bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of floodplain restoration on flow and sediment dynamics in an urban river
Authors: Ahilan S. , Guan M. , Sleigh A. , Wright N. , Chang H.
Published: May 2016

A study of floodplain sedimentation on a recently restored floodplain is presented. This study uses a two‐dimensional hydro‐morphodynamic model for predicting flow and suspended‐sediment dynamics in the downstream of Johnson Creek, the East Lents reach, where the bank of the river has been reconfigured to reconnect to a restored floodplain on a 0.26 km2 (26‐ha) site. The simulation scenarios include 10‐, 50‐, 100‐ and 500‐year event‐based deposition modelling of flood events and long‐term modelling using the 64 historical flood events between 1941 and 2014. Simulation results showed that the restored floodplain significantly attenuates the upstream flood peak by up to 25% at the downstream. Results also indicated that approximately 20%–30% of sediment from the upstream is deposited on the East Lents floodplain. Furthermore, deposited sediment over the simulated period (1941–2014) is approximately 0.1% of the basin's flood storage capacity; however, the reduction in the storage does not offset the overall flood resilience impact of the flood basin. The sediment conservation at the East Lents flood basin as predicted by the model reduces the annual sediment loading of the Johnson Creek by 1% at the confluence with Willamette River, providing both improved water quality and flood resilience further downstream.
Unleashing the Kraken: on the maximum length in giant squid (Architeuthis sp.)
Authors: Paxton C. G. M.
Published: May 2016

Giant squid are among the largest invertebrates known, but a consensus on their maximum size is lacking. Statistical investigation of various measures of body length and beak size in Architeuthis suggests that squid of at least 2.69 m (99.9% prediction interval: 1.60–3.83 m) mantle length (ML) may be handled by large bull sperm whales but perhaps not females. Given the relationship of squid ML to standard (from tip of mantle to end of arms) and total (from tip of mantle to end of tentacles) length, the observed spread of individual lengths, along with a longest reliably measured ML of 2.79 m, purported squid of 10 m standard length and even 20 m total length are eminently plausible.
The Rule of Law between England and Sudan: Hay, Thompson, and Massoud
Authors: Krygier Martin
Published: May 2016

Two significant writings, one by Douglas Hay and the other by E. P. Thompson, appeared in 1976. Both sought to explain relationships between law and social (specifically, ruling‐class) power in a manner that avoided treating law either simply as a coercive instrument of class domination (“vulgar Marxism”), or as a good for all “(liberal legalism”). They overlapped and each was influenced by the other, but they differed significantly, in substance, in tone, and in admirers. Mark Massoud sensibly and thoughtfully draws inspiration from both. This article queries, however, whether his account of the role and rule of law in Sudan manages to resolve a significant tension between Hay and Thompson. This results in a certain ambivalence in the telling, a sometimes anguished oscillation between two interpretive modes, perhaps sensibilities, represented by Hay and Thompson, each of which can lead in different directions.
Chronological clinical and pathological documentation of porcine ulcerative dermatitis
Authors: Zeeh Friederike , Suter Maja M. , Mueller Eliane , Brünisholz Natalia , Zimmerman Werner , Ricklin Meret , Rüfenacht Silvia , Olivry Thierry , Roosje Petra J.
Published: May 2016

Background

Porcine ulcerative dermatitis syndrome (PUDS) is a rare disease of breeding sows with an unknown pathogenesis.

Objective

To describe the evolution of clinical and histopathological lesions over the course of the disease and to elucidate the pathogenesis.

Animal

A 24‐month‐old, pluriparous, large white sow presented during gestation with ulcerations around the teats compatible with PUDS.

Methods and results

Clinical and histopathological lesions were monitored over the course of the disease (i.e. during and after the subsequent pregnancy). A clear gestation‐dependent flare of the lesions was observed with partial resolution occurring postpartum. The histological pattern presented as a lymphocytic interface dermatitis.

Conclusions and clinical importance

The findings in this case report link gestation with the development of clinical signs and histological changes. Multiparity appears to enhance severity and may finally result in a self‐perpetuating disease. Therefore, it seems advisable to cull breeding sows after they have developed PUDS.
Thermal Instability of Convection in a Rotating Nanofluid Saturated Porous Layer Placed at a Finite Distance From the Axis of Rotation
Authors: Govender S.
Published: May 2016

An analytical investigation for the onset of convection in a vertical porous layer saturated by a nanofluid is presented when the porous layer is placed some finite distance from the axis of rotation. A linear stability analysis is used to determine the convection threshold in terms of the key parameters for the nanofluid. This study reconfirms that the Taylor number and gravity effects are passive, and that the most critical mode is roll cells aligned with the vertical axis of rotation. The critical Rayleigh number is presented in terms of the nanofluid parameters and offset distance for stationary convection.
Relationships Between Internal and External Training Load in Team-Sport Athletes: Evidence for an Individualized Approach
Authors: Bartlett Jonathan D. , O’Connor Fergus , Pitchford Nathan , Torres-Ronda Lorena , Robertson Samuel J.
Published: May 2016

Purpose:

The aim of this study was to quantify and predict relationships between rating of perceived exertion (RPE) and GPS training-load (TL) variables in professional Australian football (AF) players using group and individualized modeling approaches.

