LC-MS/MS based detection and characterization of covalent glutathione modifications formed by reactive drug of abuse metabolites.

Conjugation with the tripeptide glutathione (GSH) is a common mechanism of detoxification of many endogenous and exogenous compounds. This phenomenon typically occurs through the formation of a covalent bond between the nucleophilic free thiol moiety of GSH and an electrophilic site on the compound of interest. While GSH adducts have been identified for many licit drugs, there is a lack of information on the ability of drugs of abuse to adduct GSH. The present study utilized a metabolic assay with GSH as a nucleophilic trapping agent to bind reactive drug metabolites formed in situ. Extracted ion MS spectra were collected via LC-QqQ-MS/MS for all potentially significant ions and examined for fragmentation common to GSH-containing compounds, followed by confirmation of adduction and structural characterization performed by LC-QTOF-MS/MS. In addition to the two positive controls, of the 14 drugs of abuse tested, 10 exhibited GSH adduction, with several forming multiple adducts, resulting in a total of 22 individual identified adducts. A number of these are previously unreported in the literature, including those for diazepam, naltrexone, oxycodone and Δ9-THC.

Uses of Health Care System Medical Care Services by Athletes After Injury at the High School Level.

BACKGROUND: Health care utilization can vary by age group, geographic location, and socioeconomic status (SES). A paucity of information exists regarding the availability and utilization of medical care by injured scholastic athletes. The purpose of this study was to describe and compare injuries and health care service utilization by school SES over an academic year. METHODS: Injury and health care service data was collected from 1 large school district. Percentage of free and reduced lunch (FRPL) for each school was calculated to stratify schools into high (<50% FRPL) and low (≥50.1% FRPL) SES groups. Incidence proportion and relative risk (RR) with 95% confidence intervals (95% CI) were calculated. RESULTS: About 1756 injuries were reported among over 7000 participating athletes from 14 high schools. Similar injury incidence proportions were reported between high and low SES schools (RR = 1.10 [1.00-1.20]). Athletes from low SES schools were twice (RR = 2.01 [1.21-3.35]) and over three (RR = 3.42 [1.84-6.55]) times more likely to receive emergency and physical therapy care. SES was not associated with the use of physician, imaging, or surgery services. IMPLICATIONS FOR SCHOOL HEALTH, POLICY, AND EQUITY: School medical providers and administrators should have ready and provide a list of trusted outside primary care and specialty providers that have experience in sports medicine. They should also enquire and follow up on which outside provider the high school athlete will seek care when referring out to outside providers. CONCLUSIONS: Injury incidence was similar between high and low SES schools. However, athletes from low SES high schools were over 2-fold more likely to use emergency department services. Understanding factors influencing health care services choice and usage by student athletes from different socioeconomic backgrounds may assist sport medicine clinicians in identifying barriers and potential solutions in improving time to health restoration, athlete outcomes, and health care monetary burden.

A prospective randomized single-blind comparison of three methods of bowel preparation for outpatient flexible sigmoidoscopy.

BACKGROUND: Preparation for outpatient flexible sigmoidoscopy using a self-administered phosphate enema is the standard practice in our unit, but it provides acceptable bowel preparation in only 80% of patients. This study compared two methods of bowel preparation with the current standard in an attempt to improve efficacy and acceptability. METHODS: From January to September 2003, patients scheduled for out-patient flexible sigmoidoscopy were prospectively randomized to 3 groups: group 1: one Fleet enema 2 h pre-procedure; group 2: two Fleet enemas, one on the evening prior to sigmoidoscopy and one 2 h pre-procedure; group 3: lactulose 30 ml orally 48 and 24 h prior to sigmoidoscopy, plus a single Fleet enema 2 h pre-procedure. A patient questionnaire was used to assess side effects and tolerance. The endoscopists questionnaire assessed the indication for the procedure, quality of preparation, depth of insertion, and pathological findings identified. Power calculations were based on the 80% acceptable preparation rate obtained using a single enema. RESULTS: For this study, 305 patients were randomized to the three groups. Patient data were available for 261 patients (group 1 = 105; group 2 = 81; group 3 = 75), and endoscopist data were available for 251 patients (group 1 = 97; group 2 = 79; group 3 = 75). No difference was noted between the groups with regard to age, gender, procedure indication, grade of endoscopist, or patient acceptability variables (ease of use: p = 0.09; assistance required: p = 0.11; cramps experienced: p = 0.84; alternative method: p = 0.25). There was no significant difference between the groups in terms of depth of insertion (p = 0.42-chi-squared test) or abnormalities noted (p = 0.34-chi-squared test). Nor was there any difference in the quality of preparation of patients in group 1 versus group 2 (p = 0.39-Fishers exact test) or group 1 versus group 3 (p = 0.13-Fishers exact). However, lactulose + Fleet resulted in significantly fewer patients with acceptable preparation compared with those who administered two Fleet enemas (p = 0.02- Fishers exact test). CONCLUSIONS: The addition of a Fleet enema or oral lactulose over and above a single Fleet enema gives no significant improvement in the acceptability or efficacy of bowel preparation.

