BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis.

The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.

Sorafenib cardiotoxicity increases mortality after myocardial infarction.

RATIONALE: Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism. OBJECTIVE: Determining the mechanism of sorafenib-mediated cardiotoxicity. METHODS AND RESULTS: Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2'-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated. CONCLUSIONS: Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality.

Coralline algal structure is more sensitive to rate, rather than the magnitude, of ocean acidification.

Marine pCO2 enrichment via ocean acidification (OA), upwelling and release from carbon capture and storage (CCS) facilities is projected to have devastating impacts on marine biomineralisers and the services they provide. However, empirical studies using stable endpoint pCO2 concentrations find species exhibit variable biological and geochemical responses rather than the expected negative patterns. In addition, the carbonate chemistry of many marine systems is now being observed to be more variable than previously thought. To underpin more robust projections of future OA impacts on marine biomineralisers and their role in ecosystem service provision, we investigate coralline algal responses to realistically variable scenarios of marine pCO2 enrichment. Coralline algae are important in ecosystem function; providing habitats and nursery areas, hosting high biodiversity, stabilizing reef structures and contributing to the carbon cycle. Red coralline marine algae were exposed for 80 days to one of three pH treatments: (i) current pH (control); (ii) low pH (7.7) representing OA change; and (iii) an abrupt drop to low pH (7.7) representing the higher rates of pH change observed at natural vent systems, in areas of upwelling and during CCS releases. We demonstrate that red coralline algae respond differently to the rate and the magnitude of pH change induced by pCO2 enrichment. At low pH, coralline algae survived by increasing their calcification rates. However, when the change to low pH occurred at a fast rate we detected, using Raman spectroscopy, weaknesses in the calcite skeleton, with evidence of dissolution and molecular positional disorder. This suggests that, while coralline algae will continue to calcify, they may be structurally weakened, putting at risk the ecosystem services they provide. Notwithstanding evolutionary adaptation, the ability of coralline algae to cope with OA may thus be determined primarily by the rate, rather than magnitude, at which pCO2 enrichment occurs.

Rigid bronchoscopic management of complications related to endobronchial stents after lung transplantation.

OBJECTIVES: We reviewed the utility of rigid bronchoscopy in the management of complications resulting from placement of metallic endobronchial stents after lung transplantation. METHODS: A retrospective review was performed of all lung transplant patients who required metallic endobronchial stenting between 2005 and 2009. The patients' medical records were reviewed, and details regarding stent placement, complications, and removal were recorded. RESULTS: A total of 43 metallic stents were placed in 22 patients who had unilateral or bilateral lung transplantation. Stent complications occurred in 18 cases (42%) at a mean of 285 days after placement and included stent collapse, stent breakdown, stent migration, ingrowth of granulation tissue, and coughing up of fractured pieces of stent. Of the 43 stents placed, only 4 (9%) had to be removed. Removal was readily accomplished by rigid bronchoscopic techniques, even when some endothelial ingrowth had occurred. CONCLUSIONS: Lung transplantation presents unique challenges in airway management. Endobronchial stenting plays an important role in the management of anastomotic stenosis and bronchomalacia in these patients. Although metallic stents have significant advantages, complications often arise that occasionally necessitate their removal. Rigid bronchoscopy is a valuable tool in the management of endobronchial stent complications after lung transplantation.

Unilateral vs bilateral total knee arthroplasty risk factors increasing morbidity.

Because surgeons are electing to perform simultaneous bilateral total knee arthroplasty (TKA), it is important to identify which patients are at increased risk. We performed a retrospective cohort analysis of 150 patients with unilateral TKA vs 150 patients with simultaneous bilateral TKA. The bilateral group demonstrated a 2.1 times greater mean overall complication rate as well as increased transfusion rates. Patients older than 70 years exhibited significantly higher complication rates. Having a preexisting pulmonary disorder in the bilateral cohort carried nearly a 3-fold risk of complications. Patients with body mass indices greater than 30 displayed a complication rate of 0.97 in the bilateral group as opposed to 0.44 in the control group. Our study demonstrated that age, body mass index, and a preexisting pulmonary disorder resulted in increased complications.

Termination of electrocution-induced ventricular fibrillation by an implantable cardioverter defibrillator.

