Evaluating digestibility and toxicity of native warm-season grasses for equines.

Introduced cool-season grasses are dominant in Virginia's grasslands, but their high digestible energy and nonstructural carbohydrate (NSC) levels pose a risk for horses prone to obesity and laminitis. Native warm-season grasses (NWSGs) have lower digestible energy and NSC levels that may be more suitable for horses susceptible to laminitis. Although NWSGs have desirable characteristics, they are novel forages for horses. Little is known about NWSG intake or potential toxicity to horses or how grazing by horses may affect NWSG swards. The overall objectives of this research were to 1) assess voluntary intake, toxicological response, and apparent digestibility of NWSG hays fed to horses; and 2) evaluate the characteristics of three NWSG species under equine grazing. For the first objective, a hay feeding trial using indiangrass (IG) (Sorghastrum nutans) and big bluestem (BB) (Andropogon gerardii) was conducted with nine Thoroughbred geldings in a replicated 3 × 3 Latin square design. Voluntary dry matter intake of IG and BB hays by horses were 1.3% and 1.1% of BW/d, lower than orchardgrass (Dactylis glomerata), an introduced cool-season grass, at 1.7% of BW/d (P = 0.0020). Biomarkers for hepatotoxicity remained within acceptable ranges for all treatments. Apparent dry matter digestibility (DMD) did not differ among hays, ranging from 39% to 43%. NSC levels ranged from 4.4% to 5.4%, below maximum recommended concentrations for horses susceptible to laminitis. For the second objective, a grazing trial was conducted comparing IG, BB, and eastern gamagrass (EG) (Tripsacum dactyloides) yields, forage losses, changes in vegetative composition, and effects on equine bodyweight. Nine, 0.1-ha plots were seeded with one of the three native grass treatments, and each plot was grazed by one Thoroughbred gelding in two grazing bouts, one in July and another in September 2019. IG had the greatest available forage, at 4,340 kg/ha, compared with 3,590 kg/ha from BB (P < 0.0001). EG plots established poorly, and had only 650 kg/ha available forage during the experiment. Grazing reduced standing cover of native grasses in IG and BB treatments by about 30%. Horses lost 0.5-1.5 kg BW/d on all treatments. Findings suggest IG and BB merit further consideration as forages for horses susceptible to obesity and pasture-associated laminitis.

Pharmacokinetics and safety of repeated oral dosing of acetaminophen in adult horses.

BACKGROUND: There are no published studies on the pharmacokinetics of acetaminophen at the dosage used clinically (20 mg/kg), nor has the safety of multiple doses in horses been investigated. OBJECTIVE: Define the pharmacokinetic parameters of oral acetaminophen at 20 mg/kg in adult horses as a single dose, and twice daily for 14 days to assess the safety of multiple dosing. STUDY DESIGN: Pharmacokinetic study, multiple dose safety study. METHODS: Eight healthy Thoroughbred geldings were given acetaminophen (20 mg/kg; 500 mg tablets) orally as a single dose followed by doses every 12 h for 14 days. Serial blood samples were collected for determination of plasma acetaminophen concentrations using high performance liquid chromatography with ultraviolet detection. Serum biochemical analysis, gastroscopy and liver biopsy were examined during the safety study. RESULTS: Following a single dose, mean maximum concentration (Cmax ) was 16.61 µg/mL at 1.35 h (Tmax ), and drug concentration was below the lower limit of detection in most horses by 24 h. Elimination half-life (T1/2 ) was 2.78 h. No significant accumulation was noted following multiple doses. Average Cmax of acetaminophen following multiple oral dosing was 15.85 µg/mL, with a Tmax of 0.99 h and T1/2 of 4 h. Serum activities of sorbitol dehydrogenase were significantly decreased and total bilirubin concentrations were significantly increased following the last dose. No statistically significant changes were noted in gastroscopy scores. MAIN LIMITATIONS: Only one dose level (20 mg/kg) was studied, sample size was small and only a single breed and sex was used, with no pretreatment liver biopsies. CONCLUSION: This study described the pharmacokinetics of acetaminophen following single and multiple 20 mg/kg oral doses in adult horses and demonstrated the safety of acetaminophen with multiple oral dosing over 14 days. The summary is available in Portuguese - see Supporting information.

