bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles
Authors: Matin Nusrat , Fisher Courtney , Jackson William F. , Dorrance Anne M.
Published: March 2016

Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.
DNA methylation profiles in preeclampsia and healthy control placentas
Authors: Yeung Kristen R. , Chiu Christine L. , Pidsley Ruth , Makris Angela , Hennessy Annemarie , Lind Joanne M.
Published: March 2016

Preeclampsia is a hypertensive disorder of pregnancy that affects 3–5% of all pregnancies. There is evidence to suggest that epigenetic mechanisms, such as DNA methylation, play a role in placental development and function. This study compared DNA methylation profiles of placentas from preeclampsia-affected pregnancies with placentas from healthy pregnancies to identify gene-specific changes in DNA methylation that may contribute to the development of preeclampsia. The methylation status of eight placental biopsies taken from preeclampsia-affected and 16 healthy pregnancies was analyzed using the Illumina Infinium Methylation 450 BeadChip array. Bisulfite pyrosequencing was used to confirm regions found to be differentially methylated between preeclampsia and healthy placentas. A total of 303 differentially methylated regions, 214 hypermethylated and 89 hypomethylated, between preeclampsia cases and controls were identified, after adjusting for gestational age (adjusted P < 0.05). Functional annotation found cell adhesion, wingless type MMTV Integration Site family member 2 (Wnt) signaling pathway, and regulation of transcription were significantly enriched in these gene regions. Hypermethylation of WNT2, sperm equatorial segment protein ( SPESP1), NADPH oxidase 5 ( NOX5), and activated leukocyte cell adhesion molecule ( ALCAM) in preeclampsia placentas was confirmed with pyrosequencing. This study found differences in methylation in gene regions involved in cell signaling ( WNT2), fertilization and implantation ( SPESP1), reactive oxygen species signaling ( NOX5), and cell adhesion ( ALCAM). These results build on recently published studies that have reported significant differences in DNA methylation in preeclampsia placentas.
Reduced mucociliary clearance in old mice is associated with a decrease in Muc5b mucin
Authors: Grubb Barbara R. , Livraghi-Butrico Alessandra , Rogers Troy D. , Yin Weining , Button Brian , Ostrowski Lawrence E.
Published: March 2016

Respiratory infections are a major cause of morbidity and mortality in the elderly. Previous reports have suggested that mucociliary clearance (MCC) is impaired in older individuals, but the cause is unclear. To unravel the mechanisms responsible for the age-associated decline in MCC, we investigated the MCC system in young (3 mo) and old (2 yr) C57BL/6 mice. We found that old mice had significantly reduced MCC function in both the upper and lower airways compared with young mice. Measurement of bioelectric properties of isolated tracheal and bronchial tissue revealed a significant decrease in Cl− secretion, suggesting that the older mice may have a reduced ability to maintain a sufficiently hydrated airway surface for efficient MCC. Ciliary beat frequency was also observed to be reduced in the older animals; however, this reduction was small relative to the reduction in MCC. Interestingly, the level of the major secreted mucin, Muc5b, was found to be reduced in both bronchioalveolar lavage and isolated tracheal tissue. Our previous studies of Muc5b−/− mice have demonstrated that Muc5b is essential for normal MCC in the mouse. Furthermore, examination of Muc5b+/− and wild-type animals revealed that heterozygous animals, which secrete ∼50% of the wild-type level of Muc5b, also demonstrate a markedly reduced level of MCC, confirming the importance of Muc5b levels to MCC. These results demonstrate that aged mice exhibit a decrease in MCC and suggest that a reduced level of secretion of both Cl− and Muc5b may be responsible.
Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension
Authors: Tang Haiyang , Yamamura Aya , Yamamura Hisao , Song Shanshan , Fraidenburg Dustin R. , Chen Jiwang , Gu Yali , Pohl Nicole M. , Zhou Tong , Jiménez-Pérez Laura , Ayon Ramon J. , Desai Ankit A. , Goltzman David , Rischard Franz , Khalpey Zain , Black Stephan M. , Garcia Joe G. N. , Makino Ayako , Yuan Jason X. J.
Published: March 2016

An increase in cytosolic free Ca2+concentration ([Ca2+]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. Previously, we demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca2+influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here, we report that CaSR functionally interacts with TRPC6 to regulate [Ca2+]cytin PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca2+-induced [Ca2+]cytincrease in IPAH-PASMC (in which CaSR is upregulated), whereas overexpression of CaSR or TRPC6 enhanced Ca2+-induced [Ca2+]cytincrease in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, whereas blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice ( casr−/−) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.
Calcium-dependent phospholipase A2modulates infection-induced diaphragm dysfunction
Authors: Supinski Gerald S. , Alimov Alexander P. , Wang Lin , Song Xiao-Hong , Callahan Leigh A.
Published: March 2016

Calpain activation contributes to the development of infection-induced diaphragm weakness, but the mechanisms by which infections activate calpain are poorly understood. We postulated that skeletal muscle calcium-dependent phospholipase A2(cPLA2) is activated by cytokines and has downstream effects that induce calpain activation and muscle weakness. We determined whether cPLA2activation mediates cytokine-induced calpain activation in isolated skeletal muscle (C2C12) cells and infection-induced diaphragm weakness in mice. C2C12 cells were treated with the following: 1) vehicle; 2) cytomix (TNF-α 20 ng/ml, IL-1β 50 U/ml, IFN-γ 100 U/ml, LPS 10 μg/ml); 3) cytomix + AACOCF3, a cPLA2inhibitor (10 μM); or 4) AACOCF3 alone. At 24 h, we assessed cell cPLA2activity, mitochondrial superoxide generation, calpain activity, and calpastatin activity. We also determined if SS31 (10 μg/ml), a mitochondrial superoxide scavenger, reduced cytomix-mediated calpain activation. Finally, we determined if CDIBA (10 μM), a cPLA2inhibitor, reduced diaphragm dysfunction due to cecal ligation puncture in mice. Cytomix increased C2C12 cell cPLA2activity ( P < 0.001) and superoxide generation; AACOCF3 and SS31 blocked increases in superoxide generation ( P < 0.001). Cytomix also activated calpain ( P < 0.001) and inactivated calpastatin ( P < 0.01); both AACOCF3 and SS31 prevented these changes. Cecal ligation puncture reduced diaphragm force in mice, and CDIBA prevented this reduction ( P < 0.001). cPLA2modulates cytokine-induced calpain activation in cells and infection-induced diaphragm weakness in animals. We speculate that therapies that inhibit cPLA2may prevent diaphragm weakness in infected, critically ill patients.
Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy
Authors: Birket Susan E. , Chu Kengyeh K. , Houser Grace H. , Liu Linbo , Fernandez Courtney M. , Solomon George M. , Lin Vivian , Shastry Suresh , Mazur Marina , Sloane Peter A. , Hanes Justin , Grizzle William E. , Sorscher Eric J. , Tearney Guillermo J. , Rowe Steven M.
Published: March 2016

Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies.
A three-dimensional human model of the fibroblast activation that accompanies bronchopulmonary dysplasia identifies Notch-mediated pathophysiology
Authors: Sucre Jennifer M. S. , Wilkinson Dan , Vijayaraj Preethi , Paul Manash , Dunn Bruce , Alva-Ornelas Jackelyn A. , Gomperts Brigitte N.
Published: March 2016

Bronchopulmonary dysplasia (BPD) is a leading complication of premature birth and occurs primarily in infants delivered during the saccular stage of lung development. Histopathology shows decreased alveolarization and a pattern of fibroblast proliferation and differentiation to the myofibroblast phenotype. Little is known about the molecular pathways and cellular mechanisms that define BPD pathophysiology and progression. We have developed a novel three-dimensional human model of the fibroblast activation associated with BPD, and using this model we have identified the Notch pathway as a key driver of fibroblast activation and proliferation in response to changes in oxygen. Fetal lung fibroblasts were cultured on sodium alginate beads to generate lung organoids. After exposure to alternating hypoxia and hyperoxia, the organoids developed a phenotypic response characterized by increased α-smooth muscle actin (α-SMA) expression and other genes known to be upregulated in BPD and also demonstrated increased expression of downstream effectors of the Notch pathway. Inhibition of Notch with a γ-secretase inhibitor prevented the development of the pattern of cellular proliferation and α-SMA expression in our model. Analysis of human autopsy tissue from the lungs of infants who expired with BPD demonstrated evidence of Notch activation within fibrotic areas of the alveolar septae, suggesting that Notch may be a key driver of BPD pathophysiology.
Chronic Pain in Canada ‐ Prevalence, Treatment, Impact and the Role of Opioid Analgesia
Authors: Moulin Dwight E , Clark Alexander J , Speechley Mark , Morley-Forster Patricia K
Published: March 2016

OBJECTIVE: To assess the prevalence, treatment and impact of chronic pain in Canada.