Methods:

TL data (GPS and RPE) for 41 professional AF players were obtained over a period of 27 wk. A total of 2711 training observations were analyzed with a total of 66 ± 13 sessions/player (range 39–89). Separate generalized estimating equations (GEEs) and artificial-neural-network analyses (ANNs) were conducted to determine the ability to predict RPE from TL variables (ie, session distance, high-speed running [HSR], HSR %, m/min) on a group and individual basis.

Results:

Prediction error for the individualized ANN (root-mean-square error [RMSE] 1.24 ± 0.41) was lower than the group ANN (RMSE 1.42 ± 0.44), individualized GEE (RMSE 1.58 ± 0.41), and group GEE (RMSE 1.85 ± 0.49). Both the GEE and ANN models determined session distance as the most important predictor of RPE. Furthermore, importance plots generated from the ANN revealed session distance as most predictive of RPE in 36 of the 41 players, whereas HSR was predictive of RPE in just 3 players and m/min was predictive of RPE in just 2 players.

Conclusions:

This study demonstrates that machine learning approaches may outperform more traditional methodologies with respect to predicting athlete responses to TL. These approaches enable further individualization of load monitoring, leading to more accurate training prescription and evaluation.
Chronic Bacterial Pathogens: Mechanisms of Persistence
Authors: Byndloss Mariana X. , Tsolis Renee M.
Published: May 2016

Many bacterial pathogens can cause acute infections that are cleared with the onset of adaptive immunity, but a subset of these pathogens can establish persistent, and sometimes lifelong, infections. While bacteria that cause chronic infections are phylogenetically diverse, they share common features in their interactions with the host that enable a protracted period of colonization. This article will compare the persistence strategies of two chronic pathogens from the
Proteobacteria
,
Brucella abortus
and
Salmonella enterica
serovar Typhi, to consider how these two pathogens, which are very different at the genomic level, can utilize common strategies to evade immune clearance to cause chronic intracellular infections of the mononuclear phagocyte system.
Mechanism and Function of Type IV Secretion During Infection of the Human Host
Authors: Gonzalez-Rivera Christian , Bhatty Minny , Christie Peter J.
Published: May 2016

Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic hosts. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant “superbugs,” detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This article summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.
The Versatile Type VI Secretion System
Authors: Alteri Christopher J. , Mobley Harry L.T.
Published: May 2016

Bacterial type VI secretion systems (T6SSs) function as contractile nanomachines to puncture target cells and deliver lethal effectors. In the 10 years since the discovery of the T6SS, much has been learned about the structure and function of this versatile protein secretion apparatus. Most of the conserved protein components that comprise the T6SS apparatus itself have been identified and ascribed specific functions. In addition, numerous effector proteins that are translocated by the T6SS have been identified and characterized. These protein effectors usually represent toxic cargoes that are delivered by the attacker cell to a target cell. Researchers in the field are beginning to better understand the lifestyle or physiology that dictates when bacteria normally express their T6SS. In this article, we consider what is known about the structure and regulation of the T6SS, the numerous classes of antibacterial effector T6SS substrates, and how the action of the T6SS relates to a given lifestyle or behavior in certain bacteria.
A qualitative analysis of Māori and Pacific smokers' views on informed choice and smoking
Authors: Gifford Heather , Tautolo El-Shadan , Erick Stephanie , Hoek Janet , Gray Rebecca , Edwards Richard
Published: May 2016

Objectives

Tobacco companies frame smoking as an informed choice, a strategy that holds individuals responsible for harms they incur. Few studies have tested this argument, and even fewer have examined how informed indigenous smokers or those from minority ethnicities are when they start smoking. We explored how young adult Māori and Pacific smokers interpreted ‘informed choice’ in relation to smoking.

Participants

Using recruitment via advertising, existing networks and word of mouth, we recruited and undertook qualitative in-depth interviews with 20 Māori and Pacific young adults aged 18–26 years who smoked.

Analyses

Data were analysed using an informed-choice framework developed by Chapman and Liberman. We used a thematic analysis approach to identify themes that extended this framework.

Results

Few participants considered themselves well informed and none met more than the framework's initial two criteria. Most reflected on their unthinking uptake and subsequent addiction, and identified environmental factors that had facilitated uptake. Nonetheless, despite this context, most agreed that they had made an informed choice to smoke.

Conclusions

The discrepancy between participants' reported knowledge and understanding of smoking's risks, and their assessment of smoking as an informed choice, reflects their view of smoking as a symbol of adulthood. Policies that make tobacco more difficult to use in social settings could help change social norms around smoking and the ease with which initiation and addiction currently occur.
Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus
Authors: Venkatasubramanian Sowmya , Noh Radzi M , Daga Shruti , Langrish Jeremy P , Mills Nicholas L , Waterhouse Brian R , Hoffmann Ethan , Jacobson Eric W , Lang Ninian N , Frier Brian M , Newby David E
Published: May 2016

Objective

Arterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus.

