Predictive Value of Transrectal Ultrasonic Doppler and Elastographic Features in Prostate Cancer Detection in Lagos University Teaching Hospital.

Introduction: This study aimed at determining the predictive value (PV) of transrectal ultrasonic Doppler and elastographic features in prostate cancer (PCa) detection among patients in Lagos University Teaching Hospital. Materials and Methods: This prospective study involved patients that underwent evaluation for PCa. Participants had digital rectal examination (DRE), prostate-specific antigen (PSA) assay, and transrectal ultrasound-guided prostate biopsy using colour Doppler (CD) and elastography. All cores were sent for histopathology. Data were analysed using Statistical Package for the Social Sciences Version 22.0. CD and elastography PV in PCa detection and their relationships to the Gleason score (GS) were analysed (P < 0.05). Results: Seventy men (aged between 45 and 87 years) were enrolled. Forty-three (61.4%) patients had PCa with a mean age of 69.37 ± 8.22years. The sensitivity, specificity, positive PV (PPV), negative PV (NPV) and accuracy of CD were 8.50%, 97.44%, 64.10%, 66.42% and 66.31%, respectively. The sensitivity, specificity, PPV, NPV and accuracy of elastography were 84.21%, 94.59%, 88.89%, 92.11% and 91.07%, respectively. Conclusion: There is a significant association between decreased elasticity (elastography) and PCa detection but a weak association between increased vascularity (CD) and PCa detection. A positive correlation exists between extent of prostatic stiffness and GS.

Standard of Care Versus Octreotide in Angiodysplasia-Related Bleeding (the OCEAN Study): A Multicenter Randomized Controlled Trial.

BACKGROUND & AIMS: Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We investigated the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting. METHODS: The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least 4 red blood cell (RBC) units or parental iron infusions, or both, in the year preceding randomization. Patients were allocated (1:1) to 40-mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was 1 year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least 1 octreotide injection or followed standard of care for at least 1 month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up. RESULTS: We enrolled 62 patients (mean age, 72 years; 32 men) from 17 Dutch hospitals in the octreotide (n = 31) and standard of care (n = 31) groups. Patients required a mean number of 20.3 (standard deviation, 15.6) transfusion units and 2.4 (standard deviation, 2.0) endoscopic procedures in the year before enrollment. The total number of transfusions was lower with octreotide (11.0; 95% confidence interval [CI], 5.5-16.5) compared with standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5). CONCLUSIONS: Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia. CLINICALTRIALS: gov, NCT02384122.

A Local and Abscopal Effect Observed with Liposomal Encapsulation of Intratumorally Injected Oncolytic Adenoviral Therapy.

This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an 'in situ vaccination' by stimulating cytotoxic T cells.

Effects of dietary supplementation of Pseudomonas aeruginosa FARP72 on the immunomodulation and resistance to Edwardsiella tarda in Pangasius pangasius.

Edwardsiella tarda is one of the serious bacterial pathogens infecting both cultured and wild catfish urging an immediate need for effective protection strategies. This study assessed the effects of dietary supplementation of Pseudomonas aeruginosa FARP72 at 108 cells/g feed (PA diet) for 30 days on the innate immunity parameters, viz., respiratory oxidative burst (ROB) activity, lysozyme, ceruloplasmin, myeloperoxidase, in-vitro nitric oxide (NO) production in addition to the expression of immune genes encoding interleukin-1ß, C3 and transferrin in yellowtail catfish Pangasius pangasius and their resistance to Edwardsiella tarda challenge at a sub-lethal dose of 1.50 × 107 cells/fish. A significant increase in the innate immunity parameters was noted in PA diet-fed catfish on 30 dpf compared to the control. Post E. tarda challenge, the levels of immune parameters increased significantly and peaked at 5 dpi irrespective of feeding to confer protection against E. tarda. Their levels, however, decreased on and from 10 dpi. The results on the expression of immune genes encoding interleukin-1ß, C3 and transferrin in the kidney and liver tissue samples of PA diet-fed P. pangasius upon challenge with E. tarda further confirmed the ability of P. aeruginosa to stimulate primary immune organs at the gene level. The effects of feeding P. aeruginosa FARP72 on the immune functions of catfish as examined by the functional immune assays, thus, demonstrating the innate immune responses of catfish that are differentially stimulated by the PA diet. The findings of our study would help evolve management strategies to confer protection against E. tarda infection in commercial catfish aquaculture.

