Biomedical subjects
Publications and source records attributed to K Anderson.
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This Letter reports results from the MINOS experiment based on its initial exposure to neutrinos from the Fermilab NuMI beam. The rates and energy spectra of charged current nu(mu) interactions are compared in two detectors located along the beam axis at distances of 1 and 735 km. With 1.27 x 10(20) 120 GeV protons incident on the NuMI target, 215 events with energies below 30 GeV are observed at the Far Detector, compared to an expectation of 336+/-14 events. The data are consistent with nu(mu) disappearance via oscillations with |Delta(m)2/32|=2.74 +0.44/-0.26 x10(-3)eV(2) and sin(2)(2theta(23))>0.87 (68% C.L.).
Renal function is a component of the Model for End Stage Liver Disease (MELD), We queried the 1999-2004 OPTN/UNOS database to determine whether preoperative renal function remained an important determinant of survival in primary deceased donor liver transplant alone patients (DDLTA) or primary combined kidney liver transplant patients (KLTX). We examined preoperative creatinine, renal replacement therapy (RRT), incidence of KLTX, and patient survival in the 34 months before and after introduction of MELD and performed a multivariate Cox regression analysis of time to death. Preoperative renal function is an independent predictor of survival in DDLTA but not in KLTX. When compared to DDLTA with a preoperative serum creatinine of 0-0.99 mg/dL, patients with serum creatinine from 1-1.99 mg/dL, >2.0 mg/dL, those requiring RRT, and those receiving KLTX had a relative risk of death following transplant of 1.11, 1.58, 1.77, and 1.44 respectively. KLTX requiring RRT had better survival than DDLTA requiring RRT. Since introduction of MELD, KLTX, preoperative creatinine, and number of patients requiring preoperative RRT have increased. Despite this, patient survival following orthotopic liver transplant (OLTX) in the 34 months after introduction of MELD is not different than prior to introduction of MELD.
New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.
Stabilizing phosphorus (P) in poultry waste to reduce P losses from manured soils is important to protect surface waters, while pathogens in manures are an emerging issue. This study was conducted to evaluate CaO and Ca(OH)2 for killing manure bacterial populations (pathogens) and stabilizing P in poultry wastes and to investigate the influence on soils following amendment with the treated wastes. Layer manure and broiler litter varying in moisture content were treated with CaO and Ca(OH)2 at rates of 2.5, 5, 10, and 15% by weight. All treated wastes were analyzed for microbial plate counts, pH, and water-soluble phosphorus (WSP), while a few selected layer manures were analyzed by phosphorus X-ray absorption near edge structure (XANES). A loamy sand and a silt loam were amended with broiler litter and layer manure treated with CaO at rates of 0, 2.5, 5, 10, and 15% and soil WSP and pH were measured at times 1, 8, and 29 d. Liming reduced bacterial populations, with greater rates of lime leading to greater reductions; for example 10% CaO applied to 20% solids broiler litter reduced the plate counts from 793,000 to 6500 mL-1. Liming also reduced the WSP in the manures by over 90% in all cases where at least 10% CaO was added. Liming the manures also reduced WSP in soils immediately following application and raised soil pH. The liming process used successfully reduced plate counts and concerns about P losses in runoff following land application of these limed products due to decreased WSP.
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We have designed a new effect-site controlled, patient-maintained sedation system for delivering propofol. In the previous systems we developed, the patients retained the use of the handset throughout the procedure and were able to increase the level of sedation. However, it was found that this could potentially lead to oversedation. In the present system, the patients were able to increase their level of sedation until a level was reached that was judged by the patients as being adequate to allow them to tolerate the injection of dental local anaesthetic. The handset was then taken from the patients and the effect site concentration of propofol was maintained at that level for the remainder of the procedure. To assess its safety and efficacy, the system was used to sedate 40 patients presenting for dental procedures under sedation. The system was used successfully and treatment was completed in 39 patients. The system was found to be safe. Both surgeon and patient approval scores were high. Although this study demonstrates the efficacy of effect-site controlled, patient-maintained propofol sedation in this group of patients, further work is required to confirm its safety.
Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis have identified signaling pathways that have become potential therapeutic targets. It has clearly been established that intracellular regulatory proteins and interactions between malignant plasma cells and the bone marrow microenvironment play an important role in their survival and drug resistance. Several new agents associated with molecular targets are currently being investigated to design new treatment strategies aimed at prolonging survival and improving quality of life. This review illustrates their mechanisms of action and the possible future clinical applications.
The effect of Mannheimia haemolytica infection on the penetration of ceftiofur and desfuroylceftiofur metabolites into tissue chambers was studied in cattle after subcutaneous administration of ceftiofur crystalline free acid sterile suspension (CCFA-SS). Four tissue chambers were implanted subcutaneously in each of 12 calves. Approximately 45 days after implantation, two chambers were inoculated with M. haemolytica (10(6) colony-forming units per chamber) while the remaining two chambers were inoculated with sterile phosphate-buffered saline. Twenty-four hours after inoculation, CCFA-SS was administered subcutaneously in the middle third of the caudal ear pinna of each calf. Chamber fluid and blood samples were collected at predetermined times for 10 days following dosing and analyzed for ceftiofur and desfuroylceftiofur metabolites by high-performance liquid chromatography. Concentrations of ceftiofur and desfuroylceftiofur metabolites in plasma and tissue chamber fluid remained above a threshold of 0.2 microg/mL for at least 8 days. Infected tissue chamber fluid concentrations of ceftiofur and desfuroylceftiofur metabolites were significantly higher than those in non-infected tissue chamber fluid, which correlated with significantly higher total protein concentration in infected tissue chambers. These results indicate that single subcutaneous administration of CCFA-SS at 6.6 mg/kg can be expected to provide effective therapy of susceptible bacterial infections for a period of at least 1 week.
Automatic wheeze detection has several potential benefits compared with reliance on human auscultation: it is experience independent, an automated historical record can easily be kept, and it allows quantification of wheeze severity. Previous attempts to detect wheezes automatically have had partial success but have not been reliable enough to become widely accepted as a useful tool. In this paper an improved algorithm for automatic wheeze detection based on auditory modelling is developed, called the frequency- and duration-dependent threshold algorithm. The mean frequency and duration of each wheeze component are obtained automatically. The detected wheezes are marked on a spectrogram. In the new algorithm, the concept of a frequency- and duration-dependent threshold for wheeze detection is introduced. Another departure from previous work is that the threshold is based not on global power but on power corresponding to a particular frequency range. The algorithm has been tested on 36 subjects, 11 of whom exhibited characteristics of wheeze. The results show a marked improvement in the accuracy of wheeze detection when compared with previous algorithms.
Structural engineering analysis tools have been used to improve the understanding of the biomechanical behaviour of the cornea. The research is a multi-disciplinary collaboration between structural engineers, mathematical and numerical analysts, ophthalmologists and clinicians. Mathematical shell analysis and nonlinear finite-element modelling have been used in conjunction with laboratory experiments to study the behaviour of the cornea under different loading states and to provide improved predictions of the mechanical response to disease and injury. The initial study involved laboratory tests and mathematical back analysis to determine the corneal material properties and topography. These data were then used to facilitate the construction of accurate finite-element models that are able to reliably trace the performance of cornea upon exposure to disease, injury or elevated intra-ocular pressure. The models are being adapted to study the response to keratoconus (a disease causing loss of corneal tissue) and to tonometry procedures, which are used to measure the intra-ocular pressure. This paper introduces these efforts as examples of the application of structural engineering analysis tools and shows their potential in the field of corneal biomechanics.