The amyloid architecture provides a scaffold for enzyme-like catalysts.

Natural biological enzymes possess catalytic sites that are generally surrounded by a large three-dimensional scaffold. However, the proportion of the protein molecule that participates in the catalytic reaction is relatively small. The generation of artificial or miniature enzymes has long been a focus of research because enzyme mimetics can be produced with high activity at low cost. These enzymes aim to mimic the active sites without the additional architecture contributed by the protein chain. Previous work has shown that amyloidogenic peptides are able to self-assemble to create an active site that is capable of binding zinc and catalysing an esterase reaction. Here, we describe the structural characterisation of a set of designed peptides that form an amyloid-like architecture and reveal that their capability to mimic carbonic anhydrase and serve as enzyme-like catalysts is related to their ability to self-assemble. These amyloid fibril structures can bind the metal ion Zn2+via a three-dimensional arrangement of His residues created by the amyloid architecture. Our results suggest that the catalytic efficiency of amyloid-like assembly is not only zinc-dependent but also depends on an active centre created by the peptides which is, in turn, dependent on the ordered architecture. These fibrils have good esterase activity, and they may serve as good models for the evolution of modern-day enzymes. Furthermore, they may be useful in designing self-assembling fibrils for applications as metal ion catalysts. This study also demonstrates that the ligands surrounding the catalytic site affect the affinity of the zinc-binding site to bind the substrate contributing to the enzymatic activity of the assembled peptides.

Representing virus-host interactions and other multi-organism processes in the Gene Ontology.

BACKGROUND: The Gene Ontology project is a collaborative effort to provide descriptions of gene products in a consistent and computable language, and in a species-independent manner. The Gene Ontology is designed to be applicable to all organisms but up to now has been largely under-utilized for prokaryotes and viruses, in part because of a lack of appropriate ontology terms. METHODS: To address this issue, we have developed a set of Gene Ontology classes that are applicable to microbes and their hosts, improving both coverage and quality in this area of the Gene Ontology. Describing microbial and viral gene products brings with it the additional challenge of capturing both the host and the microbe. Recognising this, we have worked closely with annotation groups to test and optimize the GO classes, and we describe here a set of annotation guidelines that allow the controlled description of two interacting organisms. CONCLUSIONS: Building on the microbial resources already in existence such as ViralZone, UniProtKB keywords and MeGO, this project provides an integrated ontology to describe interactions between microbial species and their hosts, with mappings to the external resources above. Housing this information within the freely-accessible Gene Ontology project allows the classes and annotation structure to be utilized by a large community of biologists and users.

Gene Ontology annotations and resources.

The Gene Ontology (GO) Consortium (GOC, http://www.geneontology.org) is a community-based bioinformatics resource that classifies gene product function through the use of structured, controlled vocabularies. Over the past year, the GOC has implemented several processes to increase the quantity, quality and specificity of GO annotations. First, the number of manual, literature-based annotations has grown at an increasing rate. Second, as a result of a new 'phylogenetic annotation' process, manually reviewed, homology-based annotations are becoming available for a broad range of species. Third, the quality of GO annotations has been improved through a streamlined process for, and automated quality checks of, GO annotations deposited by different annotation groups. Fourth, the consistency and correctness of the ontology itself has increased by using automated reasoning tools. Finally, the GO has been expanded not only to cover new areas of biology through focused interaction with experts, but also to capture greater specificity in all areas of the ontology using tools for adding new combinatorial terms. The GOC works closely with other ontology developers to support integrated use of terminologies. The GOC supports its user community through the use of e-mail lists, social media and web-based resources.

Can stormwater harvesting restore pre-development flows in urban catchments in South East Queensland?