Increased cholecystectomy rate in the laparoscopic era: a study of the potential causative factors.

BACKGROUND: It has been suggested that an increased cholecystectomy rate in the laparoscopic era may be due to a reduced threshold for surgery or diagnostic confusion with irritable bowel syndrome (IBS). This study aims to determine the validity of these suggestions. METHODS: Questionnaires were sent to patients who had undergone cholecystectomy between 1988-1990 (open) and 1998-2000 (laparoscopic). Patients were asked about abdominal pain, fatty food intolerance, jaundice, and indigestion pre- and postoperatively. Questionnaires included Rome II criteria for the diagnosis of IBS and SF-36 quality-of-life data. Histological severity of gallbladder disease was assessed using a standard scoring system. RESULTS: A total of 124 of 196 patients in the open group and 264 of 400 patients in the laparoscopic group replied. There was no difference between the groups in gender, age at surgery, IBS incidence, or quality-of-life scores. The laparoscopic group reported a lower incidence of preoperative fat intolerance (45.8 vs 58.1%, p < 0.05) and a higher incidence of persistent postoperative abdominal pain (27.3 vs 17.7%, p < 0.05). Mean histopathology severity scores were higher in the open group (4.42 vs 3.95, p < 0.01). CONCLUSIONS: Increased cholecystectomy rate in the laparoscopic era cannot be attributed to diagnostic confusion with IBS. However, a reduction in the threshold for surgery may have contributed to the increased rate of cholecystectomy.

Re-Staging Following Long-Course Chemoradiotherapy For Rectal Cancer: Does It Influence Management?

BACKGROUND: In patients with locally advanced or low rectal cancers, long-course chemoradiotherapy (LCCRT) is recommended prior to surgical management.1 The need for restaging afterwards has been questioned as it may be difficult to interpret imaging due to local tissue effects of chemoradiotherapy. The purpose of this study was to determine if restaging affected the management of patients receiving long-course chemoradiotherapy for rectal cancer. METHODS: A retrospective review of patients with rectal cancer discussed at the South Eastern Health and Social Care Trust Lower Gastrointestinal Multi-Disciplinary Team Meeting (LGIMDT) in 2013 who had received long-course chemoradiotherapy was performed. Patients were identified from the Trust Audit Department, LGIMDT notes and patient records. Imaging results and outcomes from meetings were obtained through the Northern Ireland Picture Archiving and Communications System® (NIPACS) and Electronic Care Record® (ECR). Data including patient demographics, initial radiological staging and LGIMDT discussion, restaging modality and result, outcome from post-treatment LGIMDT discussion and recorded changes in management plans were documented using a proforma. RESULTS: Seventy-one patients with rectal cancer were identified as having LCCRT in 2013 (M:F 36:35; age range 31 - 85 years). Fifty-nine patients were restaged following long-course treatment with computed tomography (CT) and magnetic resonance imaging (MRI). Twelve patients did not undergo restaging. Data was not available for 6 patients, one patient underwent emergency surgery, two patients were not fit for treatment, one failed to attend for restaging and two patients died prior to completion of treatment. Of the 59 patients restaged, 19 patients (32%) had their management plan altered from that which had been proposed at the initial LGIMDT discussion. The most common change in plan was not to operate. Ten patients had a complete clinical and radiological response to treatment and have undergone intensive follow-up. Nine patients had disease progression, with 3 requiring palliative surgery and 6 referred for palliative care. CONCLUSION: Of those patients who were restaged, 32% had their management plan altered from that recorded at the initial LGIMDT discussion. Seventeen per cent of patients in this group had a complete clinical and radiological response to treatment. Fifteen percent demonstrated disease progression. We recommend, therefore, that patients with rectal cancer be restaged with CT and MRI following long-course chemoradiotherapy as surgery may be avoided in up to 27% of cases.

Hot super-Earths stripped by their host stars.

