Refining the level for anticipated hepatotoxicity in acetaminophen poisoning

Treatment of an acetaminophen overdose with N-acetyl cysteine usually is based on the position of the 4-h acetaminophen (APAP) level on the Rumack-Matthew nomogram; however, there is disagreement on the level at which clinically relevant hepatotoxicity occurs. A retrospective review of all acute adult formulation APAP exposures reported to our poison center between 1986 and 1993 was performed and cases corresponding to the "possible risk or toxicity" range on the nomogram were identified. Our current poison center protocol for APAP poisoning does not recommend treatment with N-acetylcysteine (NAC) in low-risk patients if the 4-h serum APAP level or the extrapolated equivalent falls within the possible toxicity range on the nomogram. Seventeen cases met the inclusion criteria for the study and received no NAC; six additional patients met inclusion criteria but received one or two doses of NAC before therapy was discontinued. No patients in either group demonstrated clinical evidence of hepatotoxicity. This pilot study suggests that patients with no risk factors and APAP levels in the "possible risk" range may not require NAC therapy.     

Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup

BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCA) have been consistently detected in a subgroup of patients with Crohn's disease (CD). This study was designed to determine whether serum ANCA expression in patients with CD characterizes an identifiable clinical subgroup. METHODS: The study population consisted of 69 consecutive patients with an established diagnosis of CD as determined by a combination of characteristic clinical, radiographic, endoscopic, and histopathologic criteria. Sera from the patients were analyzed for the presence of ANCAs using the fixed neutrophil enzyme-linked immunosorbent assay (ELISA) assay. Perinuclear ANCA (pANCA)-positive and cytoplasmic ANCA (cANCA)-positive results by ELISA were confirmed by indirect immunofluorescence staining. Clinical profiles of the ANCA-positive patients with CD were compared with those of patients with CD not expressing ANCA (ANCA-negative). RESULTS: pANCA-positive patients with CD have endoscopically and/or histopathologically documented left-sided colitis and symptoms of left-sided colonic inflammation, clinically reflected by rectal bleeding and mucus discharge, urgency, and treatment with topical agents. One hundred percent of patients with CD expressing pANCA had "UC-like" features. CONCLUSIONS: In patients with CD, serum pANCA expression characterizes a UC-like clinical phenotype. Stratification of CD by serum pANCA provides evidence of heterogeneity within CD and suggests a common intestinal mucosal inflammatory process among a definable subgroup of patients with CD and UC expressing this marker.     

Imaging using inelastically scattered electrons in CTEM and STEM geometry

It is shown that energy filtered transmission electron microscopy images are closely related to energy spectroscopic scanning transmission electron microscopy images. For the case of a single atom, we explore this similarity using both the coupled channels and density matrix approaches. We extend the result to the crystal case and find that the similarity persists, the limiting effects due to energy differences in the scattered electrons being small for typical specimen thicknesses in high-resolution transmission electron microscopy.     

1H-NMR resonance assignments, secondary structure, and global fold of the TR1C fragment of turkey skeletal troponin C in the calcium-free state

The TR1C fragment of turkey skeletal muscle TnC (residues 12-87) comprises the two regulatory calcium binding sites of the protein. Complete assignments of the 1H-NMR resonances of the backbone and amino acid side chains of this domain in the absence of metal ions have been obtained using 2D 1H-NMR techniques. Sequential (i,i+1) and short-range (i,i+3) NOE connectivities define two helix-loop-helix calcium binding motifs, and long-range NOE connectivities indicate a short two-stranded beta-sheet formed between the two calcium binding loops. The two calcium binding sites are different in secondary structure. In terms of helix length, site II conforms to a standard "EF-hand" motif with the first helix ending one residue before the first calcium ligand and the second helix starting one residue after the beta-sheet. In site I, the first helix ends three residues before the first calcium ligand, and the second helix starts three residues after the beta-sheet. A number of long-range NOE connectivities between the helices define their relative orientation and indicate formation of a hydrophobic core between helices A, B, and D. The secondary structure and global fold of the TR1C fragment in solution in the calcium-free state are therefore very similar to those of the corresponding region in the crystal structure of turkey skeletal TnC [Herzberg, O., & James, M.N.G. (1988) J. Mol. Biol. 203, 761-779].     

Laparoscopic vs. open wedge biopsy of the liver

The number of people smoking free-base cocaine, or "crack," has increased dramatically in recent years. Concomitantly, the literature describing complications of such use has grown as well. Adverse pulmonary effects are being increasingly noted, such as respiratory symptoms, pulmonary hemorrhage, pulmonary edema, asthma, and pulmonary barotrauma. These and other pulmonary effects are reviewed.     

