Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity

AbstractCisplatin-induced ototoxicity is one of the major factors limiting cisplatin chemotherapy. Ototoxicity results from damage to outer hair cells (OHCs) and other regions of the cochlea. At the cellular level, cisplatin increases reactive oxygen species (ROS) leading to cochlear inflammation and apoptosis. Thus, ideal otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin's chemotherapeutic efficacy. In this study, we show that epigallocatechin-3-gallate (EGCG) is a prototypic agent exhibiting these properties of an effect otoprotective agent. Rats administered oral EGCG demonstrate reduced cisplatin-induced hearing loss, reduced loss of OHCs in the basal region of the cochlea and reduced oxidative stress and apoptotic markers. EGCG also protected against the loss of ribbon synapses associated with inner hair cells and Na+/K+ ATPase α1 in the stria vascularis and spiral ligament. In vitro studies showed that EGCG reduced cisplatin-induced ROS generation and ERK1/2 and signal transducer and activator of transcription-1 (STAT1) activity, but preserved the activity of STAT3 and Bcl-xL. The increase in STAT3/STAT1 ratio appears critical for mediating its otoprotection. EGCG did not alter cisplatin-induced apoptosis of human-derived cancer cells or cisplatin antitumor efficacy in a xenograft tumor model in mice because of its inability to rescue the downregulation of STAT3 in these cells. These data suggest that EGCG is an ideal otoprotective agent for treating cisplatin-induced hearing loss without compromising its antitumor efficacy.</jats:p

Determinants of Left Ventricular Functional Recovery After Thrombolytic Therapy and/or Immediate Coronary Angioplasty in Acute Myocardial Infarction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74934/1/j.1540-8183.1988.tb00403.x.pd

Recovery from Posttraumatic Stress Symptoms: A Qualitative Study of Attributions in Survivors of War

This study was funded by a grant from the European Commission, contract number INCO-CT-2004-50917

Resilience in the Face of Disaster: Prevalence and Longitudinal Course of Mental Disorders following Hurricane Ike

Objectives: Natural disasters may increase risk for a broad range of psychiatric disorders, both in the short- and in the medium-term. We sought to determine the prevalence and longitudinal course of posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), depression, and suicidality in the first 18 months after Hurricane Ike. Methods: Six hundred fifty-eight adults representative of Galveston and Chambers Counties, Texas participated in a random, population-based survey. The initial assessment was conducted 2 to 5 months after Hurricane Ike struck Galveston Bay on September 13, 2008. Follow-up assessments were conducted at 5 to 9 and 14 to 18 months after Hurricane Ike. Results: Past-month prevalence of any mental disorder (20.6% to 10.9%) and hurricane-related PTSD (6.9% to 2.5%) decreased over time. Past-month prevalence of PTSD related to a non-disaster traumatic event (5.8% to 7.1%), GAD (3.1% to 1.8%), PD (0.8% to 0.7%), depression (5.0% to 5.6%), and suicidality (2.6% to 4.2%) remained relatively stable over time. Conclusions: PTSD, both due to the hurricane and due to other traumatic events, was the most prevalent psychiatric disorder 2 to 5 months after Hurricane Ike. Prevalence of psychiatric disorders declined rapidly over time, suggesting that the vast majority of individuals exposed to this natural disaster ‘bounced back’ and were resilient to long-term mental health consequences of this large-scale traumatic event

Validation of the PHQ-9 as a screening instrument for depression in diabetes patients in specialized outpatient clinics

Background. For the treatment of depression in diabetes patients, it is important that depression is recognized at an early stage. A screening method for depression is the patient health questionnaire (PHQ-9). The aim of this study is to validate the 9-item Patient Health Questionnaire (PHQ-9) as a screening instrument for depression in diabetes patients in outpatient clinics. Methods. 197 diabetes patients from outpatient clinics in the Netherlands filled in the PHQ-9. Within 2 weeks they were approached for an interview with the Mini Neuropsychiatric Interview. DSM-IV diagnoses of Major Depressive Disorder (MDD) were the criterion for which the sensitivity, specificity, positive- and negative predictive values and Receiver Operator Curves (ROC) for the PHQ-9 were calculated. Results. The cut-off point of a summed score of 12 on the PHQ-9 resulted in a sensitivity of 75.7% and a specificity of 80.0%. Predictive values for negative and positive test results were respectively 93.4% and 46.7%. The ROC showed an area under the curve of 0.77. Conclusions. The PHQ-9 proved to be an efficient and well-received screening instrument for MDD in this sample of diabetes patients in a specialized outpatient clinic. The higher cut-off point of 12 that was needed and somewhat lower sensitivity than had been reported elsewhere may be due to the fact that the patients from a specialized diabetes clinic have more severe pathology and more complications, which could be recognized by the PHQ-9 as depression symptoms, while instead being diabetes symptom

