When the phone rings - factors influencing its impact on the experience of patients and healthcare workers during primary care consultation: a qualitative study.

BACKGROUND: In the primary health care setting, patients interact directly with their healthcare workers (HCW), which include their primary physicians, nurses and pharmacists. Studies have shown that such interactions, when interrupted by phone calls received by either party, can lead to adverse outcomes and negative experiences. There is insufficient data however on the factors affecting the reaction and responses of both patients and HCWs when phone calls occur amidst their interaction. Understanding these factors will allow for the introduction of targeted measures to mitigate the negative impact of such interruptions and improve patient-HCW relationships. This study therefore aims to understand the impact of unplanned phone calls during primary health care consultations on patient-HCW interactions and the factors affecting the patient and the HCW responses. METHOD: This study used focus group discussions (FGD) to gather qualitative data from patients and HCWs who had visited or worked in a major public primary healthcare institution in Singapore. The FGDs were audio-recorded, transcribed, audited and analyzed using standard content analysis to identify emergent themes. RESULTS: 15 patients and 16 HCWs participated in 5 FGDs. The key themes that emerged from these FGDs were patients' and HCWs' attitudes toward professionalism and respect, task and thought interruption, call characteristics, the impact on patient safety and stakeholders' experiences. Phone calls during consultations answered by either party often resulted in the answering party feeling apologetic and would usually keep the phone conversations short as a sign of respect to the other party. Both stakeholders valued the consultation time and similarly reported negative experiences if the phone-call interruptions became prolonged. Calls from the desk phone answered by HCWs were perceived by most patients to be relevant to healthcare services, with the assumption that HCWs exercised professionalism and would not attend to personal calls during their clinical duties.HCWs expressed their concerns and distress about potential medical errors due to phone-calls interrupting their clinical tasks and thinking processes. However, they acknowledged that these same phone-calls were important to allow clarifications of instructions and improved the safety of other patients. CONCLUSION: Phone interruptions affected patient and HCW interaction during consultations and factors leading to their adverse reactions need to be recognized and addressed.

Surgical vs. transcatheter pulmonary vein isolation as first invasive treatment in patients with atrial fibrillation: a matched group comparison.

AIMS: Pulmonary vein isolation (PVI) can be considered for treatment of symptomatic atrial fibrillation (AF). Nowadays, in addition to transcatheter ablation, thoracoscopic surgical PVI is available. The aim of this study is to compare clinical outcome of surgical with transcatheter PVI as first invasive treatment strategy of AF. METHODS AND RESULTS: From June 2009 to November 2011, 33 patients underwent minimally invasive surgical PVI, and were matched (1:2 fashion) retrospectively according to age, sex, and AF type, with 66 patients who underwent transcatheter PVI. Success was defined as freedom from atrial arrhythmias on 24 h Holter monitoring without use of anti-arrhythmic drugs (AADs) at 1 year. Mean age was 52 ± 10 years, 82% were male. Paroxysmal AF was present in 76 patients (77%), persistent AF in 23 (23%) patients. None underwent prior ablations, and failed on 1.2 ± 0.6 AADs. At 12 months, complete freedom from atrial arrhythmias without AADs in the surgical PVI group was 88% compared with 41% in the transcatheter PVI group (P < 0.001). Freedom from atrial arrhythmias with AADs was 91 vs. 62%, in the surgical vs. transcatheter PVI group, respectively (P = 0.002). Complications occurred in seven (21%) surgical PVI patients, and three (5%) transcatheter PVI patients (P = 0.015). CONCLUSION: In present matched study comparing a surgical with transcatheter PVI treatment strategy in symptomatic AF patients failed on AADs, but without prior ablations, a surgical PVI strategy was more effective to prevent recurrence of atrial arrhythmias, than a transcatheter PVI treatment strategy. However, complications were more frequent with surgical PVI.

Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial.

