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Increased agricultural production within the Grand Prairie region, USA, has resulted in drainage of most natural wetlands within the landscape. Muskrats (Ondatra zibethicus (L., 1766)) in this region have shifted much of their distribution to riparian habitats that have unstable flow regimes and flood inundation times that could be related to position within watersheds. We investigated predation risk of radio-marked riparian muskrats during flooding events in relation to landscape position. We used known-fate models and an information-theoretic approach to examine effects of age, season, hydrology, and riparian width on weekly survival rates. During flooding events, muskrats positioned farther from headwaters were displaced for longer, as well as exposed to predation from terrestrial predators for longer, than those positioned closer to headwaters. However, this increased exposure during floods did not translate into lower survival because most mortalities were due to predation by American mink (Neovison vison (Schreber, 1777)) along stream edges during nonflooding periods. Weekly survival of muskrats was lower in winter (mean = 0.9377, SE = 0.1793) than in nonwinter (mean = 0.9770, SE = 0.0116) and was positively related to riparian width. Larger riparian buffers can increase muskrat survival in small streams and agricultural ditches within highly altered, human-dominated agroecosystems. Our study provides a rare example of linking riparian buffers to fitness for a stream-associated organism. L'augmentation de la production agricole dans la région des Grandes Prairies aux É.-U. a entraîné l'assèchement de la plupart des terres humides naturelles dans le paysage. Les rats musqués (Ondatra zibethicus (L., 1766)) de la région ont modifié en grande partie leur répartition pour occuper les habitats riverains qui possèdent des régimes d'écoulement instables et des périodes d'inondations de crue qui dépendent de leur position dans le bassin versant. Nous étudions le risque de prédation de rats musqués porteurs d'étiquettes radio durant des épisodes d'inondation en fonction de leur position dans le paysage. Nous utilisons des modèles de destin connu et une approche basée sur la théorie de l'information pour examiner les effets de l'âge, de la saison, de l'hydrologie et de la largeur de la zone riveraine sur les taux hebdomadaires de survie. Durant les épisodes d'inondation, les rats musqués qui habitent le plus loin des eaux d'amont se font déplacer pour plus longtemps et sont exposés aux prédateurs terrestres pour une période plus longue que ceux qui sont plus près des sources. Cependant, cette exposition prolongée durant les inondations ne se traduit pas en une survie réduite, parce que la plupart des mortalités sont dues à la prédation par les visons d'Amerique (Neovison vison (Schreber, 1777)) le long des rives des cours d'eau hors des périodes d'inondation. La survie hebdomadaire des rats musqués est plus basse en hiver (moyenne = 0,9377, ET = 0,1793) qu'aux autres saisons (moyenne = 0,9770, ET = 0,0116) et elle est reliée directement à la largeur de la zone riveraine. Les zones tampons riveraines plus grandes peuvent augmenter la survie des rats musqués dans les petits cours d'eau et les fossés agricoles dans les agroécosystèmes fortement modifiés et dominés par les humains. Notre étude fournit un des rares exemples d'un lien entre les zones tampons riveraines et la fitness d'un organisme associé aux cours d'eau. [ABSTRACT FROM AUTHOR]

As our understanding of HIV disease pathogenesis progresses, approaches to immune-based therapy are evolving. Initial therapies aiming to alter immune function in patients with HIV infection have had mixed results. Clinical benefit in the trials so far has not been dramatic, although the studies are still at an early stage, and the correct protocols for the various agents or combinations of agents have yet to be established. As might be expected, where apparent benefit has occurred, it has been more obvious in those patients whose immune system was still intact. [ABSTRACT FROM AUTHOR]

Simple neutral percolation models of ecological landscapes predict acritical threshold of landscape connectivity at ca 60 percent coverage of cells that are permeable to movement. Using such models as an inspiration, we conducted a field experiment in which we employed an experimental model system of tenebrionid beetles (Eleodes obsoleta) moving through mosaics of grass and bare ground in which grass coveragewas systematically varied from 0 percent to 80 percent in a random pattern. Three parameters of beetle movement pathways (mean step length, mean vector length, and net displacement rate) all showed a sharp reduction between 0 percent and 20 percent grass cover and no differences over further 20 percent coverage increments; the mean fractal dimension of pathways (which could not be derived for the 0 percent coverage treatment) also did not differ with increasing grass coverage from 20 percent to 80 percent. The proportion of time spent by beetlesin grass patches did not increase with increasing grass coverage, although individuals spent significantly more time steps in grass in the 20 percent grass-cover treatment than would be expected by chance. The distance moved per time step was greater when beetles moved over bare ground than in grass, but the mean step length while on grass was significantly lower when grass constituted only 20 percent of the experimental landscape than when more grass was present, perhaps because beetles stopped more frequently on grass when little of it was present. The threshold in beetle movement through the experimental landscapes differed markedly from that predicted by simple neutral percolation models, probably because, in contrast to the models, both cover types were permeable to beetle movements and individuals moved non-randomly. The results of this experiment indicate that definitions of landscape connectivity depend on both the spatial pattern of the landscape and how individuals move within and among patches. Moreover, it app [ABSTRACT FROM AUTHOR]

