bluuebunny/crossref_metadata_2025 huggingface dataset:
Disrupted NOS signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow
Authors: Datar Sanjeev A. , Gong Wenhui , He Youping , Johengen Michael , Kameny Rebecca J. , Raff Gary W. , Maltepe Emin , Oishi Peter E. , Fineman Jeffrey R.
Published: May 2016

Associated abnormalities of the lymphatic circulation are well described in congenital heart disease. However, their mechanisms remain poorly elucidated. Using a clinically relevant ovine model of a congenital cardiac defect with chronically increased pulmonary blood flow (shunt), we previously demonstrated that exposure to chronically elevated pulmonary lymph flow is associated with: 1) decreased bioavailable nitric oxide (NO) in pulmonary lymph; and 2) attenuated endothelium-dependent relaxation of thoracic duct rings, suggesting disrupted lymphatic endothelial NO signaling in shunt lambs. To further elucidate the mechanisms responsible for this altered NO signaling, primary lymphatic endothelial cells (LECs) were isolated from the efferent lymphatic of the caudal mediastinal node in 4-wk-old control and shunt lambs. We found that shunt LECs ( n = 3) had decreased bioavailable NO and decreased endothelial nitric oxide synthase (eNOS) mRNA and protein expression compared with control LECs ( n = 3). eNOS activity was also low in shunt LECs, but, interestingly, inducible nitric oxide synthase (iNOS) expression and activity were increased in shunt LECs, as were total cellular nitration, including eNOS-specific nitration, and accumulation of reactive oxygen species (ROS). Pharmacological inhibition of iNOS reduced ROS in shunt LECs to levels measured in control LECs. These data support the conclusion that NOS signaling is disrupted in the lymphatic endothelium of lambs exposed to chronically increased pulmonary blood and lymph flow and may contribute to decreased pulmonary lymphatic bioavailable NO.
Vascular smooth muscle desensitization in rabbit epigastric and mesenteric arteries during hemorrhagic shock
Authors: Ratz P. H. , Miner A. S. , Huang Y. , Smith C. A. , Barbee R. W.
Published: May 2016

The decompensatory phase of hemorrhage (shock) is caused by a poorly defined phenomenon termed vascular hyporeactivity (VHR). VHR may reflect an acute in vivo imbalance in levels of contractile and relaxant stimuli favoring net vascular smooth muscle (VSM) relaxation. Alternatively, VHR may be caused by intrinsic VSM desensitization of contraction resulting from prior exposure to high levels of stimuli that temporarily adjusts cell signaling systems. Net relaxation, but not desensitization, would be expected to resolve rapidly in an artery segment removed from the in vivo shock environment and examined in vitro in a fresh solution. Our aim was to 1) induce shock in rabbits and apply an in vitro mechanical analysis on muscular arteries isolated pre- and postshock to determine whether VHR involves intrinsic VSM desensitization, and 2) identify whether net VSM relaxation induced by nitric oxide and cyclic nucleotide-dependent protein kinase activation in vitro can be sustained for some time after relaxant stimulus washout. The potencies of phenylephrine- and histamine-induced contractions in in vitro epigastric artery removed from rabbits posthemorrhage were decreased by ∼0.3 log units compared with the control contralateral epigastric artery removed prehemorrhage. Moreover, a decrease in KCl-induced tonic, relative to phasic, tension of in vitro mesenteric artery correlated with the degree of shock severity as assessed by rates of lactate and K+ accumulation. VSM desensitization was also caused by tyramine in vivo and PE in vitro, but not by relaxant agents in vitro. Together, these results support the hypothesis that VHR during hemorrhagic decompensation involves contractile stimulus-induced long-lasting, intrinsic VSM desensitization.
Heterotrimeric G protein signaling in polycystic kidney disease
Authors: Hama Taketsugu , Park Frank
Published: May 2016

Autosomal dominant polycystic kidney disease (ADPKD) is a signalopathy of renal tubular epithelial cells caused by naturally occurring mutations in two distinct genes, polycystic kidney disease 1 ( PKD1) and 2 ( PKD2). Genetic variants in PKD1, which encodes the polycystin-1 (PC-1) protein, remain the predominant factor associated with the pathogenesis of nearly two-thirds of all patients diagnosed with PKD. Although the relationship between defective PC-1 with renal cystic disease initiation and progression remains to be fully elucidated, there are numerous clinical studies that have focused upon the control of effector systems involving heterotrimeric G protein regulation. A major regulator in the activation state of heterotrimeric G proteins are G protein-coupled receptors (GPCRs), which are defined by their seven transmembrane-spanning regions. PC-1 has been considered to function as an unconventional GPCR, but the mechanisms by which PC-1 controls signal processing, magnitude, or trafficking through heterotrimeric G proteins remains to be fully known. The diversity of heterotrimeric G protein signaling in PKD is further complicated by the presence of non-GPCR proteins in the membrane or cytoplasm that also modulate the functional state of heterotrimeric G proteins within the cell. Moreover, PC-1 abnormalities promote changes in hormonal systems that ultimately interact with distinct GPCRs in the kidney to potentially amplify or antagonize signaling output from PC-1. This review will focus upon the canonical and noncanonical signaling pathways that have been described in PKD with specific emphasis on which heterotrimeric G proteins are involved in the pathological reorganization of the tubular epithelial cell architecture to exacerbate renal cystogenic pathways.
Comprehensive database of human E3 ubiquitin ligases: application to aquaporin-2 regulation
Authors: Medvar Barbara , Raghuram Viswanathan , Pisitkun Trairak , Sarkar Abhijit , Knepper Mark A.
Published: May 2016