We describe a case in which an implantable cardioverter defibrillator (ICD) saved a patient's life after he tried to commit suicide by electrocuting himself. Deaths caused by electrocution are usually accidental and rarely suicidal. The amount of current flow is the most important factor in deciding the degree of electrical injury, which may range from transient muscle tremors to death. The ICD is electrically insulated from surrounding electromagnetic interference and the passage of electric current typically does not damage or reprogram the device. In our patient, electromagnetic interference caused by the electric current initially triggered the noise reversion mode, leading to asynchronous pacing. Ventricular fibrillation was detected and terminated only after the electromagnetic interference stopped, as depicted by the intracardiac electrogram. This case is the first documented example of an ICD-aborted fatal electrocution from ventricular fibrillation caused by an unnatural electrical source. (PACE 2010; 510-512).

Global Syntactic Variation in Seven Languages: Toward a Computational Dialectology.

The goal of this paper is to provide a complete representation of regional linguistic variation on a global scale. To this end, the paper focuses on removing three constraints that have previously limited work within dialectology/dialectometry. First, rather than assuming a fixed and incomplete set of variants, we use Computational Construction Grammar to provide a replicable and falsifiable set of syntactic features. Second, rather than assuming a specific area of interest, we use global language mapping based on web-crawled and social media datasets to determine the selection of national varieties. Third, rather than looking at a single language in isolation, we model seven major languages together using the same methods: Arabic, English, French, German, Portuguese, Russian, and Spanish. Results show that models for each language are able to robustly predict the region-of-origin of held-out samples better using Construction Grammars than using simpler syntactic features. These global-scale experiments are used to argue that new methods in computational sociolinguistics are able to provide more generalized models of regional variation that are essential for understanding language variation and change at scale.

Visceral Artery Aneurysms: Diagnosis, Surveillance, and Treatment.

Visceral artery aneurysms (VAAs) are a rare, but serious clinical entity as rupture confers a high rate of mortality. Data regarding the prevalence, treatment, and prognosis of VAAs is largely from case series, as true randomized trials are lacking. The incidence of VAAs has risen over the decades with advances in imaging technology, availability, and utilization. Even in the presence of symptoms, the prompt diagnosis of VAAs may be challenging as symptoms are often nonspecific and varied. Although there are no definitive treatment guidelines, asymptomatic VAAs require treatment in the following scenarios: when the aneurysm diameter is greater than 2 cm, when identified during pregnancy, when multiple aneurysms are present, and in the case of hepatic transplant. Similar to therapeutic trends in other vascular beds, advances in endovascular devices and techniques have driven an "endovascular first" approach for the treatment of VAAs. However, although the success rates of endovascular repair are impressive, surgical intervention is still necessary in treating centers. This paper reviews the pathophysiology, clinical features, anatomic characteristics, and management strategies required for the effective diagnosis and treatment of VAAs.

Physician failure to stratify patients hospitalized with acute pulmonary embolism.

OBJECTIVES: In 2011, the AHA recommended risk stratification of patients with acute pulmonary embolism (PE). Failure to risk stratify may cause under recognition of intermediate-risk PE and its attendant short- and long-term consequences. We sought to determine if patients hospitalized with acute PE were appropriately risk stratified according to the 2011 AHA Scientific Statement within our hospital system and whether differences exist in adherence to risk stratification by hospital or treating hospital service. We also wished to know the frequency of in-hospital consultations for acute PE which might assist in the risk stratification process. METHODS: This is a retrospective chart audit of all patients hospitalized with a diagnosis of acute PE between January 2011 and December 2013 at our 937-bed metropolitan, three hospital system comprised of academic University, neuroscience Specialty, and teaching Community hospitals. We evaluated the presence of imaging, laboratory tests, and specialty consultation within 72 h of PE diagnosis by hospital. RESULTS: 701 patients with acute PE were admitted to our hospital system during the study period. 308 patients (43.9%) met criteria for intermediate-risk PE. 347 patients (49.5%) were considered 'Low-Risk - At Risk', patients defined in a low-risk category not having undergone all recommended risk stratification testing and so truly may have been in a higher risk category. No specialty consultations were utilized for 265 patients (37.8%). CONCLUSIONS: Our large metropolitan hospital system inadequately risk stratifies hospitalized patients with acute PE. Because nearly one-half of patients with acute PE did not have all recommended testing, clinicians may be under recognizing patients with intermediate-risk PE and their risk for long-term morbidity. Specialty consultations were underutilized and may help guide medical decision-making.

Building a Successful Superficial Venous Program.

OPINION STATEMENT: As the treatment of superficial venous insufficiency transitioned from the hospital to the office setting, a remarkable increase in provider interest developed. However, the novelty of the disease process and procedural opportunities are tempered by the challenges associated with knowledge acquisition, skill development, strategic planning, and program development. Only a unique recipe of clinical growth, technical acumen, management skill, operational efficiency, and financial sense lead to program success. Despite the variety of skills required, treating superficial venous insufficiency is obtainable for both the formally and non-formally trained physicians with sufficient commitment, education, and resources.

