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Ever since the world entered the age of information, scientists have looked into the developments and applications of the growing prospects of machine learning and neural networks. In particular, the ability for deep learning machines to determine the risk, survivability, and prognosis of tumors based on medical cancer databases has intrigued healthcare researchers seeking to improve these algorithms in recent years. There are distinct aspects of medical procedures where artificial intelligence (AI) training can be applied; for example, the calculation of risk scores for patients based on mammographic screening, analysis of the presence of biomarkers like spermine and other polyamines in fluids surrounding tumors, genomic and epigenetic assessments to map genes that influence cancer expression, as well as the utilization of metabolomic data from FTIR spectroscopy of a patient’s biofluids to help make a more reproducible and conclusive diagnosis. The goal of this review is to discuss the progress of AI and deep learning in clinical procedures and applications in recent years and evaluate the efficacy of certain AI methods for tumor diagnosis, prognosis, and prediction based on patient information from available medical databases.

Antimicrobial resistance (AMR) has become an urgent public health issue, as pathogens are becoming increasingly resistant to commonly used antimicrobials. While AMR isolate data are available in the NCBI Pathogen Detection Isolates Browser (NPDIB) database, few researches have been performed to compare antimicrobial resistance detected in environmental and clinical isolates. To address this, this work conducted the first multivariate statistical analysis of antimicrobial-resistance pathogens detected in NPDIB clinical and environmental isolates for the US from 2013 to 2018. The highly occurring AMR genes and pathogens were identified for both clinical and environmental settings, and the historical profiles of those genes and pathogens were then compared for the two settings. It was found that Salmonella enterica and E. coli and Shigella were the highly occurring AMR pathogens for both settings. Additionally, the genes fosA, oqxB, ble, floR, fosA7, mcr-9.1, aadA1, aadA2, ant(2”)-Ia, aph(3”)-Ib, aph(3’)-Ia, aph(6)-Id, blaTEM-1, qacEdelta1, sul1, sul2, tet(A), and tet(B) were mostly detected for both clinical and environmental settings. Ampicillin, ceftriaxone, gentamicin, tetracycline, and cefoxitin were the antimicrobials which got the most resistance in both settings. The historical profiles of these genes, pathogens, and antimicrobials indicated that higher occurrence frequencies generally took place earlier in the environmental setting than in the clinical setting.

Background: This study aims to rigorously compare the effectiveness of the educational programs of a new integrated clinical clerkship in medicine (3 months) and surgery (3 months) at a cancer center with the conventional subspecialty-based rotations at a tertiary teaching hospital, by this prospective, pre-post comparative method. Methods: Between 2013–2016, we compared 69 students who had selected the integrated clerkship that emphasized clinical competency and medical humanities training with 138 matched peers who had completed conventional clerkships during the same period. Outcome measures for medical humanities included empathy, patient-centeredness, and other values and skills related to holistic health care professionalism by introducing prospective propensity score matching (PSM). Results: At baseline, no significant between-group differences existed. At the completion of the core clerkships, students receiving the integrative clerkship had significantly higher scores on the Patient–Practitioner Orientation Scale (PPOS) and the Professionalism Climate in Clinical Teaching Environment (PCI), and similar Jefferson Scale of Physician Empathy Student Version (JSPE) scores, as compared with the comparison group. We also found that the students in this program did not perform worse than those in the traditional internship group in the comprehensive and formative OSCE medical clinical skills test. Conclusions: Our study develops an empirical basis for rigorous evaluation to design medical education to improve the medical humanities values and skills of interns. Features of the new integrated clerkship program that we developed include substantial participation by the students in patient-centered in-hospital culture, as well as reflection, discussion, and feedback on actual clinical cases.