Aquaporin-2 (AQP2) is regulated in part via vasopressin-mediated changes in protein half-life that are in turn dependent on AQP2 ubiquitination. Here we addressed the question, “What E3 ubiquitin ligase is most likely to be responsible for AQP2 ubiquitination?” using large-scale data integration based on Bayes' rule. The first step was to bioinformatically identify all E3 ligase genes coded by the human genome. The 377 E3 ubiquitin ligases identified in the human genome, consisting predominant of HECT, RING, and U-box proteins, have been used to create a publically accessible and downloadable online database ( https://hpcwebapps.cit.nih.gov/ESBL/Database/E3-ligases/ ). We also curated a second database of E3 ligase accessory proteins that included BTB domain proteins, cullins, SOCS-box proteins, and F-box proteins. Using Bayes' theorem to integrate information from multiple large-scale proteomic and transcriptomic datasets, we ranked these 377 E3 ligases with respect to their probability of interaction with AQP2. Application of Bayes' rule identified the E3 ligases most likely to interact with AQP2 as (in order of probability): NEDD4 and NEDD4L (tied for first), AMFR, STUB1, ITCH, ZFPL1. Significantly, the two E3 ligases tied for top rank have also been studied extensively in the reductionist literature as regulatory proteins in renal tubule epithelia. The concordance of conclusions from reductionist and systems-level data provides strong motivation for further studies of the roles of NEDD4 and NEDD4L in the regulation of AQP2 protein turnover.
Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance
Authors: Stump Madeliene , Guo Deng-Fu , Lu Ko-Ting , Mukohda Masashi , Liu Xuebo , Rahmouni Kamal , Sigmund Curt D.
Published: May 2016

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.
Monte Carlo Comparison of Rival Experimental Designs For Two‐Agent Combined Action Studies
Authors: Greco William R , Sutor David C , Parsons John C , Khinkis Leonid A , Hsieh Lily , Rao Sowmya R , Tung Ying , Currie Christopher C , Susice Robin
Published: May 2016

OBJECTIVE: The combined action of two or more chemotherapeutic agents and/or biological agents can be quantitatively described wilh empirical multidimensional concenlration‐effect response surface models. This intuitive statistical approach provides a framework for suggesting experimental designs for in vitro. in vivo and possibly clinical experiments of agent combinations. Five rival 32‐point experimental designs for in vitro continuous response two‐agent combined action studies were compared using Monte Carlo simulation.

DESIGN: The designs were: factorial; central composite: one‐ray in duplicate; four‐ray; and D‐optimal.

SETTING: Datasets were simulated by generating ideal data with the authors’ flagship two‐agent combined action model. which includes six parameters: the control sunrival Econ=100 (where Econ is the full range of response that can be affected by the drug); median effective concentrations. IC50.1=10. IC50.2= 1 for drug 1 and drug 2, Respectively; slope parameters. m1 =‐ 1. m2=‐2 for drug 1 and drug 2. respectively; and the interaction parameter, α=1 or α=5. For each design, for each of four types of error (absolute. relative with 1% coefficient of variation [cv]. relative with 10% cv. and relative with 10% cv plus a noise constant of 1% of Econ) . for each of two values of the true α (1, 5). 500 Monte Carlo datasets were generated. and then flt via weighted nonlinear regression wilh lhe flagship model.

MAIN Results: For the α parameter. for relative error‐containing datasets. the D‐optimal designs had the smallest variances.

CONCLUSION: The counterintuitive D‐optimal designs may be useful for studies in which the experimental units are relatively precious. and frugal designs are essential. In addition. it may be fruitful to add the D‐optimal design points lo standard experimental designs.
Virological and Immunological Aspects of AIDS Pathogenesis
Authors: Conway Brian , Diaz-Mitoma Francisco J
Published: May 2016