Increases in the impervious area due to urbanisation have been shown to have negative impacts on the physical and ecological condition of streams, primarily through increased volume and frequency of runoff. The harvesting and detention of runoff has a potential to decrease this impact. This paper describes the effects of urbanisation on catchment flow and of stormwater harvesting on reducing those adverse impacts on a stream in South East Queensland (SEQ), Australia. A largely undeveloped catchment located southeast of Brisbane city was calibrated and validated using the Stormwater Management Model (SWMM). This model was used to investigate the effect of a range of future increases in urbanisation (represented by impervious area) on stream hydrology as well as the potential of stormwater harvesting to return the catchments to predevelopment flow conditions. Stormwater harvesting was modelled according to flow frequency measures specified in current SEQ development guidelines. These guidelines stipulate the capture of the first 10 mm of runoff from impervious areas of 0-40% and the first 15 mm from impervious areas of 40% or greater for urban developments. We found that increases in the impervious area resulted in increases in the mean, frequency and duration of high flows, and an increase in the mean rate of rise and fall for storm events in the catchment. However, the predevelopment (non-urbanised) flow distribution was very flashy in comparison with all urbanised scenarios; i.e. it had the quickest response to rainfall indicated by a high rate of rise to and fall from peak flow volume, followed by a return to zero flow conditions. Capturing the runoff according to the development guidelines resulted in a reduction in flow towards the flow distribution of a lower impervious area, however this was insufficient to meet predevelopment conditions. This suggests a stronger influence of impervious areas in this catchment on the volume of runoff than flow frequency measures are able to ameliorate.

Restoration of spinal alignment and disk mechanics following polyetheretherketone wafer kyphoplasty with StaXx FX.

BACKGROUND AND PURPOSE: EPFs sustained during VCFs degrade the disk's ability to develop IDP under load. This inability to develop pressure in combination with residual kyphotic deformity increases the risk for adjacent vertebral fractures. We tested the hypothesis that StaXx FX reduces kyphosis and endplate deformity following vertebral compression fracture, restoring disk mechanics. MATERIALS AND METHODS: Eight thoracolumbar, 5-vertebrae segments were tested. A void was selectively created in the middle vertebra. The specimens were compressed until EPF and to a grade I-II VCF. PEEK wafer kyphoplasty was then performed. The specimens were then tested in flexion-extension (±6 Nm) under 400-N preload intact, after EPF, VCF, and kyphoplasty. Endplate deformity, kyphosis, and IDP adjacent to the fractured body were measured. RESULTS: Vertebral body height at the point of maximal endplate deformity decreased after EPF and VCF and was partially corrected after StaXx FX, remaining less than intact (P = .047). Anterior vertebral height decreased after VCF (P = .002) and was partially restored with StaXx FX, remaining less than intact (P = .015). Vertebral kyphosis increased after VCF (P < .001) and reduced after StaXx FX, remaining greater than intact (P = .03). EPF reduced IDP in the affected disk in compression-flexion loading (P < .001), which was restored after StaXx FX (P = 1.0). IDP in the unaffected disk did not change during testing (P > .3). CONCLUSIONS: StaXx FX reduced endplate deformity and kyphosis, and significantly increased anterior height following VCF. Although height and kyphosis were not fully corrected, the disk's ability to pressurize under load was restored.

The influence of supply and sewerage area characteristics on water and sewerage companies responses to the Water Framework Directive.

Using the example of raw water quality this paper examines the relationship between different spatial characteristics (geographical and physical properties) of Water and Sewerage Companies (WaSCs) supply and sewage areas and response to the Water Framework Directive. Results were obtained from thematic analysis and content analysis of 14 interviews with WaSCs representatives. Principal component analysis and cluster analysis of 51 WaSCs business function characteristics was employed to derive groups of similar WaSCs. Results indicate that there is difference in how WaSCs approach raw water quality issues. It appears that small WaSCs with relatively large agricultural areas in their supply catchments are more likely to seek managerial solutions to raw water quality problems.

Physical characterization and performance comparison of active- and passive-pixel CMOS detectors for mammography.