NVP-LAQ824 is a novel potent hydroxamic acid-derived histone deacetylase inhibitor that induces apoptosis in nanomolar concentrations in myeloid leukemia cell lines and patient samples. Here we show the activity of NVP-LAQ824 in acute myeloid leukemia cells and BCR/ABL-expressing cells of mouse and human origin, both sensitive and resistant to imatinib mesylate (Gleevec, STI-571). Whereas imatinib inhibited overall cellular tyrosine phosphorylation in Ba/F3.p210 cells, NVP-LAQ824 did not inhibit tyrosine phosphorylation, and did not affect BCR/ABL or ABL protein expression. Neither compound was able to inhibit cellular tyrosine phosphorylation in the imatinib-resistant Ba/F3.p210-T315I cell line. These data taken together suggest that BCR/ABL kinase activity is not a direct target of NVP-LAQ824. Synergy between NVP-LAQ824 and imatinib was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. In addition, we show that NVP-LAQ824 was well tolerated in vivo in a pre-clinical murine leukemia model, with antileukemia activity resulting in significant prolongation of the survival of mice when treated with NVP-LAQ824 compared to control mice. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in myeloid malignancies.
Patient-maintained sedation using propofol has recently been shown to be effective for dental surgery. We compared this new technique to the established technique of operator administered midazolam. The two groups were compared before, during and after sedation. The two primary outcomes were time until discharge and oxygen saturation. Vital signs, anxiety and psychomotor skills were also compared. State anxiety was reduced to a greater extent in the propofol group (mean difference 10 (SD 4) mm; p = 0.010. Propofol patients recovered quicker (mean difference 7 (SD 1.4) min; p = 0.001). Propofol patients had a smaller reduction in arterial oxygen saturation (mean difference 0.8 (SD 0.3)%; p = 0.030), and a reduced increase in heart rate (mean difference 9 (SD 2) beats.min(-1); p < 0.001). Both techniques were well tolerated and safe. Propofol sedation offered superior anxiolysis, quicker recovery, less amnesia and less depression of simple psychomotor function.
Lung cancer is the most common visceral malignancy in males, with rapidly increasing incidence in females, and a devastatingly poor prognosis. Transforming growth factor (TGF)-beta has been shown to induce senescence in A549 lung cancer cells, and both TGF-beta and bone morphogenetic protein (BMP) 2 can suppress the transformed phenotype of A549 cells in vitro. We examined the effects of BMP4, another member of the TGF-beta superfamily, on specific oncogenic properties of A549 cancer cells. When A549 cancer cells were treated continuously with 100 ng/ml of BMP4, a senescent phenotype was observed after 2 wk of treatment. The BMP-treated cells appeared larger than untreated cells, grew more slowly, had more senescence-associated beta-galactosidase activity, and had less telomerase activity, as measured by the telomeric repeat amplification protocol assay. Invasion through Engelbreth Holm-Swarm matrix was inhibited in the senescent cell population. Senescent BMP4-treated cells had lower ERK activation, VEGF expression, and Bcl2 expression than wild-type cells, consistent with a less proliferative, less angiogenic phenotype with increased susceptibility to death by apoptosis. BMP4 treatment also resulted in sustained elevation of Smad1. In vivo xenograft studies in the flanks of nude mice confirmed that the BMP-treated cells were significantly less tumorigenic than untreated cells. Direct overexpression of Smad1 using adenoviral constructs resulted in cell death within 5 days. These studies suggest that BMP4 pathway signaling can induce senescence and thus negatively regulate the growth of A549 lung cancer cells.
Autosomal recessive proximal spinal muscular atrophy (SMA) is a severe neurodegenerative disease of childhood causing weakness and wasting secondary to motor neuron dysfunction. Over 97% of cases are caused by deletions or mutations within the survival motor neuron (SMN) gene. The SMN protein is highly expressed within brain, spinal cord and muscle, and is decreased in SMA patients. It has been shown to have an important role in RNA metabolism, but the reason for the specific motor neuron loss is still unclear. We have used a novel antibody array technology to look for differences in the expression patterns of primary muscle cultures from a type II SMA patient and a normal control. A relatively small number of differences were found within a group of proteins that function as both RNA binding proteins and transcription factors. Interactions between a number of these proteins are well established, and three of them bind in turn to p53 which interacts with SMN. A number of the changes were confirmed with western blot analysis both in the primary muscle cultures and in skeletal muscle samples from SMA patients and controls. Changes at the mRNA level were also confirmed with oligonucleotide arrays. These results suggest that a common transcription pathway may be altered in the disease state, and suggests that down-regulation of transcription factors contributes to SMA pathogenesis.
