Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration.

Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell types, during both development and adulthood. Here, we report how Runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, and that absence of runx1 results in increased myocardial survival and proliferation, and overall heart regeneration, accompanied by decreased fibrosis. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes. Both these populations cannot be identified in runx1 mutant wounds that contain less collagen and fibrin. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and upregulation of components of the fibrin degradation pathway, including plasminogen receptor annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of plasminogen. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell types and that targeting Runx1 is a novel therapeutic strategy for inducing endogenous heart repair.

The developmental origin of heart size and shape differences in Astyanax mexicanus populations.

Regulation of heart size and shape is one of the least understood processes in developmental biology. We have for the first time analysed the hearts of Astyanax mexicanus and identified several differences in heart morphology between the surface (epigean morph) and cave-dwelling (troglomorph) morphs. Examination of the adult revealed that the troglomorph possesses a smaller heart with a rounder ventricle in comparison to the epigean morph. The size differences identified appear to arise early in development, as early as 24 h post-fertilisation (hpf), while shape differences begin to appear at 2 days post-fertilisation. The heart of the first-generation cross between the cave-dwelling and river-dwelling morph shows uncoupling of different phenotypes observed in the parental populations and indicates that the cardiac differences have become embedded in the genome during evolution. The differences in heart morphology are accompanied by functional changes between the two morphs, with the cave-dwelling morph exhibiting a slower heart rate than the river-dwelling morph. The identification of morphological and functional differences in the A. mexicanus heart could allow us to gain more insight into how such parameters are regulated during cardiac development, with potential relevance to cardiac pathologies in humans.

Unlocking the Secrets of the Regenerating Fish Heart: Comparing Regenerative Models to Shed Light on Successful Regeneration.

The adult human heart cannot repair itself after injury and, instead, forms a permanent fibrotic scar that impairs cardiac function and can lead to incurable heart failure. The zebrafish, amongst other organisms, has been extensively studied for its innate capacity to repair its heart after injury. Understanding the signals that govern successful regeneration in models such as the zebrafish will lead to the development of effective therapies that can stimulate endogenous repair in humans. To date, many studies have investigated cardiac regeneration using a reverse genetics candidate gene approach. However, this approach is limited in its ability to unbiasedly identify novel genes and signalling pathways that are essential to successful regeneration. In contrast, drawing comparisons between different models of regeneration enables unbiased screens to be performed, identifying signals that have not previously been linked to regeneration. Here, we will review in detail what has been learnt from the comparative approach, highlighting the techniques used and how these studies have influenced the field. We will also discuss what further comparisons would enhance our knowledge of successful regeneration and scarring. Finally, we focus on the Astyanax mexicanus, an intraspecies comparative fish model that holds great promise for revealing the secrets of the regenerating heart.

Nasal bridling decreases feeding tube dislodgment and may increase caloric intake in the surgical intensive care unit: a randomized, controlled trial.

OBJECTIVE: To determine whether nasal bridling is a low-morbidity practice that decreases feeding tube dislodgment and results in improved caloric intake. DESIGN: Randomized, controlled trial. SETTING: Private, tertiary-care referral center. PATIENTS: A total of 80 surgical intensive care unit patients requiring nasojejunal feeding. INTERVENTION: Nasal bridling of feeding tubes. MEASUREMENTS AND MAIN RESULTS: Between January 1, 2008 and July 31, 2008, 80 patients were randomized to have their nasojejunal feeding tubes secured with either a nasal bridle or an adhesive device. Baseline characteristics examined included age, sex, concurrent nasogastric tube presence, primary diagnosis, Acute Physiology and Chronic Health Evaluation III score, need for mechanical ventilation, need for emergent surgery, Riker Sedation Score, and Glascow Coma Scale. Patients were monitored daily for prevalence and cause of feeding tube removal, percentage of goal calories received, nasal ulceration, and sinusitis. Serum albumin and prealbumin levels were collected weekly. All patients were examined, using an intention-to-treat design. Except for a higher prevalence of emergent surgery in the bridled patients, the bridled and unbridled groups had no difference in baseline characteristics. Bridled tubes were less likely to be unintentionally dislodged than unbridled tubes (18% vs. 63%, p < .0001) resulting in bridled patients receiving a higher percentage of goal calories (median 78% [interquartile range, 65%-86%] vs. 62% [interquartile range, 47%-80%], p = .016) than unbridled patients. There were five cases of mild epistaxis upon bridle insertion and four cases of superficial nasal ulceration associated with the bridle. No bridled patients were diagnosed with sinusitis during the study period. Serum albumin and prealbumin levels did not differ between the groups. CONCLUSIONS: Bridling of nasoenteric feeding tubes in critically ill patients is a low-morbidity practice that reduces the rate of unintentional tube dislodgment and may result in improved caloric intake.