Simulations predict that hot super-Earth sized exoplanets can have their envelopes stripped by photoevaporation, which would present itself as a lack of these exoplanets. However, this absence in the exoplanet population has escaped a firm detection. Here we demonstrate, using asteroseismology on a sample of exoplanets and exoplanet candidates observed during the Kepler mission that, while there is an abundance of super-Earth sized exoplanets with low incident fluxes, none are found with high incident fluxes. We do not find any exoplanets with radii between 2.2 and 3.8 Earth radii with incident flux above 650 times the incident flux on Earth. This gap in the population of exoplanets is explained by evaporation of volatile elements and thus supports the predictions. The confirmation of a hot-super-Earth desert caused by evaporation will add an important constraint on simulations of planetary systems, since they must be able to reproduce the dearth of close-in super-Earths.

The effectiveness of flexible sigmoidoscopy as the primary method for investigating colorectal symptoms in low-risk patients.

BACKGROUND: Flexible sigmoidoscopy as the preferred initial investigation for patients with low-risk colorectal symptoms requires formal evaluation. METHODS: From August 1999 to July 2001, 323 patients (166 men) attended the one-stop colorectal clinic. All the patients were examined using a 60-cm flexible sigmoidoscope. Presenting symptoms and findings were reviewed. RESULTS: The mean age of the study patients was 38.6 +/- 11.87 years, with the majority (89.1%) younger than 50 years. Rectal bleeding was the most common problem (86.6%), followed by bowel habit change (13.7%). For 65.6% of the patients, a view to the proximal sigmoid was obtained. The main reason for incomplete assessment was poor bowel preparation (67.5%). The most common finding, in 202 patients (64%), was haemorrhoids. Polyps were found in 9.9% of the patients, whereas four patients (1.2%) with cancer were identified. Overall, 269 patients (83.4%) required no further investigation. CONCLUSION: Flexible sigmoidoscopy is an effective method for assessing low-risk patients.

The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease.

Anecdotal reports suggest that smoking may be beneficial for patients with inflammatory bowel disease (IBD) as nicotine may act through inflammatory mediators within the colonic mucosa. Furthermore, there is increasing evidence that cytokines play a pathologic role in IBD. Our aim was to determine the effects of cigarette smoking on cytokine levels in the colonic mucosa of patients with and without IBD. Mucosal biopsies were obtained from 10 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 10 healthy controls. Five of 10 patients in each of the three groups were smokers and five were nonsmokers. Concentrations of interleukin (IL)-1beta, IL-2, IL-6, and IL-8 were determined using enzyme-linked immunosorbent assay (ELISA). Cytokine levels of smokers were compared with nonsmokers in each group and with controls. Results were analyzed using the Mann-Whitney test; significance was set at p<0.05. The concentration of IL-8 was significantly higher in healthy controls who smoke compared with nonsmokers and significantly reduced in smokers with CD compared with nonsmokers with CD. Moreover, concentrations of IL-1beta and IL-8 were significantly reduced in smokers with UC compared with nonsmokers with UC. Smokers had significantly elevated levels of IL-8 in the colonic mucosa. Smokers with IBD had a significant reduction in cytokine levels; specifically, IL-1beta and IL-8 for patients with UC and IL-8 for patients with CD. Further studies are warranted to determine if this reduction in cytokine levels is histologically and clinically significant.

"Wineglass" confabulations among brain-damaged alcoholics on the Wechsler Memory Scale-Revised visual reproduction subtest.

Confabulation is a clinically well-documented accompaniment of selective types of memory impairment, especially in brain-damaged alcoholics. This study reports specific occurrences of visual confabulation consisting of spontaneous alterations of Card D of the Visual Reproduction subtest of the Wechsler Memory Scale-Revised. The resemblance of a wineglass was fashioned by a 90-degree rotation into a "bowl and stem", observed in six of 30 brain-damaged alcoholics. There were no such instances in 132 other patients, including alcoholic controls, those with Parkinson's Disease, temporal lobe epileptics (pre- or post-surgery), and those with neurotoxic exposure. When asked, the subjects who identified the figure as a wineglass or similar drinking instrument reported that they had drawn it as originally shown to them. "Wineglass" confabulators had shorter periods of abstinence, longer drinking histories and lower intellectual functioning than their brain-damaged peers or an alcoholic control group. These findings lend support for the association of alcohol-related confabulation with visual, as well as previously-documented verbal material among brain-damaged alcoholics.

Complicated anorectal sepsis.

These complex anorectal conditions are difficult to diagnose because clinical features overlap. In general, an aggressive approach is reserved for hidradenitis suppurativa and necrotizing infections. Patients with Crohn's disease, hematologic disorders, or AIDS are often treated more conservatively, but the correct timing and degree of aggressiveness of surgical intervention may considerably improve the overall outcome. The increasing incidence of AIDS and the frequency with which infected patients present to surgical clinics make it imperative that all surgeons have a working knowledge of the conditions associated with this syndrome. Expertise is required not only to diagnose and treat these conditions but also to protect oneself and others from being inadvertently infected with the HIV. A high index of suspicion and constant vigilance permit the successful resolution of many of these challenging problems.