Methods

24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis).

Results

Compared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent.

Conclusions

SRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis.

Trial registration number

NCT01031108.
Flow and heat transfer to Sisko fluid with partial slip
Authors: Khan Masood
Published: May 2016

In this paper we study the partial slip effects on the flow and heat transfer of an incompressible non-Newtonian fluid over a nonlinear stretching sheet. The velocity slip boundary condition based on the Sisko constitutive fluid model is introduced. Suitable dimensionless variables are used to convert the governing partial differential equations into ordinary differential equations. Numerical solutions of these equations are obtained by the Runge–Kutta Fehlberg method. Additionally, the exact analytical solutions are presented in some special cases. The computational results for the velocity, temperature, skin-friction coefficient, and Nusselt number are presented in graphical and tabular forms. To validate the numerical results obtained, a comparison is made with the exact analytical solutions. The analysis of the results obtained shows that enhancement in the velocity slip parameter reduces the velocity as well as the momentum boundary layer thickness. However, quite the opposite is true with the temperature and corresponding thermal boundary layer thickness.
Treatment of HIV‐1 Infection with Combination Therapy: Antiretroviral Agents and Biological Response Modifiers
Authors: Schnittman Steven M
Published: May 2016

While nucleoside antiretroviral agents are effective in delaying disease progression in human immunodeficiency virus (HIV ‐ infected individuals. their activity is limited in magnitude and duration. Therefore, approaches to attacking HIV via combination therapies have recently been under investigation. In particular, since HIV infection dysregulates and destroys the immune system. it is logical to develop therapeutic approaches that would both restore the immune response and have direct antiviral activity. Preliminary evaluations of the combination of zidovudine wilh interferon alpha (IFN‐α) have demonstrated enhanced antiviral. antitumour and immunomodulatory activity. Other promising approaches include antiretroviral therapy with interleukin (IL) ‐2, and IFN‐α wilh IL‐2. The clinical research pertaining to these combinations of antiretrovirals and biological response modifiers is reviewed.
Hospital Acquired Pneumonia: Issues in Therapy
Authors: Mandell Lionel A
Published: May 2016

In December 1992. a meeting was convened in Toronto to develop guidelines for the initial treatment of hospital acquired pneumonia. Issues considered related lo the patient. the possible drugs used for treatment, and the pathogen(s). From the perspective of the patient. the two major issues were the presence or absence of risk factors for specific microbial pathogens and the severity of illness upon clinical presentation, Criteria for defining severly ill patients were developed and are presented in this paper. Drug and pathogen related issues focused on selection of antimicrobial agents thal would provide coverage for the likely pathogens. Concern was also expressed regarding use of aminoglycosides as single‐agent treatment of Gram‐negative infections in the lung. and the issue of monotherapy versus combination therapy of Pseudomonas aeruginosa infections was discussed. The use of various diagnostic tests was briefly reviewed. including the protected specimen brush and bronchoalveolar lavage. Treatment regimens are presented in tabular format.
Laboratory Diagnosis of HIV Infection
Authors: O’Shaughnessy MV , Cassol S
Published: May 2016

The laboratory diagnosis of HIV infection has progressed greatly since the introduction of the commercially prepared, HIV antibody assay in 1985. However, the antibody assay remains the gold standard since the sensitivity and specificity of properly performed tests exceed 99%. Recent progress in diagnostic test development includes the availabilily of reliable HIV p‐24 antigen capture assays with improved sensitivity due lo the elimination of immune complexes of antibody and p‐24 antigen and enhanced specificity due lo the availabilily of confirmatory (neutralizing) reagents. HIV culture procedures have been optimized and standardized with isolation rates of the virus from HIV antibody positive persons approaching 95%. This technology is labour intensive and requires special containment facilities. The polymerase chain reaction. and other amplification methods. such as the branched chain reaction. are used to search for the presence of HIV genclic informalion. These technologies are exquisitely sensitive but offer little routine advantage to the standard HIV anlibody assay. There are specific circumstances. such as the diagnosis of perinatal infections and measuring the efficacy of potential agents for the treatment of HIV disease. where this technology is appropriate. The unique performance characteristics of these two amplification procedures necessitate thal they be performed only in laboralories wilh adequate physical facilities and ongoing qualily assurance programs. Assays for determining the antiviral sensitivity of HIV to specific drugs and for phenotyping viral isolates have been developed in research centres and are presently being introduced into clinical laboratories across Canada.
The Canadian Multicentre MAC Treatment Study
Authors: Shafran Stephen D , The Canadian HIV Trials Network
Published: May 2016