IMPORTANCE: Metformin treatment is associated with improved outcome after myocardial infarction in patients with diabetes. In animal experimental studies metformin preserves left ventricular function. OBJECTIVE: To evaluate the effect of metformin treatment on preservation of left ventricular function in patients without diabetes presenting with ST-segment elevation myocardial infarction (STEMI). DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled study conducted among 380 patients who underwent primary percutaneous coronary intervention (PCI) for STEMI at the University Medical Center Groningen, The Netherlands, between January 1, 2011, and May 26, 2013. INTERVENTIONS: Metformin hydrochloride (500 mg) (n = 191) or placebo (n = 189) twice daily for 4 months. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was left ventricular ejection fraction (LVEF) after 4 months, assessed by magnetic resonance imaging. A secondary efficacy measure was the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after 4 months. The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target-lesion revascularization) was recorded until 4 months as a secondary efficacy measure. RESULTS: At 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%-54.6%) in the metformin group (n = 135), compared with 54.8% (95% CI, 53.5%-56.1%) (P = .10) in the placebo group (n = 136). NT-proBNP concentration was 167 ng/L in the metformin group (interquartile range [IQR], 65-393 ng/L) and 167 ng/L in the placebo group (IQR, 74-383 ng/L) (P = .66). MACE were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (P = .16). Creatinine concentration (79 µmol/L [IQR, 70-87 µmol/L] vs 79 µmol/L [IQR, 72-89 µmol/L], P = .61) and glycated hemoglobin (5.9% [IQR, 5.6%-6.1%] vs 5.9% [IQR, 5.7%-6.1%], P = .15) were not significantly different between both groups. No cases of lactic acidosis were observed. CONCLUSIONS AND RELEVANCE: Among patients without diabetes presenting with STEMI and undergoing primary PCI, the use of metformin compared with placebo did not result in improved LVEF after 4 months. The present findings do not support the use of metformin in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01217307.

Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy.

Serum biomarkers are promising minimally invasive outcome measures in clinical studies in Duchenne muscular dystrophy (DMD). However, biomarkers strongly associated with clinical progression and predicting performance decline are lacking. In this study we aimed to identify serum biomarkers associated with clinical performance and able to predict clinical milestones in DMD. Towards this aim we present a retrospective multi-center cohort study including serum samples and clinical data collected in research participants with DMD as part of a natural history study at the University of Florida (UF) and real-world observations at Leiden University Medical Center (LUMC) between 2009-2022. The 7K SomaScan® assay was used to analyse protein levels in in individual serum samples. Serum biomarkers predicted age at loss of ambulation (LoA), age at loss of overhead reach (OHR) and age at loss of hand to mouth function (HTM). Secondary outcomes were the association of biomarkers with age, corticosteroid (CS) usage, and clinical performance based on the North Star Ambulatory Assessment (NSAA), 10 meter run velocity (10mrv), 6 minute walk (6MWT) and Performance of the Upper Limb (PUL2.0). A total of 716 serum samples were collected in 79 participants at UF and 74 at LUMC (mean[SD] age; 10.9[3.2] vs 8.4[3.4]). 244 serum proteins showed an association with CS usage in both cohorts independent of CS type and regimen, including MMP3 and IGLL1. 318 probes (corresponding to 294 proteins) showed significant associations with NSAA, 10mrv, 6MWT and/or PUL2.0 across both cohorts. The expression of 38 probes corresponding to 36 proteins such as RGMA, EHMT2, ART3, ANTXR2 and DLK1 was associated with risk of both lower and upper limb clinical milestones in both the LUMC and UF cohort. In conclusion, multiple biomarkers were associated with CS use, motor function and upper lower and upper limb disease milestones in DMD. These biomarkers were validated across two independent cohorts, increasing their likelihood of translation for use within the broader DMD population.

Assessment of sex-related differences and outcome in patients who underwent cryoballoon pulmonary vein isolation for atrial fibrillation: an observational cohort study.