We investigated the physical characteristics of two complementary metal oxide semiconductor (CMOS) mammography detectors. The detectors featured 14-bit image acquisition, 50 microm detector element (del) size and an active area of 5 cm x 5 cm. One detector was a passive-pixel sensor (PPS) with signal amplification performed by an array of amplifiers connected to dels via data lines. The other detector was an active-pixel sensor (APS) with signal amplification performed at each del. Passive-pixel designs have higher read noise due to data line capacitance, and the APS represents an attempt to improve the noise performance of this technology. We evaluated the detectors' resolution by measuring the modulation transfer function (MTF) using a tilted edge. We measured the noise power spectra (NPS) and detective quantum efficiencies (DQE) using mammographic beam conditions specified by the IEC 62220-1-2 standard. Our measurements showed the APS to have much higher gain, slightly higher MTF, and higher NPS. The MTF of both sensors approached 10% near the Nyquist limit. DQE values near dc frequency were in the range of 55-67%, with the APS sensor DQE lower than the PPS DQE for all frequencies. Our results show that lower read noise specifications in this case do not translate into gains in the imaging performance of the sensor. We postulate that the lower fill factor of the APS is a possible cause for this result.

Agonist-dependent cannabinoid receptor signalling in human trabecular meshwork cells.

BACKGROUND AND PURPOSE: Trabecular meshwork (TM) is an ocular tissue involved in the regulation of aqueous humour outflow and intraocular pressure (IOP). CB1 receptors (CB1) are present in TM and cannabinoid administration decreases IOP. CB1 signalling was investigated in a cell line derived from human TM (hTM). EXPERIMENTAL APPROACH: CB1 signalling was investigated using ratiometric Ca2+ imaging, western blotting and infrared In-Cell Western analysis. KEY RESULTS: WIN55212-2, a synthetic aminoalkylindole cannabinoid receptor agonist (10-100 microM) increased intracellular Ca2+ in hTM cells. WIN55,212-2-mediated Ca2+ increases were blocked by AM251, a CB1 antagonist, but were unaffected by the CB2 antagonist, AM630. The WIN55,212-2-mediated increase in [Ca2+]i was pertussis toxin (PTX)-insensitive, therefore, independent of Gi/o coupling, but was attenuated by a dominant negative Galpha(q/11) subunit, implicating a Gq/11 signalling pathway. The increase in [Ca2+]i was dependent upon PLC activation and mobilization of intracellular Ca2+ stores. A PTX-sensitive increase in extracellular signal-regulated kinase (ERK1/2) phosphorylation was also observed in response to WIN55,212-2, indicative of a Gi/o signalling pathway. CB1-Gq/11 coupling to activate PLC-dependent increases in Ca2+ appeared to be specific to WIN55,212-2 and were not observed with other CB1 agonists, including CP55,940 and methanandamide. CP55940 produced PTX-sensitive increases in [Ca2+]i at concentrations>or=15 microM, and PTX-sensitive increases in ERK1/2 phosphorylation. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that endogenous CB1 couples to both Gq/11 and Gi/o in hTM cells in an agonist-dependent manner. Cannabinoid activation of multiple CB1 signalling pathways in TM tissue could lead to differential changes in aqueous humour outflow and IOP.

Person-centred planning: factors associated with successful outcomes for people with intellectual disabilities.

BACKGROUND: Recent research in the USA and UK indicates that person-centred planning (PCP) can lead to improvements in lifestyle-related outcomes for people with intellectual disabilities (ID). It is clear, however, that the introduction of PCP does not have an equal impact for all participants. The aim of the present paper was to identify factors associated with the probability of delivering a plan and with improvements in outcomes for those who did receive a plan. METHODS: Information on the life experiences of participants was collected over a period of approximately 2 years for a cohort of 93 adults with ID. RESULTS: There were powerful inequalities in both access to and the efficacy of PCP in relation to participant characteristics, contextual factors and elements of the PCP process. CONCLUSIONS: Results are discussed in relation to implications for policy and practice for increasing the effectiveness of PCP and reducing inequalities in the life experiences of people with ID.

Strategic options for sustainable water management at new developments: the application of a simulation model to explore potential water savings.