Mycobacierium avium complex (MAC) infeclion is a common complication of the advanced stages of human immunodeficiency virus (HIV) infection
causing both morbidity and premature mortality. While it is acknowledged thal MAC infection requires treatment with a combination of antimycobacterial drugs. the optimal regimen has not been defined. A Canadian Multicentre MAC Treatment Trial was proposed in 1990 and finally implemented in late 1992 via the Canadian HIV Trials Network with the assistance of 6 pharmaceutical companies. The specific drug regimens and study design are outlined and the timetable for analysis and completion are also indicated.
Collaborative, Canadian, multicentre clinical trials in HIV disease can be successfully implemented.
Anti‐Interleukin‐1 Strategies in the Treatment of the Septic Shock Syndrome
Authors: Dinarello Charles A
Published: May 2016

The septic shock syndrome has recently been termed the systemic inflammatory response syndrome (SIRS). It is an acute illness characterized by generalized activation of the endothelium. The most severe and most common form of the syndrome is found in patients wilh shock due to Gram‐negative sepsis. In this overview. both animal and limited human data are considered for the contribution of the cytokine interleukin‐1 (IL‐1) to this syndrome. Cytokines are small molecular weight, endogenously produced proteins with multiple biological effects. Laboratory investigations suggest that IL‐1 plays a critical role in SIRS by promoting the biochemical and clinical characteristics of SIRS. The biochemical changes induced by IL‐1 are similar to those of tumour necrosis factor (TNF) and include increased synthesis of nitric oxide, prostaglandins, platelet activating factor and endothelial cell adhesion molecules. Togelher, IL‐1 and TNF appear to act in a synergistic fashion in a variety of disease models. particularly SRIS. Specific blockade of IL‐1 using soluble IL‐1 receptors or IL‐1 receptor antagonist suggests that blocking this cytokine may be useful in treating human SIRS.
Advances in the Treatment of Desseminated Mycobacterium avium Complex in Adults with AIDS
Authors: Kemper Carol A
Published: May 2016

Although the prospects for successful treatment of Mycobacterium avium complex (MAC) infection in AIDS recently seemed quite dismal, the introduction of
the semisynthetic macrolides, clarithromycin and azithromycin, has altered this perspective. Several recent clinical studies have been key to our understanding of the successful management of these patients and are the basis of this review. Yet, some patients with disseminated MAC remain poorly responsive to therapy, intolerance often limits therapy, and recrudescent bacteremia often occurs. Though our understanding of this infection has been rapidly advanced in the past three years. much remains to be learned about its optimal therapeutic management.
Use of Anti‐HIV Immunotoxins as Probes of the Biology of HIV‐Infected Cells
Authors: Pincus SETH H , McClure Jan , Fang Hua
Published: May 2016

OBJECTIVE: Anti‐human immunodeficiency virus (HIV) immunotoxins are potential treatments for HIV infection. but they may also be used as probes to study the relationship between HIV and the cell it infects. Data from the present study indicate the complexity of this relationship.

DESIGN: A panel of monoclonal antibodies directed against different epitopes on the HIV envelope protein(s) gp l20 and gp 41 was conjugated to ricin A chain. The activity of these immunotoxins on HIV‐infected cell lines was studied.

RESULTS: The data demonstrate that HIV‐infected cell lines may be killed by some, but not all, of these
immunotoxins. The killing is not directly proportional to the binding of the antibody to the infected cell and is influenced by the viral strain. The immunotoxins were used to select persistently infected cell lines for immunotoxin‐resistant variants: these demonstrate several different viral or cellular defects. The incubation of infected cells with a soluble form of the viral receptor increases the sensitivity of the cells to anti‐gp41, but not anti‐gpl20, immunotoxins by altering both the levels of expression and internalization of the viral envelope. Drugs that inhibit lysosomal degradation (ammonium chloride, monensin. chloroquine) enhance the efficacy of these immunotoxins.

CONCLUSIONS: Because immunotoxins must be internalized to function, they may be used to study the intracellular trafficking of the target antigens. In the present study, this was done using the HIV‐envelope protein as expressed in infected cells as the target antigen
Clinical Development of Biological Response Modifiers
Authors: Siegel Jay P
Published: May 2016

OBJECTIVE: To present perspectives on selected issues that frequently arise during the clinical development of biological response modifier (BRM) therapies.

DATA SOURCES: The perspectives and opinions presented herein were developed over several years of reviewing and consulting on the clinical development of BRM therapies at the United States Food and Drug Administration.