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus ( HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention ( CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels. [ABSTRACT FROM AUTHOR]

Pan-drug-resistant (PDR) Pseudomonas aeruginosa is one of the three top-priority pathogens identified by the WHO, and bacteriophages have been investigated as an alternative therapy. However, knowledge on the pharmacokinetics/pharmacodynamics (PK/PD) of phage therapy is sparse, limiting its clinical applications. This study aimed to evaluate the PK/PD of the antipseudomonal phage øPEV20 in vivo following intravenous administration. Healthy Sprague-Dawley rats were given øPEV20 as a single intravenous bolus of ~6, 9 and 11-log 10 PFU/rat. Arterial blood was sampled over 72 h. At 72 h, the animals were killed and multiple tissues were harvested for biodistribution studies. A PK model was developed using the importance sampling algorithm and deterministic simulations with a PD model were performed. A three-compartment model with non-linear clearance described the exposure of øPEV20 in blood. Model evaluation indicated that the model was robust and parameter estimates were accurate. The median (standard error) values of model-predicted PK parameters for V C , V P1 , V P2 , Q 1 , Q 2 , V m and K m were 111 mL/rat (8.5%), 128 mL/rat (4.97%), 180 mL/rat (4.59%), 30.4 mL/h/rat (19.2%), 538 mL/h/rat (4.97%), 4.39 × 1010 PFU/h/rat (10.2%) and 1.64 × 107 PFU/mL/rat (3.6%), respectively. The distribution of øPEV20 was not homogeneous; there was preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of the host immune system in facilitating phage-mediated bacterial elimination. We developed a robust PK model to describe the disposition of phages in healthy rats. This model may have significant potential in facilitating future preclinical and clinical PK/PD investigations. [ABSTRACT FROM AUTHOR]

Objective: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available.Participants: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995.Evidence: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999.Consensus Process: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive.Conclusions: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field. [ABSTRACT FROM AUTHOR]

We examined the long-term safety and efficacy of zidovudine therapy in 229 subjects with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex who previously participated in a placebo-controlled study of zidovudine. One hundred two placebo recipients (delayed treatment group) and 127 zidovudine recipients (original treatment group) were followed up while receiving zidovudine therapy for a mean of 21 months. Survival rates for the original treatment group were 84.5% and 57.6% at 12 and 21 months, respectively; for the delayed treatment group, 78.8% and 64.6% at 12 and 21 months, respectively, and 78.8% and 47.5% at 12 and 21 months, respectively, for 77 subjects with AIDS and 93.0% and 71.8%, respectively, for 50 subjects with AIDS-related complex in the original treatment group. Adverse reactions decreased over time and newly observed toxic reactions were unusual. The clinical course of these subjects suggests continued survival benefits with long-term zidovudine therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine the extent to which lymphocytes, particularly those with the CD4 surface antigen, are a surrogate marker for the development of the acquired immunodeficiency syndrome (AIDS) in persons with asymptomatic human immunodeficiency virus (HIV) infection.Design: Analysis of data from the AIDS Clinical Trials Group Protocol 019, a placebo-controlled, double-blind, randomized trial.Setting: University-based referral centers.Patients: Asymptomatic HIV-infected patients with 500 or fewer CD4+ cells/mm3 at baseline who were given placebo (350 patients) or one of two daily doses of zidovudine (725 patients).Measurements: Baseline and interim measurements of CD4+ and other leukocytes were assessed. Patients were followed for progression to AIDS.Results: Patients' lymphocyte levels were correlated with progression to AIDS (P < 0.001; relative risk for each depletion of 50 CD4+ cells/mm3, 1.75; 95% CI, 1.53 to 2.01); however, only a small portion (0% to 37%) of the effect of zidovudine on this progression was statistically explained by its effect on CD4+ lymphocyte levels. A substantial portion of zidovudine's effect on delaying progression to AIDS that was independent of the levels of these markers occurred within the first 16 weeks of therapy. In patients who had not progressed to AIDS by week 16, most of the subsequent zidovudine effect in reducing the risk for progression could be explained by its effect on net CD4+ percent (percentage of CD4+ lymphocytes among all leukocytes) for the first 16 weeks of therapy.Conclusion: Levels of CD4+ lymphocytes are an incomplete surrogate marker for progression to AIDS, and the association is especially weak during the first 16 weeks of zidovudine therapy. [ABSTRACT FROM AUTHOR]