The most common and serious problem associated with long term antiretroviral therapy is waning efficacy over time. To date. a number of studies has suggested an association between drug resistance and clinical deterioration. However. a precise causal relationship has yet to be demonstrated. In a large American clinical trial. resistance to zidovudine (ZDV) was predictive of subsequent disease progression if this therapy was continued. Surprisingly. this was also predictive of deterioration if therapy was changed to didanosine (ddl). This suggests that other factors (perhaps virological and immunological) which may be present in addition to resistance. were as important (if not more so) in predicting clinical outcomes. It is likely that viral load. resistance. viral phenotype and alterations in immune function interact in this regard. Proper· studies may allow us to determine a “threshold” for a composite virological and immunological parameter beyond which disease progression will occur. As more antiretroviral agents become available. we will be in a position to intervene to “improve” laboratory markers and monitor them prospectively. potentially to maintain clinical latency for an indefinite period of time. In the authors′ laboratories, a quantitative polymerase chain reaction assay for the evaluation of circulating proviral load has been developed. In an initial study of 70 patients. proviral load/ 106 CD4 cells was clearly associated with the severity of immune disease. with up to 9.6% of cells being infected in subjects with CD4 cell counts below 200/µL. However. large variability in proviral load among individuals with comparable or dissimilar CD4 cell counts precludes the use of this measurement as an individual marker of the severity of immune disease. More recent work evaluated the combined use of proviral load (expressed as a dichotomous variable based on values above or below one copy/a03 CD4 cells) and resistance in a prospective fashion. In five patients with high proviral loads and isolates resistant to their current therapy. a mean decrease of 72 CD4 cells/µL was observed over 12 months of observation. In contrast. in six patients with low proviral loads and sensitive isolates. there was a mean increase of 43 CD4 cells/µL. It appears that virological markers are associated with immune disease progression in this small cohort of patients. The association appears most marked when the two virological parameters are considered together rather than individually. The association is not always a tight one. and this may relate to a number of unmeasured factors. including viral phenotype. plasma viremia. and the immune response to HIV infection. Additional work incorporating these parameters into analysis is currently underway in the authors’ centre.
The Potential of Vaccines for the Control of AIDS
Authors: Johnston Margaret I , Fast Patricia E , Walker Mary Clare , Hoth Daniel
Published: May 2016

The goal of a prophylactic human immunodeficiency (HIV) vaccine is to elicit immune response(s) that will, upon subsequent exposure to HIV. prevent lnfection and/or disease. On the other hand. therapeutic administration of a vaccine to an individual in whom infection is already established might benefit the individual by augmenting existing functional immune responses or inducing new ones. Development of vaccines for the prevention of AIDS offers unique challenges. Concerns regarding the safely
of attenuated and whole‐killed products have led to the pursuit of alternativc designs. including recombinant proteins, vectors and particles, synthetic peptides and naked DNA. Seven recombinant envelope. two recombinant vector and four other candidate vaccines that have entered into phase 1 trials in noninfected individuals have proven safe to date, and have differed In their ability lo induce functional antibody and Cytotoxic T lymphocytes. Two recombinant envelope products have recently progressed to phase 2 testing, Five envelope‐based and six other products have entered trial in HIV‐infected and individuals and have appeared to be safe, Evidence of new antibody, increased T cell proliferation and lncreased cytotoxic T lymphocyte activity have been reported. Additional placebo controlled trials will be required to evaluate the impact of therapeutic vaccination on CD4 cell count. viral burdrn and clinical end‐points. The status of HIV/AIDS vaccine development is reviewed. with emphasis on the challenging task of finding an effieacious, safe, prophylactic vaccine.
A Prospective Open‐Label Multicentre Trial on the Use of 1 G, Once Daily Ceftriaxone in Lower Respiratory Tract Infections
Authors: Low Donald E , Mandell Lionel A
Published: May 2016

This prospective. single open‐label sludy was conducted in 14 Canadian centres to assess lhe efncacy of I g, once a day intravenous ceftriaxone treatment administered for a minimum of three days in patients with lower respiratory tract infection. There were 137 patients enrolled. Age varied between 19 and 95 years (mean 68 years). Mosl patients (91 %) were diagnosed with community acquired pneumonia without bacteremia. Most of the cases (82%) were defined as modcralc or severe. Patients received ceftriaxone treatment for an average or five days. Macrolidcs or metronidazole were administered concomitantly wilh ceftriaxone in 34 patienls (25%). After a minimum of three days of ceftriaxone treatment. 59 palicnls (43%) were switched to oral antibiotics. Favourable treatment outcome was found in 92.9% and treatment failure (including relapse of infection) in 7.1 % o lpalicnls. Evaluable patients accounted for 91 % of patients enrolled
in the study. Clinical cure and clinical improvement were achieved in 64.6 and 28.3% of the evaluable patients. respectively. Relapse of infection occurred in two patients (1.8%). and treatment failure was recorded in six cases (5.3%). Twelve patients (8.8%) died clue to reasons unrelated to the sludy treatment. Three adverse event (hives, diarrhea and phlebitis at the injection site) were possibly related to the study drug. A cross‐Canada in vitro susceptibility surveillance study of bacterial pathogens. frequently the cause of pneumonia. found ceftriaxone to have minimal inhibitory concentrations in 90% of isolates that would support such a dosing regimen. with the exception of Enterobacter species. These rcsults support the use of 1 g, once daily ceftriaxone for the empirical treatment of pneumonia in those patients requiring hospitalization.
Newer Clinical Strategies for Combining Interferon and Cytotoxic Agents Against Solid Tumours and Hematological Malignancies
Authors: Wadler Scott
Published: May 2016

