Low androgen signaling rescues genome integrity with innate immune response by reducing fertility in humans.

Development of the gonads under complex androgen regulation is critical for germ cells specification. In this work we addressed the relationship between androgens and genomic integrity determining human fertility. We used different study groups: individuals with Differences of Sex Development (DSD), including Complete Androgen Insensitivity Syndrome (CAIS) due to mutated androgen receptor (AR), and men with idiopathic nonobstructive azoospermia. Both showed genome integrity status influenced by androgen signaling via innate immune response activation in blood and gonads. Whole proteome analysis connected low AR to interleukin-specific gene expression, while compromised genome stability and tumorigenesis were also supported by interferons. AR expression was associated with predominant DNA damage phenotype, that eliminated AR-positive Sertoli cells as the degeneration of gonads increased. Low AR contributed to resistance from the inhibition of DNA repair in primary leukocytes. Downregulation of androgen promoted apoptosis and specific innate immune response with higher susceptibility in cells carrying genomic instability.

Accessibility of osteochondral lesion at the capitellum during elbow arthroscopy: an anatomical study.

INTRODUCTION: Osteochondrosis dissecans (OCD) at the capitellum is a common pathology in young patients. Although arthroscopic interventions are commonly used, there is a lack of information about the accessibility of the defects during elbow arthroscopy by using standard portals. MATERIALS AND METHODS: An elbow arthroscopy using the standard portals was performed in seven fresh frozen specimens. At the capitellum, the most posterior and anterior cartilage surface reachable was marked with K-wires. Using a newly described measuring method, we constructed a circular sector around the rotational center of the capitellum. The intersection of K-wire "A" and "B" with the circular sector was marked, and the angles between the K-wires and the Rogers line, alpha angle for K-Wire "A" and beta angle for K-wire "B", and the corridor not accessible during arthroscopy was digitally measured. RESULTS: On average, we found an alpha angle of 53° and a beta angle of 104°. Leaving a sector of 51° which was not accessible via the standard portals during elbow arthroscopy. CONCLUSION: Non-accessible capitellar lesions during elbow arthroscopy should be considered preoperatively, and the informed consent discussion should always include the possibility of open procedures or the use of flexible instruments.

Impact of sex on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC). Subgroup analysis of the PanaMa-study (AIO-KRK-0212).

BACKGROUND: Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest. METHODS: PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy. RESULTS: In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis. CONCLUSIONS: In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).

BACKGROUND: Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. PATIENTS AND METHODS: Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1-4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. RESULTS: The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06-2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79-1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. CONCLUSION: EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

Nitrogen metabolism and protein requirements for maintenance of growing Red Norte bulls.

Dietary protein adjustments can reduce environmental impact and economic losses in production systems. However, we lack information regarding nitrogen (N) metabolism and protein requirements for maintenance of crossbred animals such as Red Norte breed, precluding a precise dietary management. The objective was to evaluate the effect of increasing dietary CP levels (9%, 11%, 13%, 15% and 17%) on intake, digestibility and N balance, as well as to estimate the metabolizable protein requirements for maintenance (MPm) of growing Red Norte bulls. Thirty five animals averaging 280 ± 4.0 kg BW were fed during 45 days in a 60 : 40 forage : concentrate ratio diet in which the last 5 days were used for the digestibility trial. Intakes of CP and non-fibrous carbohydrates (NFCs) and feed efficiency linearly increased (P < 0.05) as CP levels increased, while DM, NDF, nitrogen efficiency use and ether extract were not influenced by CP levels (P > 0.05). Digestibilities of DM, organic matter, ether extract, NFC and CP as well as metabolizable energy intake linearly increased (P < 0.05), and true digestibility of CP was not affected (P > 0.05) by treatments. Urinary N and retained N linearly increased (P < 0.05) with the increase in dietary N. The MPm were estimated as 4.46 g/BW0.75 and the efficiency of use of MPm was 0.673. In conclusion, obtained MPm requirements of growing Red Norte bulls are greater than the values reported in literature for Zebu cattle and dietary CP levels of 15% and 17% exhibited great responses for growing Red Norte cattle. However, a cost-benefit evaluation should be done before its use.

Antiviral effect of a derivative of isonicotinic acid enisamium iodide (FAV00A) against influenza virus.