Premature ovarian failure (POF) is a typical form of pathological aging with complex pathogenesis and no effective treatment. Meanwhile, recent studies have reported that a high-fat and high-sugar (HFHS) diet adversely affects ovarian function and ovum quality. Here, we investigated the therapeutic effect of thymopentin (TP-5) as a treatment for murine POF derived from HFHS and its target. Pathological examination and hormone assays confirmed that TP-5 significantly improved murine POF symptoms. And, TP-5 could reduce oxidative stress injury and blood lipids in the murine POF derived from HFHS. Flow cytometry and qPCR results suggested that TP-5 attenuated activation of CD3+ T cells and type I macrophages. RNA-Seq results indicated somedifferences in gene transcription between the TP-5 intervention group and the control group. KEGG analysis indicated that the expression of genes involved in the mTOR signaling pathway was the most significantly different between the two groups. Additionally, compared with the control groups, the expression levels of interleukin, NFκB, and TNF families of genes were significantly downregulated in the POF+TP-5 group, whereas expression of the TGFβ/Smad9 genes was significantly upregulated. Finally, immunofluorescence staining and qPCR confirmed that TP-5 promoted the polarization of Mo2 cells in the ovary by activating the expression of the BMP4/Smad9 signalling pathway. Thus, our study confirmed that TP-5 has a significant therapeutic effect on POF by upregulating BMP4/Smad9 signalling pathway so as to promote the balance and polarization of immune cell and reducing the release of inflammatory factors and reduce lipid oxidative stress injury.

The use of magnetic resonance imaging (MRI) in healthcare and the emergence of radiology as a practice are both relatively new compared with the classical specialties in medicine. Having its naissance in the 1970s and later adoption in the 1980s, the use of MRI has grown exponentially, consequently engendering exciting new areas of research. One such development is the use of computational techniques to analyze MRI images much like the way a radiologist would. With the advent of affordable, powerful computing hardware and parallel developments in computer vision, MRI image analysis has also witnessed unprecedented growth. Due to the interdisciplinary and complex nature of this subfield, it is important to survey the current landscape and examine the current approaches for analysis and trend trends moving forward.

Macrolide-streptogramin type B resistance (the MSB phenotype) is a multidrug resistance phenotype in Staphylococcus aureus conferred by the resistance gene msrA. However, bacteria having the MSB phenotype are susceptible to lincosamides and 16-membered ring macrolides, which makes profiling resistance genes necessary and urgent for timely and appropriate use of antimicrobials. In this study, the loop-mediated isothermal amplification (LAMP) assay was optimized for prompt detection of the msrA gene. msrA gene sequences were obtained from the National Center for Biotechnology Information (NCBI) database and primers were designed using the LAMP primer designing software PrimerExplorer v.4, which together recognize seven distinct regions of the msrA gene. The specific LAMP primer set designed in this study could amplify the msrA gene within 25min at an isothermal temperature of 62°C. More importantly, the msrA gene could be detected at a sensitivity as low as 100pg. Furthermore, this optimized LAMP assay provided swift detection of the msrA gene even directly from human specimens. In conclusion, this assay may have great clinical application potential for detection of the msrA gene.

Background: Emergency Department (ED) crowding has been proven to lead to longer length of stay (LOS) minutes per patient’s arrival. Within AHMC HealthSystem (AHMC) in Fiscal Year (FY) 2016, all facilities experienced a 6.3% census increase from 181,818 in FY 2015 to 193,215. The need for increased efficiency and effectiveness in meeting increased demand was recognized by health system and emergency department leadership. Objective: AHMC implemented an ED initiative task force of 5 goals for all facilities to follow and achieve by the end of Fiscal Year 2016. Methods: This initiative required all facilitiesʼ EDs to achieve door to doctor time 70%. AHMC utilized prospective improvement process tools such as LEAN, monthly site visits, best practice and quality meetings, and social media reviews. AHMC implemented an internal centralized online data collection tool through all facilities and AHMC corporate with the ability to track Centers for Medicare and Medicaid Services (CMS) mandated metrics. Results: By the end of FY 2016, AHMC hospitals reduced their LOS from over 200 minutes to 180 minutes, LWBS rates decreased from 3-5% to less than 1%, door to doctor times decreased to an average of 31 minutes, and EDPEC satisfaction scores increased from 44% to 50%. Conclusion: AHMC’s EDsʼ significant improvement demonstrated the strong potential of replicating their efforts on improving patient experience and quality measures to other departments and community hospitals.

