Respiratory Paradoxical Adverse Drug Reactions Associated with Acetylcysteine and Carbocysteine Systemic Use in Paediatric Patients: A National Survey

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence

Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

Hospital use of systemic antifungal drugs

BACKGROUND: Sales data indicate a major increase in the prescription of antifungal drugs in the last two decades. Many new agents for systemic use that only recently have become available are likely to be prescribed intensively in acute care hospitals. Sales data do not adequately describe the developments of drug use density. Given the concerns about the potential emergence of antifungal drug resistance, data on drug use density, however, may be valuable and are needed for analyses of the relationship between drug use and antifungal resistance. METHODS: Hospital pharmacy records for the years 2001 to 2003 were evaluated, and the number of prescribed daily doses (PDD, defined according to locally used doses) per 100 patient days were calculated to compare systemic antifungal drug use density in different medical and surgical service areas between five state university hospitals. RESULTS: The 3-year averages in recent antifungal drug use for the five hospitals ranged between 8.6 and 29.3 PDD/100 patient days in the medical services (including subspecialties and intensive care), and between 1.1 and 4.0 PDD/100 patient days in the surgical services, respectively. In all five hospitals, systemic antifungal drug use was higher in the hematology-oncology service areas (mean, 48.4, range, 24 to 101 PDD/100 patient days, data for the year 2003) than in the medical intensive care units (mean, 18.3, range, 10 to 33 PDD/100) or in the surgical intensive care units (mean, 10.7, range, 6 to 18 PDD/100). Fluconazole was the most prescribed antifungal drug in all areas. In 2003, amphotericin B consumption had declined to 3 PDD/100 in the hematology-oncology areas while voriconazole use had increased to 10 PDD/100 in 2003. CONCLUSION: Hematology-oncology services are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased. The data may be useful as a benchmark for focused interventions to improve prescribing quality

mRNA expression of the DNA replication-initiation proteins in epithelial dysplasia and squamous cell carcinoma of the tongue

<p>Abstract</p> <p>Background</p> <p>The tongue squamous cell carcinomas (SCCs) are characterized by high mitotic activity, and early detection is desirable. Overexpression of the DNA replication-initiation proteins has been associated with dysplasia and malignancy. Our aim was to determine whether these proteins are useful biomarkers for assessing the development of tongue SCC.</p> <p>Methods</p> <p>We analyzed the mRNA expression of CDC6, CDT1, MCM2 and CDC45 in formalin-fixed, paraffin-embedded benign and malignant tongue tissues using quantitative real-time PCR followed by statistical analysis.</p> <p>Results</p> <p>We found that the expression levels are significantly higher in malignant SCC than mild precancerous epithelial dysplasia, and the expression levels in general increase with increasing grade of precancerous lesions from mild, moderate to severe epithelial dysplasia. CDC6 and CDC45 expression is dependent of the dysplasia grade and lymph node status. CDT1 expression is higher in severe dysplasia than in mild and moderate dysplasia. MCM2 expression is dependent of the dysplasia grade, lymph node status and clinical stage. The expression of the four genes is independent of tumor size or histological grade. A simple linear regression analysis revealed a linear increase in the mRNA levels of the four genes from the mild to severe dysplasia and SCC. A strong association was established between CDC6 and CDT1, and between MCM2 and CDC45 expression. The nonparametric receiver operating characteristic analysis suggested that MCM2 and CDC45 had a higher accuracy than CDC6 and CDT1 for distinguishing dysplasia from tongue SCC.</p> <p>Conclusion</p> <p>These proteins can be used as biomarkers to distinguish precancerous dysplasia from SCC and are useful for early detection and diagnosis of SCC as an adjunct to clinicopathological parameters.</p

Inherent Interfacial Mechanical Gradients in 3D Hydrogels Influence Tumor Cell Behaviors

Cells sense and respond to the rigidity of their microenvironment by altering their morphology and migration behavior. To examine this response, hydrogels with a range of moduli or mechanical gradients have been developed. Here, we show that edge effects inherent in hydrogels supported on rigid substrates also influence cell behavior. A Matrigel hydrogel was supported on a rigid glass substrate, an interface which computational techniques revealed to yield relative stiffening close to the rigid substrate support. To explore the influence of these gradients in 3D, hydrogels of varying Matrigel content were synthesized and the morphology, spreading, actin organization, and migration of glioblastoma multiforme (GBM) tumor cells were examined at the lowest (<50 µm) and highest (>500 µm) gel positions. GBMs adopted bipolar morphologies, displayed actin stress fiber formation, and evidenced fast, mesenchymal migration close to the substrate, whereas away from the interface, they adopted more rounded or ellipsoid morphologies, displayed poor actin architecture, and evidenced slow migration with some amoeboid characteristics. Mechanical gradients produced via edge effects could be observed with other hydrogels and substrates and permit observation of responses to multiple mechanical environments in a single hydrogel. Thus, hydrogel-support edge effects could be used to explore mechanosensitivity in a single 3D hydrogel system and should be considered in 3D hydrogel cell culture systems

