HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations.

Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as cis-regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the histone deacetylase 9 (HDAC9) protein-coding sequence are associated with disruption of TWIST1 regulatory elements that reside within the HDAC9 sequence. Based on SVs within the HDAC9-TWIST1 locus, we defined the 3'-HDAC9 sequence as a critical TWIST1 regulatory region, encompassing craniofacial TWIST1 enhancers and CTCF sites. Deletions of either Twist1 enhancers (eTw5-7Δ/Δ) or CTCF site (CTCF-5Δ/Δ) within the Hdac9 protein-coding sequence led to decreased Twist1 expression and altered anterior/posterior limb expression patterns of SHH pathway genes. This decreased Twist1 expression results in a smaller sized and asymmetric skull and polydactyly that resembles Twist1+/- mouse phenotype. Chromatin conformation analysis revealed that the Twist1 promoter interacts with Hdac9 sequences that encompass Twist1 enhancers and a CTCF site, and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entire Hdac9 sequence (Hdac9 INV/+) in mice that does not disrupt Hdac9 expression but repositions Twist1 regulatory elements showed decreased Twist1 expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidates essential components of TWIST1 transcriptional machinery that reside within the HDAC9 sequence. It suggests that SVs encompassing protein-coding sequences could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene.

Spatial, temporal and network analyses provide insights into the dynamics of the bacterial communities associated with two species of Caribbean octocorals and indicate possible key taxa.

Despite the current decline of scleractinian coral populations, octocorals are thriving on reefs in the Caribbean Sea and western North Atlantic Ocean. These cnidarians are holobiont entities, interacting with a diverse array of microorganisms. Few studies have investigated the spatial and temporal stability of the bacterial communities associated with octocoral species and information regarding the co-occurrence and potential interactions between specific members of these bacterial communities remain sparse. To address this knowledge gap, this study investigated the stability of the bacterial assemblages associated with two common Caribbean octocoral species, Eunicea flexuosa and Antillogorgia americana, across time and geographical locations and performed network analyses to investigate potential bacterial interactions. Results demonstrated that general inferences regarding the spatial and temporal stability of octocoral-associated bacterial communities should not be made, as host-specific characteristics may influence these factors. In addition, network analyses revealed differences in the complexity of the interactions between bacteria among the octocoral species analyzed, while highlighting the presence of genera known to produce bioactive secondary metabolites in both octocorals that may play fundamental roles in structuring the octocoral-associated bacteriome. Supplementary Information: The online version contains supplementary material available at 10.1007/s13199-023-00923-x.

Ion Heating and Flow Driven by an Instability Found in Plasma Couette Flow.

We present the first observation of instability in weakly magnetized, pressure dominated plasma Couette flow firmly in the Hall regime. Strong Hall currents couple to a low frequency electromagnetic mode that is driven by high-ß (>1) pressure profiles. Spectroscopic measurements show heating (factor of 3) of the cold, unmagnetized ions via a resonant Landau damping process. A linear theory of this instability is derived that predicts positive growth rates at finite ß and shows the stabilizing effect of very large ß, in line with observations.

Laboratory Resolved Structure of Supercritical Perpendicular Shocks.

Supermagnetosonic perpendicular flows are magnetically driven by a large radius theta-pinch experiment. Fine spatial resolution and macroscopic coverage allow the full structure of the plasma-piston coupling to be resolved in laboratory experiment for the first time. A moving ambipolar potential is observed to reflect unmagnetized ions to twice the piston speed. Magnetized electrons balance the radial potential via Hall currents and generate signature quadrupolar magnetic fields. Electron heating in the reflected ion foot is adiabatic.

Weakly Magnetized, Hall Dominated Plasma Couette Flow.

A novel plasma equilibrium in the high-ß, Hall regime that produces centrally peaked, high Mach number Couette flow is described. Flow is driven using a weak, uniform magnetic field and large, cross field currents. Large magnetic field amplification (factor 20) due to the Hall effect is observed when electrons are flowing radially inward, and near perfect field expulsion is observed when the flow is reversed. A dynamic equilibrium is reached between the amplified (removed) field and extended density gradients.

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.

BACKGROUND: Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/δ activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo. METHODS: A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed. RESULTS: Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg-1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). CONCLUSIONS: Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Preweaned heifer management on US dairy operations: Part V. Factors associated with morbidity and mortality in preweaned dairy heifer calves.