CONCLUSIONS: BRM therapies encompass a broad spectrum of products used to treat a wide variety of diseases. Due to this diversity. most principles of clinical trial design and conduct applicable to the majority of BRMS are those that are applicable to all therapies. Nevertheless, the clinical development of BRM therapies often raises specific issues and problems in the areas of selecting animal models, defining the study population, adverse reactions, dosing and defining end‐points. Over 10 years’ experience in testing biotechnology derived BRMS in clinical trials has created a database from which we can draw valuable generalizations for guidance in future studies.
Biological Response Modifiers and Parasitic Infections: Experimental Aspects of Toxoplasmosis
Authors: Beaman Miles H
Published: May 2016

Parasitic infections are important causes of disease in the developing world and, since the advent of AIDS, the developed world. Over the past decade, in vitro and in vivo studies have established the important role that biological response modifiers play in pathogenesis of parasitic disease. These basic studies have resulted in successful clinical trials of interferon gamma (IFN‐γ) in human leishmaniasis. Toxoplasmic encephalitis is a major opportunistic infection in patients with AIDS. and current therapy is often problematic. IFN‐γ has been shown in in vitro and in vivo animal studies to be critical for host defence against Toxoplasma gondii. Tumour necrosis factor alpha plays a critical role in mediating IFN‐γ effect in vitro, but its role in vivo is under further study. lnterleukin (1L)‐6 and IL‐10 have both recently been shown to enhance T gondii replication in vitro and to antagonize the beneficial effects of IPN‐γ. In addition, in certain mouse strains. IL‐6 has been shown to worsen mortality from T gondii infection. Future strategies for therapy of T gondii may include administration of exogenous IFN‐γ or IL‐12 with or without antibody to antagonistic cytokines such as IL‐6 (or possibly IL‐10).
Current Use of Nucleoside Analogues in the Treatment of HIV Infection
Authors: Montaner Julio SG , Zala Carlos , Spour Leila
Published: May 2016

Nucleoside analogues continue to play a central role in the
treatment of HIV infection. The recently published Concorde I.rial has been misinterpreted as demonstrating
a Jack of efficacy of zidovudine in the treatment of HIV disease. This is clearly not the case because zidovudine
was prescribed to patients in both arms of the study. The Concorde study did confirm, however, the
limitations of monotherapy in the treatment of this disease. Increased availability of other nucleoside
analogues has allowed the development of newer therapeutic strategies. In this context, sequential use of
zidovudine, followed by didanosine, has proved to be safe and effective in patients in varying stages of HIV
disease. Preliminary results suggest that this strategy could be improved upon by using simultaneous
combinations of zidovudine with didanosine or zalcitabine in full closes. The relative efficacy of these
combinations remains to be established by phase III clinical trials, currently underway, Several new agents,
including d4T, 3TC, nevirapine, other non‐nucleoside reverse transcriptase inhibitors and the more recent
protein inhibitors. are being tested either a lone or in combination therapy regimens. It is anticipated that
one or more of these agents will be clinically available soon. At present. the British Columbia Centre for
Excellence in HIV/AIDS continues to recommend initiation of antiretroviral therapy with zidovudine in doses
of 500 mg/day for all HIV‐infected individuals who are symptomatic (ie. who have AIDS or AIDS‐related
complex) and for those who are asymptomatic with a CD4 count consistently below 500/mm3. If the CD4
count is lower than 350/mm3, it is recommended that combination antiretroviral therapy be considered.
namely zidovudine plus didanosine or zalcitabine in full doses. Obviously, the available evidence should
be thoroughly discussed with eligible individuals to ensure that they have a full understanding of the
potential benefits, adverse effects and limitations of currently available therapy.
Once‐Daily Dosing of Aminoglycosides
Authors: Craig William A
Published: May 2016

OBJECTIVE: To review the pharmacodynamic rationale for once‐daily dosing of aminoglycosides and to
summarize thee results of comparative trials in animals and humans.
DATA SOURCES: Published articles on the pharmacodynamics of aminoglycosides and those comparing the
therapeutic efficacy and toxicity of once‐daily administration will more frequent closing regimens.
DATA SELECTION: Fourteen randomized studies in infected patients that compared the efficacy and toxicity
of once‐daily aminoglycoside dosing with twice‐ or thrice‐daily dosing regimens were available for review.
Ten studies comparing the efficacy and toxicity of different an1inoglycoside dosing regimens in animal
models were also reviewed .
DATA EXTRACTION: Frequency of clinical response, nephrotoxicity and ototoxicity with each dosing regimen
were compared graphically and by x2 for statistical significance (P<0.05).
DATA SYNTHESIS: Once‐daily dosing was consistently less toxic than more frequent dosing in animals. When
human pharmacokinetics were simulated in animals, efficacy of once‐daily dosing was similar or enhanced
over more frequent dosing regimens. Once‐daily dosing in patients, compared with twice‐ or thrice‐daily
administration, was statistically more effective in two studies, less nephrotoxic in six studies, and less
ototoxic in one study. Similar efficacy and toxicity were observed in all the oilier studies.
CONCLUSIONS: Once‐daily dosing of aminoglycosides has the potential to enhance efficacy, reduce toxicity
and lower administration costs for this drug class. The once‐daily dosing regimen deserves serious
consideration for routine use of the aminoglycosides.
Diarrhea in the HIV‐Infected Patient
Authors: Phillips Peter
Published: May 2016