Full Remission of CAR-Deficient Tumors by DOTAP-Folate Liposome Encapsulation of Adenovirus.

Adenovirus (Ad)-based vectors have shown considerable promise for gene therapy. However, Ad requires the coxsackievirus and adenovirus receptor (CAR) to enter cells efficiently and low CAR expression is found in many human cancers, which hinder adenoviral gene therapies. Here, cationic 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-folate liposomes (Df) encapsulating replication-deficient Ad were synthesized, which showed improved transfection efficiency in various CAR-deficient cell lines, including epithelial and hematopoietic cell types. When encapsulating replication-competent oncolytic Ad (TAV255) in DOTAP-folate liposome (TAV255-Df), the adenoviral structural protein, hexon, was readily produced in CAR-deficient cells, and the tumor cell killing ability was 5× higher than that of the non-encapsulated Ad. In CAR-deficient CT26 colon carcinoma murine models, replication-competent TAV255-Df treatment of subcutaneous tumors by intratumoral injection resulted in 67% full tumor remission, prolonged survival, and anti-cancer immunity when mice were rechallenged with cancer cells with no further treatment. The preclinical data shows that DOTAP-folate liposomes could significantly enhance the transfection efficiency of Ad in CAR-deficient cells and, therefore, could be a feasible strategy for applications in cancer treatment.

Development of Adenovirus Containing Liposomes Produced by Extrusion vs. Homogenization: A Comparison for Scale-Up Purposes.

Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad (p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.

Neurosurgical Patients' Experiences and Surgical Outcomes Among Single Tertiary Hospitals in Ethiopia and the United States.

Background In 2020, we published findings on reported outcomes of anterior cervical decompression and fusion surgery among neurosurgeons in Africa and North America. We found more similarities in outcomes than expected, however, differences still existed. Most notable was the length of stay of patients postoperatively in Africa compared to North America. We sought to examine the neurosurgical practices more closely at a single hospital in Ethiopia and compare it to our own institution, the University of Missouri in Columbia (UMC). Methods Two authors spent one week at Aabet Hospital (AH) in Ethiopia. Throughout the week, one author rotated in the clinic and OR gathering the information. Data collection for patients at UMC was collected through retrospective chart review over one week. Results A total of eight elective surgeries and four emergency procedures occurred at AH and 18 clinic patients were included in the study. The intraoperative data was collected during the elective procedures at AH. At UMC there were 99 clinic patients, and 29 elective surgeries and one emergency procedure were performed. Procedures at both institutions included cranial, spinal, vascular, and implantable/other cases. Distance travelled by patients to UMC was an average of 57 miles compared to 85 miles at AH. The median pre-op and post-op stays at AH were 2.5 and 6 days compared to 0.2 and 2.1 at UMC, respectively. Blood loss was greater at AH with a median blood loss of 175 mL. Median blood loss at UMC was 50 mL. Conclusion We found notable differences among neurosurgical practice and patient demographics at AH compared to UMC. This information will serve as the cornerstone for gathering more information about neurosurgical practice in Ethiopia where electronic medical records are unavailable.

First Case of Infective Endocarditis With Streptococcus equinus in an Immunocompetent Patient in North America: A Case Report and Review of Literature.

Infective endocarditis (IE) can be caused by bacterial or fungal infections invading the endocardial surface of the heart, such as its valves and chambers. Staphylococcus and Streptococcus species are mainly responsible for IE. Streptococcus equinus (S. equinus) has been rarely noted to cause IE. We present a case of a 69-year-old white male with a past medical history of severe aortic regurgitation, who during an elective aortic heart valve replacement surgery was noted to have multiple plaque-like vegetations at the base of the mitral valve that were positive for S. equinus. To date, there are only four cases of S. equinus endocarditis reported worldwide, with a high possibility of our case being the first reported in North America.

Predicting Mortality in COPD with Validated and Sensitive Biomarkers; Fibrinogen and Mid-Range-Proadrenomedullin (MR-proADM).