How and why community hospital clinicians document a positive screen for intimate partner violence: a cross-sectional study

BACKGROUND: This two-part study examines primary care clinicians' chart documentation and attitudes when confronted by a positive waiting room screen for intimate partner violence (IPV). METHODS: Patients at community hospital-affiliated health centers completed a screening questionnaire in waiting rooms that primary care providers (PCPs) were subsequently given at the time of the visit. We first reviewed the medical records of patients who screened positive for IPV, evaluating the presence and quality of documentation. Next we administered a survey to PCPs that measured their knowledge, attitudes and practice regarding IPV. RESULTS: Seventy-two percent of charts contained some documentation of IPV, however only 10% contained both a referral and safety plan. PCPs were more likely to refer patients (p < .05) who screened positively for mood or anxiety disorders, disclosed that they feared for their safety or were economically disadvantaged. Those that feared for their safety or endorsed mood or anxiety disorders were more likely to have notation of a safety plan in their records. When surveyed, 81.6% of clinicians strongly agreed that it is their role to inquire about IPV, but only 68% expressed confidence in their ability to manage it. In contrast, 93% expressed confidence in managing depression. Sixty-seven percent identified time constraints as a barrier to care. Predictors of PCP confidence in treating patients who have experienced IPV (p < .05) included hours of recent training and clinical experience with IPV. CONCLUSION: Mandatory waiting room screening for IPV does not result in high levels of referral or safety planning by PCPs. Despite the implementation of a screening process, clinicians lack confidence and time to address IPV in their patient populations suggesting that alternative methods of training and supporting PCPs need to be developed

Screening for Domestic Violence Among Adult Women in the United States

BACKGROUND: Domestic violence is a problem frequently encountered in health care settings and a risk factor for physical and mental health problems. OBJECTIVE: To provide nationally representative estimates of rates of domestic violence screening among women, to identify predictors of screening, and to describe settings where women are screened. DESIGN AND PARTICIPANTS: We examined 4,821 women over the age of 18 from the second wave of Healthcare for Communities, a nationally representative household telephone survey conducted in 2000–2001. MEASUREMENTS: Self-reports concerning whether the respondent was ever asked about domestic or family violence by any health care provider. RESULTS: Only 7% (95% CI, 6%–8%) of women reported they were ever asked about domestic violence or family violence by a health care professional. Of women who were asked about abuse, nearly half (46%) were asked in a primary care setting, and 24% were asked in a specialty mental health setting. Women with risk factors for domestic violence were more likely to report being asked about it by a health care professional, but rates were still low. CONCLUSIONS: Self-reported rates of screening for domestic violence are low even among women at higher risk for abuse. These findings reinforce the importance of developing training and raising awareness of domestic violence and its health implications. This is especially true in primary care and mental health specialty settings

Impact of leg lengthening on viscoelastic properties of the deep fascia

<p>Abstract</p> <p>Background</p> <p>Despite the morphological alterations of the deep fascia subjected to leg lengthening have been investigated in cellular and extracellular aspects, the impact of leg lengthening on viscoelastic properties of the deep fascia remains largely unknown. This study aimed to address the changes of viscoelastic properties of the deep fascia during leg lengthening using uniaxial tensile test.</p> <p>Methods</p> <p>Animal model of leg lengthening was established in New Zealand white rabbits. Distraction was initiated at a rate of 1 mm/day and 2 mm/day in two steps, and preceded until increases of 10% and 20% in the initial length of tibia had been achieved. The deep fascia specimens of 30 mm × 10 mm were clamped with the Instron 1122 tensile tester at room temperature with a constant tensile rate of 5 mm/min. After 5 load-download tensile tests had been performed, the specimens were elongated until rupture. The load-displacement curves were automatically generated.</p> <p>Results</p> <p>The normal deep fascia showed typical viscoelastic rule of collagenous tissues. Each experimental group of the deep fascia after leg lengthening kept the properties. The curves of the deep fascia at a rate of 1 mm/day with 20% increase in tibia length were the closest to those of normal deep fascia. The ultimate tension strength and the strain at rupture on average of normal deep fascia were 2.69 N (8.97 mN/mm²) and 14.11%, respectively. The increases in ultimate tension strength and strain at rupture of the deep fascia after leg lengthening were statistically significant.</p> <p>Conclusion</p> <p>The deep fascia subjected to leg lengthening exhibits viscoelastic properties as collagenous tissues without lengthening other than increased strain and strength. Notwithstanding different lengthening schemes result in varied viscoelastic properties changes, the most comparable viscoelastic properties to be demonstrated are under the scheme of a distraction rate of 1 mm/day and 20% increase in tibia length.</p

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur