Low dose oral anticoagulation therapy in Chinese children with congenital heart disease

BACKGROUND: Most patients with osteoarthritis (OA) are treated by primary care physicians (in this article, primary care physicians are family physicians and general internists). OBJECTIVE: To describe and compare the self-reported practice patterns of family physicians and general internists for the evaluation and management of severe OA of the knee, including factors that might influence referral for total knee replacement. DESIGN, SETTING, AND PARTICIPANTS: A survey was developed and mailed to randomly selected community family physicians and general internists practicing in Indiana. MAIN OUTCOME MEASURE: Self-reported physician practice patterns regarding OA of the knee. RESULTS: Physical examination was the most common method of evaluating OA of the knee. Family physicians were more likely to examine for crepitation, joint stability, and quadriceps muscle strength than were general internists (P<.05). Patients with OA of the knee treated by family physicians were more likely to receive nonsteroidal anti-inflammatory drugs or oral corticosteroids and were less likely to receive aspirin, acetaminophen, or narcotics compared with patients treated by general internists. Six patient characteristics were rated as positive factors favoring a referral for possible total knee replacement, 8 characteristics were rated as negative, and 5 were rated as not a factor in the decision about referral. CONCLUSIONS: Results from this study suggest that additional research is needed to determine the evaluative techniques for OA of the knee that provide the most useful information for management decisions, the management techniques that maximize patient outcomes, and the criteria that should be used to select patients who would benefit most from referral for possible total knee replacement.     

Passive transfer of Lambert-Eaton myasthenic syndrome induces dihydropyridine sensitivity of ICa in mouse motor nerve terminals

Mice were injected for 30 days with plasma from three patients with Lambert-Eaton Myasthenic Syndrome (LEMS). Recordings were made from the perineurial sheath of motor axon terminals of triangularis sterni muscle preparations. The objective was to characterize pharmacologically the identity of kinetically distinct, defined potential changes associated with motor nerve terminal Ca2+ currents (ICa) that were affected by LEMS autoantibodies. ICa elicited at 0.01 Hz were significantly reduced in amplitude by approximately 35% of control in LEMS-treated nerve terminals. During 10-Hz stimulation, ICa amplitude was unchanged in LEMS-treated motor nerve terminals, but was depressed in control. During 20- or 100-Hz trains, facilitation of ICa occurred in LEMS-treated nerve terminals whereas in control, no facilitation occurred during the trains at 20 Hz and marked depression occurred at 100 Hz. Saturation for amplitude and duration of ICa in control terminals occurred at 2 and 4-6 mM extracellular Ca2+, respectively; in LEMS-treated terminals, the extracellular Ca2+ concentration had to increase by two to three times of control to cause saturation. Amplitude of the two components of ICa observed when the preparation was exposed to 50 microM 3,4-diaminopyridine and 1 mM tetraethylammonium were both reduced by LEMS plasma treatment. The fast component (ICa,s) was reduced by 35%, whereas the slow component (ICa, s) was reduced by 37%. omega-Agatoxin IVA (omega-Aga-IVA; 0.15 microM) and omega-conotoxin-MVIIC (omega-CTx-MVIIC; 5 microM) completely blocked ICa in control motor nerve terminals. The same concentrations of toxins were 20-30% less effective in blocking ICa in LEMS-treated terminals. The residual ICa remaining after treatment with omega-Aga-IVA or omega-CTx-MVIIC was blocked by 10 microM nifedipine and 10 microM Cd2+. Thus LEMS plasma appears to downregulate omega-Aga-IVA-sensitive (P-type) and/or omega-CTx-MVIIC-sensitive (Q-type) Ca2+ channels in murine motor nerve terminals, whereas dihydropyridine (DHP)-sensitive (L-type) Ca2+ channels are unmasked in these terminals. Acute exposure (90 min) of rat forebrain synaptosomes to LEMS immunoglobulins (Igs; 4 mg/ml) did not alter the binding of [3H]-nitrendipine or [125I]-omega-conotoxin-GVIA (-omega-CgTx GVIA) when compared with synaptosomes incubated with an equivalent concentration of control Igs. Conversely, LEMS Igs significantly decreased the Bmax for [3H]-verapamil to approximately 45% of control. The apparent affinity of verapamil (KD) for the remaining receptors was not significantly altered. Thus acute exposure of isolated central nerve terminals to LEMS Igs does not increase DHP sensitivity, whereas it reduces the number of binding sites for verapamil but not for nitrendipine or omega-CgTx-GVIA. These results suggest that chronic but not acute exposure to LEMS Igs either upregulates or unmasks DHP-sensitive Ca2+ channels in motor nerve endings.     