Although fibrinogen is a FDA qualified prognostic biomarker in COPD, it still lacks sufficient resolution to be clinically useful. Next to replication of findings in different cohorts also the combination with other validated biomarkers should be investigated. Therefore, the aim of this study was to confirm in a large well-defined population of COPD patients whether fibrinogen can predict mortality and whether a combination with the biomarker MR-proADM can increase prognostic accuracy. From the COMIC cohort study we included COPD patients with a blood sample obtained in stable state (n = 640) and/or at hospitalization for an acute exacerbation of COPD (n = 262). Risk of death during 3 years of follow up for the separate and combined biomarker models was analyzed with Cox regression. Furthermore, logistic regression models for death after one year were constructed. When both fibrinogen and MR-proADM were included in the survival model, a doubling in fibrinogen and MR-proADM levels gave a 2.2 (95% CI 1.3-3.7) and 2.1 (95% CI 1.5-3.0) fold increased risk of dying, respectively. The prediction model for death after 1 year improved significantly when MR-proADM was added to the model with fibrinogen (AUC increased from 0.78 to 0.83; p = 0.02). However, the combined model was not significantly more adequate than the model with solely MR-proADM (AUC 0.83 vs 0.82; p = 0.34). The study suggests that MR-proADM is more promising than fibrinogen in prediciting mortality. Adding fibrinogen to a model containing MR-proADM does not significantly increase the predictive capacity of the model.

Influence of Fluctuating Water Temperature and Dietary Oxytetracycline on the Safety of Monosex Nile Tilapia Oreochromis niloticus Fries.

The influence of fluctuating water temperature and dietary oxytetracycline (OTC) at 0 (0X), 80 (1X), 240 (3X), 400 (5X) and 800 mg (10X)/kg biomass/day for 30 consecutive days on the safety of monosex (all male) Nile tilapia Oreochromis niloticus fries in terms of feeding, growth, survival and histopathology of vital organs were assessed. A dose-dependent decline in feed intake and biomass was recorded. The OTC-dosed groups recorded higher mortalities than the control. The therapeutic OTC-dosing (1X) in conjunction with low temperature caused 75.56 ± 8.01% mortality and 25.75% reduced feed intake in 30 days. The mortalities increased with increasing OTC-doses from 85.19 ± 3.39% (1X) to 95.56 ± 2.22% (10X) and fluctuating temperature (12.00-21.50°C) even after the withdrawal of OTC. Relatively mild to moderate histopathological lesions were observed in the kidney, liver and intestine of OTC-dosed fries. These results suggested that dietary OTC and low water temperature may cause adverse effects on monosex O. niloticus fries.

Adhesion and colonization of potential probiont Pseudomonas aeruginosa FARP72 in the intestine of yellowtail catfish, Pangasius pangasius.

Adhesion is recognized as the first important step of a probiont for intestinal colonization. This study assessed the ability of an antagonistic Pseudomonas aeruginosa FARP72 to adhere and colonize the intestine of yellowtail catfish, Pangasius pangasius both in vitro and in vivo. For the in vitro assay, the whole intestines of each of two starved P. pangasius were introduced separately into tubes containing bluish-green pigment-producing P. aeruginosa FARP72 at 8.00 log10 CFU/mL and physiological saline (0.85% sodium chloride) and incubated for 1 h at 30 ± 1 °C. The homogenate mucus solutions from the intestine samples were serially diluted and plated onto Pseudomonas isolation agar to determine the counts of bluish-green pigment-producing P. aeruginosa (BPPAC). The difference between the numbers of BPPAC and presumptive Pseudomonas counts (PPC) in the treated and control intestines was attributed to the adherence of P. aeruginosa FARP72. The levels of BPPAC and PPC in the treated intestines were 6.09 ± 0.59 log10 CFU/g. Similarly, following 30 days of feeding P. pangasius with P. aeruginosa FARP72 supplemented diet, the intestine of catfish recorded the BPPAC of 5.83 ± 0.64 log CFU/g. In control samples, the BPPACs were recorded as < 3.00 log10 CFU/g. The scanning electron micrograph of the intestines of P. pangasius following the in vitro and in vivo adhesion assays confirmed the ability of this bacterium to strongly adhere to the intestine, thus making it most suitable candidate probiont for use in freshwater catfish aquaculture.