METHODS: A stratified random sample of 2012 adult Canadians (weighted by sex, age and region according to 1996 census data) was surveyed by telephone in 2001 to determine the prevalence of chronic pain, defined as continuous or intermittent pain for at least six months. A second sample of 340 chronic pain sufferers who were taking prescription medication for their pain was studied in detail to determine current therapeutic approaches and to assess the social and economic impact of chronic pain.

RESULTS: Chronic noncancer pain was reported by 29% of the respondents, with increased frequency in women and older age groups. The average duration of pain was 10.7 years and the average intensity was 6.3 (on a scale from 1 to 10), with 80% reporting moderate or severe pain. Anti‐inflammatory agents were prescribed for 49% of respondents and opioid analgesics were prescribed for 22% (two‐thirds of these were codeine). Almost 70% were worried about addiction potential, and one‐third felt that strong analgesics should be reserved for terminal illnesses. Almost one‐half were unable to attend social and family events, and the mean number of days absent from work in the past year due to chronic pain was 9.3.

INTERPRETATION: Chronic noncancer pain is common in Canadian adults and has a major social and economic impact. Despite growing evidence supporting the efficacy and safety of major opioid analgesics for chronic noncancer pain, less than 10% of chronic pain patients taking prescription medication were treated with a major opioid. Chronic pain is undertreated in Canada, and major opioid analgesics are probably underutilized in the management of moderate to severe pain as part of a multidisciplinary treatment program.
Evidence of a Relationship between Adult Attachment Variables and Appraisals of Chronic Pain
Authors: Meredith Pamela J , Strong Jenny , Feeney Judith A
Published: March 2016

OBJECTIVE: Although threat and challenge appraisals of pain have been linked to both the acute and laboratory‐induced pain experience, these appraisals have not yet been explored in relation to chronic pain. In addition, although attachment theory has been separately linked to the chronic pain experience and to responses to perceived threat, it has not been explored in the context of threat and challenge appraisals of chronic pain. The present paper addresses these two main goals.

METHODS: A sample of 141 participants reporting noncancer pain longer than two months in duration completed a battery of assessments before commencing treatment in one of two multidisciplinary rehabilitation programs.

RESULTS: Analysis of the pain appraisal inventory produced two factors (threat and challenge), replicating earlier findings. Reliability coefficients for the two extracted scales were 0.87 and 0.86, respectively. Links between the two pain appraisal scales and adult attachment variables proved to be significant. In particular, comfort with closeness was strongly related to challenge appraisal, while anxiety over relationships was strongly associated with threat appraisal. As expected, both appraisals and attachment variables were also related to catastrophizing and emotional distress.

CONCLUSIONS: Results support use of the pain appraisal inventory as an evaluation tool for those with chronic pain. Findings further suggest a substantial association between adult attachment and pain appraisal, supporting the need for more in‐depth analysis and consideration of implications for treatment.
A Case of Atypical Croup
Authors: Cuvelier Geoff , El-Hawrani Amged , El-Hakim Hamdy , Robinson Joan L
Published: March 2016

Case Presentation A previously healthy eight‐month‐old girl was admitted to the pediatric intensive care unit at Stollery Children′s Hospital (Edmonton, Alberta) following a waxing and waning course of respiratory distress. She had initially presented 11 days earlier to the emergency room with stridor and a brassy cough, and laryngotracheobronchitis was diagnosed. Treatment with racemic adrenaline and one dose of oral dexamethasone was effective and she was discharged after overnight observation. Nasopharyngeal aspirate was negative by direct fluorescent antibody and by viral culture for influenza A and B, parainfluenza and respiratory syncytial virus. Over the next three days, the child had increasing stridor and was admitted and again treated with racemic adrenaline and a four‐day course of oral dexamethasone. She was subsequently discharged. White lesions were noted on the tongue and were treated with topical nystatin. Four days later, the child presented to the emergency room with recurrence of stridor and fever and new onset of drooling. She had a respiratory rate of 44 breaths/min, heart rate of 170 beats/min, blood pressure of 90/58 mmHg, oxygen saturation of 98% and temperature of 39.6°C. She was in moderate respiratory distress, with marked stridor. Examination of the oropharynx revealed ulcerative lesions on the anterior tongue, hard and soft palate, and posterior pharynx. Laboratory studies revealed a white blood cell count of 18.1x109/L (74% neutrophils, 23% lymphocytes and 3% monocytes). Other hematological values were normal. A laryngobronchoscopy was performed and revealed that the mucosa of the laryngopharynx was studded with discrete white lesions on a background of mucosal inflammation with severe reduction of airway calibre requiring intubation (Figure 1). The subglottis and the tracheobronchial tree were severely inflamed but had no discrete lesions.
Management of Chronic Hepatitis C: Consensus Guidelines
Authors: Sherman Morris , Shafran Stephen , Burak Kelly , Doucette Karen , Wong Winnie , Girgrah Nigel , Yoshida Eric , Renner Eberhard , Wong Philip , Deschênes Marc
Published: March 2016