Research on appropriate technologies and infrastructures to support water reuse has progressed rapidly over recent decades and there are now a wide range of source--treatment--reuse options for planners to choose from. Although the economics of water reuse schemes favours application to new developments rather than retrofit projects, there are few studies which have sought to address strategic option selection issues for large developments. The potential advantages of using treatment and reuse systems in new developments require an understanding of the relationships between a wide variety of social, environmental, technological, and operational factors. The operational effectiveness and economic efficiency of specific technology choices will vary as a function of network configuration, wastewater characteristics, how different technologies respond to dynamic loading (variability of feed strength and flow) and potential spiking, as well as equipment reliability, climate and household behaviour. Using a commercially available software package, the study reports the design and implementation of a low resolution simulation tool to explore sustainable water management options for a live case study site in the south of England (a peri-urban development of 4,500 new homes) with particular reference to opportunities for rainwater harvesting, and water reuse.

Cardiac rehabilitation for community-based patients with myocardial infarction: factors predicting discharge recommendation and participation.

Although there is substantial evidence that cardiac rehabilitation is beneficial for post myocardial infarction (MI) patients, such programs are currently under utilized. This study examined systematic criteria predicting physician referral to and patients' participation in cardiac rehabilitation programs. Patients discharged for MI were interviewed in-hospital and at 6-12 weeks post discharge to determine referral, participation, and completion. Stepwise logistic regression analyzed factors associated with rehabilitation. Factors associated with referral to rehab were catheterization (p < 0.001), bypass surgery (p < 0.01), cardiologist/cardiac surgeon appointment (p < 0.02), and age (p < 0.01). Participation was increased for those with bypass surgery (p < 0.001), and referral to cardiologist or cardiac surgeon (p < 0.001). Type of provider significantly influences referral to and participation in cardiac rehabilitation. This suggests that encouragement plays a strong role in attendance for rehabilitation. The same strong encouragement should be given to the broader range of MI patients who stand to benefit from cardiac rehabilitation.

How government policy decisions affect seniors' quality of life: findings from a participatory policy study carried out in Toronto, Canada.

Toronto seniors explored how government policy decisions were influencing their health and well-being. In this participatory policy study, emphasis was upon the lay and critical knowledge of highly informed seniors. Focus groups and interviews revealed that all three levels of governments were seen as not listening to seniors' voices. In nine key policy areas identified as influencing seniors' quality of life--hearing seniors' voices, housing, acute illness care, long-term care, income supports, transportation and mobility, promoting healthy lifestyles, access to information, and hearing voices from cultural communities--many concerns were raised. The gap between government rhetoric and government action on seniors' issues merits public health attention.

Do race and gender influence the use of invasive procedures?

OBJECTIVE: To assess the influence of race and gender influence on the use of invasive procedures in patients with acute myocardial infarction (AMI) in community hospitals. DESIGN: Prospective, observational. SETTING: Five mid-Michigan community hospitals. PATIENTS: All patients (838) identified with AMI between January 1994 and April 1995 in 1 of these hospitals. MEASUREMENTS AND MAIN RESULTS: After adjusting for age, hospital of admission, insurance type, severity of AMI, and comorbidity, using white men as the reference group, the rate of being offered cardiac catheterization (CC) was 0.88 (95% confidence interval [95% CI], 0.60 to 1.29) for white women; 0.79 (95% CI, 0.41 to 1.50) for black men; and 1.14 (95% CI, 0.53 to 2.45)for black women. Among patients who underwent CC, after also adjusting for coronary artery anatomy, the rate of being offered angioplasty, using white men as the reference group, was 1.22 (95% CI, 0.75 to 1.98) for white women; 0.61 (5% CI, 0.29 to 1.28, P =.192) for black men; and 0.40 (95% CI, 0.14 to 1.13) for black women The adjusted rate of being offered bypass surgery was 0.47 (95% CI, 0.24 to 0.89) for white women; 0.36 (95% CI, 0.12 to 1.06) for black men; and 0.37 (95% CI, 0.11 to 1.28)for black women. CONCLUSIONS: Our study shows that white women are less likely than white men to be offered bypass surgery after AMI. Although black men and women with AMI are less likely than white men to be offered percutaneous transluminal coronary angioplasty or coronary artery bypass grafting in both unadjusted and adjusted analyses, these findings did not reach statistical significance. Our study is limited in power due to the small number of blacks in the sample.