With only a single class of antiviral drugs existing for treatment of influenza (neuraminidase inhibitors), the search for novel effective compounds is urgently needed. We evaluated a low molecular mass compound, enisamium iodide (FAV00A), against influenza virus infections in primary differentiated normal human bronchial epithelial (NHBE) cells, and in ferrets. FAV00A (500 µg/ml) markedly inhibited influenza virus replication and reduced viral M-gene expression in NHBE cells. Treatment of ferrets with FAV00A (200 mg/kg once daily for 7 days) initiated 24 h after inoculation with 105 TCID50 of influenza A/Wisconsin/67/2005 (H3N2) virus resulted in a significant decrease in virus titers in the upper respiratory tract. Our data show that FAV00A exhibits an antiviral effect against influenza virus in NHBE cells and provides some benefits in a ferret model. Thus, further Keywords: antiviral agents; enisamium iodide; influenza virus; MDCK cells; NHBE cells; ferrets.

A reference genome for Nicotiana tabacum enables map-based cloning of homeologous loci implicated in nitrogen utilization efficiency.

BACKGROUND: Tobacco (Nicotiana tabacum) is an important plant model system that has played a key role in the early development of molecular plant biology. The tobacco genome is large and its characterisation challenging because it is an allotetraploid, likely arising from hybridisation between diploid N. sylvestris and N. tomentosiformis ancestors. A draft assembly was recently published for N. tabacum, but because of the aforementioned genome complexities it was of limited utility due to a high level of fragmentation. RESULTS: Here we report an improved tobacco genome assembly, which, aided by the application of optical mapping, achieves an N50 size of 2.17 Mb and enables anchoring of 64% of the genome to pseudomolecules; a significant increase from the previous value of 19%. We use this assembly to identify two homeologous genes that explain the differentiation of the burley tobacco market class, with potential for greater understanding of Nitrogen Utilization Efficiency and Nitrogen Use Efficiency in plants; an important trait for future sustainability of agricultural production. CONCLUSIONS: Development of an improved genome assembly for N. tabacum enables what we believe to be the first successful map-based gene discovery for the species, and demonstrates the value of an improved assembly for future research in this model and commercially-important species.

Impact of intravenous thrombolysis on recanalization rates in patients with stroke treated with bridging therapy.

BACKGROUND AND PURPOSE: Randomized controlled trials have shown that bridging endovascular therapy (EVT) after intravenous thrombolysis (IVT) therapy improves outcome in patients with stroke with large-artery anterior circulation stroke compared with IVT alone. It remains unknown whether IVT adds any benefit to EVT in these patients. The aim of this study was to assess recanalization rates and thrombus dislocation before initiation of EVT in patients receiving bridging therapy. METHODS: All patients in the Bernese stroke registry (2008-2015) in whom bridging therapy was considered were included in this analysis. Relevant recanalization before EVT, thrombus dislocation and increase in thrombus load between initial and control imaging were assessed retrospectively. RESULTS: A total of 319 patients were included. Relevant recanalization before EVT occurred in 8.8% and thrombus dislocation in 7.2% of patients before EVT. Recanalization rates were significantly higher in distal compared with large and more proximal vessel occlusions of the anterior circulation (occlusion of internal carotid artery, 5.4%; middle cerebral artery segment M1, 8.1%; middle cerebral artery segment M2, 17.6%) and in drip-and-ship patients compared with mother-ship patients. In multivariable regression analysis the occlusion site was the only independent predictor of relevant recanalization before EVT (P = 0.046). CONCLUSIONS: Relevant recanalization after IVT and prior to EVT in patients receiving bridging therapy was highly dependent on the occlusion site. These findings suggest that future randomized controlled trials should consider occlusion site and treatment paradigm to specify patients who benefit most from bridging therapy in comparison to EVT or IVT alone.

A simple metal staining procedure for identification and visualization of single cells by LA-ICP-MS.

High lateral resolution of metal detection in single cells by use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) demands powerful staining methods. In this work different staining procedures for the single cell analysis with LA-ICP-MS were optimized. An iridium intercalator was utilized to stain the cell nuclei whereas the whole cell was stained by the use of maleimido-mono-amide-DOTA (mDOTA) complexing lanthanide(iii) ions. The content of the artificially introduced metals per cell was quantified using a matrix matched calibration approach based on cellulose membranes onto which standards were spotted by a microarray spotter. Absolute metal stain amounts in the range of 2.34 to 9.81 femtomole per cell were determined. The metal staining procedures allow direct identification and visualization of single cells and their cell compartments by element microscopy without the use of bright field images of the sample.