The objective of this study was to evaluate morbidity and mortality in preweaned dairy heifer calves based on different health, feeding, and management practices, as well as environmental factors. This study was conducted as part of the calf component of the National Animal Health Monitoring System's Dairy 2014 study, which included 104 dairy operations in 13 states. The calf component was an 18-mo longitudinal study focused on dairy heifer calves from birth to weaning; data were collected on 2,545 calves. The percentage morbidity for all calves enrolled in the study was 33.9%. Backward elimination model selection was used after univariate screening to determine which management practices and environmental factors significantly affected morbidity and mortality. The final morbidity model included birth weight, serum IgG concentration, ventilation type, and average temperature-humidity index (THI) during the preweaning period. After controlling for other independent variables in the model, calves born at a higher birth weight had a lower predicted risk of morbidity than calves with a lower birth weight. An increase in serum IgG concentration was associated with decreased morbidity. Calves housed in positive- or cross-ventilated systems had a 2.2 times higher odds of developing disease compared with calves housed in natural ventilation systems. Average THI during the preweaning period was inversely correlated with morbidity; as THI increased, the predicted morbidity risk decreased. The percent mortality for all calves enrolled in the study was 5.0%. The final mortality model included birth weight, serum IgG concentration, amount of fat/day in the liquid diet, and morbidity. After controlling for other independent variables in the model, calves born at a higher birth weight had a lower risk of mortality. An increase in serum IgG concentration decreased the risk of mortality. The odds of mortality were 3.1 times higher in calves fed ≤0.15 kg of fat/d in the liquid diet compared with calves fed ≥0.22 kg of fat/d. The odds of mortality were 4.7 times higher in calves that experienced any disease throughout the preweaning period than in calves with no disease. In summary, morbidity and mortality were both associated with birth weight and serum IgG concentration. Additionally, morbidity was associated with ventilation type and average monthly THI, and mortality was associated with amount of fat per day in the liquid diet and morbidity.

Preweaned heifer management on US dairy operations: Part II. Factors associated with colostrum quality and passive transfer status of dairy heifer calves.

Passive transfer of immunity is essential for the short- and long-term health of dairy calves. The objective of this study was to evaluate factors associated with colostrum quality and passive transfer status of US heifer calves. This study included 104 operations in 13 states that participated in the calf component of the National Animal Health Monitoring System's Dairy 2014 study. This 18-mo longitudinal study included 1,972 Holstein heifer calves from birth to weaning. Multivariable mixed linear regression models were selected using backward elimination model selection after univariate screening to determine which factors were associated with colostrum IgG and serum IgG concentrations. The mean colostrum IgG concentration was 74.4 g/L with 77.4% of colostrum samples having IgG concentrations >50 g/L. The final model for colostrum IgG included colostrum source and a categorized temperature-humidity index value (cTHI) for the month before calving. Mean colostrum IgG concentrations were highest for dams in third and higher lactations (84.7 g/L) and lowest for commercial colostrum replacers (40.3 g/L). Colostrum IgG concentrations were highest for cTHI ≥70 (72.6 g/L) and lowest for cTHI <40 (64.2 g/L). The mean serum IgG concentration was 21.6 g/L, with 73.3% of calves having serum IgG concentrations >15 g/L. The final model for serum IgG concentration included region, heat treatment of colostrum, colostrum source, timing to first feeding, volume of colostrum fed in the first 24 h, age of the calf at blood sampling, and colostrum IgG concentration. Mean serum IgG concentrations were highest for calves that received colostrum from first-lactation dams (25.7 g/L) and lowest for calves fed commercial colostrum replacer (16.6 g/L). Serum IgG concentrations were higher for calves fed heat-treated colostrum (24.4 g/L) than for calves fed untreated colostrum (20.5 g/L). Serum IgG concentration was positively associated with the volume of colostrum fed in the first 24 h and colostrum IgG concentration, and negatively associated with the number of hours from birth to colostrum feeding and age (days) at blood collection. Dairy producers should be encouraged to measure the quality of colostrum before administering it to calves and to measure serum IgG or a proxy such as serum total protein or Brix to evaluate passive immunity and colostrum management programs.

Preweaned heifer management on US dairy operations: Part I. Descriptive characteristics of preweaned heifer raising practices.