BackgroundGenome-wide association studies (GWAS) have identified 25 risk variants for glioma, which explain ~30% of heritable risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis ide7ntified sex-specific glioma risk variants, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex.MethodsResults from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for autosomal SNPs found to be nominally significant (p−6in ⅔ algorithms.Results25 genes within five regions and 19 genes within six regions reached the set significance threshold in at least 2/3 algorithms in males and females, respectively.EGFRandRTEL1-TNFRSF6Bwere significantly associated with all glioma and glioblastoma in males only, and a female-specific association inTERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Telomeres, Telomerase, Cellular Aging, and Immortality pathway in both males and females.ConclusionsThese results suggest that there may be biologically relevant significant differences by sex in genetic risk for glioma. Additional gene- and pathway-based analyses may further elucidate the biological processes through which this risk is conferred.

We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of bladder cancer during surveillance.Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and randomization to blue light flexible cystoscopy. All suspicious lesions were documented. Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy. All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel. The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy. Additional end points were the false-positive rate, carcinoma in situ detection and additional tumors detected only with blue light cystoscopy.Following surveillance 103 of the 304 patients were referred, including 63 with confirmed malignancy, of whom 26 had carcinoma in situ. In 13 of the 63 patients (20.6%, 95% CI 11.5-32.7) recurrence was seen only with blue light flexible cystoscopy (p0.0001). Five of these cases were confirmed as carcinoma in situ. Operating room examination confirmed carcinoma in situ in 26 of 63 patients (41%), which was detected only with blue light cystoscopy in 9 of the 26 (34.6%, 95% CI 17.2-55.7, p0.0001). Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients (46%). The false-positive rate was 9.1% for white and blue light cystoscopy. None of the 12 adverse events during surveillance were serious.Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer and it is safe when used for surveillance. Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy.

Genome-wide association studies (GWAS) have identified 26 risk variants for glioma, and these explain ~27% and ~34% of heritability for glioblastoma and lower grade glioma, respectively. Genetic risk for these tumors is likely polygenic; gene- and pathway-based analyses may increase power to detect new sources of genetic risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis has identified glioma risk variants that differ by sex, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex. Sex-specific summary statistics from the Glioma International Case-Control Study were used as a discovery set. Data from three prior glioma GWAS were used for validation. For both the discovery and validation datasets, summary statistics where generated using sex-stratified logistic regression models to estimate betas, standard errors, and p values for the autosomal chromosomes. Pascal was used to estimate gene- and pathway-based scores corrected for linkage disequilibrium structure, and empirical p values were calculated for glioma overall in both datasets. 12,711 genes contained ≥10 SNPs, and results were considered significant at 1.9x10-6 (Bonferroni correction 0.05/(12,711 genes * 2 for each sex)). 14 genes were significantly associated with all glioma in males, and 8 genes in females. EGFR was significantly associated with glioma in males only (Males: pdiscovery=5.31x10-9 pvalidation=0.0025; Females: pdiscovery=0.01, pvalidation=0.1299). Statistics were calculated for 217 pathways (defined by Biocarta), and considered significant at p

Brain injury in the premature infant is associated with a high risk of neurodevelopmental disability. Previous small-animal models of brain injury attributable to extreme prematurity typically fail to generate a spectrum of pathology and behavior that closely resembles that observed in humans, although they provide initial answers to numerous cellular, molecular, and therapeutic questions. We tested the hypothesis that exposure of rats to repeated hypoxia from postnatal day 1 (P1) to P3 models the characteristic white matter neuropathological injury, gray matter volume loss, and memory deficits seen in children born extremely prematurely. Male Sprague Dawley rats were exposed to repeated hypoxia or repeated normoxia from P1 to P3. The absolute number of pre-oligodendrocytes and mature oligodendrocytes, the surface area and g-ratio of myelin, the absolute volume of cerebral white and gray matter, and the absolute number of cerebral neurons were quantified stereologically. Spatial memory was investigated on a radial arm maze. Rats exposed to repeated hypoxia had a significant loss of (1) pre-oligodendrocytes at P4, (2) cerebral white matter volume and myelin at P14, (3) cerebral cortical and striatal gray matter volume without neuronal loss at P14, and (4) cerebral myelin and memory deficits in adulthood. Decreased myelin was correlated with increased attention deficit hyperactivity disorder-like hyperactivity. This new small-animal model of extreme prematurity generates a spectrum of short- and long-term pathology and behavior that closely resembles that observed in humans. This new rat model provides a clinically relevant tool to investigate numerous cellular, molecular, and therapeutic questions on brain injury attributable to extreme prematurity.

