Mood disorders are a major public health problem and are associated with considerable burden of disease, suicides, physical comorbidities, high economic costs, and poor quality of life. Approximately 30%-40% of patients with major depression have only a partial response to available pharmacological and psychotherapeutic interventions. Complementary and alternative medicine (CAM) has been used either alone or in combination with conventional therapies in patients with mood disorders. This review of the literature examines evidence-based data on the use of CAM in mood disorders. A search of the PubMed, Medline, Google Scholar, and Quertile databases using keywords was conducted, and relevant articles published in the English language in the peer-reviewed journals over the past two decades were retrieved. Evidence-based data suggest that light therapy, St John's wort, Rhodiola rosea, omega-3 fatty acids, yoga, acupuncture, mindfulness therapies, exercise, sleep deprivation, and S-adenosylmethionine are effective in the treatment of mood disorders. Clinical trials of vitamin B complex, vitamin D, and methylfolate found that, while these were useful in physical illness, results were equivocal in patients with mood disorders. Studies support the adjunctive role of omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid in unipolar and bipolar depression, although manic symptoms are not affected and higher doses are required in patients with resistant bipolar depression and rapid cycling. Omega-3 fatty acids are useful in pregnant women with major depression, and have no adverse effects on the fetus. Choline, inositol, 5-hydroxy-L-tryptophan, and N-acetylcysteine are effective adjuncts in bipolar patients. Dehydroepiandrosterone is effective both in bipolar depression and depression in the setting of comorbid physical disease, although doses should be titrated to avoid adverse effects. Ayurvedic and homeopathic therapies have the potential to improve symptoms of depression, although larger controlled trials are needed. Mind-body-spirit and integrative medicine approaches can be used effectively in mild to moderate depression and in treatment-resistant depression. Currently, although CAM therapies are not the primary treatment of mood disorders, level 1 evidence could emerge in the future showing that such treatments are effective.

Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently under clinical trials for cancer, however many tumor cells, including hepatocellular carcinoma (HCC) develop resistance to TRAIL-induced apoptosis. Hence, novel agents that can alleviate TRAIL-induced resistance are urgently needed. In the present report, we investigated the potential of emodin to enhance apoptosis induced by TRAIL in HCC cells. As observed by MTT cytotoxicity assay and the externalization of the membrane phospholipid phosphatidylserine, we found that emodin can significantly potentiate TRAIL-induced apoptosis in HCC cells. When investigated for the mechanism(s), we observed that emodin can downregulate the expression of various cell survival proteins, and induce the cell surface expression of both TRAIL receptors, death receptors (DR) 4 as well as 5. In addition, emodin increased the expression of C/EBP homologous protein (CHOP) in a time-dependent manner. Knockdown of CHOP by siRNA decreased the induction of emodin-induced DR5 expression and apoptosis. Emodin-induced induction of DR5 was mediated through the generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of DR5 and the induction of apoptosis. Also, the knockdown of X-linked inhibitor of apoptosis protein by siRNA significantly reduced the sensitization effect of emodin on TRAIL-induced apoptosis. Overall, our experimental results clearly indicate that emodin can indeed potentiate TRAIL-induced apoptosis through the downregulation of antiapoptotic proteins, increased expression of apoptotic proteins, and ROS mediated upregulation of DR in HCC cells.

SESSION TYPE: DVT/PE/Pulmonary Hypertension Posters IPRESENTED ON: Wednesday, October 24, 2012 at 01:30 PM - 02:30 PM

INTRODUCTION:

In patients presenting with volatile alcohol toxicity early diagnosis and treatment is critical to prevent organ damage and death. The goal standard for diagnosing methanol and ethylene glycol (EG) toxicity is gas chromatography. Results can take up to days and many hospitals are not equipped to provide such test. Clinicians must rely on the clinical presentation and other laboratory tests such osmolar gap (OG) to make a diagnosis. An OG of >10 indicates the presence of other osmoles in the blood such as methanol or EG. We present a case with severe methanol toxicity and a normal OG.

CASE PRESENTATION:

A 48 year old Caucasian male was admitted to a community hospital where he presented 20 minutes after ingesting over 500 tablets of extra-strength Tylenol. Upon presentation, N-acetylcysteine infusion was initiated. Subsequently patient required intubation and mechanical ventilation due to impending respiratory failure. Initial laboratory work up revealed an Acetaminophen level of 86 mg/L, normal OG, high anion gap metabolic acidosis, negative urine analysis and serum drug screen. He was then transferred to our hospital for further management. Upon arrival to our hospital (tertiary center), the patient had multisystem organ failure. Acetaminophen level was >800 mg/L, therefore activated charcoal was administered. On Hospital day 2 metabolic acidosis persisted, therefore, volatile gas screen was ordered. Results reported in 3 hours were positive for methanol. The patient was started on renal replacement therapy and Fomepizole.The remaining of the hospital course was significant for development of cerebral edema for which hypothermia protocol was initiated. Also, the patient developed an upper gastrointestinal bleed, which was consistent with caustic ingestion. After 2 weeks in the intensive care unit, the patient eventually made a miraculous recovery and returned to baseline mental status and function.