Lausannevirus Encodes a Functional Dihydrofolate Reductase Susceptible to Proguanil.

Lausannevirus belongs to the family Marseilleviridae within the group of nucleocytoplasmic large DNA viruses (NCLDVs). These giant viruses exhibit unique features, including a large genome, ranging from 100 kb to 2.5 Mb and including from 150 to more than 2,500 genes, as well as the presence of genes coding for proteins involved in transcription and translation. The large majority of Lausannevirus open reading frames have unknown functions. Interestingly, a bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is encoded in the Lausannevirus genome. The enzyme plays central roles in DNA precursor biosynthesis. DHFR is the pharmacological target of antifolates, such as trimethoprim, pyrimethamine, and proguanil. First, the functionality of Lausannevirus DHFR-TS was demonstrated by the successful complementation of a DHFR-deficient Saccharomyces cerevisiae strain with a plasmid expressing the heterologous gene. Additionally, using this heterologous expression system, we demonstrated the in vitro susceptibility of Lausannevirus DHFR-TS to proguanil and its resistance to pyrimethamine and trimethoprim. Proguanil may provide a unique and useful treatment if Lausannevirus proves to be a human pathogen. To our knowledge, this is the first time that a DHFR-TS has been described and characterized in an NCLDV.

Genomics of Parallel Experimental Evolution in Drosophila.

What are the genomic foundations of adaptation in sexual populations? We address this question using fitness-character and whole-genome sequence data from 30 Drosophila laboratory populations. These 30 populations are part of a nearly 40-year laboratory radiation featuring 3 selection regimes, each shared by 10 populations for up to 837 generations, with moderately large effective population sizes. Each of 3 sets of the 10 populations that shared a selection regime consists of 5 populations that have long been maintained under that selection regime, paired with 5 populations that had only recently been subjected to that selection regime. We find a high degree of evolutionary parallelism in fitness phenotypes when most-recent selection regimes are shared, as in previous studies from our laboratory. We also find genomic parallelism with respect to the frequencies of single-nucleotide polymorphisms, transposable elements, insertions, and structural variants, which was expected. Entirely unexpected was a high degree of parallelism for linkage disequilibrium. The evolutionary genetic changes among these sexual populations are rapid and genomically extensive. This pattern may be due to segregating functional genetic variation that is abundantly maintained genome-wide by selection, variation that responds immediately to changes of selection regime.

Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States.

OBJECTIVES: The Centers for Disease Control and Prevention considers carbapenem-resistant Enterobacteriaceae (CRE) an urgent public health threat; however, its economic burden is unknown. METHODS: We developed a CRE clinical and economics outcomes model to determine the cost of CRE infection from the hospital, third-party payer, and societal, perspectives and to evaluate the health and economic burden of CRE to the USA. RESULTS: Depending on the infection type, the median cost of a single CRE infection can range from $22 484 to $66 031 for hospitals, $10 440 to $31 621 for third-party payers, and $37 778 to $83 512 for society. An infection incidence of 2.93 per 100 000 population in the USA (9418 infections) would cost hospitals $275 million (95% CR $217-334 million), third-party payers $147 million (95% CR $129-172 million), and society $553 million (95% CR $303-1593 million) with a 25% attributable mortality, and would result in the loss of 8841 (95% CR 5805-12 420) quality-adjusted life years. An incidence of 15 per 100 000 (48 213 infections) would cost hospitals $1.4 billion (95% CR $1.1-1.7 billion), third-party payers $0.8 billion (95% CR $0.6-0.8 billion), and society $2.8 billion (95% CR $1.6-8.2 billion), and result in the loss of 45 261 quality-adjusted life years. CONCLUSIONS: The cost of CRE is higher than the annual cost of many chronic diseases and of many acute diseases. Costs rise proportionally with the incidence of CRE, increasing by 2.0 times, 3.4 times, and 5.1 times for incidence rates of 6, 10, and 15 per 100 000 persons.

Next generation of labeling reagents for quantitative and multiplexing immunoassays by the use of LA-ICP-MS.

