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Mortality in acute kidney injury (AKI) patients remains very high, although very important advances in understanding the pathophysiology and in diagnosis and supportive care have been made. Most commonly, adverse outcomes are related to extra-renal organ dysfunction and failure. We and others have documented inflammation in remote organs as well as microvascular dysfunction in the kidney after renal ischemia. We hypothesized that abnormal microvascular flow in AKI extends to distant organs. To test this hypothesis, we employed intravital multiphoton fluorescence imaging in a well-characterized rat model of renal ischemia/reperfusion. Marked abnormalities in microvascular flow were seen in every organ evaluated, with decreases up to 46% observed 48 hours postischemia (as compared to sham surgery, p = 0.002). Decreased microvascular plasma flow was found in areas of erythrocyte aggregation and leukocyte adherence to endothelia. Intravital microscopy allowed the characterization of the erythrocyte formations as rouleaux that flowed as one-dimensional aggregates. Observed microvascular abnormalities were associated with significantly elevated fibrinogen levels. Plasma flow within capillaries as well as microthrombi, but not adherent leukocytes, were significantly improved by treatment with the platelet aggregation inhibitor dipyridamole. These microvascular defects may, in part, explain known distant organ dysfunction associated with renal ischemia. The results of these studies are relevant to human acute kidney injury.

Hypoxic acute kidney injury, a major unresolved problem, initiates, or aggravates, renal functional and structural decline. There is no treatment for hypoxic acute renal injury and its sequelae. We tested the hypothesis that human kidney tubular cells, or their extracellular vesicles (exosomes), prevent renal injury when infused intravenously 24 hours after 50 minutes of bilateral renal ischemia in Nude rats. Cells and their exosomes were from harvested human kidneys declined for transplantation. Injections of either cells or exosomes, given after 24 and 48 hours of reperfusion, preserved renal function and structure in both treatment groups. However, exosomes were superior to cells; and maintained renal vascular and epithelial networks, prevented renal oxidant stress, and apoptosis; and restrained activation of pro-inflammatory and pro-fibrogenic pathways. Exosomes worked in 24 hours, consistent with functional rather than regenerative activity. Comprehensive proteomic analysis identified 6152 renal proteins from all cellular compartments; and 628 were altered by ischemia at all cell levels, while 377 were significantly improved by exosome infusions. We conclude that renal damage from severe ischemia was broad, and human renal exosomes prevented most protein alterations. Thus, exosomes seem to acutely correct a critical and consequential abnormality during reperfusion. In their absence, renal structure and cells transition to a chronic state of fibrosis and extensive renal cell loss.

Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

The mutation rate at 54 perfect (uninterrupted) dinucleotide microsatellite loci is estimated by direct genotyping of 96 Arabidopsis thaliana mutation accumulation lines. The estimated rate differs significantly among motif types with the highest rate for AT repeats (2.03 x 10(-3) per allele per generation), intermediate for CT (3.31 x 10(-4)), and lowest for CA (4.96 x 10(-5)). The average mutation rate per generation for this sample of loci is 8.87 x 10(-4) (s.e.=2.57 x 10(-4)). There is a strong effect of initial repeat number, particularly for AT repeats, with mutation rate increasing with the length of the microsatellite locus in the progenitor line. Controlling for motif and initial repeat number, chromosome 4 exhibited an elevated mutation rate relative to other chromosomes. The great majority of mutations were gains or losses of a single repeat. Generally, the data are consistent with the stepwise mutation model of microsatellite evolution. Several lines exhibited multiple step changes from the progenitor sequence, but it is unclear whether these are multi-step mutations or multiple single-step mutations. A survey of dinucleotide repeats across the entire Arabidopsis genome indicates that AT repeats are most abundant, followed by CT, and CA.