Gastrointestinal manifeslations may be encountered throughout, the course of HIV disease. The problems range from asymptomatic hairy leukoplakia lo overwhelming diarrhea due to opportunistic infections such as cryptosporidiosis. Diarrheal disease is an important contributing factor to wasting in advanced HIV disease. Considerable progress has been made in recents years regarding our understanding or HIV‐related diarrhea, including etiological agents, diagnostic methods and treatment.
Identification of Mutations that Encode Drug Resistance in the Polymerase Gene of the Human Immunodeficiency Virus
Authors: Gu Zhengxian , Fang Hengsheng , Salomon Horacio , Gao Qing , Wainberg Mark A
Published: May 2016

In vitro selection in MT‐4 cells was used to generate human immunodeficiency virus‐type 1
(HIV 1) variants that are resistant to 2′,3′‐dideoxycytidine (ddC), 2′,3′‐didcoxyinosine (ddI) and the (‐) enantiomer
of 2′ ,3′‐dideoxy‐3′‐thiacytidine (3TC). The complete reverse transcriptase open reading frames of these
viruses, and portions of flanking protease and integrase within the pol gene, were cloned and sequenced
by polymerase chain reaction (PCR) techniques. Mulalions were observed at each of amino acid sites 65 (Lys
→ Arg: AAA → AGA) and 184 (Met → Val: ATG → GTG) when ddC was used in this protocol, and at site 184
only when either 3TC or ddl was employed. These mutations were introduced into the pol gene of infectious
recombinant HXB2‐D DNA by site‐directed mutagenesis to confirm, by viral replication assay, their
importance in conferring resistance against these drugs. A recombinant virus containing the site 65
mutation only possessed greater than 10‐fold resistance against ddC compared with parental HXB2‐D.
Moreover, cross‐resistance of about 20‐fold and threefold, respectively, was delectable against 3TC and dell
but not against 3′‐azido‐3′‐deoxthymidine (AZT). When the 65 and 184 mutations were combined into
HXB2‐D, the resultant construct did not possess higher levels of resistance lo any of these drugs than
observed with the site 65 or 184 mutation alone. These mutations were further demonstrated by PCH analysis
of peripheral blood mononuclear cells from 10 patients on long term ddC therapy, although variable patterns
were observed in terms of which of the two mutations or both were present. Sometimes, the wild‐type site
65 codon was also detected, indicating the presence of mixtures of viral quasi‐species. Direct cloning and
sequencing revealed the site 65 mutation in viruses isolated from patients on prolonged ddC therapy.
The Threat of the Emergence of Antimicrobial‐Resistant Gram‐Positive Pathogens in Canada
Authors: Low Donald E , Willey Barbara M , McGeer Allison J
Published: May 2016

Since the early 1980s, much attention has been focused on the emergence or resistance in nosocomially acquired Gram‐negative pathogens. However, in the 1990s we are witnessing in North America the development and spread or multiple resistance in Gram‐positive pathogens in the hospital selling as well as in the community. Methicillin resistant Staphylococcus aureus and vancomycin‐resistant enterococci are now endemic in many urban centres in the United States, although less so in Canada. In some states, penicillin ‐resistant Streptococcus pneumoniae in the community selling has gone from rates of less than 5% in 1988 to 50% in 1994, including: resistance to third‐generation cephalosporins and carbapenems. Although these same pathogens have now been identified in Canada, we may still be in a position to limit or prevent their spread.
Epidemiology of Human Disease Caused by Mycobacterium Avium Complex
Authors: Horsburgh C Robert
Published: May 2016

Mycobacterium avium complex (MAC) is a ubiquitous organism.
Human infection with this agent causes one of three clinical syndromes: pulmonary disease in
persons whose systemic immunity is intact; cervical lymphadenitis, also a disease of normal hosts;
and disseminated disease, usually in persons with advanced human immunodeficiency virus
infection. While data are sparse, all three clinical syndromes appear to be increasing in frequency.
However, the environmental reservoirs and modes of acquisition of MAC have not been elucidated.
and strategies for avoidance of MAC infection remain to be defined.
Cyotkines as Potential Therapies for Human Immunodeficiency Virus Infections
Authors: Sidwell Robert W , Morrey John D , Warren Reed P
Published: May 2016

Cytokines are attracting increased interest
as potential therapies for human immunodeficiency virus (HIV) infections. This attraction has particularly
arisen as these cytokines have become more commercially available through recombinant technologies.
This review focuses on the effects of these biological response modifiers on preclinical HIV and related
retrovirus infections. Cytokines that have particularly been considered for HIV disease control include:
interferons ‐α , ‐β and ‐γ, interleukins‐2. ‐3. ‐4. ‐6 and ‐7; tumour necrosis factors ‐α and ‐β; and the colony
stimulating factors. Efficacy has especially been seen when these cytokines have been used in combination
with the more conventional antiviral agents. Due to the many biological functions exerted by cytokines and
their interweaving of biological effects with other cytokines, they appear to have the potential to both inhibit
as well as enhance viral infections, depending upon how they are used, and caution is therefore urged in
their use.
Diagnosis of Respiratory Tract Infection and the Use of the Laboratory
Authors: Grossman Ronald F
Published: May 2016