The Role of Postural Support in Young Adults' Control of Stationary Kicking.

PURPOSE: The requirement for postural stability during the performance of motor skills has been clearly demonstrated in infants, but the necessity for such a postural substrate is not well documented in adults. The present study investigated the role of postural stability during a ballistic ball-kicking task in adults by providing varying degrees of external postural support. METHOD: In the 1st experiment, 30 participants performed 20 maximal-velocity kicks under each of 3 conditions: grasping a rigid stable handle, light fingertip touch, and grasping a suspended elastic tube. A 2nd experiment with 16 participants varied the position of the stable handle to examine if the handle position in Experiment 1 might simply act as a fulcrum to enhance torque generation. RESULTS: In Experiment 1, ball velocity was significantly higher in the stable-grasp condition in both men and women with the men showing greater improvement relative to the other conditions. Experiment 2 showed that the position of the stable handle did not significantly affect kicking velocity, indicating that the handle was not simply acting as a fulcrum during the kick. CONCLUSION: Together, the findings suggest that postural stability may be a rate limiter in the performance of dynamic motor tasks in adults.

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection.

The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen-presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen-specific CD8+ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte-derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to Mtb infection and mediates the power of DC efferocytosis and cross-presentation.

Toward a psychoanalytic way of teaching psychoanalysis.

The author's orientation to psychoanalytic education blends its subjective and objective ways of knowing, its cognitive and experiential aspects. Lear's (2003) definition of psychoanalysis as a subjective category contextualizes psychoanalytic teaching as a lived-out demonstration of its conceptual learning and generates a confident humility in how teachers express theoretical content. The author emphasizes teachers' gut-level psychological impacts on candidates, and the value of teachers conveying psychoanalytic knowledge as an internalized expression of their personal experience and meaning (identification), while simultaneously maintaining an objective perspective. A literature review of psychoanalytic education and discussion of Stanislavski's (1936, 1949) dramatic acting "Method" clarifies the author's pedagogy.

Nirschl surgical technique for concomitant lateral and medial elbow tendinosis: a retrospective review of 53 elbows with a mean follow-up of 11.7 years.

BACKGROUND: Combined lateral elbow tendinosis (tennis elbow) and medial elbow tendinosis (golfer's elbow) can be a disabling condition that, if unresponsive to nonoperative treatments, may be effectively treated surgically. The authors are not aware of any study that reports the outcome of a combined operation for lateral and medial elbow tendinosis (country club elbow) performed in the same operative setting. HYPOTHESIS: Combined surgical treatment of country club elbow in the same operative setting has similar outcomes to those seen in the literature for single operative procedures. STUDY DESIGN: Case series; Level of evidence 4. METHODS: Outcome measurements included the Numeric Pain Intensity Scale, the Nirschl tennis elbow scoring system, and the American Shoulder and Elbow Surgeons elbow form. Forty-eight patients (53 clinical elbows) were available by telephone, with a minimum time to follow-up of 5 years (range, 5-19 years; mean, 11.7 years). RESULTS: The average Nirschl tennis elbow score improved from 16.7 preoperatively to 70.8 postoperatively (P < .01). The average American Shoulder and Elbow Surgeons elbow score improved from 45.2 to 90.4 (P < .01). The Numeric Pain Intensity Scale score improved from 8.8 to 1.7 (P < .01). By the criteria of the Nirschl tennis elbow score, results were rated excellent in 38 elbows, good in 7 elbows, fair in 5 elbows, and poor in 3 elbows, with 85% (45 of 53) good to excellent results. Patient satisfaction with the surgery averaged 8.7 out of 10. Of the 46 patients who played sports, 44 (96%) reported returning to their sports. CONCLUSION: When nonoperative treatment of lateral and medial elbow tendinosis fails, combined surgical intervention via the Nirschl operative techniques for country club elbow is highly effective, with results similar to those of single-sided intervention.

Quetiapine-induced peripheral edema.

Quetiapine fumarate is an atypical antipsychotic with relatively benign side-effect profile. Here we report a rare side-effect of quetiapine use. This is the second reported case of peripheral edema with quetiapine use. Unaware of this rare side-effect, patient had to endure extensive investigations.

Surgical anatomy of latissimus dorsi muscle in transfers about the shoulder.