Prompt fission neutron spectra (PFNS) are crucial to any neutronic simulation of critical nuclear systems. An experimental setup dedicated to the measurements of PFNS of very high accuracy was developed at the Los Alamos Neutron Science Center (LANSCE) some ten years ago. It allows for the measurement of PFNS for neutron induced fission at the Weapon Neutron Research (WNR) neutron source of the LANSCE. A measurement of the PFNS from the 235U(n,f) reaction was realized recently and is currently analyzed. Preliminary results are presented here and are compared to present nuclear data evaluations.

The pathophysiology of ischemic acute renal failure is complex, and the role of leukocyte adhesion in this process is not well defined. A monoclonal antibody (mAb) against intracellular adhesion molecule 1 (anti-ICAM-1), administered at the time of bilateral renal ischemia in the rat, prevented both functional impairment and histologic changes of acute renal failure. Plasma creatinine measured (mg/dl) 24 hr after 30 min of ischemia was 0.61 ± 0.05 in the anti-ICAM-1-treated animals compared with 2.4 ± 0.14 (P < 0.0001) in the vehicle-treated ischemic group. Forty-eight hours after ischemia, creatinine values were 0.46 ± 0.05 and 2.03 ± 0.22 (P < 0.0001) in anti-ICAM-1 and vehicle-treated groups, respectively. A low dose of anti-ICAM-1 that was itself nonprotective, when given with partially protective doses of a mAb against lymphocyte function-associated antigen-1 (anti-LFA-1), acted synergistically to prevent renal failure. Anti-ICAM-1 mAb also protected the kidney when administered 0.5 or 2 hr but not 8 hr after restoration of blood flow and when the ischemic period was extended to 40 min. Ischemia-induced increases in tissue myeloperoxidase, a marker of neutrophil infiltration, were mitigated with anti-ICAM-1 treatment. Thus, anti-ICAM-1 mAb protected the kidney against ischemic renal failure, even when the antibody was administered after the ischemic period. These results suggest a critical role for leukocytes and adhesion molecules in the pathophysiology of ischemic injury and may have important therapeutic implications.

Postoperative analgesia for male circumcision surgery has been traditionally provided by a landmark-based dorsal penile nerve block (DPNB-LM) or by caudal epidural analgesia (CEA). In this study we report on a retrospective analysis of the effectiveness and safety of CEA, DPNB-LM and ultrasound-guided dorsal penile nerve block (DPNB-US) in our institution over a six-year period. Information was gathered from each patient's medical record. A total of 216 circumcisions were performed on patients aged from five months to 15 years. One hundred and fifteen patients received CEA, 46 DPNB-LM and 55 DPNB-US. Patients in the DPNB-LM group required rescue morphine administration in the recovery unit more frequently (30.4%) than either the DPNB-US (3.5%) or CEA groups (3.6%). Similarly, the DPNB-LM group required a larger total dose of morphine, and had longer recovery ward stays than CEA or DPNB-US groups. Time to first analgesia was greatest for the CEA group while there was no significant difference between time to first analgesia for DPNB-LM and DPNB-US. Sixty-three percent of patients in the DPNB-LM group, 1.7% of CEA and 5.5% of the DPNB-US required intraoperative opiates (P <0.0001). There was no difference in time to hospital discharge.