Immuno imaging by the use of Laser Ablation Inductively Coupled Mass Spectrometry (LA-ICP-MS) is a growing research field in life sciences such as biology and biomedicine. Various element labeling strategies for antibodies have been developed for the application of multiplex immunoassays analyzed by the use of LA-ICP-MS. High multiplexing capabilities, a wide linear dynamic range and the possibility of absolute quantification are the main advantages of ICP-MS. But in the context of immuno imaging by the use of LA-ICP-MS, quantification of analytes is limited due to non-controllable antibody labeling chemistry. In the presented proof-of-principle a novel antibody labeling technique has been investigated which results in a controlled labeling degree. A small affinity protein based on the C2 domain of protein G was modified with conventional metal coded tags (MeCAT) after introducing a cysteine into the C-terminus of the protein. The modified C2 domain photo-crosslinks to the Fc or Fab region of the IgG and allows specific and covalent labeling of antibodies for multiplex immunoassay analysis by the use of LA-ICP-MS. In combination with a house-made calibration membrane the amount of labeled antibody-antigen complexes in a multiplex western blot immunoassay was determined by LA-ICP-MS.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Ricebase: a breeding and genetics platform for rice, integrating individual molecular markers, pedigrees and whole-genome-based data.

Ricebase (http://ricebase.org) is an integrative genomic database for rice (Oryza sativa) with an emphasis on combining datasets in a way that maintains the key links between past and current genetic studies. Ricebase includes DNA sequence data, gene annotations, nucleotide variation data and molecular marker fragment size data. Rice research has benefited from early adoption and extensive use of simple sequence repeat (SSR) markers; however, the majority of rice SSR markers were developed prior to the latest rice pseudomolecule assembly. Interpretation of new research using SNPs in the context of literature citing SSRs requires a common coordinate system. A new pipeline, using a stepwise relaxation of stringency, was used to map SSR primers onto the latest rice pseudomolecule assembly. The SSR markers and experimentally assayed amplicon sizes are presented in a relational database with a web-based front end, and are available as a track loaded in a genome browser with links connecting the browser and database. The combined capabilities of Ricebase link genetic markers, genome context, allele states across rice germplasm and potentially user curated phenotypic interpretations as a community resource for genetic discovery and breeding in rice.

[Specific anosmia as a principle of olfactory perception]. / Spezifische Anosmie als Prinzip olfaktorischer Wahrnehmung.

Specific anosmia, the inability to perceive a specific odor, while olfactory perception is otherwise intact, is known as a rather seldom phenomenon. By testing the prevalence of specific anosmia to 20 different odors in a sample of 1600 people, we were able to estimate the general prevalence of anosmia. This revealed that specific anosmia is not rare at all. In contrast, the general likelihood for specific anosmia approaches 1. In addition, specific anosmia can be very well reversed by "smell training" during the course of 3 months. To summarize, specific anosmia seems to be a rule, not an exception, of olfactory sensation. The lack of perception of certain odors may constitute a flexible peripheral filter mechanism, which can be adapted by exposure to odors.

Factor for felons: how can we provide haemophilia care to the incarcerated?

OBJECTIVES: In 2011, 6.98-million offenders were documented in the adult correctional system, with state operating costs designated 12% towards medical care ($11.97 day per inmate) for the general population. Common co-existing health problems identified are: arthritis (13%), hypertension (11%), asthma (10%) and heart problems (6%). Less than 5% of inmates have health issues related to cancer, diabetes, liver or renal problems and communicable diseases. The leading cause of death is suicide (33.2%), followed by heart disease (26.1%). Despite these statistics quality is lacking. Given these statistics, one would expect that a small proportion of patients from Hemophilia Treatment Center (HTC) will spend some time within the justice system. Currently there are no data addressing haemophilia care needs while incarcerated. METHODS: This article will review the current health care issues in the adult correctional system. Additionally, six case reports of incarcerated haemophiliacs will be highlighted exploring the successes and challenges with maintaining haemophilia care addressing the priority of meeting the haemophilia care needs verses the penal system regulations. SUMMARY: It can be expected that at some point, the HTC will experience a patient incarcerated for some period of time. The HTC will continue to advocate for their patient within this system, despite the many challenges faced. CONCLUSIONS: Despite the challenges outlined, ongoing communication and education with the correctional system, education of the medical personnel and prison personnel remains the priority as we advocate for our patients. Continued strategies in these areas are paramount.