Heart Regeneration in the Mexican Cavefish.

Although Astyanax mexicanus surface fish regenerate their hearts after injury, their Pachón cave-dwelling counterparts cannot and, instead, form a permanent fibrotic scar, similar to the human heart. Myocardial proliferation peaks at similar levels in both surface fish and Pachón 1 week after injury. However, in Pachón, this peak coincides with a strong scarring and immune response, and ultimately, cavefish cardiomyocytes fail to replace the scar. We identified lrrc10 to be upregulated in surface fish compared with Pachón after injury. Similar to cavefish, knockout of lrrc10 in zebrafish impairs heart regeneration without affecting wound cardiomyocyte proliferation. Furthermore, using quantitative trait locus (QTL) analysis, we have linked the degree of heart regeneration to three loci in the genome, identifying candidate genes fundamental to the difference between scarring and regeneration. Our study provides evidence that successful heart regeneration entails a delicate interplay between cardiomyocyte proliferation and scarring.

Evaluating Diagnosis and Treatment Patterns of COPD in Primary Care.

OBJECTIVE: Many patients with COPD are misdiagnosed or under-treated. The characteristics of COPD patients and the patterns of treatment have not been well characterized in primary care settings. The objective of this study was to identify patterns of COPD onset, diagnosis and treatment with the goal of facilitating appropriate treatment at earlier stages. METHODS: A national electronic medical record database was used to identify patients with at least a 6-month history prior to a diagnosis of COPD (ICD-9 codes 491.xx, 492.xx, and 496). Pulmonary function test (PFT) results closest to the first diagnosis of COPD were evaluated to characterize disease severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Prescription data were evaluated at the time of diagnosis. All descriptive statistics were conducted using STATA statistical software. RESULTS: A total of 14 691 patients met the study criteria. Prescription data were available for 9354 (64%) of these patients. Of this group, only slightly over 50% (n = 5264) had a respiratory-related prescription on the date of diagnosis. For those not having a respiratory drug at the time of diagnosis, the average time between diagnosis and the first respiratory-related prescription was 106 (SD +/- 256.4) days. Only 389 (<3%) patients had any PFT data recorded on or prior to the day of their first diagnosis of COPD, and only 273 (2%) had sufficient PFT data available to determine their GOLD severity class. The average time between diagnosis and first COPD prescription was greatest for patients in the lowest severity category (Class 0/I; 163 +/- 288.2 days), and smallest for patients in the highest severity category (Class IV; 124 +/- 152.3 days). CONCLUSION: COPD is often not diagnosed or treated until the later stages of disease, and spirometry is not used routinely to diagnose, stage or guide treatment decisions.

The economic impact of GERD and PUD: examination of direct and indirect costs using a large integrated employer claims database.