Cloning and characterization of a novel human histone deacetylase, HDAC8.

Histone deacetylases (HDACs) are a growing family of enzymes implicated in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. HDACs are known to have key roles in the regulation of cell proliferation [Brehm, Miska, McCance, Reid, Bannister and Kouzarides (1998) Nature (London) 391, 597-600], and aberrant recruitment of an HDAC complex has been shown to be a key step in the mechanism of cell transformation in acute promyelocytic leukaemia [Grignani, De Matteis, Nervi, Tomassoni, Gelmetti, Cioce, Fanelli, Ruthardt, Ferrara, Zamir et al. (1998) Nature (London) 391, 815-818; Lin, Nagy, Inoue, Shao, Miller and Evans (1998), Nature (London) 391, 811-814]. Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs. The predicted 377-residue HDAC8 product contains a shorter C-terminal extension relative to other members of its class. After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhibitable HDAC activity on histone H4 peptide substrates as well as on core histones. Expression profiling reveals the expression of HDAC8 to various degrees in every tissue tested and also in several tumour lines. Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity. Finally, linkage analysis after radiation hybrid mapping has localized HDAC8 to chromosomal position Xq21.2-Xq21.3. These results confirm HDAC8 as a new member of the HDAC family.

The use of angiotensin-converting enzyme inhibitors in patients with acute myocardial infarction in community hospitals. Michigan State University Inter-Institutional Collaborative Heart (MICH) Study Group.

BACKGROUND: Previous studies documenting underutilization of angiotensin-converting enzyme inhibitors (ACEIs) in acute myocardial infarction (AMI) have been limited to Medicare populations. HYPOTHESIS: This study examines ACEI prescription rates and predictors in a community sample of hospitalized patients with AMI. METHODS: The charts of 1163 community patients with AMI, prospectively identified at admission between January 1, 1994, and April 30, 1995, were reviewed. RESULTS: Only 64 of 158 (40%) patients considered ideal candidates for ACEI prescription were discharged with a prescription for an ACEI. In a multivariate logistic regression model, prior ACEI utilization [adjusted odds ration (OR) = 3.26; 95% confidence interval (CI) = 2.05-5.20], presence of congestive heart failure (OR = 2.33; CI = 1.50-3.61) and black race (OR = 2.20; CI = 1.34-3.64) were identified as positive predictors of ACEI prescription. Conversely, lack of left ventricular ejection fraction (LVEF) measurement (OR = 0.46; CI = 0.28-0.75), LVEF > 40 ( OR = 0.27; CI = 0.18-0.40), and acute renal failure (OR = 0.08; CI = 0.01-0.44) were negative predictors. Women were also less likely to be discharged with an ACEI prescription (OR = 0.71; CI = 0.48-1.05). Furthermore, women were significantly less likely to have LVEF measured prior to discharge than were males (77 vs. 85%, p = 0.001). CONCLUSION: This study underscores the need for improvement in the utilization of ACEI in eligible patients with AMI. It also identifies opportunities for improvement in prescription rates, especially in women.

Initiation of protein synthesis with fluorophore-Met-tRNA(f) and the involvement of IF-2.