OBJECTIVES: Pulmonary vein isolation (PVI) is widely accepted as an effective and safe treatment for symptomatic atrial fibrillation (AF). However, data on sex-related differences and associations with clinical outcome and safety of PVI with cryoballoon ablation are limited. We sought to compare sexrelated efficacy and safety of cryoballoon ablation and identify sex-related associations with clinical outcomes. METHODS AND RESULTS: We included 650 consecutive patients with AF undergoing PVI with cryoballoon ablation at our institution between 2013 and 2017. The efficacy outcome was the first documented recurrence (>30 s) of AF, atrial flutter or atrial tachycardia (AF/AT) or repeat ablation during follow-up, after a 90-day blanking period. The safety outcome was the incidence of periprocedural complications. Mean age of the population was 58±10, and 210 (32.3%) patients were women. Women were older, had a higher body mass index, had more renal dysfunction and less coronary artery disease as compared with men. The rate of AF/AT recurrence was similar between women and men at 12-month follow-up (27.6% vs 24.8%, p=0.445). The incidence of periprocedural complications was higher in women (12.9% vs 4.6%; p<0.001), specifically groin haematomas and phrenic nerve palsy. On multivariate analysis, left atrial volume index (adjusted OR 1.05, 95% CI 1.00 to 1.10; p=0.032) was associated with the incidence of procedural complications in women. For men, no relation with complications could be found. CONCLUSION: The efficacy of cryoballoon ablation was similar between women and men; however, women had a higher risk of procedural complications.

Initial experience with pulsed field ablation for atrial fibrillation.

Introduction: Pulsed field ablation (PFA) was recently introduced for the treatment of symptomatic atrial fibrillation (AF) with the claim of selectively ablating the myocardium while sparing surrounding tissues. We present our initial experience with a PFA catheter for pulmonary vein isolation (PVI) and describe procedural findings and peri-procedural safety of the first 100 patients. Materials and methods: We investigated 100 patients treated for symptomatic AF using the FARAWAVE PFA catheter (Farapulse, Menlo Park, CA, USA) between July 2021 and March 2022. Procedure workflow and electrophysiological findings at the time of ablation, peri-procedural complications, and operator learning curves are described. Results: The mean age of patients was 62.9 ± 9.4 years, 62% were male subjects and 80% had paroxysmal AF. The median CHA2DS2-VASc score was 1.5 (IQR: 1.0-2.0) and the mean left atrial volume index was 35.7 ± 9.6 ml/m2. In 88 (88%) patients, PVI alone was performed and in 12 (12%) patients additional ablation of the posterior wall was performed. 3D-electroanatomic mapping was performed in 18 (18%) patients. Procedures without mapping lasted for 52.3 ± 16.6 min. The mean number of applications per pulmonary vein (PV) was 8.1 ± 0.6. In all patients (100%), all PVs were confirmed to be isolated. The learning curves of the two operators who performed > 20 procedures showed a negligible variation of performance over time and practice did not significantly predict procedure time [Operator 1 (senior): R 2 = 0.034, p = 0.35; Operator 2 (junior): R 2 = 0.004, p = 0.73]. There was no difference between the procedure times between senior and junior operators (Operator 1: 46.9 ± 9.7 min vs. Operator 2: 45.9 ± 9.9 min; p = 0.73). The only complications observed were two cases of bleeding at the site of percutaneous access. Conclusion: Our initial experience shows that use of the PFA catheter for pulmonary vein isolation (PVI) is safe, fast, and easy to learn.

Low Frequency Dielectric and Optical Behavior on Physicochemical Properties of Hydroxyapatite/Cornstarch Composite.