DISCUSSION:

Perhaps a OG of < 10 should be considered elevated as there may be patients with a normal osmolar gap of -2 +/- 6 (as in children). Also, once methanol is converted to its toxic metabolite, formic acid, this compound is no longer osmotically active and thus the OG will return to normal.

CONCLUSIONS:

Methanol toxicity can be managed effectively if diagnosed early during the clinical course. Although an elevated OG is highly sensitive for volatile alcohol intoxication, a normal OG does not necessarily rule-it out (not specific). Therefore, treatment should be started immediately if volatile gas toxicity is suspected by the treating clinician.1) Jammalamadaka, Divakar MD, et al. Ethylene Glycol, Methanol and Isopropyl Alcohol Intoxication. American Journal of the Medical Sciences. 339(3):276-281, March 2010.DISCLOSURE: The following authors have nothing to disclose: Maria Herrera, Christiane MbiandaNo Product/Research Disclosure InformationMedical College of Wisconsin, Milwaukee, WI.

Context. N-acetylcysteine (NAC) is acknowledged as an effective antidote for paracetamol overdose. However, adverse effects to NAC are common and may be a point of concern for the patient and the treating physician.

Objective.

The aim of the present study was to further analyse possible risk factors of anaphylactoid adverse effects to intravenous NAC in order to identify individual patients or groups of patients at particular risk. Methods. This study is an observational case series of adverse effects to NAC administered according to the standard guidelines in patients who presented with paracetamol overdose between March 1999 and September 2011.

Results.

A total of 1218 admissions for paracetamol overdose receiving intravenous NAC were recorded in 950 patients. Anaphylactoid adverse effects occurred in 18.6%. The proportion of cases with adverse effects gradually declined from 25.9% in cases with undetectable p-paracetamol to 6.3% in cases with p-paracetamol above 1.5 mmol/L (226 μg/mL) (Spearman Rank R-test: p < 0.00001). The proportion of cases with adverse effects was significantly higher in cases of non-Danish origin than that of Danish origin (28.5% vs. 15.1%; Chi-square: p < 0.00001). In patients with repeated exposure to NAC, the rate of adverse effects on re-exposure was significantly higher in patients with a previous reaction to NAC compared to those without a previous reaction (Rate Ratio 6.2; 95% CI 2.9-17.1).

Conclusion.

The development of anaphylactoid adverse effects to intravenous NAC was strongly associated with a low p-paracetamol, non-Danish origin and a history of previous reaction to NAC. These adverse effects are common, but usually mild and easily manageable. The incidence of adverse effects may be reduced by pre-treating selected patients with antihistamines, in particular those with a previous reaction to NAC.

A greater reduction in cancer risk associated with mushroom diet rich in fungus polysaccharides is generally accepted. Meanwhile, edible Pleurotus abalonus as a member of Abalone mushroom family is a popular nutritional supplement that purportedly prevents cancer occurrence. However, these anecdotal claims are supported by limited studies describing tumor-inhibitory responses to the promising polysaccharides, and the molecular mechanisms underlying these properties have not yet been elucidated. METHODOLOGYPRINCIPAL FINDINGS: We here fractionated the crude polysaccharide preparation from the fruiting bodies of P. abalonus into three fractions, namely PAP-1, PAP-2 and PAP-3, and tested these fractions for antiproliferative activity in human breast cancer MCF-7 cells. The largest PAP-3, an acidic polysaccharide fraction with a molecular mass of 3.68×10(5) Da, was the most active in inhibiting MCF-7 cancer cells with an IC50 of 193 µg/mL. The changes in cell normal morphology were observed by DAPI staining and the PAP-3-induced apoptosis was confirmed by annexin V/propidium iodide staining. The apoptosis was involved in mitochondria-mediated pathway including the loss of mitochondrial membrane potential (Δψm), the increase of Bax/Bcl-2 ratio, caspase-9/3 activation, and poly(ADP-ribose) polymerase (PARP) degradation, as well as intracellular ROS production. PAP-3 also induced up-regulation of p53, and cell cycle arrest at the S phase. The incubation of MCF-7 cells with antioxidant superoxide dismutase (SOD) and N-acetylcysteine (NAC) significantly attenuated the ROS generation and apoptosis caused by PAP-3, indicating that intracellular ROS plays a pivotal role in cell death. CONCLUSIONSSIGNIFICANCE: These findings suggest that the polysaccharides, especially acidic PAP-3, are very important nutritional ingredients responsible for, at least in part, the anticancer health benefits of P. abalonus via ROS-mediated mitochondrial apoptotic pathway. It is a major breakthrough bringing new insight of the potential use of the polysaccharides as health-care food or medicine to provide significant natural defense against human cancer.