The role of interferons in the treatment of cancer continues to evolve. Despite limited single agent activity against solid tumours, interferons now appear to have an important role as modulators of the activity of a variety of cytotoxic drugs. Clinical benefits have been observed for combinations of interferons and alkylating agents against low grade lymphomas, interferons and dacarbazine against malignant melanoma, and interferons and 5‐fluorouracil against gastrointestinal and genitourinary malignancies. Further progress will depend on a grealer understanding of the biology of the interaction.
Prophylaxis Against Mycobacterium avium Complex Infection in AIDS
Authors: Cameron DW
Published: May 2016

Disseminated Mycobacterium avium complex (MAC) infection in AIDS is increasing in frequency, although it remains under‐recognized due to unlocalized clinical manifestations and subtle initial presentation, if not the need for specialized laboratory diagnostic methods. Ultimately, MAC accounts for much of the “wasting syndrome” in the natural history of human immunodeficiency virus disease. Multidrug treatment of MAC in AIDS is problematic. That MAC is preventable has been demonstrated, and how much clinical benefit can be had from successful prophylaxis remains to be evaluated in the face of improved efficacy of both treatment and prophylaxis regimens under investigation.
Intravenous to Oral Stepdown Antibiotic Therapy: Another Cost‐Effective Strategy in an Era of Shrinking Health Care Dollars
Authors: Louie Thomas J
Published: May 2016

The rapid transition from intravenous to oral antimicrobial therapy in hospitalized patients is being catalyzed by the need to gain further efficiencies in health care delivery without Compromising patient cure. The successful transition to oral therapy reduces complication from intravenous access devices. reduces cost of therapy and facilitates early discharge. both older and newer antimicrobials can be used as stepdown therapy. Although there are gaps in our information base with regards to outcome studies. the application of newer “pharmacodynamic” principles of antimicrobials action and careful selection of antimicrobials based on in vitro activity and pharmacokinetics will maximize the effectiveness of stepdown treatment of infections.
Home Intravenous Self‐Injection of Antibiotic Therapy
Authors: Martel Alain Y
Published: May 2016

The current medical climate has forced all health care providers to search for alternative methods for the delivery of health care. This search has led to the use of sites outside the conventional hospital walls for peritoneal dialysis, parenteral hyperalimentation, blood or blood product transfusions, etc. Home intravenous self‐injection of antibiotics is such an alternative to prolonged and/or repeated hospitalization for patients requiring intravenous antibiotics administration only. This alternative was started as a pilot study and soon became a usual service in the Centre hospitalier de l’Université Laval following receipt of a grant from the National Health Research and Development Program. After careful development of inclusion/exclusion criteria and a teaching manual for patient and health care providers. and the standardization of medical. pharmaceutical and nursing approach, a clinical, psychosocial and economical analysis of patients who agreed to participate in a clinical study comparing the two methods of health care delivery (hospital versus home) was started. Patients who met inclusion/exclusion criteria, agreeing to finish their treatment at home instead of staying hospitalized to receive intravenous antibiotics only, were taught the various techniques of intravenous self‐injection. Once they were judged to be able to self‐administer the antibiotics, they were sent home with the material needed to carry on their treatment, To date, more than 100 patients have participated in the home‐treatment, of which 50 were analyzed. The duration of home treatment varied from two days to several months. Most patients had osteomyelitis, septic arthritis, septic bursitis, bacterial cellulitis or lung infections. The therapy allowed some newly defined patients with complicated infections (AIDS patients with cytomegalovirus retinitis) to continue their treatment at home. The clinical outcome of patients treated at home was identical to the outcomes of those treated in the hospital. Side effects were comparable with the hospital treatment and were mainly catheter‐related. Compared with hospitalization. home treatment was preferred by the majority of patients. Psychological analysis of the patients showed that those who choose home therapy had a higher internal “locus of control” than those who preferred to stay in the hospital for the entire length of therapy. The economical analysis showed a potential reduction of cost varying between $941.00 and $3325.00 per treatment. Home intravenous self‐injection of antibiotics allowed health self‐monitoring by the patients or/and their friends or family and increased health care efficiency.
Pharmacoeconomics of Antibiotic Therapy
Authors: Lorier Jacques Le
Published: May 2016

During the past few years new drugs with greatly improved efficacy have become available to physicians
and their patients. The higher purchase price of these new drugs is quite important and is quoted as a
significant cause of the escalating cost of health care. Antibiotics have played a highly visible role in this
therapeutic scene and account for $1.2 billion of the yearly national pharmaceutical budget in the United
States. From an economic point of view, costs arise because resources are limited and have alternative
uses. The real cost of prescribing a new, more expensive drug, may be that other drugs and/or services
become unavailable. Unsurprisingly, considering the magnitude of the slakes, we have seen the recent
development and expansion of subsets of the field of health economics. Of these, cost of illness studies and
pharmacoeconomics have played a prominent role. The ultimate objective of these relatively new tools is
to help clinicians and decision makers in selling priori lies. A pharmacoeconomic study can have different
perspectives. Cost and benefits can be calculated with respect to the patients′, society′s, the payers, or the
health care providers, point of view. The perspective chosen for a study determines what is counted as cost
or benefit; therefore, the economic impact of an intervention may be quite different depending on the
perspective taken. Pharmacoeconomics is particularly relevant to antibiotic therapy since it can demonstrate
that the price of acquisition of the drug plays a relatively modest part in the global pharmacoeconomic
aspect of tl1c treatment of bacterial infections. This is easily understood when it is realized that failure to
treat a bacterial infection due to an inadequate choice of antibiotic promptly can result in avoidable
hospitalization, prolongation of hospitalization, permanent disability and even death.
Pharmaceutical, Pharmacokinetic and Other Considerations for Intravenous to Oral Stepdown Therapy
Authors: Jewesson Peter J
Published: May 2016