The complicity of initiation factor 2 (IF-2) in causing the observed low incorporation of N-terminal fluorophore from fluorophore-methionyl-tRNA(f) during protein synthesis in an in vitro coupled transcription/translation system was investigated. The low incorporation in comparison to formyl-methionine was not due to the lack of interaction of fluorophore-Met-tRNA(f) with IF-2. Fluorescence measurements of cascade yellow-, eosin-, pyrene-, or coumarin-Met-tRNA(f) determined that all were capable of binding IF-2 at 4 mM Mg(2+) and 37 degrees C. Filter binding assays conducted in the absence of magnesium ions on fMet-tRNA(f), eosin-Met-tRNA(f), and cascade yellow-Met-tRNA(f) confirmed the previously reported value for the dissociation constant of fMet-tRNA(f) of about 1 microM and placed the binding constants for the two fluorophore derivatives about three-fold higher. Binding of the fluorophore-Met-tRNA(f) species to salt-washed ribosomes showed a more significant decrease compared to fMet-tRNA(f). Stimulation in the amount of tRNA bound to the ribosomes upon the addition of IF-2 was observed in each case. All ribosome-bound cascade yellow-Met-tRNA(f) and eosin-Met-tRNA(f) were as puromycin-reactive as fMet-tRNA(f). Cumulatively, the effects observed for the fluorophore-Met-tRNA species in partial reactions of initiation may account for the reduced incorporation of these probes at the N terminus of polypeptides.

The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2, and bcl-x genes through the trans-activation domain of Stat5.

Studies assessing the role of Stat5 in the IL-2 proliferative signal have produced contradictory, and thus inconclusive, results. One factor confounding many of these studies is the ability of IL-2R to deliver redundant mitogenic signals from different cytoplasmic tyrosines on the IL-2R beta-chain (IL-2Rbeta). Therefore, to assess the role of Stat5 in mitogenic signaling independent of any redundant signals, all cytoplasmic tyrosines were deleted from IL-2Rbeta except for Tyr510, the most potent Stat5-activating site. This deletion mutant retained the ability to induce Stat5 activation and proliferation in the T cell line CTLL-2 and the pro-B cell line BA/F3. A set of point mutations at or near Tyr510 that variably compromised Stat5 activation also compromised the proliferative signal and revealed a quantitative correlation between the magnitude of Stat5 activation and proliferation. Proliferative signaling by a receptor mutant with a weak Stat5 activating site could be rescued by overexpression of wt Stat5a or b. Additionally, the ability of this receptor mutant to induce c-myc, bcl-x, and bcl-2 was enhanced by overexpression of wt Stat5. By contrast, overexpression of a version of Stat5a lacking the C-terminal trans-activation domain inhibited the induction of these genes and cell proliferation. Thus, Stat5 is a critical component of the proliferative signal from Tyr510 of the IL-2R and regulates expression of both mitogenic and survival genes through its trans-activation domain.

Surgical decompression of ductal obstruction in patients with chronic pancreatitis.

BACKGROUND: Recurrent acute pancreatitis often leads to chronic obstructive ductal disease requiring operative decompression. METHODS: From 1983 through 1998, 124 patients with ductal obstruction underwent lateral pancreaticojejunostomy (78 patients), distal pancreatectomy with end-to-side pancreaticojejunostomy (27 patients), distal pancreatectomy with placement of a pancreas with a filleted duct within a jejunal limb (15 patients), or pancreaticoduodenectomy (4 patients). Preoperative symptoms included abdominal and back pain (99%), nausea with vomiting (99%), and diarrhea with weight loss (11%). Associated conditions included hypertension (20%) and diabetes mellitus (12%). Endoscopy in 106 patients demonstrated distal stricture (37%), proximal stricture (36%), pseudocyst (30%), chain of lakes (15%), calcification and debris (19%), and bile duct stricture (8%). RESULTS: Two patients died, one of an unrecognized esophageal perforation during intubation and the other of leakage of a 1-layer pancreaticojejunostomy. Thirty-six patients developed 53 complications including intra-abdominal abscess (7 patients) and bleeding requiring reoperation in 1 patient. Pain relief was complete in 61 patients, substantial in 39 patients, moderate in 11 patients, minimal in 8 patients, and nonexistent in 3 patients with multiple stones and narrow duct. Ten patients died, with 6 deaths as a result of pancreatic cancer Two other patients may have died of pancreatic cancer. CONCLUSIONS: Lateral pancreaticojejunostomy is the procedure of choice in most patients. Recurrent pancreatitis usually follows alcoholic binges. Long-term follow-up must assess for pancreatic cancer.