Since the last consensus conference on the management of chronic viral hepatitis, a number of studies looking at modifications of the standard course of treatment have been published. These changes have been sufficiently substantive to warrant review to determine whether any changes in the recommended treatment algorithms are needed. A consensus development conference was held in January 2007, and the present document highlights the results of the presentations and discussion about these issues. It reviews the epidemiology of hepatitis C in Canada, treatment of acute hepatitis C and new algorithms in chronic hepatitis C, including retreatment of previous treatment failures. In addition, sections on management of hepatitis C in special populations have been updated. There is also a section on the use of hematopoietic growth factors to help manage patients on therapy. The document should be read in conjunction with the previous document to identify changes. Some recommendations made in the previous document remain and are not discussed here.
Treatment Persistence and Compliance with Medications for Chronic Obstructive Pulmonary Disease
Authors: Cramer Joyce A , Bradley-Kennedy Carole , Scalera Alissa
Published: March 2016

BACKGROUND AND OBJECTIVE: Inhaled beta‐agonist, anticholinergic and glucocorticoid medications are used to treat asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the patterns of persistence with the above mentioned inhaled medications.

METHODS: Prescription claims data from the Ontario Drug Benefit Program were analyzed to assess persistence (time to discontinuation) and compliance (percentage of days with doses available divided by days to last refill) of patients prescribed inhaled medications. Patients were grouped as naive (no inhaled medication in the previous year) or experienced (previous or current treatment), and by age (18 to 65 years of age and older than 65 years of age). Medications included ipratropium, ipratropium plus salbutamol, formoterol, formoterol plus budesonide, salmeterol, salmeterol plus fluticasone, and tiotropium.

RESULTS: The database included 31,368 patients (4888 naive and 26,480 experienced) who were prescribed at least one of these medications. Fifteen per cent to 63% of patients continued on the index drug for more than six months, which decreased to 7% to 53% at 12 months, and 5% to 47% at 18 months. At 12 months, patients taking tiotropium had significantly longer persistence compared with other therapies (53% versus 7% to 30%; all P<0.0001), and fewer switches to alternative medications. Most naive patients had significantly shorter treatment persistence than experienced patients for all drugs (all P<0.0001), including tiotropium (27% versus 55%, P<0.0001). Compliance rates were similar for all drugs (ie, 76% to 94%) but were highest for tiotropium.

CONCLUSIONS: These data demonstrated that persistence with inhaled treatment was low overall, but patients treated with tiotropium remained on therapy significantly longer than when treated with other medications, and patients naive to inhaled treatment had shorter treatment persistence than experienced patients.
Ileocolonic Ulcer Treated by Endoscopic Application of Collagen-Polyvinylpyrrolidone
Authors: de Hoyos Garza Andrés , Aguilar Edgar A Esparza , Checa Richards Griselda
Published: March 2016

Ulceration is a complication that may occur after an ileocolonic anastomosis. Most of the etiologies remain speculative. The case of a 33-year-old woman with eosinophilic colitis is reported, in whom a colectomy with an ileocolonic anastomosis was performed. After four months, the patient presented with a stenosis in the ileocolonic anastomosis, necessitating surgical restoration. Four weeks later, the patient presented with rectal bleeding, and a colonoscopy showed an ulcer in the anastomosis. Collagen-polyvinylpyrrolidone was applied into and on the surface of the ulcer, and five days later the procedure was repeated. Follow-up endoscopies at seven days and three months showed complete healing of the ulcer and the patient remained without bleeding throughout a further four weeks of follow-up tests. It was concluded that this biological product could be an excellent treatment for these lesions.
Pyogenic Ventriculitis Complicating Aggregatibacter aphrophilus Infective Endocarditis: A Case Report and Literature Review
Authors: Jung Gordon W , Parkins Michael D , Church Deirdre
Published: March 2016