The etiology of sarcoidosis is unknown, but epidemiology suggests that environmental agents are a factor. Because firefighters are exposed to numerous toxins, we questioned whether sarcoidosis was increased in this cohort. The New York City Fire Department (FDNY), employing > 11,000 firefighters and nearly 3,000 emergency medical services (EMS) health-care workers (HCWs). In 1985, FDNY initiated a surveillance program to determine the incidence, prevalence, and severity of biopsy-proven sarcoidosis in firefighters. In 1995, EMS HCWs were added as control subjects. Between 1985 and 1998, 4 prior cases and 21 new cases of sarcoidosis were found in FDNY firefighters. Annual incidence proportions ranged from 0 to 43.6/100,000, and averaged 12.9/100,000. On July 1, 1998, the point prevalence was 222/100,000. For EMS HCWs, annual incidence proportions were zero. Radiographic stage 0 or stage 1 sarcoidosis was found in 19 firefighters (76%), and stage 3 was found in 1 firefighter (4%). Pulmonary function (FVC, FEV1, and diffusing capacity for carbon monoxide) was normal in 17 firefighters (68%), and reduced to ≤ 65% predicted in 2 firefighters (8%). Maximum oxygen consumption (M▪o2) was normal in 10 of 17 firefighters (59%), and reduced to 65% predicted in 3 firefighters (12%). Five of seven firefighters (71%) with abnormal M▪o2 had gas exchange abnormalities, and none had O2 desaturation. All returned to fire fighting. Annual incidence proportions and point prevalence were increased in FDNY firefighters as compared to EMS HCWs and historical controls. Radiographs and physiologic measurements demonstrated only minimal impairment.

The U.S. Food and Drug Administration's Bacteriological Analytical Manual recommends two enumeration methods for Bacillus cereus: (i) standard plate count method with mannitol-egg yolk-polymyxin (MYP) agar and (ii) a most-probable-number (MPN) method with tryptic soy broth (TSB) supplemented with 0.1% polymyxin sulfate. This study compared the effectiveness of MYP and MPN methods for detecting and enumerating B. cereus in raw and high-temperature, short-time pasteurized skim (0.5%), 2%, and whole (3.5%) bovine milk stored at 4°C for 96 h. Each milk sample was inoculated with B. cereus EZ-Spores and sampled at 0, 48, and 96 h after inoculation. There were no differences (P > 0.05) in B. cereus populations among sampling times for all milk types, so data were pooled to obtain overall mean values for each treatment. The overall B. cereus population mean of pooled sampling times for the MPN method (2.59 log CFU/ml) was greater (P < 0.05) than that for the MYP plate count method (1.89 log CFU/ml). B. cereus populations in the inoculated milk samples ranged from 2.36 to 3.46 and 2.66 to 3.58 log CFU/ml for inoculated milk treatments for the MYP plate count and MPN methods, respectively, which is below the level necessary for toxin production. The MPN method recovered more B. cereus, which makes it useful for validation research. However, the MYP plate count method for enumeration of B. cereus also had advantages, including its ease of use and faster time to results (2 versus 5 days for MPN).

To validate how packaging and storage reduces Listeria monocytogenes on whole-muscle beef jerky and smoked pork and beef sausage sticks, four packaging systems (heat sealed [HS] without vacuum, heat sealed with oxygen scavenger, nitrogen flushed with oxygen scavenger [NFOS], and vacuum) and four ambient temperature storage times were evaluated. Commercially available whole-muscle beef jerky and smoked pork and beef sausage sticks were inoculated with a five-strain L. monocytogenes cocktail, packaged, and then stored at 25.5 °C until enumerated for L. monocytogenes at 0, 24, 48, and 72 h and 30 days after packaging. The interaction of packaging and storage time affected L. monocytogenes reduction on jerky, but not on sausage sticks. A >2-log CFU/cm(2) reduction was achieved on sausage sticks after 24 h of storage, regardless of package type, while jerky had <2-log reductions for all packaging types. At 48 h, log reductions were similar (P. 0.05) for all types of jerky packaging, ranging from 1.26 to 1.72 log CFU/cm(2); however, at 72 h, mean L. monocytogenes reductions were >2 log CFU/cm(2), except for NFOS (1.22-log CFU/cm(2) reduction). Processors could package beef jerky in HS packages with oxygen scavenger or vacuum in conjunction with a 24-h holding time as an antimicrobial process to ensure a >1-log CFU/cm(2) L. monocytogenes reduction or use a 48-h holding time for HS- or NFOS-packaged beef jerky. A >3-log CFU/cm(2) mean reduction was observed for all beef jerky and sausage stick packaging systems after 30 days of 25.5 °C storage.