infarction, and complex regional pain syndrome.

Online Profile of Canadian Diagnostic Radiology Residents: Do Residents Alter Their Profile When Applying for Fellowships?

This article was migrated. The article was marked as recommended. Objective: Survey the online profile of Canadian Diagnostic Radiology residents at the University of Alberta and determine whether residents alter it when applying for fellowships, due to the perceived assessment of their profile by Fellowship Selection Committees. Methods: A cross-sectional study was performed by distributing an anonymous questionnaire to 31 residents at the University of Alberta. Descriptive and ANOVA statistical analyses were performed. P-value less than 0.01 was considered statistically significant. Results: 26 questionnaires were completed. The average age was 28.9. 91.4% of residents have Facebook, followed by Instagram (30.4%) and ResearchGate (30.4%). 52.5% viewed their profile at least once daily, although 83.3% make changes to it less than once per month. The profiles were primarily for personal use (72.7%) and none were solely for professional use. 53.8% felt that Fellowship Selection Committees assess their profile and 69.2% were neutral or agreed with this. In anticipation, 70.6% would restrict profile viewership, while 29.4% would change their profile name, predominantly due to the sensitive and personal information. 92.8% would make the changes at least 2 months prior to the application deadline. There was no statistical difference between age and having a profile (p=0.597), agreement with Fellowship Selection Committees using a resident's profile for selection (p=0.91), how often residents viewed (p=0.827) or changed (p=0.934) their profile. Conclusion: Nearly all Canadian residents at our institution have an online profile and over half view it at least once daily. The majority of residents perceived that their profile is assessed by Fellowship Selection Committees, but are not against it. In anticipation, most residents would alter their profile prior to the application deadline mainly due to the sensitive and personal information.

Medical specialty preferences in early medical school training in Canada.

Objectives: To understand what medical students consider when choosing their specialty, prior to significant clinical exposure to develop strategies to provide adequate career counseling. Methods: A cross-sectional study was performed by distributing optional questionnaires to 165 first-year medical students at the University of Ottawa in their first month of training with a sample yield of 54.5% (n=90).  Descriptive statistics, analysis of variance, Spearman's rank correlation, Cronbach's alpha coefficient, Kaiser-Meyer-Olkin Measure, and exploratory factor analyses were used to analyze the anonymized results. Results: "Job satisfaction", "lifestyle following training" and, "impact on the patient" were the three highest rated considerations when choosing a specialty.  Fifty-two and seventeen percent (n=24) and 57.89% (n=22) of males and females ranked non-surgical specialties as their top choice. Student confidence in their specialty preferences was moderate, meaning their preference could likely change (mean=2.40/5.00, SD=1.23). ANOVA showed no significant differences between confidence and population size (F(2,86)=0.290, p=0.75) or marital status (F(2,85)=0.354, p=0.70) in both genders combined. Five underlying factors that explained 44.32% of the total variance were identified. Five themes were identified to enhance career counseling. Conclusions: Medical students in their first month of training have already considered their specialty preferences, despite limited exposure. However, students are not fixed in their specialty preference. Our findings further support previous results but expand what students consider when choosing their specialty early in their training. Medical educators and administrators who recognize and understand the importance of these considerations may further enhance career counseling and medical education curricula.

The Biomechanics and Optimization of the Needle-Syringe System for Injecting Triamcinolone Acetonide into Keloids.