Pyogenic ventriculitis (PV) is an uncommon, but frequently fatal infection that results from inflammation of the ventricular ependymal lining associated with a purulent ventricular system. PV has been rarely reported as a secondary complication of infective endocarditis. Prompt diagnosis and treatment with appropriate culture‐directed antibiotics with adequate central nervous system penetration is crucial when managing patients who are suspected of having PV. The present study reports on a fatal case of a previously well 42‐year‐old alcoholic woman with infective endocarditis caused by Aggregatibacter aphrophilus, with secondary brain abscess and spontaneous rupture into the ventricles causing PV.
Canadian Sleep Society/Canadian Thoracic Society position paper on the use of portable monitoring for the diagnosis of obstructive sleep apnea/hypopnea in adults
Authors: Blackman Adam , McGregor Catherine , Dales Robert , Driver Helen S , Dumov Ilya , Fleming Jon , Fraser Kristin , George Charlie , Khullar Atul , Mink Joe , Moffat Murray , Sullivan Glendon E , Fleetham John A , Ayas Najib , Bradley T Douglas , Fitzpatrick Michael , Kimoff John , Morrison Debra , Ryan Frank , Skomro Robert , Series Frederic , Tsai Willis
Published: March 2016

The present position paper on the use of portable monitoring (PM) as a diagnostic tool for obstructive sleep apnea/hypopnea (OSAH) in adults was based on consensus and expert opinion regarding best practice standards from stakeholders across Canada. These recommendations were prepared to guide appropriate clinical use of this new technology and to ensure that quality assurance standards are adhered to. Clinical guidelines for the use of PM for the diagnosis and management of OSAH as an alternative to in-laboratory polysomnography published by the American Academy of Sleep Medicine Portable Monitoring Task Force were used to tailor our recommendations to address the following: indications; methodology including physician involvement, physician and technical staff qualifications, and follow-up requirements; technical considerations; quality assurance; and conflict of interest guidelines. When used appropriately under the supervision of a physician with training in sleep medicine, and in conjunction with a comprehensive sleep evaluation, PM may expedite treatment when there is a high clinical suspicion of OSAH.
A Case of Adalimumab‐Induced Pneumonitis in a 45‐Year‐Old Man with Crohn’s Disease
Authors: Reid James D , Bressler Brian , English John
Published: March 2016

Adalimumab is a human monoclonal antibody against tumour necrosis factor‐alpha that has been associated with acute lung toxicity, mainly in patients with rheumatoid arthritis. Descriptions of similar patterns of lung injury in patients treated with adalimumab for inflammatory bowel disease are emerging in the literature. A case involving a 45‐year‐old man with Crohn’s disease who developed a nonbronchiolitis inflammatory nodular pattern of lung injury after starting adalimumab is reported.
Patient Satisfaction with Medication for Gastroesophageal Reflux Disease: A Systematic Review
Authors: van Zanten Sander Veldhuyzen , Henderson Catherine , Hughes Nesta
Published: March 2016

BACKGROUND: Patient satisfaction is increasingly regarded as an important aspect of measuring treatment success in individuals with gastroesophageal reflux disease (GERD).

OBJECTIVE: To review how satisfied patients with GERD are with their medication, and to analyze the usefulness of patient satisfaction as a clinical end point by comparing it with symptom improvement.

METHODS: Systematic searches of the PubMed and EMBASE databases identified clinical trials and patient surveys published between 1966 and 2009.

RESULTS: Twelve trials reported that 56% to 100% of patients were ‘satisfied’ or ‘very satisfied’ with proton pump inhibitor (PPI) treatment for GERD. Patient satisfaction levels were higher for PPIs than other GERD medications in two trials. The sample-size-weighted average proportion of patients ‘satisfied’ with their PPI after four weeks of treatment in trials was 93% (95% CI 87% to 99%), with 73% (95% CI 62% to 83%) being ‘very satisfied’. In four surveys, the average proportion of patients ‘satisfied’ with their PPI treatment was 82% (95% CI 73% to 90%) and 62% (95% CI 48% to 75%) were ‘very satisfied’. Seven trials found a positive association between patient satisfaction and symptom improvement, and two surveys between satisfaction and improved health-related quality of life. Three trials found that continuous treatment yielded higher rates of satisfaction than on-demand therapy.

