Protective action of luminal bile salts in necrotizing acute pancreatitis in mice.

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.     

Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action

Benzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part of the exploration of structure-activity relationships within this series, we synthesized the 2-isopropylamino derivative (3322W93) of 1H-beta-D-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and the biologically unnatural L-sugars corresponding to both compounds. One of the L derivatives, 1H-beta-L-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed significant antiviral potency in vitro against both laboratory HCMV strains and clinical HCMV isolates, including those resistant to ganciclovir (GCV), foscarnet, and BDCRB. 1263W94 inhibited viral replication in a dose-dependent manner, with a mean 50% inhibitory concentration (IC(50)) of 0.12 +/- 0.01 microM compared to a mean IC(50) for GCV of 0.53 +/- 0.04 microM, as measured by a multicycle DNA hybridization assay. In a single replication cycle, 1263W94 treatment reduced viral DNA synthesis, as well as overall virus yield. HCMV mutants resistant to 1263W94 were isolated, establishing that the target of 1263W94 was a viral gene product. The resistance mutation was mapped to the UL97 open reading frame. The pUL97 protein kinase was strongly inhibited by 1263W94, with 50% inhibition occurring at 3 nM. Although HCMV DNA synthesis was inhibited by 1263W94, the inhibition was not mediated by the inhibition of viral DNA polymerase. The parent benzimidazole D-riboside BDCRB inhibits viral DNA maturation and processing, whereas 1263W94 does not. The mechanism of the antiviral effect of L-riboside 1263W94 is thus distinct from those of GCV and of BDCRB. In summary, 1263W94 inhibits viral replication by a novel mechanism that is not yet completely understood.     

Iron deposition in multiple sclerosis lesions measured by susceptibility-weighted imaging filtered phase: a case control study

Purpose:

To investigate phase lesions identified on susceptibility‐weighted imaging (SWI)‐filtered phase images in patients with multiple sclerosis (MS), clinically isolated syndrome (CIS) and healthy controls (HC). To relate phase lesion characteristics to other clinical and MRI outcomes.

Materials and Methods:

95 relapsing‐remitting (RR), 40 secondary‐progressive (SP) MS patients, as well as 19 CIS patients and 49 age‐ and sex‐matched HC, were scanned on a 3T scanner. Phase‐, T1‐, and T2‐lesion characteristics were determined. Overlap of T1‐ and T2‐weigthed imaging (WI) lesions with phase lesions (T1P and T2P), as well as brain atrophy outcomes, was assessed.

Results:

MS patients showed significantly greater numbers and larger volume of phase lesions, compared with HC (P < 0.001). 23.6% of T2 lesions overlapped with phase lesions, whereas the same figure for T1 lesions was 37.3%. Conversely, 33.4% and 69.7% of phase lesions were not visible on T2‐ or T1‐WI, respectively. Phase, T1P and T2P lesions were not related to clinical outcomes, but phase lesions were related to ventricular enlargement.

Conclusion:

Phase lesions were present in both MS and CIS patients, and showed partial overlap with lesions observed using conventional MRI. The role of phase lesions in clinical progression remains unclear and should be further explored. J. Magn. Reson. Imaging 2012;36:73–83. © 2012 Wiley Periodicals, Inc.     

A constipation assessment scale for use in pediatric oncology.

Constipation is prevalent in pediatric oncology patients because of treatment with vinca alkaloids and/or narcotics and lifestyle changes secondary to disease process. Sequelae of constipation include anorexia, nausea, vomiting, abdominal pain, emergency department visits, and a decrease in quality of life. There are no reliable instruments to measure constipation in children. A pilot study (N = 21) evaluating the presence and severity of constipation and the reliability and validity of a modified version of the adult Constipation Assessment Scale (CAS) in children with cancer was conducted. Patients receiving weekly vinca alkaloids and/or narcotics = 2 times per day were recruited. Initial bowel function assessments included standardized nursing and nutrition assessments, history/physical review, and baseline CAS score repeated at 1 hour to assess test-retest reliability. Subsequent assessments included CAS administered 3 times per week and daily patient bowel diaries. Test-retest reliability was evident (r = .93; P = .000). Acceptable construct validity was indicated by a difference in mean CAS scores (t = 4.4, P <.001). Patients reported difficulty with CAS questions and response selections. Symptoms asked on CAS were often not viewed as a problem.     