Purpose. Injecting triamcinolone acetonide (TA) into a keloid is physically challenging due to the density of keloids. The purpose was to investigate the effects of various syringe and needle combinations on the injection force to determine the most ergonomic combination. Materials and Methods. A load cell was used to generate and measure the injection force. Phase 1: the injection force of 5 common syringes was measured by injecting water into air. The syringe that required the lowest injection force was evaluated with various needle gauges (25, 27, and 30 G) and lengths (16, 25, and 38 mm) by injecting TA (40 mg/mL) into air. The needle-syringe combination with the lowest injection force (CLIF) was deemed the most ergonomic combination. Phase 2: comparisons between the CLIF and a standard combination (SC) were performed by injecting TA into air and tap water into a keloid specimen. Intraclass Correlation Coefficient (ICC) and independent t-test were used. Results. Increasing the syringe caliber, injection speed, and needle gauge and length significantly increased the injection force (p value < 0.001). The SC required a maximum force of 40.0 N to inject water into keloid, compared to 25.0 N for the CLIF. Injecting TA into keloid using the SC would require an injection force that was 103.5% of the maximum force female thumbs could exert compared to 64.8% for the CLIF. ICC values were greater than 0.4. Conclusions. The 1 mL polycarbonate syringe with a 25 G, 16 mm needle (CLIF) was the most ergonomic combination. The SC required a substantial injection force, which may represent a physical challenge for female thumbs.

A Comparison of Psychological Response, Body Image, Sexuality, and Quality of Life between Immediate and Delayed Autologous Tissue Breast Reconstruction: A Prospective Long-Term Outcome Study.

BACKGROUND: This is the first study to use generic distress, cancer-specific, and procedure-specific measures to prospectively evaluate psychological responses, body image, sexuality, and health-related quality of life in immediate compared with delayed breast reconstruction. METHODS: Consecutive patients undergoing autologous immediate and delayed breast reconstruction (June of 2009 to December of 2010) completed the Hospital Anxiety and Depression Scale, Body Image Scale, Sexuality Scale, and BREAST-Q preoperatively and postoperatively (6, 12, and 18 months). Linear mixed-effects analyses between each outcome and time point were performed. RESULTS: One hundred six women underwent mastectomy with immediate (n = 30) and delayed breast reconstruction (n = 76). Before reconstruction, 26 percent of patients had abnormal anxiety scores and 9 percent had abnormal depression scores, with no significant differences between groups. Patients awaiting delayed breast reconstruction had significantly impaired prereconstruction body image (p = 0.01) and sexuality (p = 0.01) and worse satisfaction with breast (p < 0.01), psychological (p < 0.01), and sexual well-being (p < 0.01). At 18 months after immediate and delayed breast reconstruction, there was significant improvement in anxiety, depression, body image, sexuality, and health-related quality of life. CONCLUSIONS: This single-center study shows that mastectomy with immediate breast reconstruction may protect breast cancer patients from a period of psychosocial distress, poor body image, and diminished sexual well-being compared with those waiting for delayed breast reconstruction. In patients who are oncologically eligible and strongly interested in breast reconstruction, efforts should be made to provide immediate breast reconstruction to decrease the interval of psychosocial distress, poor body image, and impaired sexuality.

Third-degree burns caused by ignition of chlorhexidine: A case report and systematic review of the literature.

Ignition of chlorhexidine by an electrocautery unit is rare but can have devastating consequences for the patient and the surgeon. A case involving a 77-year-old man who underwent removal of an indwelling artificial urethral sphincter is presented. The chlorhexidine was ignited when the urologist activated the electrocautery unit, causing third-degree burns to the patient. A plastic surgeon treated the burns with surgical debridement and split-thickness skin grafting. A systematic review of the literature was performed with best practice recommendations. To the authors' knowledge, the present case is the ninth such case reported.

Il est rare que la chlorhexidine s'enflamme à cause d'un dispositif d'électrocautérisation, mais un tel incident peut avoir des conséquences dévastatrices, à la fois pour le patient et pour le chirurgien. Les auteurs présentent le cas d'un homme de 77 ans qui s'est fait enlever un sphincter urétral artificiel à demeure. La chlorhexidine s'est enflammée lorsque l'urologue a activé le dispositif d'électrocautérisation, ce qui a brûlé le patient au troisième degré. Un chirurgien plasticien a traité les brûlures par débridement chirurgical et greffe dermo-épidermique. Les auteurs ont effectué une analyse bibliographique et extrait les recommandations exemplaires. En autant qu'ils le sachent, le présent cas est le neuvième du genre à être déclaré.