Parenteral to oral stepdown therapy represents an effective cost containment strategy which can minimize intravenous therapy associated morbidity and may facilitate earlier hospital discharge. Several oral anti‐infectives are available to the prescriber and there are as many opportunities to stepdown to the same agent as there are to other drugs of the same class or other classes. Recognition of the pharmacokinetic characteristics of these oral agents is essential lo successful therapy. Good bioavailability may not always be assured. A simple regimen will promote compliance.
Nutritional and Pharmacological Enhancement of the Gut‐Associated Lymphoid Tissue
Authors: Hanna M Keith , Kudsk Kenneth A
Published: May 2016

There has been an
explosion of research in the field of nutrition over the past quarter
century. Clinical studies have demonstrated the effectiveness of
providing nutrition by the enteral route in reducing septic morbidity
in critically ill patients. These improved outcomes have been
substantiated by animal models that show that enteral nutrition
decreases gut permeability while maintaining the gut‐associated
lymphoid tissue (GALT) in mucosal immunity. Evidence points
to the important immunological role of the gut in the maintenance
of mucosal immunity at both intestinal and extraintestinal
sites. The preservation of this mucosal immunity by enteral nutrition
is consistent with the lower morbidity seen in severely injured
patients who receive nutrition via the gastrointestinal tract. For
patients who are unable to be fed by the enteral route and who require
parenteral nutrition, several supplements show promise in
enhancing the mucosal immune system defenses. The nutritional
and pharmacological tactics that may enhance the GALT and
thereby maintain mucosal immunity are examined.
Canadian Consensus Conference on the Management of Viral Hepatitis
Authors:   Association for Study of the Liver (CASL) Consensus Conference Rapporteur Group
Published: May 2016

These proceedings of a consensus conference on the management of viral hepatitis were sponsored by the Canadian Association for Study of the Liver (CASL) and Health Canada. Experts in various aspects of viral hepatitis presented a review of the medical literature on assigned topics. Three expert panels were convened; they debated assigned topics, which corresponded to the reviews presented earlier. Attempts were made to reach consensus on a number of recommendations about the management of viral hepatitis. The content of the literature reviews, the debates and consensus statements were synthesized into a preliminary document. The report gives some background and offers recommendations aimed at both the general practitioner and the specialist.
Constipation: A Physiological Approach
Authors: Thompson W Grant
Published: May 2016

The first step in
managing a patient with constipation is to understand the precise
nature of the complaint. Is the onset recent? What are the frequency
and form of the stools, and how much effort is required to
defecate? Is constipation steady or alternating as in irritable bowel
syndrome? Are there structural, metabolic or pharmacological
confounders? Is the patient depressed? Has dietary fibre been tried
at a sufficient dose? What are the patient’s understanding and beliefs
about the symptoms? Has there been sufficient and appropriate
investigation? Armed with the answers to these questions,
physicians can help most patients through lifestyle, dietary and
pharmacological adjustments, along with supplementary fibre.
Some patients may require regular doses of an osmotic laxative.
Those few that fail these measures should have their transit time
estimated while on a high fibre diet; if it is normal, further testing
is unlikely to help. The above efforts should be re‐emphasized, and
reassurance should be offered. Some patients may require a psychological
assessment. If transit time is prolonged and the patient
may benefit from surgery for colonic inertia or biofeedback for anismus,
then colon and anorectal function should be assessed. The
decision to perform further tests should be made carefully, and unrealistic
expectations should be discouraged. Before surgery is offered,
the patient should have the benefit of receiving an expert
opinion. Biofeedback helps some patients with isolated anorectal
dysfunction.
Biology of Inflammation in Crohn's Disease: Mechanisms of Action of Anti-TNF-αAlpha Therapy
Authors: Targan Stephan R
Published: May 2016

Several recent trials of intravenously administered antitumour necrosis factor-alpha (TNF-α) monoclonal antibody have shown dramatic responses among patients with Crohn’s disease. These results indicate a primary role for TNF-αin the mediation of altered mucosal immune function in this disease. Clinical responses in patients treated with a single infusion of anti-TNF-αpersisted for as long as one year. The prolonged period of clinical benefit shows that the effect of short term TNF-αelimination remains long after the monoclonal antibody has cleared the body. Corresponding in vitro investigation has shown that T helper 1 (Th1) -mediated cytokine production of interferon-gamma is downregulated in the involved mucosa to a level consistent with that seen in uninflamed mucosa. These results suggest that TNF-α-specific augmentation of mucosal Th1 function is the process that is altered by removal of TNF-αand that produces such persistent responses. Understanding how TNF-αmodulates mucosal Th1 function may lead to the definition of a key feature of Crohn’s disease pathogenesis.
Diagnosis and Treatment of Gastroesophageal Reflux Disease in Infants and Children
Authors: Vandenplas Yvan
Published: May 2016