An investigation on relationship among the physicochemical, optical and dielectric properties of the hydroxyapatite/cornstarch (HA/Cs) composites with the starch proportion of 30, 40, 50, 60, 70, 80 and 90 wt% is presented in this work. The HA/Cs composites have been characterized via FTIR, XRD, DRS and impedance analyzer. This work depicts that the strong interaction is exhibited between the hydroxyapatite nanoparticles and starch as the starch proportion increases. This increment trend results in the higher crystallinity of the HA/Cs composites. The highly crystallized HA/Cs with hydroxyapatite nucleation center presents low optical properties (diffuse reflectance and optical band gap energy). The HA/Cs composite with 80 wt% starch proportion (H2C8) show higher dielectric properties (dielectric constant, loss factor and conductivity) due to the stronger interfacial interaction and close-packed HA/Cs crystalline structure. The relationship among the physicochemical, optical and dielectric properties of the HA/Cs composite is studied in this work for potential of instrumentation design.

Dielectric and material analysis on physicochemical activity of porous hydroxyapatite/cornstarch composites.

This paper provides a comprehensive analysis of the dielectric and physicochemical properties of the porous hydroxyapatite/cornstarch (HAp/Cs) composites in a new perspective. The porous composites have been characterized via SEM, FTIR, XRD and dielectric spectroscopy. The dielectric permittivity spectra were obtained in Ku-band (12.4-18.0 GHz) and it was correlated with the physicochemical properties of the porous HAp/Cs. Porous HAp/Cs composites exhibits low ε' and negative ε″, which influenced by the microstructural morphology, interaction between Hap and Cs, as well as crystalline features due to the various proportion of the HAp/Cs. The physicochemical effect of the composites results in the dielectric polarization and energy loss. This phenomenon indicates the presence of the three obvious relaxation responses in the ε' spectrum (13.2-14.0, 15.2-16.0, and 16.6-17.4 GHz) and the negative behaviours in the ε″ spectrum. The relationships between physicochemical and dielectric properties of the porous composite facilitate the development of the non-destructive microwave evaluation test for the porous composite.

Brn3a regulates the transition from neurogenesis to terminal differentiation and represses non-neural gene expression in the trigeminal ganglion.

The POU-domain transcription factor Brn3a is expressed in developing sensory neurons at all levels of the neural axis, including the trigeminal ganglion, hindbrain sensory ganglia, and dorsal root ganglia. Changes in global gene expression in the trigeminal ganglion from E11.5 to E13.5 reflect the repression of early neurogenic genes, exit from the cell cycle, and initiation of the expression of definitive markers of sensory function. A majority of these developmental changes are perturbed in the trigeminal ganglia of Brn3a knockout mice. At E13.5, Brn3a(-/-) trigeminal neurons fail to repress a battery of developmental regulators that are highly expressed at E11.5 and are normally down-regulated as development progresses, and also fail to appropriately activate a set of definitive sensory genes. Remarkably, developing Brn3a(-/-) trigeminal neurons also ectopically express multiple regulatory genes associated with cardiac and/or cranial mesoderm development, although definitive myogenic programs are not activated. The majority of these genes are not ectopically expressed in the dorsal root ganglia of Brn3a null mice, perhaps due to redundant mechanisms of repression at spinal levels. These results underscore the importance of gene repression in regulating neuronal development, and the need for unbiased screens in the determination of developmental gene regulatory programs.

Feasibility and outcome of epicardial pulmonary vein isolation for lone atrial fibrillation using minimal invasive surgery and high intensity focused ultrasound.