Early outcomes of arthroplasty of the first carpometacarpal joint using pyrocarbon spherical implants.

The first carpometacarpal joint (CMC) is the most common hand joint to develop osteoarthritis. A survey found that many hand surgeons have revisited implant arthroplasty because it preserves critical structures. However, there is currently no implant with an ideal design and material composition. The present study was the first to use and evaluate early outcomes of pyrocarbon spherical implants for arthroplasty of the first CMC in patients with Eaton-Littler stage II and III osteoarthritis. A single surgeon performed 24 arthroplasties (23 patients [20 women, three men] with a mean age of 56 years [range 46 to 75 years]) of the first CMC (nine right hands and 15 left hands) using pyrocarbon spherical implants from May 2010 to April 2013. All patients failed conservative management. At a mean (± SD) of 18.5±11.16 months postoperatively (range 4.3 to 38.9 months), the mean Kapandji score was 8.8 of 10 (range 7 to 10), the average pre- and postoperative values on the visual pain scale were 8.96±0.64 of 10 (range 8 to 10) and 1.13±1.22 of 10 (range 0 to 4), respectively. All patients were either very satisfied (score = 5) or satisfied (score = 4) with the procedure, with a mean satisfaction score of 4.76±0.44 of 5.00 (range 4 to 5). The mean postoperative Disabilities of the Arm, Shoulder and Hand (DASH) score was 11.79±14.29 (range 0 to 49.17). The most recent radiographic evaluations confirmed that all implants were stable with no erosion of nearby cancellous bone. There were no implant subluxations, dislocations or revisions. Early outcomes show promising results and support continued use of this implant for arthroplasty. However, longer-term follow-up will be needed to confirm these results.

La première articulation carpométacarpienne (CMC) est l'articulation de la main la plus touchée par l'arthrose. Une enquête a révélé que de nombreux chirurgiens de la main ont revu l'arthroplastie avec implant parce qu'elle en préserve les structures essentielles. La présente étude était la première à utiliser et à évaluer les résultats cliniques précoces d'implants sphériques en pyrocarbone pour l'arthroplastie de la première CMC chez des patients atteints d'arthrose de stades II et III selon la classification d'Eaton-Littler. Un seul chirurgien a effectué 24 arthroplasties de la première CMC (neuf de la main droite et 15 de la main gauche), au moyen d'implants sphériques en pyrocarbone, chez 23 patients (20 femmes, trois hommes) d'un âge moyen de 56 ans (plage de 46 à 75 ans) entre mai 2010 et avril 2013. Tous les patients ont échoué à une prise en charge prudente. Après une moyenne (± ÉT) de 18,5±11,16 mois après l'opération (plage de 4,3 à 38,9 mois), l'indice de Kapandji moyen était de 8,8 sur 10 (plage de 7 à 10), les valeurs préopératoires et postopératoires moyennes sur l'échelle visuelle de la douleur s'établissaient à 8,96±0,64 sur 10 (plage de 8 à 10) et à 1,13±1,22 sur 10 (plage de 0 à 4), respectivement. Tous les patients étaient soit très satisfaits (indice = 5) ou satisfaits (indice = 4) de l'intervention, et leur indice de satisfaction moyen s'élevait à 4,76±0,44 sur 5,00 (plage de 4 à 5). Le score DASH moyen d'incapacité du bras, de l'épaule et de la main était de 11,79±14,29 (plage de 0 à 49,17). Les évaluations radiographiques les plus récentes ont confirmé la stabilité de tous les implants, sans érosion de l'os spongieux avoisinant. Il n'y avait pas eu de subluxation, de dislocation ou de révision de l'implant. Les résultats cliniques précoces donnent des résultats prometteurs et appuient l'utilisation de cet implant en cas d'arthroplastie. Cependant, un suivi à plus long terme s'impose pour confirmer ces résultats.