Gastroesophageal reflux is a frequent,
nonspecific phenomenon in infants and children. The
recommended approach for infants with uncomplicated regurgitation
is the reassurance of the parents about the physiological nature
of excessive regurgitation, and if necessary, completed with
dietary recommendations for formula‐fed infants. If, despite these
efforts, the symptoms persist, the administration of prokinetics
such as cisapride is recommended before investigations such as
esophageal pH monitoring are begun. Cisapride is the drug of
choice because it has the best efficacy and safety profile. In infants
and children presenting with symptoms that suggest esophagitis,
endoscopy of the upper gastrointestinal tract is recommended. If
there is severe esophagitis, acid suppression with H2 receptor antagonists
or proton pomp inhibitors is recommended, eventually
in combination with prokinetics. In life‐threatening situations, or
in patients who are resistant to or dependent on acid suppressive
medication, a surgical procedure such as laparoscopic Nissen
should be considered.

Esophageal pH monitoring is recommended to document gastroesophageal
reflux disease in children presenting with unusual presentations
such as chronic respiratory disease. Treatment consists
of prokinetics and/or acid suppressive drugs, and surgery should be
considered in many of these patients.
Treatment of HCV Infection in Children
Authors: Francavilla Ruggiero , Mieli-Vergani Giorgina
Published: May 2016

HepatitisCvirus (HCV) infection is the most common cause of chronic liver disease in the western world. Despite extensive epidemiological data in adults, the exact number of children infected is still unknown, and little is known about the natural history of chronic HCV infection in childhood. The authors review studies focusing onHCVinfection in children, and summarize the results, including the efficacy of interferon, and interferon plus ribavirin combination treatment of HCV hepatitis in childhood.
Intravenous Pantoprazole: A New Tool for Acutely Ill Patients Who Require Acid Suppression
Authors: Trépanier Eric F
Published: May 2016

Until now, oral proton pump inhibitors
have not been available as parenteral therapy in the acute
care setting. Pantoprazole is the first parenteral proton pump inhibitor
to become available in Canada. This agent is superior to
the parenteral histamine2 receptor antagonists with respect to
acid suppressive effects and is not associated with tolerance development.
Another advantage over the histamine2 receptor antagonists
is that pantoprazole does not require dosage adjustment in
patients with renal impairment. Dosage adjustments are also not
required for elderly patients or those with hepatic impairment
when the drug is used at the usual dose for a limited period of time.
Contrary to intravenous cimetidine and ranitidine, which have
negative inotropic and chronotropic effects, intravenous pantoprazole
is well tolerated and has no significant effect on heart rate,
contractility or blood pressure. The lack of drug interactions for
this agent also simplifies its use, especially in patients who may require
multiple drugs during hospitalization. Parenteral pantoprazole
is effective in the treatment of reflux esophagitis. It is also
promising for the treatment of upper gastrointestinal bleeding and
in the perioperative care of patients with Zollinger‐Ellison syndrome,
but further research in these areas is necessary. Once the
patient is able to tolerate oral medications, parenteral therapy can
be easily converted to oral therapy using an oral dose that was
equivalent to the parenteral dose (ie, 40 mg given intravenously is
equivalent to 40 mg given orally).
Thrombocytopenia in Liver Disease
Authors: Peck-Radosavljevic Markus
Published: May 2016

Moderate thrombocytopenia
is a frequent finding in cirrhosis of the liver and well
tolerated in most instances. The pathophysiology of thrombocytopenia
in liver disease has long been associated with the concept
of hypersplenism, where portal hypertension was thought to cause
pooling and sequestration of all corpuscular elements of the blood,
predominantly thrombocytes in the enlarged spleen. The concept of
hypersplenism was never proven beyond any doubt but was widely
accepted for the lack of alternative explanations.

With the discovery of the lineage‐specific cytokine thrombopoietin
(TPO) the missing link between hepatocellular function
and thrombopoiesis was found. TPO is predominantly produced
by the liver and constitutively expressed by hepatocytes.TPOproduction
in humans is dependent on functional liver cell mass and
is reduced when liver cell mass is severely damaged. This leads to
reduced thrombopoiesis in the bone marrow and consequently to
thrombocytopenia in the peripheral blood of patients with
advanced‐stage liver disease.