DRw antigen matching and B-cell antibody crossmatching: their effect on clinical outcome of renal transplants.

In a series of 36 cadaver transplants, we have found that matching the DR antigens had greater value in predicting good transplant outcome than did matching the A and B antigens. A much larger series of transplants utilizing DR antigen matching will be necessary to confirm these promising results; however, it would appear that performed donor-specific BLC detected at room temperature have no relationship to subsequent transplant outcome. It is, however, important to differentiate them from weak HLA-A,B,C antibodies which have been proven to lead to accelerated rejection. We recommend that the clinical crossmatch include simultaneous B-cell-depleted and B-cell-enriched tests to avoid this problem.

Pentachlorophenol intoxication: report of a fatal case, with comments on the clinical course and pathologic anatomy.

A case of a 33-yr-old man who died following occupational exposure to pentachlorophenol is presented. Postmortem examination revealed cerebral edema and fatty degeneration of the viscera. Review of the literature indicates that the clinical syndrome of poisoning with the compound results from mitochondrial toxicity with derangement of aerobic metabolism.

Kepler detected gravity-mode period spacings in a red giant star.

Stellar interiors are inaccessible through direct observations. For this reason, helioseismologists made use of the Sun's acoustic oscillation modes to tune models of its structure. The quest to detect modes that probe the solar core has been ongoing for decades. We report the detection of mixed modes penetrating all the way to the core of an evolved star from 320 days of observations with the Kepler satellite. The period spacings of these mixed modes are directly dependent on the density gradient between the core region and the convective envelope.

HD 181068: a red giant in a triply eclipsing compact hierarchical triple system.

Hierarchical triple systems comprise a close binary and a more distant component. They are important for testing theories of star formation and of stellar evolution in the presence of nearby companions. We obtained 218 days of Kepler photometry of HD 181068 (magnitude of 7.1), supplemented by ground-based spectroscopy and interferometry, which show it to be a hierarchical triple with two types of mutual eclipses. The primary is a red giant that is in a 45-day orbit with a pair of red dwarfs in a close 0.9-day orbit. The red giant shows evidence for tidally induced oscillations that are driven by the orbital motion of the close pair. HD 181068 is an ideal target for studies of dynamical evolution and testing tidal friction theories in hierarchical triple systems.

Ensemble asteroseismology of solar-type stars with the NASA Kepler mission.

In addition to its search for extrasolar planets, the NASA Kepler mission provides exquisite data on stellar oscillations. We report the detections of oscillations in 500 solar-type stars in the Kepler field of view, an ensemble that is large enough to allow statistical studies of intrinsic stellar properties (such as mass, radius, and age) and to test theories of stellar evolution. We find that the distribution of observed masses of these stars shows intriguing differences to predictions from models of synthetic stellar populations in the Galaxy.

A prospective randomized single blind trial of Fleet phosphate enema versus glycerin suppositories as preparation for flexible sigmoidoscopy.

AIM: This study compared the efficacy and patient acceptability of two methods of bowel preparation for flexible sigmoidoscopy. METHODS: Patients attending for outpatient flexible sigmoidoscopy were prospectively randomized to receive one Fleet ready-to-use enema or 2 x 4 g glycerin suppositories, 2 h preprocedure. Patient and endoscopist questionnaires were used to compare the outcomes. RESULTS: From November 2000 to August 2001, 203 (male = 95; female = 108) patients were randomized. Patient data available for 163 patients (enema = 93; suppository = 70) revealed: ease of use (enema = 52; suppository = 25; P < 0.02, Fisher's exact); assistance required (enema = 19; suppository = 3; P < 0.005, Fisher's exact); grade of effectiveness (enema = 83; suppository = 44; P < 0.0001, Fisher's exact), and whether patients wished to try another preparation in future (enema = 16; suppository = 24; P = 0.016, Fisher's exact). Endoscopist data available for 151 patients (enema = 76; suppository = 75) revealed: average depth of insertion (enema = 53.6 +/- 11.6 cm; suppository 46.3 +/- 13.7 cm; P < 0.001, Student's t test); acceptable (excellent + good) quality of preparation [enema = 60 (78.9%); suppository = 34 (45.3%); P < 0.0001, Fisher's exact]. CONCLUSION: Bowel preparation for flexible sigmoidoscopy using a single Fleet enema is acceptable to patients and more effective than glycerin suppositories.