Elevation as a treatment for fasciotomy wound closure.

There are currently numerous techniques described in the literature that attempt to optimize wound closure following a fasciotomy. However, primary closure of fasciotomy wounds continues to be difficult to accomplish successfully because of the underlying edema sustained from the compartment syndrome. The approach described in the present report is simple and physiologically sound, and addresses the underlying pathology. The authors focus on alleviating edema by strictly elevating the limb, followed by primary closure. Twelve consecutive fasciotomy wounds, referred from 2005 to 2012, were closed using this approach. The average wound closure time was 3.4 days (range three to five days) following the initial consultation. All 12 fasciotomy wounds responded with no revisions, complications, failures or loss of skin sensation. The approach was successful in all anatomical locations that were closed and conversion to any techniques currently available in the literature was not necessary. There are no costs associated with this approach, making it practical in settings with limited resources. It has a high success rate, superior cosmetic results and, most importantly, it achieves an efficient closure time. Therefore, this approach is superior to current techniques and should be a part of a plastic surgeon's armamentarium.

De nombreuses techniques sont décrites dans les publications pour optimiser la fermeture de la plaie après une fasciotomie. Cependant, il est toujours difficile de fermer ce type de plaie, à cause de l'œdème sous-jacent attribuable au syndrome des loges. La démarche décrite dans le présent rapport a le mérite d'être simple, d'être solide sur le plan physiologique et de régler la pathologie sous-jacente. Les auteurs s'attachent à soulager l'œdème en soulevant rigoureusement le membre, puis à procéder à la fermeture primaire. Douze (12) plaies de fasciotomie consécutives, aiguillées entre 2005 et 2012, ont été fermées grâce à cette approche. Le délai moyen de fermeture des plaies étaient de 3,4 jours (plage de trois à cinq jours) après la consultation initiale. Les 12 plaies de fasciotomie ont répondu sans révisions, complications, échecs ou sensations de perte cutanée. La démarche a fonctionné dans tous les foyers anatomiques fermés, et il n'a pas été nécessaire d'envisager l'une des techniques actuellement proposées dans les publications. Cette démarche ne coûte rien, ce qui est pratique dans les lieux aux ressources limitées. Celle-ci est liée à un taux de succès élevé, à des résultats esthétiques supérieurs et, par-dessus tout, à un délai de fermeture efficace. Par conséquent, cette démarche est supérieure aux techniques actuelles et devrait faire partie de l'arsenal du plasticien.

Niacin extended-release therapy in phase III clinical trials is associated with relatively low rates of drug discontinuation due to flushing and treatment-related adverse events: a pooled analysis.

BACKGROUND AND OBJECTIVE: Niacin is a highly effective agent for increasing low high-density lipoprotein cholesterol (HDL-C) levels. It also has beneficial effects on key pro-atherogenic lipoprotein parameters. However, the side effect of flushing can challenge patient adherence to treatment. In this study, we pooled safety data from available trials of at least 16 weeks' duration to evaluate the impact of flushing on patient adherence to niacin extended-release (NER) therapy. METHODS: Data were pooled from eight NER studies (administered as NER with a maximum dosage of 1000, 1500, and 2000 mg/day, either as monotherapy or in combination with simvastatin 20 or 40 mg/day [NER/S], or lovastatin 20 or 40 mg/day [NER/L]) to evaluate rates of study discontinuation due to flushing or any treatment-related adverse events. RESULTS: While 66.6% of patients experienced flushing, only 5.2% of patients discontinued treatment due to flushing. Of the total number of patients treated with NER (n = 307), NER/S (n = 912), or NER/L (n = 928), 34 (11%), 105 (11%), and 127 (14%) patients discontinued due to any treatment-related adverse event, respectively, while 14 (5%), 43 (5%), and 55 (6%) discontinued due to flushing. Discontinuation for flushing did not differ with regard to maximum dose, or to the presence or type of statin combined with NER. CONCLUSION: Although flushing was common with NER treatment, discontinuation due to flushing occurred in only 5-6% of patients in this pooled analysis. This could be due to several factors, including the fact that all patients in the NER trials were educated about flushing and its management. Translation of methodology employed in these trials into clinical practice may improve long-term adherence to NER therapy, which would enhance the therapeutic benefit of NER for reducing cardiovascular risk.

