A Case of 5-Fluorouracil–Induced Acute Psychosis

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used in a number of solid malignancies, including colorectal cancer. Herein, we report the first case of 5-FU–induced psychosis. Psychosis occurred after the first 2 cycles of 5-FU, oxaliplatin, leucovorin, plus bevacizumab and recurred upon rechallenge with further 5-FU and leucovorin.     

Survey of provider perceptions of enhanced recovery after surgery and perioperative surgical home protocols at a tertiary care hospital

Enhanced recovery after surgery (ERAS) and perioperative surgical home (PSH) initiatives are widely utilized to improve quality of patient care. Despite their established benefits, implementation still has significant barriers. We developed a survey for perioperative clinicians to gather information on perception and knowledge of ERAS/PSH programs to guide future expansion of these programs at our institution. The survey included questions about familiarity with ERAS/PSH and perceived value, perceived barriers to protocol implementation, preferred learning methods and prioritization of various ERAS/PSH protocol elements into care delivery and provider education. Faculty surgeons and anesthesiologists, in addition to advanced practice nurses and postgraduate physician trainees in the Departments of Surgery and Anesthesiology were asked to complete the survey. Overall survey participation was 25% (223/888). About half of survey respondents had provided care to a patient on an ERAS/PSH protocol, and a majority felt at least somewhat knowledgeable about ERAS/PSH protocols. Perception of the value of ERAS/PSH was positive. Participants were enthusiastic about on-going learning, with multimodal pain management being the topic of most interest and learning by direct participation in care of protocol patients being the favored educational approach. A significant majority of participants felt that upcoming health providers should receive formal ERAS/PSH education as part of their training. Based on our survey results, we plan to explore teaching methods that successfully engage learners of all levels of clinical expertise and also overcome the major barriers to gaining knowledge about ERAS/PSH identified by study participants, most notably lack of time for busy clinicians.     

Determinants of right ventricular failure in patients admitted with acute left heart failure

Pulmonary hypertension, which may lead to right ventricular (RV) failure, increases with left ventricular (LV) diastolic dysfunction severity. The prevalence and determinants of RV failure were analyzed in 120 patients admitted with acute left heart (LH) failure. Patients were divided into RV failure (n=50) and non-RV failure (n=70) groups. The prevalence of RV failure was found to be 42%. In both groups, two thirds of the patients had isolated LV diastolic dysfunction and the rest had combined LV systolic and diastolic dysfunction. Patients in the RV failure group were characterized by higher LV diastolic grade (2.2 ± 0.6 vs 1.84 ± 0.7; P=.0070), pulmonary artery systolic pressure (PASP; 57.8 ± 15.3 vs 50.14 ± 12.1 mm Hg; P=.0028), right atrial enlargement (92% vs 25.7%; P=.000001), and more-than-moderate tricuspid regurgitation (58% vs 27.1%; P=.0006). RV failure is a frequent finding in patients with advanced LH failure. It is strongly associated with the severity of LV diastolic dysfunction and the severity of PASP.     

Comparative Study of Nigella sativa and Triple Therapy in Eradication of Helicobacter pylori in Patients with Non-Ulcer Dyspepsia

Background/Aim:

A large number of diseases are ascribed to Helicobacter pylori (H. pylori), particularly chronic active gastritis, peptic ulcer disease and gastric cancer. Successful treatment of H. pylori infection with antimicrobial agents can lead to regression of H. pylori–associated disorders. Antibiotic resistance against H. pylori is increasing, and it is necessary to find new effective agents. Nigella sativa seed (NS), a commonly used herb, possesses in vitro anti-helicobacter activity. The present study was undertaken to evaluate the efficacy of NS in eradication of H. pylori infection in non-ulcer dyspeptic patients.