OBJECTIVE: The objective of this study was to examine the relationship of work loss associated with gastro- the relationship of work loss associated with gastro- the relationship of work loss associated with gastro-esophageal reflux disease (GERD) and peptic ulcer disease (GERD) and peptic ulcer disease (PUD) in a large population of employed individuals in the United States (US) and quantify the individuals in the United States (US) and quantify the economic impact of these diseases to the employer. METHODS: A proprietary database that contained work place absence, disability and workers' compensation data in addition to prescription drug and medical claims was used to answer the objectives. Employees with a medical claim with an ICD-9 code for GERD or PUD were identified from 1 January 1997 to 31 December 2000. A cohort of controls was identified for the same time period using the method of frequency matching on age, gender, industry type, occupational status, and employment status. Work absence rates and health care costs were compared between the groups after adjusting for demo graphic, and employment differences using analysis of covariance models. RESULTS: There were significantly lower (p < 0.05) prescription, and outpatient costs in the controls compared to the disease groups, although the eta-square values were very low. The mean work absence attributed to sick days was 2.8 (+/- 2.3) for controls, 3.4 (+/- 2.5) for GERD, 3.2 (+/- 2.6) for PUD, and 3.2 (+/- 2.3) days for GERD + PUD. For work loss, a significantly higher (p < 0.05) rate of adjusted all-cause absenteeism and sickness-related absenteeism were observed between the disease groups versus the controls. In particular, controls had an average of 1.2 to 1.6 days and 0.4 to 0.6 lower all-cause and sickness-related absenteeism compared to the disease groups. The incremental economic impact projected to a hypothetical employed population was estimated to be $3441 for GERD, $1374 for PUD, and $4803 for GERD + PUD per employee per year compared to employees without these diseases. CONCLUSIONS: Direct medical cost and work absence in employees with GERD, PUD and GERD + PUD represent a significant burden to employees and employers.

Shortage of penicillin G: impact on antibiotic prescribing at a US tertiary care centre.

A six-year retrospective study was undertaken to examine the effect of the recent penicillin G (penG) shortage on antibiotic prescribing practices at a tertiary care centre in the US. Prior to the shortage, penG was predominantly used for intrapartum prophylaxis of group B streptococcal disease. As the supply of penG ended temporarily in October 1999, penG use declined dramatically, ampicillin replaced penG in obstetrics and a shift to broad-spectrum agents was noted in non-obstetric patients potentially eligible for penG treatment. Shortage-triggered treatment changes had a negative effect on prescribing patterns, which may contribute to antibiotic resistance.

Naturalistic impact of second-generation antipsychotics on weight gain.

BACKGROUND: While second-generation antipsychotics (SGAs) have had benefits over earlier antipsychotic treatments, their use has been associated with reports of weight gain. Body mass index (BMI) has been studied in clinical trials with limited comparison between drugs. OBJECTIVE: To investigate the impact of each SGA on the risk of weight increase in an adult population. METHODS: Using a national electronic medical records database, a naturalistic impact of SGAs on BMI was evaluated. Patients (aged >/=18 y) receiving a prescription for an antipsychotic drug between January 1995 and March 2004 were identified. An adverse event was defined as at least a 7% increase in BMI from baseline within one year of antipsychotic prescription and a post-increase BMI of at least 25 kg/m(2). RESULTS: A total of 9394 patients were identified, with 1514 cases of increased BMI after initial prescription. Risperidone (OR 1.39; 95% CI 1.16 to 1.66), quetiapine (OR 1.36; 95% CI 1.13 to 1.64), and olanzapine (OR 1.76; 95% CI 1.50 to 2.07) were significantly more likely to cause BMI increase compared with first-generation antipsychotics (FGAs). Aripiprazole (OR 0.72; 95% CI 0.36 to 1.46), ziprasidone (OR 0.68; 95% CI 0.39 to 1.18), and clozapine (OR 1.01; 95% CI 0.56 to 1.81) were less likely to induce weight gain compared with FGAs. CONCLUSIONS: This study provides a foundation for understanding how SGAs impact weight gain in a naturalistic, as opposed to a clinical trial, setting and provides evidence that there are differential risks of weight gain between SGAs. Because of negative long-term health effects of weight gain, physicians need to take all factors into consideration when recommending pharmaceutical therapy for patients with severe mental illness.