Regulation of CovR expression in Group B Streptococcus impacts blood-brain barrier penetration.

Group B Streptococcus (GBS) is an important cause of invasive infections in humans. The pathogen encodes a number of virulence factors including the pluripotent beta-haemolysin/cytolysin (beta-H/C). As GBS has the disposition of both a commensal organism and an invasive pathogen, it is important for the organism to appropriately regulate beta-H/C and other virulence factors in response to the environment. GBS can repress transcription of beta-H/C using the two-component system, CovR/CovS. Recently, we described that the serine/threonine kinase Stk1 can phosphorylate CovR at threonine 65 to relieve repression of beta-H/C. In this study, we show that infection with CovR-deficient GBS strains resulted in increased sepsis. Although CovR-deficient GBS showed decreased ability to invade the brain endothelium in vitro, they were more proficient in induction of permeability and pro-inflammatory signalling pathways in brain endothelium and penetration of the blood-brain barrier (BBB) in vivo. Microarray analysis revealed that CovR positively regulates its own expression and regulates the expression of 153 genes. Collectively, our results suggest that the positive feedback loop which regulates CovR transcription modulates host cell interaction and immune defence and may facilitate the transition of GBS from a commensal organism to a virulent meningeal pathogen.

Toward an ecological perspective of resident teaching clinic.

Teaching clinic managers struggle to convert performance data into meaningful behavioral change in their trainees, and quality improvement measures in medicine have had modest results. This may be due to several factors including clinical performance being based more on team function than individual action, models of best practice that are over-simplified for real patients with multiple chronic diseases, and local features that influence behavior but are not aligned with core values. Many are looking for a new conceptual structure to guide them. In this paper we briefly review several theories of action from the social and complexity sciences, and synthesize these into a coherent 'ecological perspective'. This perspective focuses on stabilizing features and narrative, which select for behaviors in clinic much like organisms are selected for in an ecosystem. We have found this perspective to be a useful guide for design, measurement, and joint learning in the teaching clinic.

Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: The SUPREME Study.

BACKGROUND: Aggressive treatment of low-density lipoprotein cholesterol (LDL-C) fails to prevent most cardiovascular (CV) events. Concurrent treatment of LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) should be considered in patients with dyslipidemia. OBJECTIVE: The efficacy and safety of a proprietary niacin extended-release and simvastatin (NER/S) combination were compared to atorvastatin monotherapy in a multicenter, Prospective, Randomized (3:2), Open-label, Blinded Endpoint (PROBE) study. METHODS: Following ≥4 weeks without lipid-modifying therapies, 193 patients with dyslipidemia were treated with NER/S (n = 114; 1000/40 mg/day, weeks 1 to 4; 2000/40 mg/day weeks 5 to 12) or atorvastatin (n = 79; 40 mg/day, weeks 1 to 12). RESULTS: Compared to atorvastatin, NER/S had a larger beneficial effect on HDL-C (primary end point: 30.1 ± 2.3% and 9.4 ± 2.6%, respectively; P <.001), TG (P = .02), and lipoprotein(a) (Lp[a]; P <.001), and similar effects on LDL-C and non-HDL-C. Two-thirds of patients treated with NER/S concurrently attained LDL-C (CV risk-adjusted goals), HDL-C (≥40 mg/dL), and TG (<150 mg/dL) targets, compared to one-third of patients treated with atorvastatin (P <.001). Flushing was the most common treatment-emergent adverse event (TEAE) (67.5% NER/S and 10.1% atorvastatin; P <.001). Seventy-five percent of flushing episodes were mild to moderate. More patients treated with NER/S discontinued due to TEAEs (21.1% and 3.8%; P <.001); the most common TEAE was flushing. CONCLUSION: Compared to atorvastatin, NER/S provided superior improvements in HDL-C, TG, and Lp(a) and comparable improvements in non-HDL-C and LDL-C. Treatment with NER/S should be considered for patients with dyslipidemia requiring comprehensive lipid control.