CONCLUSIONS: More than one-half of patients were satisfied with their PPI medication in trials, and more patients were satisfied with PPIs than other medication types. An association between patient satisfaction and symptom resolution was found, suggesting that patient satisfaction is a useful end point for evaluating GERD treatment success.
Autoimmune Hepatitis: Focusing on Treatments other than Steroids
Authors: Czaja Albert J
Published: March 2016

BACKGROUND: Corticosteroid therapy has been the time-honoured treatment for autoimmune hepatitis; however, the emergence of new immunosuppressive agents has afforded opportunities to improve or replace the standard regimens.

OBJECTIVE: To describe technological advances and feasible treatment interventions that promise to supplant the current generation of corticosteroids.

METHODS: A review of the MEDLINE database for published experiences from 1984 to 2011 was conducted.

RESULTS: Cyclosporine and tacrolimus have been uniformly successful as salvage therapies for steroid-refractory autoimmune hepatitis. Ten reports of cyclosporine therapy involving 133 patients had positive outcomes in 93%, whereas therapy with tacrolimus in three reports involving 41 patients had positive outcomes in 98%. Salvage therapy with mycophenolate mofetil had a favourable outcome in 47%, especially in patients with azathioprine intolerance. Front-line therapy with mycophenolate mofetil normalized liver parameters in 88% and allowed corticosteroid tapering in 58%. Front-line therapy with budesonide combined with azathioprine for six months normalized liver parameters more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than prednisone combined with azathioprine. Monoclonal antibodies to CD3 and recombinant cytotoxic T lymphocyte antigen 4 fused with immunoglobulin represent feasible molecular interventions for study in autoimmune hepatitis.

DISCUSSION: Nonstandard drug therapies must be used in highly selected clinical situations including steroid failure (calcineurin inhibitors), azathioprine intolerance (mycophenolate mofetil), and mild disease or fragile patients (budesonide combined with azathioprine). Molecular interventions for autoimmune hepatitis are feasible for study because of their use in other immune-mediated diseases.

CONCLUSION: Opportunities to improve or replace standard corticosteroid regimens have emerged.
Chemical Neurolysis of the Inferior Hypogastric Plexus for the Treatment of Cancer‐Related Pelvic and Perineal Pain
Authors: Mohamed Sahar Abd-Elbaky , Ahmed Doaa Gomaa , Mohamad Mohamad Farouk
Published: March 2016

BACKGROUND: Various interventions, including the superior hypogastric plexus block and ganglion impar block, are commonly used for the treatment of pelvic or perineal pain caused by cancer. The inferior hypogastric plexus block (performed using a trans‐sacral approach under fluoroscopy and using a local anesthetics/steroid combination) for the diagnosis and treatment of chronic pain conditions involving the lower pelvic viscera was first described in 2007. Neurolysis of the inferior hypogastric plexus may be useful for the treatment of pelvic and perineal pain caused by cancer.

OBJECTIVES: To assess the feasibility, safety and efficacy of the newly introduced inferior hypogastric plexus block, performed using a trans‐sacral approach, for the relief of cancer‐related pelvic and perineal pain.

METHODS: A total of 20 patients with cancer pain in the pelvis and/or perineum were injected with 6 mL to 8 mL of 10% phenol bilaterally by passing a spinal needle through the sacral foramen to perform the inferior hypogastric block. Pain intensity (measured using a visual analogue scale), sleep score, activity score, psychological score and oral morphine consumption pre‐ and postprocedure were measured.

RESULTS: Two of the 20 patients died during the follow‐up period and were, therefore, excluded from the study. All patients presented with cancer‐related pelvic, perineal or pelviperineal pain. Pain scores were reduced from a mean (± SD) of 7.22±1.31 preprocedurally to 4.06±1.73 one week postprocedurally (P<0.05). In addition, the mean consumption of morphine (delivered via 30 mg sustained‐release morphine tablets) was reduced from 106.67±32.90 mg to 61.67±40.48 mg after one week (P<0.05). No complications or serious side effects were encountered during or after the block.

DISCUSSION AND CONCLUSION: The approach provides a good alternative technique for the treatment of low pelvic and perineal cancer‐related pain. Additional studies are required for evaluation and refinement of the technique using other radiological techniques.
2012 Canadian Guidelines for the Diagnosis and Management of Fibromyalgia Syndrome: Executive Summary
Authors: Fitzcharles Mary-Ann , Ste-Marie Peter A , Goldenberg Don L , Pereira John X , Abbey Susan , Choinière Manon , Ko Gordon , Moulin Dwight E , Panopalis Pantelis , Proulx Johanne , Shir Yoram , the National Fibromyalgia Guideline Advisory Panel
Published: March 2016

BACKGROUND: Recent neurophysiological evidence attests to the validity of fibromyalgia (FM), a chronic pain condition that affects >2% of the population.

