Measuring accuracy of International Classification of Diseases codes in identification of patients with non-cystic fibrosis bronchiectasis.

Introduction: Non-cystic fibrosis bronchiectasis is a disease which is increasing in incidence and prevalence worldwide. The incidence of the disease is frequently estimated using databases that rely on International Classification of Diseases, ninth and tenth revisions, clinical modification (ICD-9-CM/ICD-10-CM) discharge diagnoses. Code accuracy has proved to be a major issue for other diagnoses using ICD codes. This study aims to investigate the accuracy of the ICD codes for the diagnosis of non-cystic fibrosis bronchiectasis. Methods: This is a retrospective diagnostic accuracy study which compares the radiologist's diagnosis of bronchiectasis with the ICD code reflection of that diagnosis at discharge. Results: Sensitivities were 34% (same for both ICD-9-CM and ICD-10-CM windows) and specificities ranged from 69% for the ICD-9-CM window to 81% for ICD-10-CM window. Conclusion: We observed that ICD codes are an insufficient method to identify patients with a radiologist diagnosis of bronchiectasis.

Two-component nematic superconductivity in 4Hb-TaS2.

Most superconductors have an isotropic, single component order parameter and are well described by the standard (BCS) theory for superconductivity. Unconventional, multiple-component superconductors are exceptionally rare and are much less understood. Here, we combine scanning tunneling microscopy and angle-resolved macroscopic transport for studying the candidate chiral superconductor, 4Hb-TaS2. We reveal quasi-periodic one-dimensional modulations in the tunneling conductance accompanied by two-fold symmetric superconducting critical field. The strong modulation of the in-plane critical field, Hc2, points to a nematic, unconventional order parameter. However, the imaged vortex core is isotropic at low temperatures. We suggest a model that reconciles this apparent discrepancy and takes into account previously observed spontaneous time-reversal symmetry breaking at low temperatures. The model describes a competition between a dominating chiral superconducting order parameter and a nematic one. The latter emerges close to the normal phase. Our results strongly support the existence of two-component superconductivity in 4Hb-TaS2 and can provide valuable insights into other systems with coexistent charge order and superconductivity.

A case of diffuse panbronchiolitis caused by Mycoplasma amphoriforme.

Mycoplasma amphoriforme is a novel specie which was discovered in 2003 and associated with congenital immune deficiency. It has been described as an underlying cause of bronchopneumonia. There is limited description of the in vitro sensitivities. In this article, we present the first description of M. amphoriforme as the causative agent of diffuse panbronchiolitis in a patient with X-linked hypogammaglobulinema and bronchiectasis, with symptoms improved by treatment with azithromycin. We also describe the difficulty obtaining this organism through routine culture and the need to consider culture independent methods of recovery when the suspicion is high.

The effect of a training webinar on decreasing inter-observer variability in making a radiologic diagnosis of bronchiectasis.

Non-cystic fibrosis bronchiectasis is a clinically important disease with an estimated 340,000-522,000 persons living with the disease and 70,000 being diagnosed annually. The radiographic diagnosis remains a pivotal part of recognizing the disease due to its protean clinical manifestations. As physicians are sensitized to this disease, a greater proportion of patients are being diagnosed with mild to moderate bronchiectasis. Despite the established use of CT chest as the main tool for making a radiologic diagnosis of bronchiectasis, the literature supporting the process of making that diagnosis is somewhat sparse. Concurrently, there has been an increased trend to have Web-based radiologic tutorials due to its convenience, the ability of the learner to set the pace of learning and the reduced cost compared to in-person learning. The COVID-19 pandemic has accelerated this trend. We wanted to look carefully at the effect of a Web-based training session on interrater reliability. Agreement was calculated as percentages and kappa and prevalence adjusted kappa calculated. We found that a single Web-based training session had little effect on the variability and accuracy of diagnosis of bronchiectasis. Larger studies are needed in this area with multiple training sessions.