Fixed-dose combination of extended-release niacin plus simvastatin for lipid disorders.

Coronary heart disease (CHD) carries significant morbidity and mortality worldwide. Elevated LDL-cholesterol and reduced HDL-cholesterol levels are well-recognized CHD risk factors. Despite guideline recommendations for intensive therapy among patients at high risk for CHD to lower LDL-cholesterol, such lowering has failed to prevent approximately two-thirds of cardiovascular events. As a result of new data, guidelines have begun to focus on non-HDL-cholesterol, HDL-cholesterol and triglycerides as treatment targets, with the end result being a recommendation for combination therapy, such as niacin plus statin for the treatment of dyslipidemia. Compared with statin monotherapy, a combination of niacin and statin therapy provides beneficial effects on a broad range of lipid particles and some evidence suggests a further reduction in CHD risk. Recent studies have shown that the combination of a fixed dose of extended-release niacin plus simvastatin reduces non-HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol:HDL-cholesterol ratio by approximately 50% while increasing HDL-cholesterol by 25%. The safety of this combination is consistent with the safety profiles of each individual component and is well tolerated. A long-term study is currently being conducted to evaluate whether this combination therapy confers an additive impact on clinical end points.

Nicotinic acid: recent developments.

PURPOSE OF REVIEW: To review the recent progress in niacin research that is made in two major areas: new preparations to decrease flushing and niacin's mechanism of action. RECENT FINDINGS: Flushing, an adverse effect of niacin, results from GPR109A-mediated production of prostaglandin D2 and E2 in Langerhans' cells which act on DP1 and EP2/4 receptors in dermal capillaries causing their vasodilatation. DP1 receptor antagonist (laropiprant) attenuates the niacin flush in animals and humans. A reformulated preparation of extended-release niacin lowers flushing compared with the extended-release niacin (Niaspan, Abbott Laboratories, Chicago, Illinois, USA). Aspirin pretreatment attenuates flushing from Niaspan. Recent data on niacin's mechanism of action indicate that it directly inhibits hepatic diacylglycerolacyl transferase 2 resulting in an inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; niacin, by inhibiting the surface expression of hepatic ATP synthase beta chain, decreases the hepatic holoparticle high-density lipoprotein catabolism and raises high-density lipoprotein levels; and niacin increases redox potential in arterial endothelial cells resulting in the inhibition of redox-sensitive genes. SUMMARY: Recent developments suggest that the niacin receptor GPR109A is involved in flushing, but it does not explain multiple actions of niacin. Actions of niacin on diacylglycerolacyl transferase 2, ATP synthase beta chain, and redox state may explain the multiple actions of niacin.

Regulation of cytotoxin expression by converging eukaryotic-type and two-component signalling mechanisms in Streptococcus agalactiae.