In vitro antioxidant and antihypertensive properties of sesame seed enzymatic protein hydrolysate and ultrafiltration peptide fractions.

The objective of this study was to determine the in vitro antioxidant and antihypertensive potentials of sesame seed protein hydrolysate and its membrane ultrafiltration peptide fractions in comparison to the unhydrolyzed protein. Sesame seed protein isolate (SESPI) was prepared from the defatted sesame seed meal and then hydrolyzed using consecutive additions of pepsin and pancreatin to yield sesame protein hydrolysate (SESPH). The SESPH was subjected to membrane ultrafiltration consecutively to obtain fractions with peptide sizes of <1, 1-3, 3-5, and 5-10 kDa, respectively, which were then assayed for in vitro antioxidant and antihypertensive properties. The results showed that protein hydrolysis and fractionation led to significant (p < .05) increases in the content of hydrophobic amino acids. Radical scavenging and metal ion chelation were also significantly (p < .05) enhanced by these treatments. Inhibition of linoleic acid oxidation was stronger with the 1.0 mg/ml of sesame peptide samples in comparison to the mild inhibitory effect exhibited by the 0.5 mg/ml of samples. The <1 kDa peptide fraction was the most active inhibitor (81%) against angiotensin converting enzyme, whereas the bigger peptides (>3-5 and 5-10 kDa) were the most effective (75%-85% ) inhibitors against renin. These sesame products could be used as therapeutic agents in the development of health enhancing foods for the prevention and management of chronic diseases. PRACTICAL APPLICATIONS: Bioactive peptides have been produced from plant protein sources through in vitro enzymatic activities. Sesame seed peptides have demonstrated multifunctional potential to act as antioxidative and antihypertensive agents that could be utilized as ingredients for the development of novel functional foods and nutraceuticals.

Discontinuous spirals of stability in an optically injected semiconductor laser.

We report a new kind of discontinuous spiral with stable periodic orbits in the parameter space of an optically injected semiconductor laser model, which is a combination of the intercalation of fish-like and cuspidal-like structures (the two normal forms of complex cubic dynamics). The spiral has a tridimensional structure that rolls up in at least three directions. A turn of approximately 2π radians along the spiral and toward the center increases the number of peaks in the laser intensity by one, which does not occur when traversing the discontinuities. We show that as we vary the linewidth enhancement factor (α), discontinuities are created (destroyed) through disaggregation (collapses) from (into) the so-called shrimp-like structures. Future experimental verification and applications, as well as theoretical studies to explain its origin and relation with homoclinic spirals that exist in its neighborhood, are needed.

Tricorn-like structures in an optically injected semiconductor laser.

This study reports the existence of tricorn-like structures of stable periodic orbits in the parameter plane of an optically injected semiconductor laser model (a continuous-time dynamical system). These tricorns appear inside tongue-like structures that are created through simple Shi'lnikov bifurcations. As the linewidth enhancement factor-α of the laser increases, these tongues invade the laser locking zone and extends over the zone of stable period-1 orbits. This invasion provokes a rich overlap dynamics of the parameter planes that produces an abundant multistability. As α increases, the tricorn exhibits a phenomenon of codimension-3 rotating in the clockwise and counterclockwise directions in the plane of the injected field rate K vs its detuning ω. We hope that the numerical evidence of the tricorns presented herein motivates the study of mathematical conditions for their genesis. We also encourage the experimental verification of these tricorn-like structures because our results also open new possibilities for optical switching between several different laser outputs in the neighborhood of these structures.

Narrow Optical Line Widths in Erbium Implanted in TiO2.