With recombinant TPOs in development, patients with liver disease
and TPO seem to be the ideal target population for this drug.
Once the efficacy of thrombopoietin in patients with liver disease
is proven, a potent yet safe drug may be available to treat cirrhotic
patients undergoing invasive or surgical procedures, during bleeding
episodes or when undergoing therapy with myelosuppressive
drugs such as interferon‐alpha.
Chronic Lymphoid Leukemia Complicated with Ascites
Authors: Mamode Chemir , Beauregard Patrice , Langevin Serge , Mongeau Charles-Jacques
Published: May 2016

Ascites are common in
malignancies of the gastrointestinal tract but are rarely associated
with chronic lymphoid leukemia. An unusual progression of
chronic lymphoid leukemia, rapidly complicated with ascites, is
presented, followed by a discussion of the causes and types of ascites
found in solid and blood malignancies.
Why and How to Treat Chronic Hepatitis C
Authors: Hadziyannis Stephanos J
Published: May 2016

Chronic hepatitis C (CHC) is a major health problem worldwide, with approximately 200 million affected individuals and a significant rate of progression to end-stage cirrhosis and hepatocellular carcinoma (HCC). If hepatitis C virus (HCV) infection is left untreated in the population, then the number of liver-related deaths will soon double and the need for liver transplantation may increase to five times that seen today. Available therapies for CHC are restricted to interferon alpha (IFN-α ) monotherapy and to the combination of IFN-α and ribavirin. Despite their high cost and side effects, both of these therapies have proved to be cost effective, particularly combination therapy. IFN-α monotherapy for one year can induce sustained response (SR) rates of approximately 10% in naive patients infected with HCV genotype 1, and above 50% in those infected with other genotypes. Combination therapy can double or even triple the rate of SR in genotype 1 infections and may further increase the SR rate in the other HCV genotypes. Combination therapy has also been proven to be effective in approximately 50% of relapsed responders to IFN-α monotherapy. In clinical practice, the decision to treat should be individualized and tailored on the basis of several virus- and host-related factors, particularly the grade and stage of liver disease, HCV genotype and levels of viremia. Appropriate monitoring of therapy by careful clinical evaluation, liver biochemistry and serumHCVRNAtesting is mandatory. IFN-α therapy may also prove to be effective in reducing the rate of HCC development in CHC regardless of whether a virological response is achieved, but this remains to be established.
Medical Therapy of Steroid-Resistant Crohn's Disease
Authors: Sands Bruce E
Published: May 2016

Glucocorticosteroids are commonly used in the treatment of moderate to severe Crohn’s disease and are effective for the short term amelioration of symptoms. However, not all patients respond to corticosteroid therapy. Approximately 20% of patients fail to respond to initial treatment with steroids, while 36% of patients may be considered steroid dependent. Sharp distinctions between steroid-dependent and steroid-resistant populations are difficult to draw because steroid responsiveness is often dose dependent. Clearer distinctions may be drawn between those who fail to respond to initial treatment with corticosteroids and those who have secondary failure later in the course of their disease on repeated treatment. Effective therapies for steroid-resistant Crohn’s disease include azathioprine and 6-mercaptopurine, methotrexate, cyclosporine and infliximab. Limited data are available on the use of tacrolimus, mycophenolate mofetil and thalidomide. Steroid-resistant Crohn’s disease, while involving a small minority of patients, continues to present a difficult therapeutic challenge.
Nutrition and Gastric Cancer
Authors: La Vecchia Carlo , Franceschi Silvia
Published: May 2016

The reasons for
the worldwide decline in stomach cancer incidence and mortality
rates are not fully understood, but dietary changes are clearly implicated.
While the possible mechanisms of gastric carcinogenesis
and the impact of Helicobacter pylori eradication remain open to
debate, at least two practical recommendations – to increase fruit
and vegetable intake, and to reduce consumption of salt – are already
supported by epidemiological evidence. These dietary recommendations
may also be beneficial in the prevention of other
cancers and chronic diseases. Promising evidence of a favourable
effect of certain vitamins, such as vitamin C and E and betacarotene,
and minerals, such as selenium, justifies additional investigation.
Nutrition of Liver Transplant Patients
Authors: Weimann Arved , Plauth Mathias , Bischoff Stefan C , Kuse Ernst R
Published: May 2016

Good cooperation between the hepatologist, surgeon
and anesthesiologist is required to determine the appropriate perioperative
nutritional management for the liver transplant patient.
For preoperative risk stratification, nutritional assessment
according to resting energy expenditure by indirect calorimetry,
and body cell mass by bioelectrical impedence analysis, may be superior
to anthropometric parameters. When considering impaired
glucose tolerance in the early postoperative period, requirements
of energy intake and macronutrients are no different from those established
in major abdominal surgery. Preference should be made
to use the enteral route whenever possible. Fat emulsions containing
medium‐ and long‐chain triglycerides have neither a negative
impact on reticulo‐endothelial system recovery of the graft, nor
any obvious metabolic advantages. There is no evidence for the
routine use of branched‐chain amino acids. Even in the case of
good graft function, long term dietary evaluation and counselling
may be useful. Impaired glucose tolerance, hyperlipidemia and hypercholesterolemia
should be considered carefully. The role of
preoperative nutritional therapy using oral supplements and the
value of immune‐enhancing substrates should be evaluated with
special regard to a decrease in postoperative septic complications
and for possible impact on immune tolerance after transplantation.
Fasciitis Complicating Subcutaneous Injection of Interferon Beta
Authors: Cooper Curtis L , Gerstein Rachel , Kaita Kelly
Published: May 2016