OBJECTIVES: To present the evidence‐based guidelines for the diagnosis, management and patient trajectory of individuals with FM.

METHODS: A needs assessment following consultation with diverse health care professionals identified questions pertinent to various aspects of FM. A literature search identified the evidence available to address these questions; evidence was graded according to the standards of the Oxford Centre for Evidence‐Based Medicine. Drafted recommendations were appraised by an advisory panel to reflect meaningful clinical practice.

RESULTS: The present recommendations incorporate the new clinical concepts of FM as a clinical construct without any defining physical abnormality or biological marker, characterized by fluctuating, diffuse body pain and the frequent symptoms of sleep disturbance, fatigue, mood and cognitive changes. In the absence of a defining cause or cure, treatment objectives should be patient‐tailored and symptom‐based, aimed at reducing global complaints and enhancing function. Healthy lifestyle practices with active patient participation in health care forms the cornerstone of care. Multimodal management may include nonpharmacological and pharmacological strategies, although it must be acknowledged that pharmacological treatments provide only modest benefit. Maintenance of function and retention in the workforce is encouraged.

CONCLUSIONS: The new Canadian guidelines for the treatment of FM should provide health professionals with confidence in the complete care of these patients and improve clinical outcomes.
Six Minute Walk Distance Is a Predictor of Survival in Patients with Chronic Obstructive Pulmonary Disease Undergoing Pulmonary Rehabilitation
Authors: Dajczman Esther , Wardini Rima , Kasymjanova Goulnar , Préfontaine David , Baltzan Marc Alexander , Wolkove Norman
Published: March 2016

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive and distressing disease with a trajectory that is often difficult to predict.

OBJECTIVE: To determine whether initial 6 min walk distance (6MWD) or change in 6MWD following inpatient pulmonary rehabilitation (PR) predicted survival.

METHODS: Patients referred for PR in 2010 were studied in a retrospective chart review. Measures of 6MWD before and following PR were recorded. Initial 6MWD was categorized as ≥250 m, 150 m to 249 m and ≤149 m. Government databases provided survival status up until December 2013 and survival analyses were performed. Initial 6MWD and a minimally important difference (MID) of ≥30 m were used for survival analysis.

RESULTS: The cohort consisted of 237 patients (92 men, 145 women) with severe COPD. Mean (± SD) forced expiratory volume in 1 s (FEV1) was 0.75±0.36 L, with a mean FEV1/forced vital capacity (FVC) ratio of 0.57±0.16. Overall three‐year survival was 58%. Mean survival for the study period as per predefined categories of 6MWD of ≥250 m, 150 m to 249 m and ≤149 m was 42.2, 37.0 and 27.8 months (P<0.001), respectively, with a three‐year survival of 81%, 66% and 34% observed, respectively. Overall mean change in 6MWD was 62±57 m, and a minimal improvement of ≥30 m was observed in 72% of patients. In the lowest walking group, early mortality was significantly higher among those who did not achieve minimal improvement. Older age, male sex and shorter initial 6MWD were negative predictors of survival.

CONCLUSION: In patients with severe COPD, initial 6MWD was predictive of survival. Overall survival at three years was only 58% and was especially poor (34%) in patients with low (<150 m) initial walk distance.
Antimicrobial Use Over a Four‐Year Period Using Days of Therapy Measurement at a Canadian Pediatric Acute Care Hospital
Authors: Dalton Bruce R , MacTavish Sandra J , Bresee Lauren C , Rajapakse Nipunie , Vanderkooi Otto , Vayalumkal Joseph , Conly John
Published: March 2016

BACKGROUND: Antimicrobial resistance is a concern that is challenging the ability to treat common infections. Surveillance of antimicrobial use in pediatric acute care institutions is complicated because the common metric unit, the defined daily dose, is problematic for this population.

OBJECTIVE: During a four‐year period in which no specific antimicrobial stewardship initiatives were conducted, pediatric antimicrobial use was quantified using days of therapy (DOT) per 100 patient days (PD) (DOT/100 PD) at the Alberta Children’s Hospital (Calgary, Alberta) for benchmarking purposes.

METHODS: Drug use data for systemic antimicrobials administered on wards at the Alberta Children’s Hospital were collected from electronic medication administration records. DOT were calculated and rates were determined using 100 PD as the denominator. Changes over the surveillance period and subgroup proportions were represented graphically and assessed using linear regression.