The objective of this study was to describe preweaned dairy heifer calf management practices on dairy operations across the United States that were used to analyze factors associated with colostrum quality and passive transfer, Cryptosporidium and Giardia, morbidity and mortality, and average daily gain. This study included 104 dairy operations in 13 states that participated in the National Animal Health Monitoring System's Dairy 2014 calf component study. This 18-mo longitudinal study focused on dairy heifer calves from birth to weaning, and data were collected on 2,545 heifer calves. Descriptive statistics were generated regarding colostrum feeding, preweaning housing, milk feeding and consumption, growth, morbidity and mortality, and weaning practices. The majority of calves enrolled were Holsteins (89.4%). Over half the calves (63.2%) enrolled in the study received the majority of their colostrum via bottle; however, 22.1% of calves from 51.0% of operations received colostrum via suckling from their dams. For all calves, the mean time to the first colostrum feeding was 2.8 h, and the average amount of colostrum at the first feeding was 2.9 L, with 4.5 L provided in the first 24 h. The mean serum IgG of all calves was 21.7 g/L; however, 76.0% of operations had at least 1 calf with failure of passive transfer of immunity with a serum IgG below 10 g/L. The majority of calves in the study were housed individually (86.6%). Nonetheless, 20.2% of operations housed some calves in groups, representing 13.4% of all calves. Approximately one-half of the calves in the study (52.3%) were dehorned or disbudded during the preweaning period, with only 27.8% of these calves receiving analgesics or anesthetics during the procedure. Whole or waste milk was the liquid diet type fed to 40.1% of calves, and milk replacer was fed to 34.8% of calves. A combination of milk and milk replacer was fed to 25.1% of calves. Calves, on average, were fed 2.6 L per feeding and fed 2.6 times/d, resulting in a total of 5.6 L of liquid diet fed per day. The mean average daily gain for all calves enrolled in the study was 0.7 kg/d. Fecal samples were collected and almost all operations had at least 1 calf positive for Cryptosporidium (94.2%) or Giardia (99.0%), and 84.6% of operations had calves that tested positive for both Cryptosporidium and Giardia. Over one-third of calves (38.1%) had at least one morbidity event during the preweaning period and the mortality rate was 5.0%. The mean age at weaning was 65.7 d. This study provides an update on dairy heifer raising practices in the United States.

Preweaned heifer management on US dairy operations: Part VI. Factors associated with average daily gain in preweaned dairy heifer calves.

The study objective was to evaluate average daily gain (ADG) in dairy heifer calves based on health, feeding, management practices, and environmental factors. This study included 102 operations in 13 states that participated in the calf component of the National Animal Health Monitoring System's Dairy 2014 study. This 18-mo longitudinal study included 1,410 Holstein heifer calves monitored from birth to weaning. The mean ADG from birth to final weight was 0.74 kg/d. Backward elimination model selection in Proc Mixed after univariate screening determined factors that significantly affected ADG. The final model included dam lactation number, singleton versus twin birth, bedding type, Giardia and Cryptosporidium fecal shedding, disease events, a categorized average temperature-humidity index for the preweaning period (pTHI), amount of protein in the liquid diet (kg/d), milk pasteurization, direct-fed microbials, and the interaction between milk pasteurization and direct-fed microbials. After controlling for other independent variables in the model, calves born to first-lactation dams gained less (0.60 kg/d) than calves from second- (0.65 kg/d) or third- or greater-lactation (0.64 kg/d) dams. Singleton calves gained 0.07 kg/d more than twins. Calves bedded with sand or no bedding gained less (0.49 kg/d) than calves on all other bedding types. Calves negative for Cryptosporidium or Giardia at the time of sampling gained 0.03 or 0.02 kg/d more, respectively, than calves that were positive for Cryptosporidium or Giardia. Calves with no disease events gained 0.07 kg/d more than calves with one or more disease events. Calves experiencing an average pTHI <50 gained more (0.67 kg/d) than calves experiencing an average pTHI from 50 to 69 (0.62 kg/d), or ≥70 (0.59 kg/d). Within the range of observed kilograms of protein fed per day in the liquid diet, every additional 0.1 kg of protein fed per day equated to 0.02 kg/d of gain. Calves fed milk replacer with a direct-fed microbial gained less (0.44 kg/d) than calves fed milk replacer without a direct-fed microbial (0.60 kg/d) and calves fed pasteurized or unpasteurized milk regardless of direct-fed microbial use. These results highlight the importance of feeding a quantity and quality of a liquid diet to achieve optimal growth, keeping calves free of disease, the type or status of bedding, and mitigating the effects of temperature and humidity on preweaning ADG.

The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Tissue pharmacokinetics and pharmacodynamics of AmBisome® (L-AmBis) in uninfected and infected animals and their effects on dosing regimens.