Study Objective: To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex.Design: Open label, escalating dosage, phase I-II tolerance trial.Setting: Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group.Instructions: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days.Measurements and Main Results: Recombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages.Conclusions: Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted. [ABSTRACT FROM AUTHOR]

Study Objective: To determine the safety and efficacy of dideoxycytidine in patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex.Design: A partially randomized phase I and II outpatient, dose-ranging study.Setting: Four university medical centers involving government-supported referral AIDS Clinical Trial Units.Patients: Sixty-one patients with AIDS or advanced AIDS-related complex and 100 pg/mL or more serum p24 antigen titers.Interventions: Dideoxycytidine was administered orally at 0.06, 0.03, 0.01, or 0.005 mg/kg body weight every 4 hours for 3 to 6 months depending on tolerance and benefit.Measurements and Main Results: In patients receiving 0.06 and 0.03 mg/kg, diffuse erythematous rash, fever, and aphthous stomatitis occurred in the first weeks of therapy, but resolved later. Hematopoietic suppression was rare. Peripheral sensory neuropathy occurred in patients receiving 0.06 mg/kg and 0.03 mg/kg and improved after discontinuation of therapy. Serum p24 antigen fell significantly (P less than 0.01) from baseline entry values in most of these patients. The CD4 lymphocytes rose transiently at the 0.03 mg/kg dosage. At the 0.005 mg/kg dosage, skin rash, fever, and aphthous stomatitis were mild or absent. Peripheral neuropathy, which occurred in all patients receiving 0.01 mg/kg was less severe than at higher dosages. At the 0.005 mg/kg dosage, peripheral neuropathy was occasionally seen. Significant suppression of serum p24 antigen was seen in most patients with AIDS-related complex receiving 0.01 mg/kg and less frequently in patients receiving 0.005 mg/kg.Conclusions: Less toxic regimens of dideoxycytidine merit clinical assessment for advanced anti-human immunodeficiency virus-1 (HIV) infection. Several studies alternating dideoxycytidine and zidovudine are in progress. [ABSTRACT FROM AUTHOR]

Two patients developed fever, interstitial pneumonitis, and pancytopenia associated with extremely high titers of antibody to replicative antigens of the Epstein-Barr virus. In contrast to most patients seropositive for Epstein-Barr virus, neither patient had an antibody response to the Epstein-Barr nuclear antigen K polypeptide. In addition, virus isolated from one patient had a deletion of the B95-8 type in the EcoRI C region of the genome. An etiologic relation between Epstein-Barr virus replication and the clinical manifestations of this syndrome is further shown by the response of each patient to acyclovir therapy. These patients have a new Epstein-Barr-virus-associated syndrome and provide additional evidence that acyclovir may play a role in therapy for selected patients with Epstein-Barr virus infection. [ABSTRACT FROM AUTHOR]

Cytomegalovirus infections can cause significant morbidity and mortality in immunosuppressed patients, and present antiviral agents have had little efficacy against these infections. We describe the use of an acyclic nucleoside 9-[2-hydroxy-1-(hydroxymethyl) ethoxy methyl]guanine (BW B759U), in the treatment of two patients with cytomegalovirus retinitis. The efficacy of this agent was evident, with healing of retinal lesions and resolution of viremia and viral shedding. BW B759U appears to be similar pharmacokinetically to intravenous acyclovir in terms of half-life, peak serum levels, and renal excretion. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) has been isolated from both male and female genital secretions. We evaluated the pattern of female genital carriage during the menstrual cycle, and its relationship to HIV viremia. Seven menstruating seropositive women and one seronegative control had cervical secretions and venous blood samples cultured at weekly intervals during a single menstrual cycle. The virus was isolated from cervical secretions in four of seven women. No specific cycle pattern was seen, and positivity for HIV at one site (blood or cervical) did not correlate with positivity at another site. Blood cultures generally, but not always, became positive earlier than cultures from cervical specimens, suggesting higher titers of virus in blood. Thus, HIV secretion may be intermittent. These findings, together with earlier reports, suggest that seropositive women may transmit HIV at any time during the menstrual cycle. [ABSTRACT FROM AUTHOR]