Dupilumab: a new contestant to corticosteroid in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a disease characterized by severe disability with recurrent wheezing and shortness of breath. The current recommended therapy is daily oral corticosteroids +/- oral antifungal therapy. Despite this, many patients continue to have severe symptoms, and others require fairly high daily oral corticosteroid dosing to achieve control, which in turn may induce the well-known effects of long term steroid use. The anti-interleukin drugs have been reported to help improve daily symptoms and reduce steroid requirements. Much of the literature highlights the benefit of omalizumab. We present a case of dupilumab as add-on therapy in a patient with ABPA, which allowed us to reduce daily steroid dosage.

Vitamin D in follicular development and oocyte maturation.

Vitamin D (VD) is a secosteroid hormone synthesized predominantly in the skin upon UV light exposure, which can also be obtained from dietary sources. In target cells, the bioactive VD binds to specific VD receptor to regulate downstream transcription of genes that are involved in a wide range of cellular processes. There is an increasing recognition that the proper physiological levels of VD are critical for optimizing reproductive potential in women. The direct VD action in the ovary was first suggested in the 1980s. Since then, research has attempted to determine the role of VD in follicular development and oocyte maturation in animal models and clinical settings. However, data published to date are inconclusive due to the complexity in VD metabolism and the fact that VD actions are pervasive in regulating physiological functions in various systems, including the reproductive, endocrine and nervous systems that control reproduction. This review summaries in vitro, in vivo, and clinical evidence regarding VD metabolism and signaling in the ovary, as well as VD-regulated or VD-associated ovarian follicular development, steroidogenic function, and oocyte maturation. It is suggested that adequate animal models are needed for well-controlled studies to unravel molecular mechanisms of VD action in the ovary. For clinical studies, follicular development and function may be evaluated more effectively in a relatively homogeneous patient population under a well-controlled experimental design. A comprehensive understanding of VD-regulated folliculogenesis and oogenesis will provide critical insight into the impact of VD in female reproductive health.

Magnetic Resonance Image-Guided Radiotherapy (MRIgRT): A 4.5-Year Clinical Experience.

AIMS: Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. MATERIALS AND METHODS: We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014-2018) to identify shifts in institutional practice patterns. RESULTS: Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. DISCUSSION: MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.

The benefit of a tough skin: bullet holes, weathering and the preservation of heritage.

Projectile damage to building stone is a widespread phenomenon. Sites damaged 100 years ago during the First World War still see daily use, while in a more contemporary setting numerous reports show the damage to buildings in Babylon, Mosul and Palmyra. While research has been carried out on the long-term effects of conflict such as fire damage, little is known about the protracted damage sustained through the impact of bullets, shrapnel and other metal projectiles outside of the field of engineering focused on ceramics and metals. To investigate alterations to mineral structure caused by projectile damage, impacts were created in medium-grained, well-compacted, mesoporous sandstone samples using 0.22 calibre lead bullets shot at a distance of 20 m. Half these samples were treated with a surface consolidant (Wacker OH 100), to mimic natural cementation of the rock surface. These samples were then tested for changes to surface hardness and moisture movement during temperature cycles of 15-65°C. Petrographic thin section analysis was carried out to investigate the micro-scale deformation associated with high-speed impact. The results surprisingly show that stress build-up behind pre-existing cementation of the surface, as found in heritage sites that have been exposed to moisture and temperature fluctuations for longer periods of time, can be alleviated with a bullet impact. However, fracture networks and alteration of the mineral matrices still form a weak point within the structure, even at a relatively low impact calibre. This initial study illustrates the need for geomorphologists, geologists, engineers and heritage specialists to work collectively to gain further insights into the long-term impact of higher calibre armed warfare on heritage deterioration.

Raman Imaging Spectroscopy of a Putative Microfossil from the ∼3.46 Ga Apex Chert: Insights from Quartz Grain Orientation.

The utility of nondestructive laser Raman for testing the biogenicity of microfossil-like structures in ancient rocks is promising, yet results from deposits like the ∼3.46 Ga Apex chert remain contentious. The essence of the debate is that associated microstructures, which are not purported to be microfossils, also contain reduced carbon that displays Raman D- and G-band peaks similar to those seen in the purported microfossils. This has led to the hypothesis that all features including reported microfossils are due to compression of nonfossil carbon during crystal growth around quartz spherulites or more angular crystals. In this scenario, the precursor to this macromolecular carbon may or may not have been of biogenic origin, while the arcuate and linear features described would be pseudofossils. To test this hypothesis, we have undertaken 2-D micro-Raman imaging of the Eoleptonema apex holotype and associated features using instrumentation with a high spatial and spectral resolution. In addition to this, we utilized the ratio of two Raman active quartz mode intensities (I129/I461) to assess quartz grain orientation and grain-splitting artifacts. These data lead us to conclude that the holotype of Eoleptonema apex is a sheet-shaped pseudofossil that appears to be a carbon infilled intragranular crack; therefore other holotypes should be carefully reexamined for syngenicity.