By selecting a unique combination of lipids and amphotericin B, the liposome composition for AmBisome® (L-AmBis) has been optimized resulting in a formulation that is minimally toxic, targets to fungal cell walls, and distributes into and remains for days to weeks in various host tissues at drug levels above the MIC for many fungi. Procedures have been standardized to ensure that large scale production of the drug retains the drug's low toxicity profile, favorable pharmacokinetics and antifungal efficacy. Tissue accumulation and clearance with single or multiple intravenous administration is similar in uninfected and infected animal species, with tissue accumulation being dose-dependent and the liver and spleen retaining the most drug. The efficacy in animals appears to be correlated with drug tissue levels although the amount needed in a given organ varies depending upon the type of infection. The long-term tissue retention of bioactive L-AmBis in different organs suggests that for some indications, prophylactic and intermittent drug dosing would be efficacious reducing the cost and possible toxic side-effects. In addition, preliminary preclinical studies using non-intravenous routes of delivery, such as aerosolized L-AmBis, catheter lock therapy, and intravitreal administration, suggest that alternative routes could possibly provide additional therapeutic applications for this antifungal drug.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Experimental Demonstration of the Collisionless Plasmoid Instability below the Ion Kinetic Scale during Magnetic Reconnection.

The spontaneous formation of magnetic islands is observed in driven, antiparallel magnetic reconnection on the Terrestrial Reconnection Experiment. We here provide direct experimental evidence that the plasmoid instability is active at the electron scale inside the ion diffusion region in a low collisional regime. The experiments show the island formation occurs at a smaller system size than predicted by extended magnetohydrodynamics or fully collisionless simulations. This more effective seeding of magnetic islands emphasizes their importance to reconnection in naturally occurring 3D plasmas.

Novel plasmid conferring kanamycin and tetracycline resistance in the turkey-derived Campylobacter jejuni strain 11601MD.

In Campylobacter spp., resistance to the antimicrobials kanamycin and tetracycline is frequently associated with plasmid-borne genes. However, relatively few plasmids of Campylobacter jejuni have been fully characterized to date. A novel plasmid (p11601MD; 44,095nt) harboring tet(O) was identified in C. jejuni strain 11601MD, which was isolated from the jejunum of a turkey produced conventionally in North Carolina. Analysis of the p11601MD sequence revealed the presence of a high-GC content cassette with four genes that included tet(O) and a putative aminoglycoside transferase gene (aphA-3) highly similar to kanamycin resistance determinants. Several genes putatively involved in conjugative transfer were also identified on the plasmid. These findings will contribute to a better understanding of the distribution of potentially self-mobilizing plasmids harboring antibiotic resistance determinants in Campylobacter spp. from turkeys and other sources.

Modelling the cost-effectiveness of adopting risk-stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland.

AIMS: To assess the cost-effectiveness of adopting risk-stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland. METHODS: A continuous-time hidden Markov model was fitted to national longitudinal screening data to derive transition probabilities between observed non-referable and referable retinopathy states. These were incorporated in a decision model simulating progression, costs and visual acuity outcomes for a synthetic cohort with a covariate distribution matching that of the Scottish diabetic screening population. The cost-effectiveness of adopting extended (2-year) screening for groups with no observed retinopathy was then assessed over a 30-year time horizon. RESULTS: Individuals with a current grade of no retinopathy on two consecutive screening episodes face the lowest risk of progressing to referable disease. For the cohort as a whole, the incremental cost per quality-adjusted life year gained for annual vs. biennial screening ranged from approximately £74 000 (for those with no retinopathy and a prior observed grade of mild or observable background retinopathy) to approximately £232 000 per quality-adjusted life year gained (for those with no retinopathy on two consecutive screening episodes). The corresponding incremental cost-effectiveness ratios in the subgroup with Type 1 diabetes were substantially lower; approximately £22 000 to £85 000 per quality-adjusted life year gained, respectively. CONCLUSIONS: Biennial screening for individuals with diabetes who have no retinopathy is likely to deliver significant savings for a very small increase in the risk of adverse visual acuity and quality of life outcomes. There is greater uncertainty regarding the long-term cost-effectiveness of adopting biennial screening in younger people with Type 1 diabetes.

Identification and Characterization of Isolates of Pythium and Phytophthora spp. from Snap Beans with Cottony Leak.