AIMS: Transvenous pulmonary vein isolation (PVI) is the cornerstone of non-pharmacological rhythm control therapy in symptomatic atrial fibrillation (AF). Success and complications rates are, however, still not optimal. New techniques and energy sources are therefore being developed. METHODS AND RESULTS: Fifteen patients with lone AF refractory for antiarrhythmic drugs (AADs) underwent PVI by minimal invasive epicardial off-pump monolateral right-sided video-assisted thoracic surgery (VATS) using the UltraCinch with high-intensity focused ultrasound (HIFU). Primary endpoint was successful ablation defined as absence of AF or atrial flutter/tachycardia after 6 months assessed by complaints, 12 lead electrocardiogram, and 96 h Holter monitoring. Secondary endpoints were ablation success at the end of follow-up irrespective of AADs use or re-ablation and complications related to the procedure. Mean age was 47 +/- 10 years and 14 (93%) were male. Eleven (73%) had paroxysmal, and 4 (27%) patients had persistent AF. Median AF history was 5 (1-12) years. At 6 months, six (40%) patients had sinus rhythm after one epicardial PVI (four on AADs). After 1.3 +/- 0.6 years, four (27%) patients had sinus rhythm after one epicardial PVI (two on AADs) and in six (40%) patients endocardial radiofrequency re-ablation was performed, which was successful in three patients (20%). Two patients (13%) were planned for re-ablation. Three others (20%) refused re-ablation. Two major complications occurred (one late tamponade and one bleeding during surgery, necessitating sternotomy). CONCLUSION: Epicardial PVI using monolateral right-sided VATS with the UltraCinch delivering HIFU is feasible, but is associated with substantial complications. Furthermore, the success rate was low. More research is therefore warranted to assess optimal ablation techniques and energy sources to perform PVI.

Pulmonary vein anatomy addressed by computed tomography and relation to success of second-generation cryoballoon ablation in paroxysmal atrial fibrillation.

BACKGROUND: Cryoballoon isolation is considered a safe and effective treatment for atrial fibrillation (AF). However, recurrence of AF after first cryoballoon ablation occurs in ~30% of patients. Pre-procedurally identifying patients at risk of AF recurrence could be beneficial. HYPOTHESIS: Our aim was to determine how pulmonary vein (PV) anatomy influences the recurrence of AF using the second-generation cryoballoon in patients with paroxysmal AF. METHODS: We included 88 consecutive patients with paroxysmal AF undergoing PVI procedure with a second-generation 28-mm cryoballoon. All patients were evaluated at 3, 6 and 12 months using a 12-lead ECG and 24-hour Holter monitoring. PV anatomy was assessed by creating three-dimensional models using computed tomography (CT) segmentations of the left atrium. RESULTS: Fifty-one patients (61%) had left PVs with a shared carina, 35 patients (42%) had a shared right carina. Nine patients (11%) were classified having a right middle PV. In total 17 (20.2%) of patients had a left common PV. At 12 months, 14 patients (17%) had experienced AF recurrence. Neither PV ovality, variant anatomy, the presence of shared carina nor a common left PV was a predictor for AF recurrence. CONCLUSIONS: No specific characteristics of PV dimensions nor morphology were associated with AF recurrence after cryoballoon ablation in patients with paroxysmal AF.

Long-term outcome of the atrioventricular node ablation and pacemaker implantation for symptomatic refractory atrial fibrillation.

AIMS: To investigate long-term outcome and to determine predictors of development of heart failure (HF) in patients with atrioventricular (AV) node ablation and permanent right ventricular pacing because of symptomatic refractory atrial fibrillation (AF). BACKGROUND: Atrioventricular node ablation and subsequent permanent pacing is a well-established therapy for patients with AF. Long-term right ventricular pacing may induce HF. METHODS AND RESULTS: In 121 (45 with previous HF) patients with drug refractory AF, AV node ablation and implantation of a pacemaker was performed. At baseline and after a mean follow-up of 4.3 +/- 3.3 years, New York Heart Association (NYHA) functional class for HF and left ventricular (LV) and atrial diameters were assessed. During and at the end of follow-up, hospitalizations for HF, mortality, and quality of life were assessed using the SF-36 and an AVN-specific questionnaire. No significant changes in NYHA functional class (87 vs. 77% in NYHA I/II at baseline vs. end of follow-up) and LV end diastolic diameter (51 +/- 7 vs. 52 +/- 8 mm) were observed. Left ventricular end systolic diameter decreased (from 37 +/- 9 to 34 +/- 7 mm, P = 0.03) and fractional shortening improved (from 28 +/- 10 to 34 +/- 9, P = 0.02) in all patients and in patients with previous HF, but not in patients without previous HF. Hospitalizations for HF occurred in 24 patients (20%), predominantly those with previous HF. All-cause mortality occurred in 31 (26%) patients. At the end of follow-up, quality of life was comparable with the control group. CONCLUSION: Long-term outcome of AV node ablation and permanent pacing is good. Atrioventricular node ablation remains a treatment option for AF.