A framework for automated contour quality assurance in radiation therapy including adaptive techniques.

Contouring of targets and normal tissues is one of the largest sources of variability in radiation therapy treatment plans. Contours thus require a time intensive and error-prone quality assurance (QA) evaluation, limitations which also impair the facilitation of adaptive radiotherapy (ART). Here, an automated system for contour QA is developed using historical data (the 'knowledge base'). A pilot study was performed with a knowledge base derived from 9 contours each from 29 head-and-neck treatment plans. Size, shape, relative position, and other clinically-relevant metrics and heuristically derived rules are determined. Metrics are extracted from input patient data and compared against rules determined from the knowledge base; a computer-learning component allows metrics to evolve with more input data, including patient specific data for ART. Nine additional plans containing 42 unique contouring errors were analyzed. 40/42 errors were detected as were 9 false positives. The results of this study imply knowledge-based contour QA could potentially enhance the safety and effectiveness of RT treatment plans as well as increase the efficiency of the treatment planning process, reducing labor and the cost of therapy for patients.

Treatment of single peripheral pulmonary emboli: patient outcomes and factors associated with decision to treat.

BACKGROUND: Increasing use of computed tomography pulmonary angiography together with higher-resolution scanners has increased the detection of peripheral filling defects. Physicians face the dilemma of whether to treat patients with these findings, especially single defects. The aims of this study were to compare the outcomes of treated and untreated patients with single peripheral filling defects (SPFD) and identify factors associated with treatment. METHODS: All cases with SPFDs over 66 months in a single institution were identified. Patient and treatment information were abstracted and data on 90-day mortality and postdischarge venous thromboembolism (VTE) were collected. RESULTS: A total of 4906 computed tomography pulmonary angiograms were reviewed. A SPFD was identified in 3.1% (n = 153). Of the 153 patients, 134 met criteria for study inclusion. In 99 of 134 (73.9%) studies, the defect was called a pulmonary embolus (PE) by the initial radiologist. Treatment was administered to 61 of 134 (45.5%) patients; 5 patients died in each group. Postdischarge VTE occurred in 3 treated and 2 untreated patients. In 52 of 153 cases, an additional study was performed. None of the patients with normal ventilation perfusion scan and compression ultrasound received treatment. Immobility (odds ratio [OR]: 3.90, 95% confidence interval [CI]: 1.45-10.60), previous VTE (OR: 3.72, 95% CI: 1.18-11.70), and determination of PE by the radiologist (OR: 24.68, 95% CI: 5.40-112.90) were associated with treatment. CONCLUSIONS: There was no difference in 90-day mortality or recurrence between treated and untreated patients. The most influential factor associated with treatment was the radiologist's interpretation. When secondary lung imaging studies were negative, no patient received treatment.

The contribution of personal and exposure characteristics to the adjustment of adolescents following war.

The study examined the unique contribution of both personal characteristics and several types of exposure variables to the adjustment of Israeli adolescents following the Second Lebanon War. Two thousand three hundred and fourteen adolescents, who lived in areas that were the target of multiple missile attacks, completed self-report questionnaires assessing personal characteristics of gender and early traumatic events, subjective exposure (i.e., measures of fear and shortage of basic necessities during the war), objective exposure (i.e., exposure to missile attacks, knowing someone who was wounded or killed) and media exposure. Fifteen percent of the adolescents reported moderate or severe post-traumatic symptoms. Girls and adolescents who experienced earlier traumatic events were at higher risk for distress. While the level of direct exposure contributed to greater distress, the contribution of subjective exposure was significantly stronger. The discussion deals with the unique contribution of both subjective and objective characteristics to post-war adjustment.