A retrospective cohort study was conducted after 2 confirmed and 8 probable cases of VTEC 0157 occurred in a schoolgroup from Somerset following a trip to France. The strain of the 2 confirmed cases was vero-cytotoxin type 2, phage type 34. Despite its low statistical power due to small numbers, this study suggested the most likely vehicle of infection was cucumber salad (crude RR=4.3, 95%CI [0.6-29], adjusted OR=107, 95%CI indeterminate, p=0.08). The cucumbers were purchased from Belgium but it was not possible to trace them back to source. The international nature of this outbreak emphasises the importance of close collaboration between organisations in the management of outbreaks, of ensuring international standards in food safety, and of agreeing a common standard in VTEC typing across Europe.
OBJECTIVES: To analyze the relationship between hydronephrosis due to urinary tract obstruction and the presence of the sonographic eggshell sign, which is a recently described crescent of increased echogenicity at the caliceal/parenchymal interface and possibly an indicator of raised intrarenal pressure. METHODS: All patients presenting between 1996 and 1999 for surgical management of pelviureteral junction obstruction or congenital posterior urethral obstruction had films reviewed for the presence of the eggshell sign. RESULTS: Of 94 patients, 40 presented postnatally and 54 had hydronephrosis detected on the antenatal ultrasound scan. Of the postnatal group, 16 (40%) had urethral obstruction, of whom 4 (25%) displayed the eggshell sign; in the 24 with pelviureteral junction obstruction, the echogenic pericaliceal crescent was seen in 5 (20.8%). Of the 54 in the prenatal group, 8 (15.4%) were found to have urethral obstruction, 5 (62.5%) of whom demonstrated the eggshell sign. Of the 46 prenatally diagnosed patients with pelviureteral junction obstruction, 31 (70.5%) displayed the eggshell sign before birth; we were unable to satisfactorily review 2 patients' ultrasound scans. CONCLUSIONS: Antenatally diagnosed hydronephrosis due to significant urinary tract obstruction seems to be related to the appearance of the eggshell sign on ultrasonography, particularly in those patients with pelviureteral junction obstruction. Those patients without significant caliceal distension and those with renal dysplasia or severe hydronephrosis with low-pressure kidneys were less likely to display the eggshell sign. Although the association with other causes of hydronephrosis is unknown, we believe these figures support the need for further investigation of the eggshell sign as a marker of raised intrarenal pressure to possibly provide another data point in the sonographic evaluation of congenital hydronephrosis.
Studies of ionotropic receptors indicate that glutamate (Glu) neurotransmission plays a role in sleep. Here, we show for the first time that metabotropic 2/3 Glu (mGlu2/3) receptors play an active or permissive role in the control of REM sleep. The potent, selective, and systemically active mGlu2/3 receptor agonist LY379268 was administered systemically in doses of 1.0 and 0.25 mg/kg sc. The drug produced a dose-dependent suppression of rapid eye movement (REM) sleep and fast (10-50 Hz) EEG in non-rapid eye movement (NREM) sleep. The 1.0-mg/kg effect on REM sleep was remarkably powerful: REM sleep was totally suppressed in the 6-h postinjection and reduced by 80% in the next 6 h. NREM duration was unchanged during the REM suppression in spite of the strong and unusual depression of EEG power in fast NREM frequencies. These sleep and EEG effects were unaccompanied by motor or behavioral abnormalities. We hypothesize that the REM and the fast EEG suppression were both caused by a depression of brain arousal levels by LY379268. If correct, depressing arousal by reducing excitatory neurotransmission with an mGlu2/3 receptor agonist produces electrophysiological effects that differ drastically from those produced by depressing arousal by enhancing neural inhibition with GABAergic drugs. This different approach to modifying the excitation/inhibition balance in the brain might yield novel therapeutic actions.