Persistent atrial fibrillation is associated with appropriate shocks and heart failure in patients with left ventricular dysfunction treated with an implantable cardioverter defibrillator.

AIM: The objective of this study was to investigate whether persistent atrial fibrillation (AF) and new-onset AF are associated with appropriate shocks, cardiovascular mortality, chronic heart failure (CHF), and inappropriate shocks in implantable cardioverter defibrillator (ICD) patients with left ventricular dysfunction. METHODS: We included 290 consecutive ICD patients with a documented left ventricular ejection fraction < or = 0.35 and compared outcomes between patients without AF (n = 207), those with persistent AF (n = 64), and those with new-onset AF (n = 19). RESULTS: The patients with persistent AF were older, more frequently had valve disease and cardiac surgery, and less frequently had coronary artery disease as compared with the patients without AF. Patients with persistent AF had a higher New York Heart Association class, however, left ventricular ejection fraction rates between these 2 groups were comparable (0.28 +/- 0.07 vs 0.29 +/- 0.08, P = not significant). No difference was found between patients with new-onset AF and those without AF. During follow-up (2.6 +/- 1.9 years), more patients with persistent AF received appropriate ICD shocks as compared with those without AF (24 [38%] vs 49 [24%], P = .04). Deterioration of CHF occurred more often in patients with persistent AF (19 [30%], P = .001) and those with new-onset AF (9 [47%], P < .001) as compared with patients without AF (31 [14%]). Multivariate analysis revealed that patients with persistent AF had an increased risk for appropriate ICD shocks (adjusted hazard ratio [HR] 1.9, 95% CI 1.2-3.2, P = .009). Persistent AF (adjusted HR 2.1, 95% CI 1.1-3.9, P = .03) and new-onset AF (adjusted HR 2.5, 95% CI 1.1-5.7, P = .02) were found to be independent risk indicators of CHF deterioration. CONCLUSIONS: In ICD patients with left ventricular dysfunction, persistent AF is associated with appropriate ICD shocks and deterioration of CHF. New-onset AF is related to deterioration of CHF.

Right ventricular pacing and the risk of heart failure in implantable cardioverter-defibrillator patients.

BACKGROUND: Right ventricular (RV) pacing in implantable cardioverter-defibrillator (ICD) patients may have detrimental effects on morbidity and mortality, in particular by inducing heart failure (HF). OBJECTIVE: We investigated whether RV pacing increases the risk of HF in an asymptomatic ICD population. METHODS: We evaluated all patients without symptomatic HF who received an ICD. The primary endpoint was the occurrence of HF, which was defined as new HF, hospitalization for HF, or death due to HF. The secondary endpoint was appropriate shocks. RESULTS: The study population consisted of 456 patients with mean left ventricular ejection fraction (LVEF) 40% +/- 13%. Mean follow-up was 31 +/- 22 months. Because of the bimodal distribution of pacing, patients were divided into two groups: paced 50% (median 96%; n = 143). HF occurred more often in the paced >50% group (20% versus 9%; P <.001). Multivariate analysis identified RV pacing >50% (adjusted hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.08-3.15; P = .03), baseline LVEF <26% (adjusted HR 3.15; 95% CI 1.77-5.59; P <.001), angina pectoris, history of atrial fibrillation, and baseline diuretic use as independent predictors of HF. RV pacing caused more HF events in patients with LVEF <26% (n = 64; 55% of paced >50% patients versus 20% of paced 50% also independently predicted appropriate shocks (adjusted HR 1.50; 95% CI 1.02-2.20; P = .04). CONCLUSION: RV pacing was associated with an increased risk of HF in asymptomatic ICD patients, particularly in those with preexistent left ventricular dysfunction.