RESULTS: Total antimicrobial use decreased from 93.6 DOT/100 PD to 75.7 DOT/100 PD (19.1%) over the 2010/2011 through to the 2013/2014 fiscal years. During this period, a 20.0% increase in PD and an essentially stable absolute count of DOT (2.9% decrease) were observed. Overall, antimicrobial use was highest in the pediatric intensive care and oncology units.

DISCUSSION: The exact changes in prescribing patterns that led to the observed reduction in DOT/100 PD with associated increased PD are unclear, but may be a topic for future investigations.

CONCLUSION: Antimicrobial use data from a Canadian acute care pediatric hospital reported in DOT/100 PD were compiled for a four‐year time period. These data may be useful for benchmarking purposes.
Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy
Authors: Sterman Daniel H. , Alley Evan , Stevenson James P. , Friedberg Joseph , Metzger Susan , Recio Adri , Moon Edmund K. , Haas Andrew R. , Vachani Anil , Katz Sharyn I. , Sun Jing , Heitjan Daniel F. , Hwang Wei-Ting , Litzky Leslie , Yearley Jennifer H. , Tan Kay See , Papasavvas Emmanouil , Kennedy Paul , Montaner Luis J. , Cengel Keith A. , Simone Charles B. , Culligan Melissa , Langer Corey J. , Albelda Steven M.
Published: March 2016

Purpose: “In situ vaccination” using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system.

Experimental Design: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNα2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured.

Results: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNα in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies.

Conclusions: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Clin Cancer Res; 22(15); 3791–800. ©2016 AACR.
Hope in the Long Road Toward the Development of a Therapeutic Human Papillomavirus Vaccine
Authors: Karaki Soumaya , Pere Helene , Badoual Cecile , Tartour Eric
Published: March 2016

A pool of long synthetic peptides derived from HPV16 proteins induce objective partial or complete histologic regression of lesions in more than 50% of patients with high-grade vulvar (VuVIN3) and vaginal intraepithelial neoplasia (VaIN3). The intensity of T-cell response induced by the vaccine was correlated with clinical response. Clin Cancer Res; 22(10); 2317–9. ©2016 AACR.

See related article by van Poelgeest et al., p. 2342
Clinical Response of Carcinomas Harboring the BRD4–NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628
Authors: Stathis Anastasios , Zucca Emanuele , Bekradda Mohamed , Gomez-Roca Carlos , Delord Jean-Pierre , de La Motte Rouge Thibault , Uro-Coste Emmanuelle , de Braud Filippo , Pelosi Giuseppe , French Christopher A.
Published: March 2016

The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4–NUT fusion oncoprotein. BRD4–NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4–NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4–NUT.

Significance: We present the first clinical proof-of-concept that targeting BRD4–NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492–500. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 461
Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
Authors: Gabrielson Andrew , Wu Yunan , Wang Hongkun , Jiang Jiji , Kallakury Bhaskar , Gatalica Zoran , Reddy Sandeep , Kleiner David , Fishbein Thomas , Johnson Lynt , Island Eddie , Satoskar Rohit , Banovac Filip , Jha Reena , Kachhela Jaydeep , Feng Perry , Zhang Tiger , Tesfaye Anteneh , Prins Petra , Loffredo Christopher , Marshall John , Weiner Louis , Atkins Michael , He Aiwu Ruth
Published: March 2016

Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3+) and cytotoxic (CD8+) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3+ and CD8+ cells and clinical outcome. High densities of both CD3+ and CD8+ T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3+ and CD8+ cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6–21.8] for CD3+ and 3.9 (95% CI, 1.1–14.1) for CD8+. Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419–30. ©2016 AACR.
TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination
Authors: Hsu Melody S. , Sedighim Shaina , Wang Tina , Antonios Joseph P. , Everson Richard G. , Tucker Alexander M. , Du Lin , Emerson Ryan , Yusko Erik , Sanders Catherine , Robins Harlan S. , Yong William H. , Davidson Tom B. , Li Gang , Liau Linda M. , Prins Robert M.
Published: March 2016

Although immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next-generation sequencing approach to determine whether quantitative assessments of tumor-infiltrating lymphocyte (TIL) content and the degree of overlap of T-cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma patients treated with autologous tumor lysate–pulsed dendritic cell immunotherapy. A statistically significant correlation was found between a higher estimated TIL content and increased time to progression and overall survival. In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, was correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response. Cancer Immunol Res; 4(5); 412–8. ©2016 AACR.