Data pertaining to 65 patients treated at the Health Sciences Center Hepatology Research Unit in Winnipeg, Manitoba describing local complications related to subcutaneous interferon (IFN) injection administered to treat hepatitis C virus infection are presented. Nine patients experienced local erythematous reactions at the injection region. No life-threatening complications were identified. One case of fasciitis complicating IFN injection – a complication not previously reported – was successfully managed with surgical debridement and antibiotic therapy. This case is a dramatic example of why sterile technique during infections must be adhered to.
Peripheral Mechanisms of Symptom Generation in Irritable Bowel Syndrome
Authors: Collins Stephen M
Published: May 2016

There is considerable interest in the mechanisms
that underlie symptom generation in irritable bowel syndrome
(IBS) and particularly those mechanisms peripheral to higher
centres in the nervous system. While the central nervous system
is important in IBS, it is restricted largely to the role of behaviour
in stress perception and symptom reporting. The gut and
the autonomic nervous system are principal areas of research in
identifying mechanisms underlying symptom generation and in
the identification of new targets for drug development. While
motility changes occur in IBS, they are neither specific nor predictable,
and this is one reason why drugs aimed at influencing
motility patterns have enjoyed limited success to date. This success
has prompted interest in sensory physiology to explain pain
and other discomforts expressed by patients with IBS. Patients
with IBS exhibit intolerance to rectal distension and other
manoeuvres of the gut, while exhibiting normal or raised thresholds
for somatic pain. The mechanisms underlying the development
of hyperalgesia or allodynia in the gut remain to be
determined. In other systems and experimental models, low
grade inflammation is a predicable inducer of these states, and
recent evidence suggests that a subpopulation of patients with
IBS develop chronic symptoms after acute gastroenteritis. This
and other inflammatory stimuli may induce a hyperalgesic state
and alter motor function in patients with IBS. Substances that
mediate these changes are not fully understood, but there is
growing recognition of the role of serotonin as a sensitizing
agent.
Management of Depression Associated with HIV/AIDS and Antiretrovial Therapy
Authors: Halman Mark
Published: May 2016

Depressed mood is a common psychiatric complaint in persons with
HIV/AIDS, with a meta‐analysis indicating that the rates of depression
within this group may be as high as double that of the general
population. Depression may result from a biological diathesis to mood
disorders, a physiological reaction to a medical illness or its treatment,
and/or a psychological reaction to challenging life circumstances.
Associated symptoms include sleep, energy and appetite disturbances;
social withdrawal; diminished capacity to experience pleasure; diminished
concentration; feelings of worthlessness, shame and guilt; and
recurrent thoughts of death, including suicidal ideation. The emotionally
and physically painful state of major depression is associated
with decreased antiretroviral adherence and poorer HIV/AIDS disease
outcomes.
Neuropsychiatric symptoms have been reported with several of the
medications taken by patients with HIV/AIDS, including lamivudine,
zidovudine, interferon and, most notably, efavirenz. However, data
from several sources demonstrate that neuropsychiatric symptoms
associated with efavirenz use are generally transient, with onset early
after treatment initiation, peaking after one week and decreasing over
the first one to four months of treatment. Recent comparative studies
have not found elevated incident rates of major depression in patients
treated with efavirenz, but they have confirmed the typical neuropsychiatric
symptoms reported in earlier open‐label studies and case
reports. Becoming skilled in the management of depression and psychiatric
symptoms is integral to the provision of comprehensive care
for patients with HIV/AIDS.
Hospital‐Acquired Methicillin‐Resistant Staphylococcus aureus: Epidemiology, Treatment and Control
Authors: Rotstein Coleman
Published: May 2016

Antimicrobial‐resistant organisms are an expanding problem, resulting
in increased morbidity and mortality, prolonged hospital stay, and
heightened health care costs for care and antimicrobial management.
Methicillin‐resistant Staphylococcus aureus (MRSA) has emerged as a
major hospital‐acquired, antimicrobial‐resistant pathogen. MRSA not
only colonizes hospitalized patients but has a propensity to produce
more serious, life‐ threatening infection than methicillin‐susceptible
strains. Numerous risk factors, including antimicrobial use and proximity
to a patient harbouring MRSA, have been linked to the acquisition
of MRSA. Although vancomycin has been the mainstay of
therapy for MRSA, failures have been reported due to reduced susceptibility
to this agent. Other available therapeutic agents for MRSA
include trimethoprim‐sulfamethoxazole, tetracycline, fusidic acid,
rifampin (in combination with other effective agents) and linezolid.
Potential therapeutic agents that are currently under investigation
include daptomycin, dalbavancin, tigecycline, ceftobiprole and
iclaprim. Only enhanced infection control practices can halt the progressive
transmission of MRSA in the hospital environment. However,
such measures have not quite fulfilled their promise in clinical studies.
Moreover, eradication of MRSA colonization is controversial and may
promote greater resistance. A multidisciplinary approach to the prevention,
containment and treatment of MRSA is necessary.