Infection and pubertal timing: a systematic review.

The decline in age of pubertal timing has serious public health implications ranging from psychosocial adjustment problems to a possible increase in reproductive cancers. One biologically plausible explanation for the decline is a decrease in exposures to infections. To systematically review studies that assess the role of infection in pubertal timing, Medline, Web of Science and EMBASE were systematically searched and retrieved studies were reviewed for eligibility. Eligible studies examined the association between infections, including microbial exposures, and physical pubertal characteristics (breast, genitalia and pubic hair development) or age at menarche. We excluded studies that were published in a language other than English, focused on precocious puberty, were case studies, and/or included youth with autoimmune diseases. We report on study design, population characteristics, measurement of infection and puberty and the main effects of infection on pubertal development. Based on our search terms we identified 1372 unique articles, of which only 15 human and five animal studies met our eligibility criteria. Not all studies examined all outcomes. Infection was associated with later breast development (4/4 human studies), with less consistent evidence for genitalia and pubic hair development. Seven studies assessed age at menarche with inconsistent findings (three supporting later, four no association). We conclude that a small but consistent literature supports that infection is associated with later breast development; the evidence for other pubertal events and age at menarche is less clear. Where fewer childhood infections coincide with the rise in incidence of hormone-related cancers.

Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice.

Brn3a/Brn-3.0 is a POU-domain transcription factor expressed in primary sensory neurons of the cranial and dorsal root ganglia and in specific neurons in the caudal CNS. Mice lacking Brn3a undergo extensive sensory neural death late in gestation and die at birth. To further examine Brn3a expression and the abnormalities that accompany its absence, we constructed a transgene containing 11 kb of Brn3a upstream regulatory sequence linked to a LacZ reporter. Here we show that these regulatory sequences direct transgene expression specifically to Brn3a peripheral sensory neurons of the cranial and dorsal root ganglia. Furthermore, expression of the 11 kb/LacZ reporter in the sensory neurons of the mesencephalic trigeminal, but not other Brn3a midbrain neurons, demonstrates that cell-specific transgene expression is targeted to a functional class of neurons rather than to an anatomical region. We then interbred the 11 kb/LacZ reporter strain with mice carrying a null mutant allele of Brn3a to generate 11 kb/LacZ, Brn3a knock-out mice. beta-Galactosidase expression in these mice reveals significant axonal growth defects, including excessive and premature branching of the major divisions of the trigeminal nerve and a failure to correctly innervate whisker follicles, all of which precede sensory neural death in these mice. These defects in Brn3a(-/-) mice resemble strongly those seen in mice lacking the mediators of sensory pathfinding semaphorin 3A and neuropilin-1. Here we show, however, that sensory neurons are able to express neuropilin-1 in the absence of Brn3a.

Cardiotoxin from cobra venom increases the level of phosphatidylinositol 4-monophosphate and phosphatidylinositol kinase activity in two cell lines.

In rat basophilic leukemia-2H3 (RBL-2H3) and Madin-Darby canine kidney (MDCK) cells, cardiotoxin from cobra venom induced a marked decrease in the level of [3H] phosphatidylinositol and a corresponding increase in the level of [3H]phosphatidylinositol 4-monophosphate over the course of 20 min as demonstrated in cells that had been labeled to equilibrium with [3H]inositol. The effect was dependent on the concentration (5-30 micrograms/ml) of the toxin. In plasma membrane-enriched fractions isolated from the two cell lines, the cardiotoxin enhanced the endogenous activity of phosphatidylinositol kinase especially at temperatures above 14 degrees C. In RBL-2H3 cells, cardiotoxin also induced release of substantial amounts of histamine and lactate dehydrogenase. The release of histamine, but not of lactate dehydrogenase, was totally dependent on external calcium and this release probably represented an exocytotic response of the cells to cardiotoxin. Although, initially, treatment with the toxin did not impair antigen-induced hydrolysis of inositol phospholipids or prevent the antigen-induced rise in the concentration of cytosol Ca2+, prolonged exposure to the toxin did result in a progressive loss of responsiveness of RBL-2H3 cells to antigen.