Inhibitors of inflammation and endogenous surfactant pool size as modulators of lung injury with initiation of ventilation in preterm sheep

<p>Abstract</p> <p>Background</p> <p>Increased pro-inflammatory cytokines in tracheal aspirates correlate with the development of BPD in preterm infants. Ventilation of preterm lambs increases pro-inflammatory cytokines and causes lung inflammation.</p> <p>Objective</p> <p>We tested the hypothesis that selective inhibitors of pro-inflammatory signaling would decrease lung inflammation induced by ventilation in preterm newborn lambs. We also examined if the variability in injury response was explained by variations in the endogenous surfactant pool size.</p> <p>Methods</p> <p>Date-mated preterm lambs (n = 28) were operatively delivered and mechanically ventilated to cause lung injury (tidal volume escalation to 15 mL/kg by 15 min at age). The lambs then were ventilated with 8 mL/kg tidal volume for 1 h 45 min. Groups of animals randomly received specific inhibitors for IL-8, IL-1, or NF-κB. Unventilated lambs (n = 7) were the controls. Bronchoalveolar lavage fluid (BALF) and lung samples were used to quantify inflammation. Saturated phosphatidylcholine (Sat PC) was measured in BALF fluid and the data were stratified based on a level of 5 μmol/kg (~8 mg/kg surfactant).</p> <p>Results</p> <p>The inhibitors did not decrease the cytokine levels or inflammatory response. The inflammation increased as Sat PC pool size in BALF decreased. Ventilated lambs with a Sat PC level > 5 μmol/kg had significantly decreased markers of injury and lung inflammation compared with those lambs with < 5 μmol/kg.</p> <p>Conclusion</p> <p>Lung injury caused by high tidal volumes at birth were decreased when endogenous surfactant pool sizes were larger. Attempts to decrease inflammation by blocking IL-8, IL-1 or NF-κB were unsuccessful.</p

Epidemiology and Genetic Epidemiology of the Liver Function Test Proteins

The liver function test (LFT) is among the most commonly used clinical investigations to assess hepatic function, severity of liver diseases and the effect of therapies, as well as to detect drug-induced liver injury (DILI)

Detection and characteristics of microvascular obstruction in reperfused acute myocardial infarction using an optimized protocol for contrast-enhanced cardiovascular magnetic resonance imaging

Several cardiovascular magnetic resonance imaging (CMR) techniques are used to detect microvascular obstruction (MVO) after acute myocardial infarction (AMI). To determine the prevalence of MVO and gain more insight into the dynamic changes in appearance of MVO, we studied 84 consecutive patients with a reperfused AMI on average 5 and 104 days after admission, using an optimised single breath-hold 3D inversion recovery gradient echo pulse sequence (IR-GRE) protocol. Early MVO (2 min post-contrast) was detected in 53 patients (63%) and late MVO (10 min post-contrast) in 45 patients (54%; p = 0.008). The extent of MVO decreased from early to late imaging (4.3 ± 3.2% vs. 1.8 ± 1.8%, p < 0.001) and showed a heterogeneous pattern. At baseline, patients without MVO (early and late) had a higher left ventricular ejection fraction (LVEF) than patients with persistent late MVO (56 ± 7% vs. 48 ± 7%, p < 0.001) and LVEF was intermediate in patients with early MVO but late MVO disappearance (54 ± 6%). During follow-up, LVEF improved in all three subgroups but remained intermediate in patients with late MVO disappearance. This optimised single breath-hold 3D IR-GRE technique for imaging MVO early and late after contrast administration is fast, accurate and allows detection of patients with intermediate remodelling at follow-up