Signal transducing mechanisms are essential for regulation of gene expression in both prokaryotic and eukaryotic organisms. Regulation of gene expression in eukaryotes is accomplished by serine/threonine and tyrosine kinases and cognate phosphatases. In contrast, gene expression in prokaryotes is controlled by two-component systems that comprise a sensor histidine kinase and a cognate DNA binding response regulator. Pathogenic bacteria utilize two-component systems to regulate expression of their virulence factors and for adaptive responses to the external environment. We have previously shown that the human pathogen Streptococcus agalactiae (Group B Streptococci, GBS) encodes a single eukaryotic-type serine/threonine kinase Stk1, which is important for virulence of the organism. In this study, we aimed to understand how Stk1 contributes to virulence of GBS. Our results indicate that Stk1 expression is important for resistance of GBS to human blood, neutrophils and oxidative stress. Consistent with these observations, Stk1 positively regulates transcription of a cytotoxin, beta-haemolysin/cytolysin (beta-H/C) that is critical for survival of GBS in the bloodstream and for resistance to oxidative stress. Interestingly, positive regulation of beta-H/C by Stk1 requires the two-component regulator CovR. Further, we show that Stk1 can negatively regulate transcription of CAMP factor in a CovR-dependent manner. As Stk1 phosphorylates CovR in vitro, these data suggest that serine/threonine phosphorylation impacts CovR-mediated regulation of GBS gene expression. In summary, our studies provide novel information that a eukaryotic-type serine/threonine kinase regulates two-component-mediated expression of GBS cytotoxins.

Testing the exportability of a tool for detecting operational problems in VA teaching clinics.

BACKGROUND: Recurrent operational problems in teaching clinics may be caused by the different medical preferences of patients, residents, faculty, and administrators. These preference differences can be identified by cultural consensus analysis (CCA), a standard anthropologic tool. OBJECTIVE: This study tests the exportability of a unique CCA tool to identify site-specific operational problems at 5 different VA teaching clinics. DESIGN: We used the CCA tool at 5 teaching clinics to identify group preference differences between the above groups. We averaged the CCA results for all 5 sites. We compared each site with the averages in order to isolate each site's most anomalous responses. Major operational problems were independently identified by workgroups at each site. Cultural consensus analysis performance was then evaluated by comparison with workgroup results. PARTICIPANTS: Twenty patients, 10 residents, 10 faculty, members, and 10 administrators at each site completed the CCA. Workgroups included at minimum: a patient, resident, faculty member, nurse, and receptionist or clinic administrator. APPROACH: Cultural consensus analysis was performed at each site. Problems were identified by multidisciplinary workgroups, prioritized by anonymous multivoting, and confirmed by limited field observations and interviews. Cultural consensus analysis results were compared with workgroup results. RESULTS: The CCA detected systematic, group-specific preference differences at each site. These were moderately to strongly associated with the problems independently identified by the workgroups. The CCA proved to be a useful tool for exploring the problems in depth and for detecting previously unrecognized problems. CONCLUSIONS: This CCA worked in multiple VA sites. It may be adapted to work in other settings or to better detect other clinic problems.

Regulation of purine biosynthesis by a eukaryotic-type kinase in Streptococcus agalactiae.

Group B streptococci (GBS) are the principal causal agents of human neonatal pneumonia, sepsis and meningitis. We had previously described the existence of a eukaryotic-type serine/threonine kinase (Stk1) and phosphatase (Stp1) in GBS that regulate growth and virulence of the pathogen. Our previous results also demonstrated that these enzymes reversibly phosphorylated an inorganic pyrophosphatase. To understand the role of these eukaryotic-type enzymes on growth of GBS, we assessed the stk1-mutants for auxotrophic requirements. In this report, we describe that in the absence of the kinase (Stk1), GBS are attenuated for de novo purine biosynthesis and are consequently growth arrested. During growth in media lacking purines, the intracellular G nucleotide pools (GTP, GDP and GMP) are significantly reduced in the Stk1-deficient strains, while levels of A nucleotides (ATP, ADP and AMP) are marginally increased when compared with the isogenic wild-type strain. We provide evidence that the reduced pools of G nucleotides result from altered activity of the IMP utilizing enzymes, adenylosuccinate synthetase (PurA) and IMP dehydrogenase (GuaB) in these strains. We also demonstrate that Stk1 and Stp1 reversibly phosphorylate and consequently regulate PurA activity in GBS. Collectively, these data indicate the novel role of eukaryotic-type kinases in regulation of metabolic processes such as purine biosynthesis.

hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair.