Intra-ventral tegmental area microinjections of urotensin II modulate the effects of cocaine.

Although the peptide urotensin II (UII) has well studied direct actions on the cardiovascular system, the UII receptor (UIIR) is expressed by neurons of the hindbrain. Specifically, the UIIR is expressed by the cholinergic neurons of the laterodorsal tegmentum (LDTg) and the pedunculopontine tegmentum (PPTg). These neurons send axons to the ventral tegmental area (VTA), for which the PPTg and LDTg are the sole source of acetylcholine. Therefore, it was hypothesized that UIIR activation within the VTA would modulate reward-related behaviors, such as cocaine-induced drug seeking. Intra-VTA microinjections of UII at high concentrations (1 nmole) established conditioned place preference (CPP), but also blocked cocaine-mediated CPP (10 mg/kg). When rats received systemic sub-effectual doses of cocaine (7.5 mg/kg) with intra-VTA injections of 1 or 10 pmole of UII CPP was formed. Furthermore, the second endogenous ligand for the UIIR, urotensin II-related peptide, had the same effect at the 10 pmole dose. The effects of low doses of UII were blocked by pretreatment with the UIIR antagonist SB657510. Furthermore, it was found that intra-VTA UII (10 pmole) further increased cocaine-mediated (7.5 mg/kg) rises in electrically evoked dopamine in the nucleus accumbens. Our study has found that activation of VTA-resident UIIR produces observable behavioral changes in rats, and that UIIR is able to modulate the effects of cocaine. In addition, it was found that UIIR activation within the VTA can potentiate cocaine-mediated neurochemical effects. Therefore, the coincident activation of the UII-system and cocaine administration may increase the liability for drug taking behavior.

Infection risk and stability of a continuous 8-h 250 mL rFVIII infusion.

This study seeks to identify the delivery method of continuous infusion using a 250 cc IV bag via pump, change every 8 h. Additionally, the study will examine the infection risk with the use of 8 h infusions. Ten hemophilia A patients were identified for the study. Each patient received a bolus factorVIII (FVIII) infusion with a pre FVIII level and 1 h post FVIII level to determine recovery levels for optimal dosing. On the day of 8-h continuous infusion, the pt received a bolus VIII (Kogenate FS (™)) for correction to 100% followed by individually calculated continuous infusion (Kogenate FS (™)) FVIII. FVIII levels were drawn from the IV bag and peripherally from the patient in the opposite arm at time points: pre infusion, 1, 2, 3, 4, 5, 6 and 8 h. Additionally, blood cultures were drawn from the IV bag and from the IV tubing at time points pre infusion, 4 and 8 h. Fourteen subjects agreed to participate in the study; 4 failed to follow up, hence 10 subjects were included in the analysis of data; 7 severe, 2 moderate, and 1 mild hemophilia A. Age range was 26-62 years. Ethnic breakdown included 5 African American, 4 Caucasian, 1 Hispanic. With all infusions, the range of FVIII was 65-135% (blood) and 62-200% (bag). After the start of infusion, there were no significant differences noted between the hourly FVIII levels in the subjects and the IV values (P-value range 0.36-0.9). Additionally, given three time points with six cultures per patient, totaling 60 points of cultures drawn for the study, all cultures from the IV bag and patient were negative. The effective delivery method and safety of an 8-h continuous infusion of FVIII (Kogenate FS (™)) has been confirmed. This method can be helpful given that many hospitals may not carry the required mini-pumps, allowing a standard safe delivery of FVIII (Kogenate FS (™)) continuous infusion by available means.

Characterization of metal-tagged antibodies used in ICP-MS-based immunoassays.

A detailed characterization of metal-tagged antibodies is the prerequisite for the implementation of quantitative concepts in inductively coupled plasma-mass spectrometry (ICP-MS)-based bioanalysis or future medical diagnosis. In this paper, the common modification with bifunctional ligands containing maleimide residues as a reactive group was investigated in detail via size exclusion chromatography (SEC)-ICP-MS and liquid chromatography-time-of-flight (LC-TOF)-MS to determine the preservation of the antibody structure after tagging. Mouse monoclonal IgG modified with metal-coded tags (MeCATs) was used as a model system. Several antibody fragments were identified carrying different numbers of metal tags. In a second step, a functionality test was performed with isolated fragments where the antigen specificity was tested in a dot blot immunoassay.