To establish whether there is superiority between contrast-induced acute kidney injury and contrast-induced nephropathy criteria as predictors of unfavorable clinical outcomes.Retrospective study carried out in a tertiary hospital with 157 patients undergoing radiocontrast infusion for propaedeutic purposes.One hundred forty patients fulfilled the inclusion criteria: patients who met the criteria for contrast-induced acute kidney injury (59) also met the criteria for contrast-induced nephropathy (76), 44.3% met the criteria for KDIGO staging, 6.4% of the patients required renal replacement therapy, and 10.7% died.The diagnosis of contrast-induced nephropathy was the most sensitive criterion for renal replacement therapy and death, whereas KDIGO showed the highest specificity; there was no correlation between contrast volume and progression to contrast-induced acute kidney injury, contrast-induced nephropathy, support dialysis or death in the assessed population.Estabelecer se há superioridade entre os critérios para predizer desfecho clínico desfavorável na lesão renal aguda e nefropatia induzidas por contraste.Estudo retrospectivo conduzido em hospital terciário com 157 pacientes submetidos à infusão de contraste radiológico para fins propedêuticos.Cumpriram os critérios para inclusão 147 pacientes. Aqueles que cumpriram os critérios de lesão renal aguda induzida por contraste (59) também cumpriram os critérios para nefropatia induzida por contraste (76); 44,3% dos pacientes cumpriram os critérios para o estadiamento pelo sistema KDIGO; 6,4% dos pacientes necessitaram utilizar terapia de substituição renal, e 10,7% dos pacientes morreram.O diagnóstico de nefropatia induzida por contraste foi o critério mais sensível para determinar a necessidade de terapia de substituição renal e óbito, enquanto o KDIGO demonstrou a maior especificidade; na população avaliada, não houve correlação entre o volume de contraste e a progressão para lesão renal induzida por contraste, nefropatia induzida por contraste, diálise de suporte ou óbito.

BACKGROUND: Premature ovarian failure (POF) is a typical condition of pathological ovarian ageing. Injuries and atrophies of blood vessels in the ovaries can lead to ovarian insufficiency, but the underlying mechanism remains unclear. AIMS: This study investigated the epigenetic mechanism by which thymopentin (TP-5) activated ovarian angiogenesis to achieve its effects on POF. MATERIALS AND METHODS: The qPCR, western blot and immunofluorescence staining were used to detecte the expression levels of gene. The hematoxylin and eosin stainingwas used to histopathological examination. The RNA-Seq sequencing was used to transcriptome detection. RESULTS: First, pathological examination revealed that TP-5 significantly increased ovary weight in the cyclophosphamide-induced POF mouse model. The proportion of atretic follicles was reduced, and the level of E2 in the peripheral blood was elevated. Meanwhile, immunofluorescence staining showed that TP-5 increased protein expression of CD31 and Tie1 in the ovarian tissues of mice with POF, suggesting that TP-5 could induce ovarian angiogenesis. RNA-Seq sequencing results suggested that TP-5 could induce the high level of Notch/Tie2 pathway expression that is associated with angiogenesis in ovarian tissues. qPCR and western blotting showed significantly increased expression of METTL3, a methyltransferase that catalyses the formation of N6-methyladenosine (m6A) in RNA. Meanwhile, the results of the dot blot suggested that the overall RNA methylation level was significantly higher in the ovarian tissues of mice in the TP-5 group than in the control group. Finally, RIP-PCR analysis showed that specific sites in the 3'-untranslated region (3'UTR) of the mRNA of key factors in the Notch/Tie2 pathway were hypermethylated in the ovaries of mice in the TP-5 treatment group. CONCLUSION: Therefore, this study demonstrated that TP-5 exerted its therapeutic effect on POF by stimulating angiogenesis. The mechanism of action is the promotion of the expression of RNA m6A methyltransferases by TP5, which increases the overall RNA m6A methylation level in mouse ovarian tissue. Specifically, the methylation ofspecific m6A sites in the 3'UTR of the RNA of key factors in the Notch/Tie2 pathway increased, which enhanced their stability and expression levels, leading to the induction of angiogenesis.