APOE polymorphism is associated with risk of severe sepsis in surgical patients

OBJECTIVE: To test for an association between apolipoprotein E (APOE) genotypes and the occurrence of severe sepsis in an elective surgical cohort. DESIGN: Prospective, observational, single cohort study. SETTING: Sixteen-bed surgical intensive care unit (ICU) at a university hospital. PATIENTS: Patients were 343 patients with planned admission to the ICU after major elective noncardiac surgery. INTERVENTIONS: Blood samples, together with demographic data, baseline clinical data, and Acute Physiology and Chronic Health Evaluation II scores, were collected on admission to the ICU and on each subsequent ICU day. APOE genotyping was conducted using a polymerase chain reaction-based assay. The primary outcome was diagnosis of severe sepsis; secondary outcomes included time on mechanical ventilation, ICU length of stay, and ICU mortality. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was diagnosed in 34 of 343 patients (9.9%). Carriers of the APOepsilon3 allele (one or two copies) had a lower incidence of severe sepsis than patients with no APOepsilon3 allele (p = .014), with a relative risk of 0.284 (95% confidence interval 0.127-0.635). The protective effect of APOepsilon3 genotype on the incidence of severe sepsis remained significant (p < .01) after adjusting for age, gender, or race in a logistic regression model. Supporting our findings, presence of the APOepsilon3 allele was also associated with fewer days spent in the ICU (p = .007). In contrast, APOE genotypes were not associated with duration of mechanical ventilation or ICU mortality. CONCLUSIONS: In an elective surgical cohort, presence of the APOepsilon3 allele is associated with decreased incidence of severe sepsis and a shorter ICU length of stay.     

The effect of pain-related fear on sexual arousal in women with superficial dyspareunia.

The role of pain-related fear in the etiology and/or maintenance of superficial dyspareunia is still unclear. The objective of this experiment was to investigate the effects of pain-related fear on sexual arousal in women with superficial dyspareunia (n=48) and women without sexual complaints (n=48). To induce pain-related fear, participants were told that they had a 60% chance of receiving painful stimuli while being exposed to one of two erotic film clips. Genital arousal was assessed using vaginal photoplethysmography. Self-reported ratings of genital sensations and affect were collected after both erotic stimulus presentations. Elevated levels of skin conductance and higher ratings of experienced threat during the pain threat condition indicated that fear was successfully elicited. Pain-related fear impeded genital arousal in all women. Women of both groups reported significantly less positive affect and more negative affect when threatened. Although women with dyspareunia did not differ in their genital responsiveness from women without sexual complaints, they experienced overall significantly more negative affect than the control group. The present results indicate that pain-related fear reduces genital and subjective sexual responding in women with and without sexual problems.We conclude that emotional appraisal of the sexual situation determines genital responsiveness in both sexually dysfunctional and functional women.     

Evidence-based practice, step by step: Critical appraisal of the evidence: part III

This is the seventh article in a series from the Arizona State University College of Nursing and Health Innovation's Center for the Advancement of Evidence-Based Practice. Evidence-based practice (EBP) is a problem-solving approach to the delivery of health care that integrates the best evidence from studies and patient care data with clinician expertise and patient preferences and values. When delivered in a context of caring and in a supportive organizational culture, the highest quality of care and best patient outcomes can be achieved. The purpose of this series is to give nurses the knowledge and skills they need to implement EBP consistently, one step at a time. Articles will appear every two months to allow you time to incorporate information as you work toward implementing EBP at your institution. Also, we've scheduled "Chat with the Authors" calls every few months to provide a direct line to the experts to help you resolve questions. See details below.     

A novel role of cannabinoids: implication in the fever induced by bacterial lipopolysaccharide

There is continuing interest in elucidating the actions of drugs of abuse on the immune system and on infection. The present study investigated the effects of the cannabinoid (CB) receptor agonist aminoalkylindole, (+)-WIN 55,212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on fever produced after injection of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, the best known and most frequently used experimental model. Intraperitoneal injection of LPS (50 mug/kg) induced a biphasic fever, with the first peak at 180 min and the second at 300 min postinjection. Pretreatment with a nonhypothermic dose of the cannabinoid receptor agonist WIN 55,212-2 (0.5-1.5 mg/kg i.p.) antagonized the LPS-induced fever. However, pretreatment with the inactive enantiomer WIN 55,212-3 [1.5 mg/kg i.p.; S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthanlenyl)methanone mesylate] did not. The inhibitory effect of WIN 55,212-2 on LPS-induced fever was reversed by SR141716 [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor antagonist, but not by SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-choro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide), a selective antagonist at the CB2 receptor. The present results show that cannabinoids interact with systemic bacterial LPS injection and indicate a role of the CB1 receptor subtype in the pathogenesis of LPS fever.