DNA mismatch repair (MMR) is essential in the surveillance of accurate transmission of genetic information, and defects in this pathway lead to microsatellite instability and hereditary nonpolyposis colorectal cancer (HNPCC). Our previous study raised the possibility that hMRE11 might be involved in MMR through physical interaction with hMLH1. Here, we show that hMRE11 deficiency leads to significant increase in MSI for both mono- and dinucleotide sequences. Furthermore, RNA-interference-mediated hMRE11-knockdown in HeLa cells results in MMR deficiency. Analysis of seven HNPCC-associated hMLH1 missense mutations located within the hMRE11-interacting domain shows that four mutations (L574P, K618T, R659P and A681T) cause near-complete disruption of the interaction between hMRE11 and hMLH1, and two mutations (Q542L and L582V) cause a 30% reduction of protein interaction. These findings indicate that hMRE11 represents a functional component of the MMR pathway and the disruption of hMLH1-hMRE11 interaction could be an alternative molecular explanation for hMLH1 mutations in a subset of HNPCC tumours.

Detection of lipid peroxidation in equine spermatozoa based upon the lipophilic fluorescent dye C1l-BODIPY581/591.

The lipophilic fluorescent probe, 4,4-difluoro-5-(4-phenyl-1 ,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid (C11-BODIPY581/591) was used to evaluate changes in lipid peroxidation in equine spermatozoa during both short-term exposure to ferrous sulfate and sodium ascorbate in the presence of cumene hydroperoxide as well as during storage of spermatozoa at 5 degrees C for 48 hours. Peroxidation of C11-BODIPY581/591 was accompanied by a shift in fluorescence from red to green, and the relative amount of nonoxidized probe was determined as the ratio of red:(red + green) fluorescence as detected by either fluorescence microplate reader or by flow cytometry. The addition of Fe2SO4 (0 to 0.5 mM), low concentrations of sodium ascorbate, and the addition of cumene hydroperoxide increased peroxidation of C11-BODIPY581/591. The addition of high concentrations (10 or 20 mM) of sodium ascorbate or alpha-tocopherol reduced peroxidation of C11-BODIPY581/591 during short-term incubations. During storage at 5 degrees C in a skim milk-based extender, equine spermatozoa demonstrated a progressive decline in motility and a small but significant increase in lipid peroxidation based upon ratiometric analysis of C11-BODIPY581/591. The addition of Fe2SO4 increased lipid peroxidation in cooled spermatozoa in a dose-dependent fashion and decreased sperm motility. The addition of alpha-tocopherol, however, did not reduce lipid peroxidation during cooled semen storage. These data demonstrate that the lipophilic fluorescent probe C11-BODIPY581/591 is a useful measurement of lipid peroxidation in equine spermatozoa and that there is an increase in lipid peroxidation during cooled storage of equine spermatozoa that is increased in the presence of ferrous promoters.

Evidence for a direct association of hMRE11 with the human mismatch repair protein hMLH1.

In both mitotic and meiotic processes, cellular surveillance of the integrity of genetic information transmission from parental cells to their subsequent generations is carried out by a network of proteins primarily involved in cell-cycle regulation, DNA replication, DNA repair, and chromosome segregation. Within this context, the mammalian MRE11 represents an essential multifunctional protein that promotes repair of DNA double-strand breaks and plays a role in the signaling of DNA damage response. Mutations in human hMRE11 gene could contribute to the rare "AT-like" disorder. However, at present time the functional roles of hMRE11 in these cellular processes are elusive. In the current study, we provide evidence that hMRE11 interacts physically with the mismatch repair protein hMLH1 through yeast two-hybrid analysis. In addition, we show that recombinant hMRE11 and hMLH1 proteins interact when these two proteins are coexpressed in bacterial cells, and both proteins can be co-immunoprecipitated from human cell extracts. Furthermore, hMRE11 and hMLH1 display similar expression patterns when examined with a human normal/tumor DNA array. Together, these data suggest that hMRE11 and hMLH1 might act in a co-operative fashion during DNA damage detection, signaling, and repair.