Objective To assess the efficacy of pegloticase in achieving and maintaining plasma urate levels of

Pegloticase is designed to convert urate into the easily excretable allantoin to treat hyperuricemia in gout. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4- and 8-mg doses or every 4 weeks at 8- or 12-mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and covariates were investigated (age, gender, race, body weight, ideal body weight, and antibody response). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1-compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (E(max)) function. Pegloticase suppressed uric acid levels up to 83%. Weight only affected clearance and volume of distribution. No covariates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2-hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.

The ability of high-density lipoprotein (HDL) to promote cholesterol efflux is an important component of its ability to protect against cardiovascular disease. In addition, the anti-inflammatory properties of HDL are important as well. As part of the innate immune system, HDL appears to have evolved to increase inflammation in the presence of an acute phase response but to inhibit inflammation in the absence of an acute phase response. In a study of humans with coronary heart disease, it was found that the patients who had proinflammatory HDL prior to statin therapy (and half of them despite a profound decrease in plasma lipids following statin therapy) continued to have proinflammatory HDL. Anti-inflammatory HDL was effective in promoting cholesterol efflux whereas proinflammatory HDL was relatively weak in its ability to promote cholesterol efflux. Oxidative alterations of the main protein of HDL, apolipoprotein A-I, impaired its capacity to promote cholesterol efflux from monocyte macrophages. Therefore, HDL composition, structure, and function appear to be more crucial than HDL cholesterol concentrations in determining risk for cardiovascular disorders.

Expression levels of the purinergic P2X receptor subunits (P2X(1) to P2X(7)) and P2Y(2) were examined in the endothelial cell layer of internal mammary artery (Ann. Thorac. Surg. 54 (1992) 652), radial artery (Ann. Thorac. Surg. 16 (1973) 111) and saphenous vein (Ann. Thorac. Surg. 20 (1975) 628) samples obtained at surgery for coronary artery bypass grafts using immunohistochemistry and confocal microscopy. Similar levels of P2X(1), P2X(2), P2X(3), P2X(7) and P2Y(2) were found in the endothelial cells in all vessels examined while the levels of P2X(5) and P2X(6) were uniformly lower. A clear difference was measured in P2X(4) expression between arteries and veins. Both radial and internal mammary arteries exhibited very low levels of P2X(4) whereas the level in the saphenous vein was 14.6 fold higher (P

The conformations of isolated rabbit fast myosin light chains (LCs) were modified using trifluoperazine (TFP), the hydrophobic calmodulin inhibitor. CD spectroscopy showed that TFP altered secondary structural content of the LCs, with half-maximal effects at TFP concentrations of approximately 14-50 microM, which is within the range required to alter muscle fiber contraction in both agonistic and antagonistic ways [Kurebayashi, N. & Ogawa, Y. (1988) J. Physiol. 403, 407-424]. EPR spectroscopy provided structural information from paramagnetic probes on C-terminal domain surfaces. In the absence of TFP, tauR (rotational correlation time) was 1.6 ns for both alkali light chains (ALCs) and 1.8 ns for light chain 2 (LC2). This was faster than expected for proteins of this size (approximately 10 ns). TFP progressively recruited the probes into populations with tauR sevenfold to 12-fold slower, with half-maximal effects at a TFP concentration of approximately 370-800 microM. The differences probably indicate that CD spectroscopy detects changes in protein conformation due to 'specific' TFP binding at the LC hydrophobic core, while less specific binding at higher TFP concentrations is required to effect conformational changes on the protein surfaces near the paramagnetic probes. TFP binding was generally not cooperative. Comparative sequence analysis between calmodulin, troponin C, and myosin LCs indicated considerable conservation between residues expected to bind TFP.