WE-G-BRB-08: TG-51 Calibration of First Commercial MRI-Guided IMRT System in the Presence of 0.35 Tesla Magnetic Field.

PURPOSE: The first real-time-MRI-guided radiotherapy system has been installed in a clinic and it is being evaluated. Presence of magnetic field (MF) during radiation output calibration may have implications on ionization measurements and there is a possibility that standard calibration protocols may not be suitable for dose measurements for such devices. In this study, we evaluated whether a standard calibration protocol (AAPM- TG-51) is appropriate for absolute dose measurement in presence of MF. METHODS: Treatment delivery of the ViewRay (VR) system is via three 15,000Ci Cobalt-60 heads positioned 120-degrees apart and all calibration measurements were done in the presence of 0.35T MF. Two ADCL- calibrated ionization-chambers (Exradin A12, A16) were used for TG-51 calibration. Chambers were positioned at 5-cm depth, (SSD=105cm: VR's isocenter), and the MLC leaves were shaped to a 10.5cm × 10.5 cm field size. Percent-depth-dose (PDD) measurements were performed for 5 and 10 cm depths. Individual output of each head was measured using the AAPM- TG51 protocol. Calibration accuracy for each head was subsequently verified by Radiological Physics Center (RPC) TLD measurements. RESULTS: Measured ion-recombination (Pion) and polarity (Ppol) correction factors were less-than 1.002 and 1.006, respectively. Measured PDDs agreed with BJR-25 within ±0.2%. Maximum dose rates for the reference field size at VR's isocenter for heads 1, 2 and 3 were 1.445±0.005, 1.446±0.107, 1.431±0.006 Gy/minute, respectively. Our calibrations agreed with RPC- TLD measurements within ±1.3%, ±2.6% and ±2.0% for treatment-heads 1, 2 and 3, respectively. At the time of calibration, mean activity of the Co-60 sources was 10,800Ci±0.1%. CONCLUSIONS: This study shows that the TG- 51 calibration is feasible in the presence of 0.35T MF and the measurement agreement is within the range of results obtainable for conventional treatment machines. Drs. Green, Goddu, and Mutic served as scientific consultants for ViewRay, Inc. Dr. Mutic is on the clinical focus group for ViewRay, Inc., and his spouse holds shares in ViewRay, Inc.

Sepsis caused by Elizabethkingia miricola successfully treated with tigecycline and levofloxacin.

Elizabethkingia miricola is a Gram-negative rod that was initially isolated from condensation water of the space station Mir. This is the 1st reported case of human disease caused by this organism.

Tri-isobutylphosphate: a prenatal toxicity study in rats.

To assess the prenatal toxicity to rats of the anti-foaming agent, tri-isobutylphosphate (CAS 126-71-6), a study was conducted in which daily dosages of 0, 100, 300 and 1000 mg/kg were administered to different treatment groups by gavage from day 6 to 15 of pregnancy. Dams were killed and foetuses examined on day 20 of pregnancy. Maternal effects during the dosing period included a dosage-related increase in the frequency, persistence and severity of post dosing salivation in all test groups and significantly increased water consumption at 1000 mg/kg. Bodyweight gain at 1000 and 300 mg/kg was lower than that of controls but the differences were not statistically significant. The lowest dosage of 100 mg/kg could be considered as the maternal 'lowest observed adverse effect level' (LOAEL) or 'no observed adverse effect level' (NOAEL) according to whether increased salivation is perceived to be a true toxic effect or simply a reaction to the taste of the test material. Neither litter values nor the prevalence of foetuses with abnormalities indicated any embryotoxic effects (including teratogenicity) at any dosage. The most notable feature of the results was the occurrence of a cluster of foetuses with the congenital abnormality referred to as 'hunched posture syndrome' or 'squat foetus syndrome'. However, the incidence of this finding was similar to that noted among background data for the same strain and, in the absence of any other embryotoxic findings, was considered likely to have arisen coincidentally.

Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide.