Lower respiratory tract infections continue to be among the most common
illnesses requiring medical attention with considerable morbidity and morality. Clinical features, including
underlying conditions, presenting signs and symptoms, basic laboratory investigations and chest
roentgenograms, are not sufficiently precise to infer an etiological agent. These investigations do permit an
assessment of severity of illness and can assist in stratification of patients into high risk groups. Properly
performed and interpreted Gram stain of sputum is still useful in the initial assessment of these patients,
but sputum cultures are less helpful. Blood cultures should be drawn in patients ill enough to require
hospitalization, but the yield is low, Pneumococcal antigen testing and serological studies do not add to
the routine management of patients with pneumonia. In patients with nosocomial pneumonia, the diagnosis
will be established by a synthesis of clinical, roentgenographic and simple laboratory results such as
sputum analysis and blood culture. Invasive investigations should be reserved for critically ill patients.
Transitional Antibiotic Therapy
Authors: Quintiliani Richard , Crowe Helen M , Nightingale Charles
Published: May 2016

With all the fiscal restraints in healthcare systems. it is crucial to develop methods to treat infections that are both clinically sound and cost‐effective. Of the various options available. the rapid transition from intravenous to oral therapy represents one of the most effective ways to attain these goals. Moreover, it has the further advantages of shortening hospital stay, reducing nosocomial bacteremia and avoiding the need to rely upon intravenous technicians and equipment. Although there is a need for more patient outcome studies with this approach, the early experience with transitional therapy appears promising.
The Antibiotic Puzzle: Guidelines for the Family Physician
Authors: Harding G , Field S , MacMahon R , Louie T , Prairie Consensus Conference Group
Published: May 2016

Choosing the most appropriate antibiotic for the treatment of common infections is becoming increasingly complex. New drugs and new classes of antibiotics are being developed and made available, and emerging resistance and pharmacoeconomics play important roles. The Canadian healthcare system presents a unique challenge for prescribing physicians because pharmacoeconomic considerations are becoming increasingly important. It is important that Canadian guidelines be developed to address the needs of Canadian physicians. A consensus conference was held in October 1996 to discuss appropriate guidelines for antibiotic recommendations for common adult respiratory, urinary tract and diabetic foot infections. In August 1997, the guidelines were reviewed and updated as part of a second meeting of the group on antimicrobial resistance. The final recommendations constitute the information in this document. The panel of physicians and pharmaceutical doctors from the Prairie provinces of Alberta, Saskatchewan and Manitoba included family physicians and specialists in internal medicine, respirology, urology, infectious diseases, medical microbiology and pharmacoeconomics.
Guidelines for the Management of Nosocomial Candida Infections in Non‐Neutropenic Intensive Care Patients
Authors: Demajo WA , Guimond J-G , Rotstein C , Tweeddale M , Canadian Candidemia Advisory Group
Published: May 2016

A consensus meeting of the Canadian Candidemia Advisory Group was held during the 16th International Symposium on Intensive Care and Emergency Medicine on March 19, 1996 in Brussels, Belgium. For this meeting, a group of 20 intensive care and infectious disease specialists were brought together to discuss the risk factors associated with Candida species colonization in intensive care units and the treatment of invasive candidiasis in nonneutropenic patients. Members of the consensus group assessed the evidence available and attempted to reach a consensus on the role of antifungal therapy in the intensive care unit setting.
Epigastric Fullness
Authors: Stacher Georg
Published: May 2016

Epigastric fullness may be caused by a disordered gastric motor function, resulting in delayed gastric emptying, but may also be caused by rapid emptying, leading to a distention of the proximal small intestine. A rational diagnostic approach to a patient complaining of epigastric fullness is needed to reveal the underlying disorder or disease and to enable an adequate, targeted therapy. The clinical impression based on symptoms is unreliable and cannot distinguish function disorders and benign disease from severe conditions.
Hepatitis C Infection: Its Sequelaie and Outcomes – State-of-the-Art Workshop, September 24 to 25, 1998
Authors: Association for Study of the Liver (CASL)
Published: May 2016

This report summarizes a state-of the- art workshop held in September 1998 on the “Natural History and Outcome of Hepatitis C Infection”. Sixteen Canadian and two internationally renowned hepatologists were invited. A practical classification of HCV infection served as a framework for the meeting. The concepts of modelling of chronic disease, the epidemiology of HCV infection before the introduction of anti-HCV testing, and the outcome of various forms of chronic hepatitis C in adults and children were presented. Lectures on the outcome of HCV cirrhosis, hepatocellular carcinoma, the role of liver transplantation, the influence of host factors on outcome, iron overload in chronic hepatitis C and possible modification of the natural history by antiviral therapy were followed by discussion and consensus statements pertaining to each presentation. “The European Experience in Assessing Chronic Hepatitis C” was presented by Prof G Dusheiko from the United Kingdom, and Prof Leonard Seeff from the National Institutes of Health (United States) presented “The Epidemiology and Outcome of Hepatitis C Infection in the United States and the World”.
Early Changes in Hepatitis C Virus (HCV) RNA Levels Predict Response to Interferon Treatment in Non-Cirrhotic HCV Patients
Authors: Fallows Glen , Kaita Kelly , Minuk Gerald , Penner Faye , Smart Gerry , Dawood Magdy , Rosser Barry
Published: May 2016

The role of hepatitis C virus (HCV) RNA quantification in determining ideal interferon (IFN) treatment of noncirrhotic HCV liver disease is uncertain. The specific aim of this study was to determine whether measurement of baseline HCV RNA or changes in HCV RNA levels ( HCV RNA) early during therapy predict response to IFN in noncirrhotic HCV patients.