Cottony leak is an important disease of snap bean in Oklahoma and nearby states. Oomycete pathogens isolated from diseased pods collected from commercial fields and research plots consisted of both Pythium spp. (n = 131) and Phytophthora spp. (n = 46). Isolates were identified to species by morphological characteristics and by sequencing a portion of the internal transcribed spacer region of representative isolates. The most common Pythium spp. were Pythium ultimum var. ultimum; Pythium 'group HS', a self-sterile form of P. ultimum that produces hyphal swellings in lieu of sporangia (n = 74); and P. aphanidermatum (n = 50). Phytophthora spp. included Phytophthora drechsleri (n = 41) and P. nicotianae (n = 5). Nearly all of the isolates (95%) and all species were pathogenic on detached pods but Pythium ultimum var. ultimum and Pythium 'group HS' were most aggressive. Phytophthora drechsleri was most aggressive on seedlings, causing preemergence damping off and seed rot. Pythium ultimum var. ultimum, Pythium 'group HS', and P. aphanidermatum were intermediate in virulence to seedlings, causing root rot, stunting, and limited postemergence damping off. Phytophthora nicotianae and Pythium diclinum (n = 4) were not pathogenic on seedlings. Most (87%) isolates were sensitive to metalaxyl-M (concentration that caused a 50% reduction in mycelial growth [EC50] < 1 µg/ml) and the rest were intermediate in sensitivity (EC50 > 1 to < 100 µg/ml). Phytophthora drechsleri was the most sensitive species (EC50 = 0.06 µg/ml) compared with Pythium aphanidermatum, which was least sensitive (EC50 = 1.3 µg/ml). Cottony leak is a disease complex caused by several oomycete species that should include Phytophthora drechsleri, a newly reported pathogen of snap bean in the United States.

High-power synchronously pumped femtosecond Raman fiber laser.

We report a high-power synchronously pumped femtosecond Raman fiber laser operating in the normal dispersion regime. The Raman laser is pumped by a picosecond Yb(3+)-doped fiber laser. It produces highly chirped pulses with energy up to 18 nJ, average power of 0.76 W and 88% efficiency. The pulse duration is measured to be 147 fs after external compression. We observed two different regimes of operation of the laser: coherent and noise-like regime. Both regimes were experimentally characterized. Numerical simulations are in a good agreement with experimental results.

Toxicity and efficacy differences between liposomal amphotericin B formulations in uninfected and Aspergillus fumigatus infected mice.

Because of the reduced toxicity associated with liposomal amphotericin B preparations, different amphotericin B liposome products have been made. In the present study, we compared the amphotericin B liposomal formulations, AmBisome(®) (AmBi) and Lambin(®) (Lbn), in uninfected and Aspergillus fumigatus infected mice, using several in vitro and in vivo toxicity and efficacy assays. The results showed that the formulations were significantly different, with Lbn 1.6-fold larger than AmBi. Lbn was also more toxic than AmBi based on the RBC potassium release assay and intravenous dosing in uninfected mice given a single 50 mg/kg dose (80% mortality for Lbn vs. 0% for AmBi). Renal tubular changes after intravenous daily dosing for 14 days were seen in uninfected mice given 5 mg/kg Lbn but not with AmBi. Survival following A. fumigatus challenge was 30% for 10 mg/kg Lbn and 60% for 10 mg/kg AmBi. When the BAL and lungs were collected 24 h after the second treatment, AmBi at 10 or 15 mg/kg or 15 mg/kg Lbn lowered the BAL fungal burden significantly vs. the controls (P ≤ 0.05), while there was no difference in lung fungal burden amongst the groups. In contrast, lung histopathology at this same early timepoint showed that AmBi was associated with markedly fewer fungal elements and less lung tissue damage than Lbn. In conclusion, given the differences in size, toxicity, and efficacy, AmBi and Lbn were not physically or functionally comparable, and these differences underscore the need for adequate testing when comparing amphotericin B liposome formulations.

Sustained pyridoxine response in primary hyperoxaluria type 1 recipients of kidney alone transplant.

Combined liver kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) given that it removes the hepatic source of oxalate production and improves renal allograft survival. However, PH1 patients homozygous for the G170R mutation can develop normal urine oxalate levels with pyridoxine therapy and may be candidates for kidney alone transplant (KTx). We examined the efficacy of pyridoxine therapy following KTx in five patients homozygous for G170R transplanted between September 1999 and July 2013. All patients were maintained on pyridoxine posttransplant. Median age at transplant was 39 years (range 33-67 years). Median follow-up posttransplant was 8.5 years (range 0.2-13.9 years). At the end of follow-up, four grafts were functioning. One graft failed 13.9 years posttransplant due to recurrent oxalate nephropathy following an acute medical illness. After tissue oxalate stores had cleared, posttransplant urine oxalate levels were <0.5 mmol/24 h the majority of times checked. Calcium oxalate crystals were noted in only 3/13 allograft biopsies. This series suggests that a subgroup of PH1 patients demonstrate sustained response to pyridoxine therapy following KTx. Therefore, pyridoxine combined with KTx should be considered for PH1 patients with a homozygous G170R mutation.