BACKGROUND: Recruitment of the intracellular tyrosine kinase Syk to activated immune-response receptors is a critical early step in intracellular signaling. In mast cells, Syk specifically associates with doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) that are found within the IgE receptor. The mechanism by which Syk recognizes these motifs is not fully understood. Both Syk SH2 (Src homology 2) domains are required for high-affinity binding to these motifs, but the C-terminal SH2 domain (Syk-C) can function independently and can bind, in isolation, to the tyrosine-phosphorylated IgE receptor in vitro. In order to improve understanding of the cellular function of Syk, we have determined the solution structure of Syk-C complexed with a phosphotyrosine peptide derived from the gamma subunit of the IgE receptor. RESULTS: The Syk-C:peptide structure is compared with liganded structures of both the SH2 domain of Src and the C-terminal SH2 domain of ZAP-70 (the 70 kDa zeta-associated protein). The topologies of these domains are similar, although significant differences occur in the loop regions. In the Syk-C structure, the phosphotyrosine and leucine residues of the peptide ligand interact with pockets on the protein, and the intervening residues are extended. CONCLUSIONS: Syk-C resembles other SH2 domains in its peptide-binding interactions and overall topology, a result that is consistent with its ability to function as an independent SH2 domain in vitro. This result suggests that Syk-C plays a unique role in the intact Syk protein. The determinants of the binding affinity and selectivity of Syk-C may reside in the least-conserved structural elements that comprise the phosphotyrosine- and leucine-binding sites. These structural features can be exploited for the design of Syk-selective SH2 antagonists for the treatment of allergic disorders and asthma.

Activation of the high-affinity immunoglobulin E receptor Fc epsilon RI in RBL-2H3 cells is inhibited by Syk SH2 domains.

Antigen-mediated aggregation of the high-affinity receptor for immunoglobulin E, Fc epsilon RI, results in the activation of multiple signaling pathways, leading to the release of mediators of the allergic response. One of the earliest responses to receptor stimulation is the tyrosine phosphorylation of the beta and gamma subunits of Fc epsilon RI and the association of the tyrosine kinase Syk with the phosphorylated receptor. This association is mediated by the SH2 domains of Syk and is believed to be critical for activating signaling pathways resulting in mediator release. To examine the importance of the interaction of Syk with Fc epsilon RI in signaling events following receptor activation, we introduced a protein containing the SH2 domains of Syk into streptolysin O-permeabilized RBL-2H3 cells. The Syk SH2 domains completely inhibited degranulation and leukotriene production following receptor aggregation, and they blocked the increase in protein tyrosine phosphorylation observed after receptor activation. Inhibition was specific for Fc epsilon RI-mediated signaling, since degranulation of cells activated by alternative stimuli was not blocked by the Syk SH2 domains. A protein containing a point mutation in the carboxy-terminal SH2 domain which abolishes phosphotyrosine binding was not inhibitory. In addition, inhibition of degranulation was reversed by pretreatment of the SH2 domains with a tyrosine phosphorylated peptide corresponding to the tyrosine-based activation motif found in the gamma subunit of Fc epsilon RI, the nonphosphorylated peptide had no effect. The association of Syk with the tyrosine-phosphorylated gamma subunit of the activated receptor was blocked by the Syk SH2 domains, and deregulation in cells activated by clustering of Syk directly without Fc epsilon RI aggregation was not affected by the Syk SH2 domains. These results demonstrate that the association of Syk with the activated Fc epsilon RI is critical for both early and late events following receptor activation and confirm the key role Syk plays in signaling through the high-affinity IgE receptor.

Interaction of p72syk with the gamma and beta subunits of the high-affinity receptor for immunoglobulin E, Fc epsilon RI.