An 18-year-old soldier had a gunshot wound to his left thigh during the Mexican Civil War (1910-1917). He presented with persistent bright red bleeding. His wound was treated by compression. A few years after the injury, he noticed a thrill, large varicose veins, limb swelling, and skin changes. A plain film showed an 8 x 10-cm midthigh mass. After a bullfighting incident, the pseudoaneurysm ruptured. Because of increased bulk and discomfort, the patient agreed 3 years later to be treated. Angiography showed a chronically obstructed femoral artery and vein. A 3000-mL hematoma was evacuated. This case illustrates the long-term sequelae of an arteriovenous fistula. This report describes a 51-year delay of treatment for causes unrelated to diagnosis. To our knowledge, this case is the longest delay in treatment of an arteriovenous fistula and its complications reported in the literature.

We reacted a fluorescent probe, N-methyl-2-anilino-6-naphthalenesulfonyl chloride (MNS-Ci), with a specific lysine residue of porcine cardiac myosin located in the S-2 region of myosin. We performed fluorescence resonance energy transfer (FRET) spectroscopy measurements between this site and three loci (Cys109, Cys125, and Cys154) located within different myosin light-chain 2s (LC2) bound to the myosin "head". We used LC2s from rabbit skeletal muscle myosin (Cys125), chicken gizzard smooth muscle myosin (Cys109), or a genetically engineered mutant of chicken skeletal muscle myosin (Cys154). The atomic coordinates of these LC2 loci can be closely approximated, and the FRET measurements were used to determine the position of the MNS-labeled lysine with respect to the myosin head. The C-terminus of myosin subfragment-1 determined by Rayment et al. ends abruptly after a sharp turn of its predominantly alpha-helical structure. We have constructed a model based on our FRET distance data combined with the known structure of chicken skeletal muscle myosin subfragment-1. This model suggests that the loci that bracket the head-rod junction will be useful for evaluating dynamic changes in this region.

Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need.To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout.Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406.Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group).Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6.In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P.001 and.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and.001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P.001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008).Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo.clinicaltrials.gov Identifier: NCT00325195.

Objective To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout. Methods Single infusions of PEG-uricase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in a phase I clinical trial. Plasma uricase activity (pUox), the plasma urate concentration (pUAc), and the uric acid–to-creatinine ratio (UAc:Cr) in urine were monitored for 21 days after dosing. Adverse events and the IgG antibody response to PEG-uricase were followed up for 35 days. Results All patients completed the trial. Maximum pUox was linearly related to the IV dose of PEG-uricase, the area under the curve (AUC) value increased linearly (up to a dose of 8 mg), and the pUox half-life was 6.4–13.8 days. After doses of 4–12 mg, the pUAc fell within 24–72 hours, from a mean ± SD value of 11.1 ± 0.6 mg/dl to 1.0 ± 0.5 mg/dl; the AUC value for the pUAc was equivalent to maintaining the pUAc at 1.2–4.7 mg/dl for 21 days postinfusion. The UAc:Cr ratio in urine fell in parallel with the pUAc. IgG antibodies to PEG-uricase, mostly IgG2 and specific for PEG, developed in 9 patients, who had more rapid enzyme clearance but no allergic reactions. All adverse events were mild to moderate, with gout flares being most common. Conclusion The bioavailability, efficacy, and tolerability of IV PEG-uricase were greater than the bioavailability, efficacy, and tolerability observed in a previous phase I trial of subcutaneous PEG-uricase. Infusing 4–12 mg of PEG-uricase every 2–4 weeks should maintain the pUAc well below the therapeutic target of 6 mg/dl and greatly reduce renal uric acid excretion. This treatment could be effective in depleting expanded tissue urate stores in patients with chronic or tophaceous gout.