PATIENTS AND METHODS: Twenty-one noncirrhotic patients with chronic HCV were treated with 3 MU IFN -2a three times per week. HCVRNA levels were determined at baseline and after two, four, six, eight and 12 weeks of treatment. BaselineHCV RNA and HCV RNA during therapy were compared with treatment response results at six months. Data were expressed as mean SE, and differences were assessed using Student’s t test.

RESULTS: Twenty-one patients initiated IFN therapy. Two patients were noncompliant and lost to follow-up. One patient discontinued IFN due to side effects. Apart from age, where responders tended to be younger than nonresponders, the baseline clinical characteristics and alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin and HCV RNA levels did not differ between IFN responders and nonresponders. Levels of HCVRNA were significantly lower after both two and four weeks of therapy in IFN responders compared with nonresponders (P<0.001). Changes in log HCV RNA levels after both two and four weeks of therapy were significantly greater in IFN responders compared with nonresponders (P<0.001). Changes in log HCV RNA of more than 1.0 after two weeks of IFN therapy identified all six-month responders, with a sensitivity of 100% and a specificity of 89%. Potential financial impact of these findings on patients’ management was also calculated. Decisions regarding discontinuation of therapy based on early changes in HCV RNA levels would result in a 40% to 50% reduction in IFN cost.

CONCLUSIONS: In noncirrhotic HCV patients, the change in quantitative HCV RNA after the first two weeks of IFN therapy identifies responders. This finding would result in a 40% to 50% cost savings if decisions about continuing IFN were based on early changes in HCVRNA levels rather than ALT or HCVRNA assessment after the completion of three months of IFN treatment.
The Artificial Anal Sphincter
Authors: Christiansen John
Published: May 2016

The artificial anal sphincter as
treatment for end stage anal incontinence was first described in
1987. Published series concern a total of 42 patients, with a success
rate of approximately 80%. Infection has been the most serious
complication, but a number of technical complications related to
the device have also occurred and required revisional procedures
in 40% to 60% of the patients. The artificial anal sphincter may be
used for the same indications as dynamic graciloplasty except in
patients with a previously irradiated or severely scarred perineum.
Muscle Cramps: A ‘Complication‘ of Cirrhosis
Authors: Marotta Paul J , Graziadei Ivo W , Ghent Cameron N
Published: May 2016

Muscle cramps are a common complaint in clinical
practice. They are associated with various metabolic, endocrine,
neurological and electrolyte abnormalities. A variety of hypotheses
have been generated to explain the cause of muscle cramping,
yet none has been able to support a consistent pathophysiological
mechanism. Muscle cramps are painful, involuntary contractions
of skeletal muscle. They occur frequently in individuals with cirrhosis,
regardless of the etiology, and are thought to be a symptom
of cirrhotic‐stage liver disease.
The pathophysiology of these cramps remains elusive; hence, a
specific therapy has not been identified. Many therapeutic approaches
have been offered, yet their efficacy, safety and mechanism
of action remain poorly defined. This review defines muscle
cramps and illuminates its prevalence in the cirrhotic individual.
Current theories relating to the pathogenesis of muscle cramps are
reviewed, and an overview of the various pharmacological agents
that have had therapeutic success for this distressing and frustrating
symptom is provided.
Are TIPS Tops in the Treatment of Portal Hypertension? A Review on the Use and Misuse of Transjugular Intrahepatic Portosystemic Shunts
Authors: Sterling Richard K , Sanyal Arun J
Published: May 2016

Complications of portal hypertension
are the Achilles heel of end‐stage liver disease. Although
initially developed in the 1960s, transjugular intrahepatic portosystemic
shunts (TIPS) have recently gained popularity for decompressing
the portal vein in patients with portal hypertension.
The main indications for TIPS are the treatment of variceal hemorrhage
unresponsive to endoscopic treatment and refractory ascites.
Although several other applications for TIPS have been
reported, they have not been tested in controlled trials. TIPS are
not appropriate as initial therapy for variceal hemorrhage and ascites.
Due to the virtually universal development of TIPS stenosis
in the majority of patients, careful monitoring of stent patency is
required. Several complications of TIPS are recognized, some of
which are potentially fatal. Consequently, careful patient selection
for TIPS is of paramount importance. Until further clinical
trials become available, TIPS should be considered as a therapeutic
option for the treatment of refractory variceal hemorrhage and
refractory ascites in selected patients.