Materials and Methods:

The study was conducted on 88 adult patients attending King Fahd Hospital of the University, Al-Khobar, Saudi Arabia, from 2007 to 2008, with dyspeptic symptoms and found positive for H. pylori infection by histopathology and urease test. Patients were randomly assigned to four groups, receiving i) triple therapy (TT) comprising of clarithromycin, amoxicillin, omeprazole [n= 23], ii) 1 g NS + 40 mg omeprazole (OM) [n= 21], iii) 2 g NS + OM [n= 21] or iv) 3 g NS + OM [n= 23]. Negative H. pylori stool antigen test four weeks after end of treatment was considered as eradication.

Results:

H. pylori eradication was 82.6, 47.6, 66.7 and 47.8% with TT, 1 g NS, 2 g NS and 3 g NS, respectively. Eradication rates with 2 g NS and TT were statistically not different from each other, whereas H. pylori eradication with other doses was significantly less than that with TT (P < 0.05). Dyspepsia symptoms improved in all groups to a similar extent.

Conclusions:

N. sativa seeds possess clinically useful anti-H. pylori activity, comparable to triple therapy. Further clinical studies combining N. sativa with antibiotics are suggested.     

A Method for Determining Optimal Mean Airway Pressure in High-Frequency Oscillatory Ventilation

Background

“Optimal” mean airway pressure (MAP) during high-frequency oscillatory ventilation (HFOV) can be defined as the pressure that allows for maximal alveolar recruitment while minimizing alveolar overdistension. Choosing a MAP near or just below the point of maximal curvature (PMC) of the volume–pressure characteristics of the lung can serve as a guide to avoid overdistention during HFOV, while simultaneously preventing derecruitment. The purpose of this study was to assess whether optimal MAP at the PMC can be determined by using measures of PaO₂ in patients with acute respiratory distress syndrome (ARDS) undergoing HFOV.

Methods

We prospectively studied seven patients with ARDS who underwent HFOV after failed conventional ventilation. In addition, 11 healthy subjects were studied to validate measurements of changes in end-expiratory lung volume (?EELV) using magnetometers. Using this validated method, plots of ?EELV and MAP were constructed during decremental changes in MAP following a recruitment maneuver in seven ventilated patients with ARDS. The PMC was defined as the point where the slope of the ?EELV versus MAP curve acutely changed. The MAP at the PMC was compared to that determined from plots of PaO₂ versus MAP.

Results

In the healthy cohort, measurements of ?EELV obtained by magnetometry approximated the line of identity when compared to those obtained by spirometry. The MAP determined using either the ?EELV or PaO₂ techniques were identical in all seven HFOV ventilated patients. Additionally, there was a significant correlation between the MAP associated changes in PaO2 and the MAP associated changes in ?EELV (p < 0.001).

Conclusions

The finding that MAP at the PMC is the same whether determined by measures of ?EELV or PaO₂ suggest that bedside measures PaO₂ may provide an acceptable surrogate for measures of EELV when determining “optimal” MAP during HFOV.     

Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function

Mitochondrial DNA mutations are the direct cause of several physiological disorders and are also associated with the aging process. The modest progress made over the past two decades towards manipulating the mitochondrial genome and understanding its function within living mammalian cells means that cures for mitochondrial DNA mutations are still elusive. Here, we report that transformed mammalian cells internalize exogenous isolated mitochondria upon simple co-incubation. We first demonstrate the physical presence of internalized mitochondria within recipient cells using fluorescence microscopy. Second, we show that xenogenic transfer of murine mitochondria into human cells lacking functional mitochondria can functionally restore respiration in cells lacking mtDNA. Third, utilizing the natural competence of isolated mitochondria to take up linear DNA molecules, we demonstrate the feasibility of using cellular internalization of isolated exogenous mitochondria as a potential tool for studying mitochondrial genetics in living mammalian cells.     