Atomic and atomlike defects in the solid state are widely explored for quantum computers, networks, and sensors. Rare earth ions are an attractive class of atomic defects that feature narrow spin and optical transitions that are isolated from the host crystal, allowing incorporation into a wide range of materials. However, the realization of long electronic spin coherence times is hampered by magnetic noise from abundant nuclear spins in the most widely studied host crystals. Here, we demonstrate that Er3+ ions can be introduced via ion implantation into TiO2, a host crystal that has not been studied extensively for rare earth ions and has a low natural abundance of nuclear spins. We observe efficient incorporation of the implanted Er3+ into the Ti4+ site (>50% yield) and measure narrow inhomogeneous spin and optical line widths (20 and 460 MHz, respectively) that are comparable to bulk-doped crystalline hosts for Er3+. This work demonstrates that ion implantation is a viable path to studying rare earth ions in new hosts and is a significant step toward realizing individually addressed rare earth ions with long spin coherence times for quantum technologies.

Triclosan exposure induces varying extent of reversible antimicrobial resistance in Aeromonas hydrophila and Edwardsiella tarda.

Triclosan (TCS) is a biocide commonly used in household and personal care items to prevent the microbial growth and is currently considered as an emerging pollutant. It has a ubiquitous distribution which can substantially contribute towards antimicrobial resistance. The present study was designed to evaluate the effect of different concentrations of TCS exposure on the antibiotic sensitivity of aquatic bacteria. Aeromonas hydrophila ATCC® 49140™ and Edwardsiella tarda ATCC® 15947™ exposed to TCS for short (30 min) and long duration (serial passages). The agar-disc diffusion assay during the serial passages of TCS exposure and subsequent exposure withdrawal showed clinically insignificant changes in the zone of inhibition for six selected antibiotics in both bacterial strains at all exposure concentrations. Four folds concentration-dependent increase in the minimum inhibitory concentrations (MICs) of TCS was observed in both the strains following TCS exposure. Similarly, a concentration-dependent increase in the MICs of oxytetracycline (OTC) up to 4 folds in A. hydrophila, and up to 8 folds in E. tarda, was also documented during the TCS exposure. In all the cases, withdrawal of TCS exposure effectively reduced the MICs of TCS and OTC in blank passages suggesting a decline in acquired resistance. The frequencies of mutation during 30 min TCS exposure for E. tarda and A. hydrophila ranged between >10-6 and 10-7 levels. Nevertheless, the TCS exposure did not cause any detectable mutation on the fabV gene of A. hydrophila indicating that the TCS may elicit phenotypic adaptation or other resistance mechanism. Although the reduction in MICs due to exposure withdrawal did not restore the bacterial susceptibility up to the initial level, the study proved that the reduced TCS use could significantly help reduce the antimicrobial-resistance and cross-resistance in pathogenic bacteria.

Pseudomonas aeruginosa FARP72 Offers Protection Against Aeromonas hydrophila Infection in Labeo rohita.

Use of probiotics as the biocontrol agent for disease prevention in aquaculture is gaining importance as an alternative to the indiscriminate use of antibiotics and other chemotherapeutics. In view of this trend, the probiotic properties of a potent antagonistic bacterium, Pseudomonas aeruginosa FARP72, was characterized in terms of safety, antagonistic activities, in vitro immunomodulation, and in vivo disease resistance. Immunomodulatory activity was ascertained by measuring the production of intracellular superoxide anion, nitric oxide, total leukocyte peroxidase content, and the leukocyte proliferation in head kidney leukocytes. The bacterium isolated from the skin mucus of freshwater catfish Clarias batrachus was harmless to Labeo rohita. It showed inhibitory activity against Aeromonas caviae, A. hydrophila, Edwardsiella tarda, Pseudomonas putida, and Streptococcus agalactiae as revealed by cross and parallel streaking methods. Significantly higher superoxide anion and nitric oxide production, peroxidase content, and proliferative responses of leucocytes delineated the strains' ability to interact with immune cells to activate the immune system in vitro. Significant growth inhibition of A. hydrophila from 1.55 × 105 CFU/mL was observed when co-cultured with P. aeruginosa FARP72 in phosphate-buffered saline (PBS) at levels ranging from 2.61 × 107 to 2.61 × 109 CFU/mL in 10 days. P. aeruginosa FARP72 increased the survival rate of rohu fingerlings against pathogenic A. hydrophila challenge in biocontrol study in vivo as determined by cohabitation challenge. These results suggest that P. aeruginosa FARP72 is a potential probiotic strain and can be used in aquaculture to improve the health status and disease resistance of fish.

Evaluation of vancomycin target trough attainment with published dosing regimens in the neonatal intensive care unit population.