Introduction: There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L) when treated with oral and IV acetylcysteine.

Methods:

Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment.

Results:

We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity.

Conclusion:

Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration.

To investigate the biphasic effects of hydrogen peroxide (H2O2) on the orbital fibroblasts of patients with Graves' ophthalmopathy (GO) and the relation to antioxidants and proinflammatory cytokines.Proliferation of cultured orbital fibroblasts from patients with GO and normal controls was evaluated in response to various concentrations of H2O2. The effect of low concentrations of H2O2 (6.25 μM) on the cellular proliferation and induction of intracellular proinflammatory cytokines, and reactive oxygen species of orbital fibroblasts were assessed. Protective effects of N-acetylcysteine and vitamin C on GO fibroblasts in response to 6.25 μM H2O2 stimulation were also investigated.When the GO fibroblasts were exposed to H2O2 at a concentration of 50 μM or above, significant cytotoxicity was observed. In contrast, lower concentrations of H2O2 (3.125-25 μM) increased the survival of GO fibroblasts with the peak cellular proliferation at 6.25 μM H2O2. However, this biphasic effect of H2O2 on the viability of orbital fibroblasts was not found in normal controls. In addition, 6.25 μM H2O2 led to significant elevation of the levels of transforming growth factor, beta 1, interleukin-1β, and superoxide anion in GO fibroblasts, but no significant change in the normal controls. Pretreatment with N-acetylcysteine or vitamin C reversed the enhanced proliferation capacity and the induction of transforming growth factor, beta 1, interleukin-1β and superoxide anion of GO fibroblasts in response to 6.25 μM H2O2.These findings revealed the biphasic effect of H2O2 on cellular proliferation of GO orbital fibroblasts. Importantly, a low level of H2O2 can stimulate proliferation of GO orbital fibroblasts and induce the production of proinflammatory cytokines, which can be inhibited by pretreatment with antioxidants. This provides a theoretical basis for the rational use of antioxidant in treating GO at an early stage.

Orthopaedics is currently the largest market of biomaterials worldwide and implant-related infections, although relatively rare, remain among the first reasons for joint arthroplasty and osteosynthesis failure. Bacteria start implant infection by adhering to biomaterials and producing biofilms, which represent a major reason for bacterial persistence, in spite of antibiotic treatment and host's defence. In the last two decades, a number of different antibiofilm agents have been studied and both in vitro and in vivo results appear now promising, even if their effective role in orthopaedics remains to be assessed. In this review, we introduce an original classification of antibiofilm agents, based on their mechanism of action and examine the available data concerning their possible application to orthopaedic implant-related infections. Molecules that interfere with biofilm production (biofilm prevention agents) include anti-adhesion compounds, quorum sensing inhibitors, non-steroideal anti-inflammatory drugs, and antimicrobial peptides; N-acetylcysteine and specific enzymes promise the greatest therapeutic possibilities by disrupting established biofilms (biofilm disrupting agents). The identification of antimicrobials able to bypass the biofilm barrier (biofilm bypassing agents), and antibiofilm vaccines are further strategies aimed to reduce the impact of biofilm-related infections, opening new pathways in controlling implant-related infections. However, this review shows that still insufficient knowledge is currently available as to regard the efficacy and safety of the investigated antibiofilm strategies to treat infection that involve bone tissue and biomaterials commonly implanted in orthopaedics, pointing out the need for further research in this promising field.

PURPOSE:

The use of N-acetylcysteine (NAC) for preventing contrast induced nephropathy (CIN) is debated in the intensive care unit. NAC may alter the concentration of serum creatinine and interfere with CIN diagnosis. The effectiveness of NAC was evaluated with a special attention on its specific effect on creatinine levels compared to cystatin C.

METHODS:

In a first period, we prospectively enrolled patients receiving saline and low osmolality contrast media for 140 exams in 2 intensive care units with opposite policies regarding the use of NAC. Renal impairment was defined by both the classical CIN and the "sensitive" Acute Kidney Injury Network (AKIN) (taking creatinine and diuresis) definitions. In a second period, we compared the evolution of serum creatinine and cystatin C after 23 additional contrast examinations under NAC.

RESULTS:

Seventy exams with and without NAC were compared in the first period. Risk factors for CIN were similar in the two intensive care unit populations. No difference in CIN incidence was found with and without NAC, using the CIN (10/70 vs 15/70) or the AKIN (24/70 vs 22/70) definition. Interestingly, NAC seemed to reduce renal impairment when the creatinine criterion of the AKIN definition was considered alone [9% vs 21%, P = .033]. Overall, the incidence of renal impairment was 18%, 33% and 15% using the CIN definition, the AKIN, or using AKIN with creatinine alone. Serum creatinine significantly decreased after exams with NAC while cystatin C remained stable.

CONCLUSION:

The incidence of CIN does not seem to be influenced by NAC, except if small changes in creatinine only are considered.