Safe and cost effective use of alteplase for the clearance of occluded central venous access devices.

PURPOSE: To determine whether cryopreserved solutions of the thrombolytic agent alteplase could be used as a safe, effective, and economically reasonable alternative to urokinase in patients presenting with occluded central venous access devices (CVADs). MATERIALS AND METHODS: Alteplase has been reported as an efficacious alternative to urokinase for treatment of occluded CVADs. However, the practicality of using alteplase as the thrombolytic of choice for this indication remained conjectural. To make this approach economically feasible, alteplase was diluted to 1 mg/mL and 2.5-mL aliquots were stored at -20 degrees C until use. A need to confirm that the cryopreserving and thawing of the reconstituted solution did not compromise the safety and efficacy reported from prior trials was recognized. A quality assessment initiative was undertaken to concurrently monitor the safety and efficacy of this approach. Patients presenting with occluded CVADs received a sufficient volume of the thawed alteplase solution to fill the occluded catheter(s). Data, including efficacy, adverse reactions, dwell time, and catheter type, were collected over a 5-month period. RESULTS: One hundred twenty-one patients accounting for 168 attempted clearances were assessable for safety and efficacy. One hundred thirty-six (81%) of the 168 catheter clearance attempts resulted in successful catheter clearance (95% confidence interval, 74% to 86%). No adverse events were reported. CONCLUSION: Cryopreserved 1-mg/mL aliquots of alteplase are safe and effective in the clearance of occluded CVADs when stored at -20 degrees C for 30 days. The ability to cryopreserve alteplase aliquots makes it an economically reasonable alternative to urokinase in the setting of CVAD occlusion.

Functional characteristics of coronary vasomotor function following intramyocardial gene therapy with naked DNA encoding for vascular endothelial growth factor165.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. VEGF gene therapy improves perfusion of ischemic myocardium in experimental models and possibly in patients with end-stage coronary artery disease. In addition to its proliferative and migratory effect on endothelial cells, it also activates and up-regulates endothelial nitric oxide synthase (eNOS). Therefore, the authors investigated coronary endothelium-dependent vasodilatation in patients before and after VEGF gene therapy. The effect of intracoronary acetylcholine infusion on coronary diameter was assessed at baseline and after 3 months follow-up in patients with end-stage coronary artery disease treated with VEGF gene and in controls scheduled for elective percutaneous transluminal coronary angioplasty (PTCA) (acetylcholine test at diagnostic angiography and before a subsequently scheduled PTCA). Five out of six VEGF patients experienced a reduction in anginal complaints. Angiographic evidence for improved collateral filling was evident in two out of six patients. The vasoconstrictive response to acetylcholine was partly converted into dilatation. In contrast, the acetylcholine response in control patients remained vasoconstrictive. In conclusion, VEGF gene therapy has an important beneficial effect on the functional characteristics of the myocardial vascular network. Therefore, this therapy can potentially play an important role in all stages of the atherosclerotic process.

Migrating esophageal foreign bodies.

UNLABELLED: Ingested foreign bodies which migrate extraluminally, although rare in occurrence, are fraught with the potential to cause life-threatening complications. PURPOSE OF THE STUDY: To discuss the management of this pathology. MATERIAL AND METHODS: A series of four patients with such occurrences is presented. CONCLUSION: A discussion on the safe management of such seemingly innocuous foreign bodies allows the authors to propose a therapeutical algorythm.