After-hours telephone coverage: the application of an area-wide telephone triage and advice system for pediatric practices

BACKGROUND: After-hours telephone calls are a stressful and frustrating aspect of pediatric practice. At the request of private practice pediatricians in Denver, a metropolitan area-wide system was created to manage after-hours pediatric telephone calls and after-hours patient care. This system, the After-Hours Program (AHP), uses specially trained pediatric nurses with standardized protocols to provide after-hours telephone triage and advice for the patients of 92 Denver pediatricians, representing 56 practices. OBJECTIVES: This report describes the AHP, presents data from 4 years' experience with the program, and describes results of our evaluation of the following aspects of the program: subscribing physician satisfaction, parent satisfaction, the accuracy and appropriateness of telephone triage, and program costs. METHODS: After-Hours Program records (including quality assurance data) for all 4 years of operation were retrospectively reviewed, tabulated, and analyzed. The results of two subscribing physician surveys and one parent caller satisfaction survey are presented. A retrospective review of after-hours patient care encounter forms assessed the necessity for after-hours visits triaged by the AHP. An analysis of the total cost of this program to 10 randomly selected subscribing physicians was conducted using current AHP data and a survey of the 10 physicians. RESULTS: In 4 years, 107,938 calls have been successfully managed without an adverse clinical outcome. Minor errors in using protocols occurred in one call out of 1450 after-hours calls. After-hours phoen calls necessitated an after-hours patient visit 20% of the time and generated one after-hours hospital admission out of every 88 calls. Just over half of the patients were managed with home care advice only, and 28% were given home care advice after-hours and seen the next day in the primary physician's office. Of all patients directed by the telephone triage nurses to be seen after hours, 78% were determined to have a condition necessitating after-hours care. Data are presented regarding call volumes by time of day, day of week, patient age, and patient's initial complaint. The 6 most common complaints accounted for more than one half of the calls, and 38 complaints accounted for more than 95% of all after-hours calls. Utilization by subscribing physicians is described. Satisfaction among subscribing pediatricians was 100%, and among parents was 96% to 99% on a variety of issues. The total cost to participating Denver pediatricians (which includes revenues "given up" as a result of not seeing patients after hours) ranged from 1% to 12% of their annual net income, depending on a variety of factors. CONCLUSIONS: Large-scale after-hours telephone coverage systems can be effective and well-received by patients, parents, and primary physicians. Data presented in this report can assist in planning the training of personnel who provide after-hours telephone advice and triage. Controversies associated with this type of program are discussed. Suggestions are made regarding the direction of future programs and research.     

Choroidal neovascular membrane in Best's vitelliform macular dystrophy

The right eye of a 9-year-old white boy with Best's vitelliform macular dystrophy had an intact egg-yolk lesion and a retinal pigment epithelial defect superiorly, suggesting an early pseudohypopyon stage. The disruptive phase of the left eye showed subretinal hemorrhages, a "signet ring," and a subretinal neovascular membrane.     

Modelling imaging based on core-loss spectroscopy in scanning transmission electron microscopy

Recent experimental realizations of atomic column resolution core-loss spectroscopy in the scanning transmission electron microscope have increased the importance of routinely modelling core-loss images. We discuss different approaches to wave function simulation and how they may be used in conjunction with the mixed dynamic form factor model to simulate images resulting from such inelastic scattering events. It is shown that, as resolution improves and in situations where the degree of thermal scattering is high, detailed quantitative comparisons will require the thermal scattering of electrons to be adequately modelled. Indeed, for sufficiently strong thermal scattering even qualitative interpretation may be affected: we give an example where this leads to a contrast reversal. We describe two methods suited to this purpose, the frozen lattice model and the scattering factor model, and explain how they may be combined with the mixed dynamic form factor approach.     

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.     

Disruption of cellular translational control by a viral truncated eukaryotic translation initiation factor 2alpha kinase homolog

Phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) is a common cellular mechanism to limit protein synthesis in stress conditions. Baculovirus PK2, which resembles the C-terminal half of a protein kinase domain, was found to inhibit both human and yeast eIF2alpha kinases. Insect cells infected with wild-type, but not pk2-deleted, baculovirus exhibited reduced eIF2alpha phosphorylation and increased translational activity. The negative regulatory effect of human protein kinase RNA-regulated (PKR), an eIF2alpha kinase, on virus production was counteracted by PK2, indicating that baculoviruses have evolved a unique strategy for disrupting a host stress response. PK2 was found in complex with PKR and blocked kinase autophosphorylation in vivo, suggesting a mechanism of kinase inhibition mediated by interaction between truncated and intact kinase domains.