BACKGROUND: Study aims to evaluate whether vancomycin dosing from published dosing algorithms correlate with the attainment of target troughs of 10 to 20 mg/L. METHODS: NICU patients who received minimum three doses of vancomycin and had a trough level met inclusion criteria. Dosing information was retrospectively evaluated to determine which published dosing regimen was followed. Dosing algorithms used were matched to NeoFax/Harriet Lane, renal-function directed dosing, and weight-directed dosing, in which the latter two can be found in Pediatric and Neonatal Lexi-Drugs. Primary outcome was percentage of troughs within therapeutic (10 to 20 mg/L) and subtherapeutic (less than 10 mg/L) levels. RESULTS: Of 97 troughs evaluated, NeoFax/Harriet Lane accounted for 86.6%, renal-function directed accounted for 5.1%, and weight-directed dosing accounted for 18.5% of dosing algorithms. NeoFax/Harriet Lane, renal-function directed, and weight-directed dosing attained therapeutic levels between 10 to 20 mg/L at a rate of 60.7%, 60%, and 50% of the time, respectively. With respect to initiation of therapy, a higher dose of 15 mg/kg versus 10 mg/kg attained therapeutic levels (p < 0.001; OR 11.22; 95% CI, 3.96 to 31.81), while a serum creatinine value below 0.5 mg/dL attained subtherapeutic levels (p = 0.028; OR 0.068; 95% CI, 0.006 to 0.74). CONCLUSIONS: NeoFax, Harriet Lane, and renal-directed dosing from Pediatric and Neonatal Lexi-Drugs achieved target troughs within the 10 to 20 mg/L range more often than weight-directed dosing from Pediatric and Neonatal Lexi-Drugs. Initiating therapy at a higher dose and patient serum creatinine value above 0.5 mg/dL were factors significantly associated with a 10 to 20 mg/L range.

Electrolyte transport pathways induced in the midgut epithelium of Drosophila melanogaster larvae by commensal gut microbiota and pathogens.

KEY POINTS: The digestive tract of larval and adult Drosophila is an excellent analogue of the mammalian gut. Enterocytes of the posterior midgut are separated by septa, with no paracellular path, and therefore perform both immune and transport functions. Using microperfusion electrophysiology, we show that larvae emerging from the embryo into sterile medium have symmetrical apical and basal membrane conductances while larvae emerging into non-sterile medium have apical membranes fivefold more conductive than basal membranes. The channels inserted into the apical membranes could originate in microbiata or host and mediate recognition of microbes. Entomopathogenic cyclic peptide toxins deplete intracellular ions reversibly, forming transient ion channels that do not conduct water, unlike an ionophore like nystatin that depletes ions irreversibly. We show the feasibility of studying the interaction of a single microbial species, or tractable combinatorials of microbial species, with only enterocytes in the primary epithelial barrier. ABSTRACT: Microbiota colonizing exposed epithelial surfaces are vital for sustenance of metazoan life, but communication between microbiota, epithelial cells and the host immune system is only beginning to be understood. We address this issue in the posterior midgut epithelium of Drosophila larvae where nutrient transport and immune functions are exclusively transcellular. We showed that larvae emerging into a sterile post-embryonic environment have symmetrical apical and basal membranes. In contrast, larvae emerging into non-sterile media, the source of microbiota, have markedly asymmetrical membranes, with apical membrane conductance more than fivefold higher than the basal membrane. As an example of pathogen action, we showed that the entomopathogenic fungal toxin destruxin A (Dx) depleted intracellular ions. Reversibility of action of Dx was verified by bilayer reconstitution in forming transient non-specific channels that conduct ions but not water. Dx was also less effective from the apical side as compared to the basal side of the epithelium. We also showed that intercellular septa are not conductive in non-sterile cells, even though most cells are isopotential. Luminal microbiota therefore impart asymmetry to the epithelium, by activation of apical membrane conductance, enhancing inter-enterocyte communication, separated by insulating septa, via the gut lumen. These results also open the possibility of studying the basis of bidirectional molecular conversation specifically between enterocytes and microbiota that enables discrimination between commensals and pathogens, establishment of the former, and elimination of the latter.