A homosexual man had Kaposi's sarcoma of the skin and lymph nodes. After a brief response to interferon, the patient developed new skin lesions. Massive bleeding in the gastrointestinal tract prompted endoscopy, which showed tumor involvement of the stomach, believed to be Kaposi's sarcoma. At autopsy, a diffuse lymphoma was found involving the skin and gastrointestinal tract, forming collision tumors in regions that contained Kaposi's sarcoma. Lymphomatous tissue, but not uninvolved lymph node or spleen, contained Epstein-Barr virus DNA, as shown by DNA hybridization studies. Epstein-Barr virus may play a role in the development of lymphoma in immunosuppressed patients. Unusual manifestations of tumors, such as the massive gastrointestinal bleeding seen in this case, may indicate the development of a second neoplasm. [ABSTRACT FROM AUTHOR]

Purpose Bacteriophages are lytic viruses that are specific for their bacterial hosts and do not infect human cells. Bacteriophages can penetrate biofilm and lyse biofilm-based bacteria. We describe the use of bacteriophage therapy (BT) as an adjunct to intravenous (IV) antibiotics in 2 cases of refractory ventricular assist device (VAD) infections. Methods BT products active in vitro against the patients' isolates were identified. We obtained approval from the Food and Drug Administration (eIND #18133 and eIND #17819) to use BT as adjunctive treatment; informed consent was obtained. Results Table 1 describes the 2 VAD infection cases in detail. Each patient received BT as outpatient parental therapy without adverse events. Case 1 had negative sternal wound cultures for MSSA at end of therapy. Case 2 developed Pseudomonas aeruginosa (PsA) bacteremia while on BT that resolved with a change in antibiotics. Bacteremic isolates from case 2 during BT remained susceptible to all 3 lytic phages; molecular sequencing confirmed that these PsA isolates were the same as at the start of therapy. In Case 2, serum neutralizing activity emerged during therapy resulting in reduction in viable phage titers in vitro. Each patient went on to successful heart transplantation. Conclusion We describe early experience using BT for treatment of biofilm-based VAD infections. BT was well tolerated. The potential relevance of serum neutralizing activity to the antimicrobial impact of BT during treatment warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction Bacteriophages are host-specific lytic viruses that are of increasing interest as adjunctive therapy for treatment of multi-drug resistant (MDR) pathogens. Case Report We describe the use of bacteriophage therapy (BT) in a 26-year-old cystic fibrosis (CF) patient awaiting lung transplantation who was admitted for respiratory failure requiring mechanical ventilation for 12 days. The hospital course was complicated by MDR Pseudomonas aeruginosa (PA) pneumonia, persistent respiratory failure, and colistin-induced renal failure (listed for concomitant kidney transplant). Due to worsening clinical status, BT was explored as an adjunct to antibiotics. The patient was approved under emergency IND#17710 by the FDA to receive AB-PA01 (combination of 4 lytic phages) active against the clinical PA isolates. This was given every 6 hours intravenously (IV) for 8 weeks. As noted in Figure 1, the patient was bed-bound due to severe dyspnea and required 30 L/min O2 via high flow nasal cannula (NC) at BT initiation. MDR PA pneumonia resolved by Day 7. Her respiratory status continued to improve and by end of therapy (EOT) she was on 4 L/min O2 via NC and was able to work with physical therapy. No adverse events related to BT occurred. There was no recurrent pneumonia or CF exacerbation within 90-days following the end of treatment. Renal failure resolved once off colistin and the patient was removed from the kidney transplant waitlist. Summary We describe the successful use of BT in a CF patient awaiting lung transplant. Given the concern for MDR PA in CF patients, BT may offer a viable anti-infective adjunct to traditional antibiotic therapy. [ABSTRACT FROM AUTHOR]

In the era of antibiotic resistance, alternative treatment options for multidrug-resistant bacterial infections are being explored. We present a case of multidrug-resistant Acinetobacter baumannii infection treated with bacteriophages. Clinical trials are needed to further investigate bacteriophage therapy as an option to treat multidrug-resistant bacterial infections. [ABSTRACT FROM AUTHOR]