Transfer of the latissimus dorsi to the greater tuberosity has been used successfully in the treatment of massive rotator-cuff deficiency. For safe release and transfer of the tendon, the variations in the tendinous insertions of the latissimus dorsi and teres major onto the humerus need to be understood. In anatomical dissection of 12 cadavers, mean width of the latissimus tendon was 3.3 cm at its insertion, and mean length was 7.3 cm. In all specimens, there were fascial connections between the latissimus and teres major and between the latissimus and the long head of the triceps. There were 3 insertion patterns of the latissimus dorsi tendon onto the humerus with respect to the tendon of the teres major: completely separate (8 cadavers), loosely bound (3 cadavers), and completely joined (1 cadaver). If the latissimus dorsi were being transferred in the last type, the teres major would need to be transferred with the latissimus dorsi as a common musculotendinous unit.

Ten- to 14-year follow-up of the Nirschl surgical technique for lateral epicondylitis.

BACKGROUND: Good to excellent short-term results have been reported for the surgical treatment of lateral epicondylitis using various surgical techniques. HYPOTHESIS: Surgical treatment for lateral epicondylitis using the mini-open Nirschl surgical technique will lead to durable results at long-term follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Records from 139 consecutive surgical procedures (130 patients) for lateral epicondylitis performed by 1 surgeon between 1991 and 1994 were retrospectively reviewed. Eighty-three patients (92 elbows) were available by telephone for a mean follow-up of 12.6 years (range, 10-14 years). Outcome measures included the Numeric Pain Intensity Scale, Nirschl and Verhaar tennis elbow-specific scoring systems, and American Shoulder and Elbow Surgeons elbow form. Preoperative data were collected retrospectively. RESULTS: The mean age of the study group was 46 years (range, 23-70 years) with 45 men and 38 women. Eighty-seven of the procedures were primary, and 5 were revision tennis elbow surgeries. Concomitant procedures were performed in 30 patients including ulnar nerve release in 24 patients, medial tennis elbow procedures in 23 patients, shoulder arthroscopy in 2 patients, carpal tunnel release in 1 patient, and triceps debridement and osteophyte excision in 1 patient. The mean duration of preoperative symptoms was 2.2 years (range, 2 months to 10 years). The mean Nirschl tennis elbow score improved from 23.0 to 71.0, and the mean American Shoulder and Elbow Surgeons score improved from 34.3 to 87.7 at a minimum of 10-year follow-up (P < .05). The Numeric Pain Intensity Scale pain score improved from 8.4 preoperatively to 2.1 (P < .05). Results were rated as excellent in 71 elbows, good in 6 elbows, fair in 9 elbows, and poor in 6 elbows by the Nirschl tennis elbow score. By the criteria of Verhaar et al, the results were excellent in 45 elbows, good in 32 elbows, fair in 8 elbows, and poor in 7 elbows. Eighty-four percent good to excellent results were achieved using both scoring systems. Ninety-two percent of the patients reported normal elbow range of motion. The overall improvement rate was 97%. Patient satisfaction averaged 8.9 of 10. Ninety-three percent of those available at a minimum of 10-year follow-up reported returning to their sports. CONCLUSION: The mini-open Nirschl surgical technique with accurate resection of the tendinosis tissue remains highly successful in the long term.

Psychiatric resident education in intellectual disabilities: one program's ten years of experience.

OBJECTIVE: The authors evaluated the confidence and willingness of resident graduates to treat individuals with intellectual disability (ID), following a residency rotation in developmental disability. METHODS: Thirty-two graduates of a single residency program were surveyed regarding their post-residency experience with patients with intellectual disability. All graduates had completed a 3 month, half-time residency rotation in intellectual disability. The anonymous 12-question survey sought feedback about satisfaction with the rotation, confidence in serving persons with ID, and actual post-residency work with ID patients. RESULTS: Twenty-three of 32 (72%) of graduates returned surveys. On a 6-point scale (1=strongly disagree; 6=strongly agree), residents most strongly endorsed that the rotation had built their capacity in ID (5.78), confidence (5.48), and satisfaction (5.37). Lowest ratings were given to professional contact in ID initiated by the graduate (2.74), identifying expertise to the community (3.22), and post-residency practice with patients with ID (3.30). Differences between respondents who identified post-residency contact with persons with ID (N=8), and respondents who did not (N=15), did not reach statistical significance. CONCLUSIONS: Psychiatric graduates appear to value specialized education and experience in working with ID patients during residency, and feel more confident as a result. In spite of this, the majority of resident graduates did not identify ID training or expertise to their practice community, or choose to work with ID patients following residency.