Activation of protein tyrosine kinases is one of the initial events following aggregation of the high-affinity receptor for immunoglobulin E (Fc epsilon RI) on RBL-2H3 cells, a model mast cell line. The protein tyrosine kinase p72syk (Syk), which contains two Src homology 2 (SH2) domains, is activated and associates with phosphorylated Fc epsilon RI subunits after receptor aggregation. In this report, we used Syk SH2 domains, expressed in tandem or individually, as fusion proteins to identify Syk-binding proteins in RBL-2H3 lysates. We show that the tandem Syk SH2 domains selectively associate with tyrosine-phosphorylated forms of the gamma and beta subunits of Fc epsilon RI. The isolated carboxy-proximal SH2 domain exhibited a significantly higher affinity for the Fc epsilon RI subunits than did the amino-proximal domain. When in tandem, the Syk SH2 domains showed enhanced binding to phosphorylated gamma and beta subunits. The conserved tyrosine-based activation motifs contained in the cytoplasmic domains of the gamma and beta subunits, characterized by two YXXL/I sequences in tandem, represent potential high-affinity binding sites for the dual SH2 domains of Syk. Peptide competition studies indicated that Syk exhibits a higher affinity for the phosphorylated tyrosine activation motif of the gamma subunit than for that of the beta subunit. In addition, we show that Syk is the major protein in RBL-2H3 cells that is affinity isolated with phosphorylated peptides corresponding to the phosphorylated gamma subunit motif. These data suggest that Syk associates with the gamma subunit of the high-affinity receptor for immunoglobulin E through an interaction between the tandem SH2 domains of SH2 domains of Syk and the phosphorylated tyrosine activation motif of the gamma subunit and that Syk may be the major signaling protein that binds to Fc epsilon RI tyrosine activation motif of the gamma subunit and that Syk may be the major signaling protein that binds to Dc epsilon tyrosine activation motifs in RBL-2H3 cells.

Identification of Src, Fyn, Lyn, PI3K and Abl SH3 domain ligands using phage display libraries.

Many proteins involved in intracellular signal transduction contain a small, 50-60 amino acid domain, termed the Src homology 3 (SH3) domain. This domain appears to mediate critical protein-protein interactions that are involved in responses to extracellular signals. Previous studies have shown that the SH3 domains from several proteins recognize short, contiguous amino acid sequences that are rich in proline residues. While all SH3 recognition sequences identified to date share a conserved P-X-X-P motif, the sequence recognition specificity of individual SH3 domains is poorly understood. We have employed a novel modification of phage display involving biased libraries to identify peptide ligands of the Src, Fyn, Lyn, PI3K and Abl SH3 domains. With biased libraries, we probed SH3 recognition over a 12 amino acid window. The Src SH3 domain prefers the sequence XXXRPLPPLPXP, Fyn prefers XXXRPLPP(I/L)PXX, Lyn prefers RXXRPLPPLPXP, PI3K prefers RXXRPLPPLPP while the Abl SH3 domain selects phage containing the sequence PPPYPPPP(I/V)PXX. We have also analysed the binding properties of Abl and Src SH3 ligands. We find that although the phage-displayed Abl and Src SH3 ligands are proline rich, they are distinct. In surface plasmon resonance binding assays, these SH3 domains displayed highly selective binding to their cognate ligands when the sequences were displayed on the surface of the phage or as synthetic peptides. The selection of these high affinity SH3 peptide ligands provides valuable information on the recognition motifs of SH3 domains, serve as new tools to interfere with the cellular functions of SH3 domain-mediated processes and form the basis for the design of SH3-specific inhibitors of disease pathways.

Toxicity of the novel anti-peptic ulcer agent catena-(S)-[mu-[Na- (3-aminopropionyl)histidinato(2-)-N1,N2,Q:N tau]-zinc in male cynomolgus monkeys.

A preliminary dose-range finding study and a 13-week toxicity study were performed in male cynomolgus monkeys with catena-(S)-[mu-[N a-(3-aminopropionyl) histidinato (2-)-N1,N2,O:N tau]-zinc] (Z-103, CAS 107667-60-7), a novel anti-peptic ulcer agent, as part of a safety evaluation program. In the preliminary ascending dose study emesis was observed in animals treated at 625 mg/kg and transient reductions in food intake with associated body weight loss in a male treated at 625 or 312.5 mg/kg. Plasma zinc levels were also increased in all animals treated at 625 or 312.5 mg/kg. As a result dosages of 0, 20, 63 and 200 mg/kg/day were selected for the 13-week toxicity study. In this study, treatment-related changes were confined to the 200 mg/kg/day dosage and consisted of emesis, piloerection and transient body weight loss in one animal, increased plasma zinc concentrations, and zinc and copper deposition in the liver and kidneys without any associated morphological change. The no observed effect level was estimated to be 63 mg/kg/day in this study.