Alcoholism is common among trauma patients and often lacks the appropriate monitoring. Alcohol withdrawal syndrome (AWS), including delirium tremens (DT), can be associated with significant postoperative morbidity and mortality. However, appropriate acute pain management may protect against delirium; the administration of intravenous patient-controlled analgesia (IV - PCA) may not only alleviate pain, but also reduce the incidence of post-operative delirium. IV-PCA is widely used today; however, little attention has been paid to its influence on the development of AWS or DT post-surgery. Here we present a case in which the administration of IV-PCA may have delayed the onset of DT that interfered with postoperative care and the initiation of psychiatric consultation. The literature was reviewed to determine the potential mechanisms behind the effects of IV-PCA on the onset of AWS or DT.IV-PCA may delay the onset of DT. It is imperative to take into consideration trauma patients' psychiatric history including answers to questions on alcoholism, so that when an IV-PCA is administered and then discontinued, adequate interventions to prevent further morbidity associated with AWS and DT can be initiated in sufficient time.

The purpose of this study was to determine the influence of the D1-selective partial agonist SKF 38393 on the odor detection performance of rats using high precision olfactometry and a go/no-go operant task. Previous studies have found that the D2 receptor partial agonist quinpirole decreases such performance, but the influences of D1 receptor activation are unknown. In experiment 1, such detection performance to the odorant ethyl acetate was enhanced by SKF 38393, relative to saline, in male rats at 7.5 and 10.0 mg/kg i.p. dose levels, but not at the lower doses of 1.0, 2.5, and 5.0 mg/kg. In experiment 2, this enhancement was replicated at the 7.5 and 10.0 mg/kg doses and was shown to occur at the 12.5 mg/kg dose as well. In experiment 3, similar enhancement was shown for the odorant eugenol in female rats at the 7.5, 10.0 and 12.5 mg/kg doses, suggesting this effect is neither sex-specific nor confined to the odorant ethyl acetate. In experiment 4, a 0.025 mg/kg dose of the D1 receptor antagonist SCH 23390 depressed the enhancement produced to ethyl acetate by 7.5 mg/kg SKF 38393 to control levels. Overall, these data demonstrate that, in contrast to quinpirole, SKF 38393 improves odor detection performance in the rat and that this phenomenon can be attenuated by the D1 receptor blocker SCH 23390.

Rabbit skeletal muscle myosin regulatory light chain-2 (LC2) contains two reactive cysteine residues, Cys125 and Cys154, and one tryptophan at position 137. Using wild-type rabbit LC2 or its genetically engineered mutant with Cys125Arg (C125R), these residues can be selectively modified with fluorescent or chromophoric probes for spectroscopic studies. We have bound suitable donor/acceptor probe pairs to the two cysteine residues and Trp137 in LC2 or C125R, and measured the distance in solution between the probes by fluorescence resonance energy transfer spectroscopy. C125R was made to facilitate specific labelling of the less reactive Cys154, thus allowing the distance between Cys154 and Trp137 to be measured. Our measurements show that these residues are in close proximity to each other, the distance between them ranging from 1.7 nm (between Cys125 and Trp137) to 2.7 nm (Cys125 and Cys154). These results suggest that Cys125, Trp137 and Cys154, spanning up to 29 residues in the sequence of LC2, are spatially close, consistent with these residues residing within a C-terminal globular domain. The distances we obtained are in agreement with previous crosslinking studies [Huber, P. A., Brunner, U. T. & Schaub, M. C. (1989) Biochemistry 28, 9116–9123; Saraswat, L. & Lowey, S. (1991) J. Biol. Chem. 266, 19777–19785] and structure predictions of LC2. LC2 is located at the head–rod junction of the myosin crossbridge, and provides the primary regulatory mechanism in molluscan and smooth muscle. In skeletal muscle, its functional role is unclear, although it has been implicated in modulating actomyosin interaction [Metzger, J. M. & Moss, R. L. (1992) Biophys. J. 63, 460–468]. The incorporation of spectroscopic probes onto the light chains of myosin in solution or in fibres has become a valuable tool for evaluating the dynamic properties of the crossbridge during force generation.

The Effects of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase (rhSOD) in Premature Infants with Respiratory Distress Syndrome (RDS)