Role of regulatory T cells in allergy: implications for therapeutic strategy

The interest in regulatory T cells (Tregs) has been revived following the discovery of developing multiorgan autoimmune diseases as a result of depleting CD4+CD25+ T cells from mice. The importance of Tregs is being recognized in various clinical fields such as tumor and microbial immunities, transplantation and allergy. Prevalence of allergic diseases such as asthma, atopic dermatitis and rhinitis is significantly increasing worldwide. A better understanding of the mechanisms of T-cell regulation in allergic diseases may help in developing more effective therapeutic strategies. The well-known role of Tregs in preventing autoimmune diseases indicates that these important cells might be involved in prevention of allergy, and allergic diseases are associated with a low frequency and/or an impaired function of Tregs. Recent data show that natural CD4+CD25+ Tregs and interleukin (IL)-10-producing Tregs are normally able to suppress Th2 responses to allergens, while such suppression is diminished in allergic conditions. In this review, I summarize the role of Tregs in allergic diseases and discuss the possibility of manipulating these cells for treating allergic diseases.     

Characterization of agonist stimulation of cAMP-dependent protein kinase and G protein-coupled receptor kinase phosphorylation of the beta2-adrenergic receptor using phosphoserine-specific antibodies

Agonist-stimulated desensitization of the beta2-adrenergic receptor (beta2AR) is caused by both a potent cAMP-dependent protein kinase (PKA)-mediated phosphorylation and a less potent, occupancy-dependent, G protein-coupled receptor kinase (GRK)-mediated phosphorylation that leads to beta-arrestin binding and internalization. In this study the kinetics of phosphorylation of the third intracellular loop PKA site Ser262 and the putative C-tail GRK sites Ser355, Ser356 of the human beta2AR overexpressed in human embryonic kidney (HEK) 293 cells were characterized using phosphoserine-specific antibodies. Specificity of the antibodies was shown by their lack of reactivity with mutant beta2ARs lacking the respective sites. In addition, overexpression of GRK2 and GRK5 increased basal levels of phosphorylation of the GRK sites Ser355, Ser356 in both COS-7 and HEK 293 cells. Epinephrine, prostaglandin E1, and forskolin at maximum concentrations stimulated phosphorylation of the beta2AR PKA site (Ser262) by 4-fold, whereas PMA stimulated it by 2-fold. Epinephrine stimulated PKA site phosphorylation with an EC50 of 20 to 40 pM. In contrast, epinephrine stimulated GRK site phosphorylation (Ser355,Ser356) with an EC50 of 200 nM (1-min treatments), which is more than 4000-fold higher relative to PKA site phosphorylation, consistent with an occupancy-driven process. After 10 to 30 min, the EC50 for epinephrine stimulation of GRK site phosphorylation was reduced to 10 to 20 nM but was still approximately 200-fold greater than for the PKA site. The EC50 for internalization correlated with GRK site phosphorylation and showed a similar shift with time of epinephrine stimulation. The kinetics of epinephrine-stimulated GRK site phosphorylation were not altered in a mutant of the beta2AR lacking the PKA consensus sites. The initial levels (2 min) of a range of agonist-stimulated GRK site phosphorylations were correlated with their efficacy for activation of adenylyl cyclase, namely epinephrine > or = formoterol = fenoterol > terbutaline = zinterol = albuterol > salmeterol > dobutamine > or = ephedrine. However, after 20 to 30 min of treatment, agonists with intermediate strengths, such as albuterol and salmeterol, stimulate GRK site phosphorylations that are approximately equal to that produced by epinephrine, and the correlation breaks down. The GRK and PKA site antibodies were also effective in detecting phosphorylation of the endogenous beta2AR expressed in A431 human epidermoid carcinoma cells. To summarize, our results show a remarkable amplification of PKA site phosphorylation relative to the putative GRK site phosphorylation, heterologous stimulation of the PKA site phosphorylation, no dependence of GRK site phosphorylation on PKA sites, and a reasonable correlation of initial levels of GRK site phosphorylation with the strength of a range of agonists.