Distinct morphological characteristics of touch, temperature, and mechanical nociceptive neurons in the crotaline trigeminal ganglia

Intrasomal recording and horseradish peroxidase injection techniques were employed in vivo to determine the morphological characteristics of touch, temperature, and mechanical nociceptive neurons in the trigeminal ganglia of crotaline snakes. The touch neurons, with a peripheral axon conducting at the A-beta range, could be subdivided into tactile and vibrotactile neurons according to their response properties, but there were no morphological differences between them. These neurons exhibited a large and oval soma and possessed a set of large stem, peripheral, and central axons which were all myelinated and equal in diameter with a constriction at the bifurcation. The temperature neurons, which conducted peripherally at the A-delta range, were physiologically separated into thermosensitive and thermo-mechanosensitive neurons, which were also morphologically indistinguishable. The temperature neurons had a round soma of medium size and a set of medium axons with varied axonal bifurcation patterns. All axons of these neurons were myelinated, but the central axon was thinner than the stem and peripheral axons. The mechanical nociceptive neurons, which had a peripheral axon conducting at the A-delta range, were morphologically heterogeneous based on their conduction velocities. The neurons conducting at the fast A-delta range were morphologically similar to the temperature neurons in the ganglion excepting their thinner central axons, whereas those at the slow A-delta range had a thinner myelinated stem axon that gave rise to a thinner myelinated peripheral axon and an unmyelinated stem axon with a bifurcation of either a triangular expansion at the bifurcating point or a central axon arising straightforwardly from the constant stem and peripheral axons. This study revealed that distinct morphological characteristics do exist for the touch and temperature neurons and the subtypes of mechanical nociceptive neurons in the trigeminal ganglion, but not for the subfunctional types of touch neurons or temperature neurons.     

Photoaffinity labeling of oxidosqualene cyclase and squalene cyclase by a benzophenone-containing inhibitor

A new orally active oxidosqualene:lanosterol cyclase (OSLC) inhibitor (Ro48-8071; Morand, O. H. et al. (1997) J. Lipid Res. 38, 373-390) showed potent noncompetitive inhibition of bacterial squalene:hopene cyclase (SHC) from Alicyclobacillus acidocaldarius (IC50 = 9.0 nM, KI = 6.6 nM) and OSLC (IC50 = 40 nM, KI = 22 nM for homogeneous rat liver OSLC). A tritium-labeled isotopomer (18.8 Ci/mmol) of this nonterpenoid inhibitor, which possesses a benzophenone (BP) photophore, was chemically synthesized as a photoaffinity label. Specific, efficient covalent modification of both OSLC and SHC enzymes was observed after UV irradiation at 360 nm. Labeling of both OSLC and SHC by [3H]Ro48-8071 was competitively displaced by coincubation with a 1000-fold molar excess of 18-thia-2, 3-oxidosqualene or the nonterpenoid inhibitor BIBX79. Displacement of labeling of OSLC was also achieved with the suicide substrate (3S)-29-methylidene-2,3-oxidosqualene. Thus, the nonsubstrate Ro48-8071 and both terpenoid and nonterpenoid inhibitors of these enzymes appear to share a common binding site.     

Closed management and percutaneous fixation of unstable proximal humerus fractures

BACKGROUND: In dealing with displaced proximal humerus fractures, there is still much controversy in treatment modalities. The latest investigations emphasize the concept of minimal exposure and rigid fixation. METHODS: The technique of closed reduction and percutaneous fixation with cannulated screws and k-pins was performed on 19 patients with two- and three-part proximal humerus fractures. The outcomes were evaluated with a mean follow-up of 21 months. RESULTS: All except one case had a solid union of the fracture. Sixteen of 19 patients (84%) acquired good or excellent results according to Neer's classification. No further collapse or avascular necrosis was found. CONCLUSION: The method of closed reduction and percutaneous fixation, although technically demanding, yields satisfactory results in displaced proximal humerus fracture. Cannulated screws provided rigid fixation that was the underlying tenet for early functional retrieval.     

Renal Effects of Water-Soluble Polyarylsulfonated C60 in Rats with An Acute Toxicity Study

Acute toxicity study of water soluble C₆₀ was conducted in young female rats with one dose intraperitoneal injection of C₆₀ ((CH₂)₄S0₃Na)_4-6. The preliminary results indicated its LD₅₀ value as approximately 600 mg/kg. The compound induced a unique phagolysosome-overload nephropathy that may serve as a biological marker in toxicity screening test for a series of synthesized water-soluble fullerenes.     

Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308)

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.     

Effect of mannitol crystallization on the stability and aerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-IgE monoclonal antibody

We have examined the stability and aerosol performance of the pharmaceutical protein recombinant humanized anti-IgE monoclonal antibody (rhuMAbE25) spray dried with mannitol. The aerosol performance was measured by the fine particle fraction (FPF), and stability was assessed by the formation of soluble aggregates. When mannitol was added to the spray-dried rhuMAbE25 formulation, its ability to stabilize the protein leveled off above about 20% (w/w, dry basis). The FPF of the spray-dried formulations was stable during storage for rhuMAbE25 containing 10% and 20% mannitol, but the 30% formulation exhibited a dramatic decrease upon storage at both 5 degreesC and 30 degreesC, due to mannitol crystallization. We tested the addition of sodium phosphate to a 60:40 rhuMAbE25:mannitol (w:w) mixture, which otherwise crystallized upon spray drying and yielded a nonrespirable powder. The presence of sodium phosphate was successful in inhibiting mannitol crystallization upon spray drying and dramatically lowering the rate of solid-state aggregation. However, over long-term storage some crystallization was observed even for the phosphate-containing samples, concomitantly with increased particle size and decreased suitability for aerosol delivery. Therefore, the physical state of mannitol (i.e., amorphous or crystalline) plays a role both in maintaining protein stability and providing suitable aerosol performance when used as an excipient for spray-dried powders. Agents which retard mannitol crystallization, e.g., sodium phosphate, may be useful in extending the utility of mannitol as an excipient in spray-dried protein formulations.     

Subclavian mycotic aneurysm presenting as mediastinal abscess

A 60-year-old man was admitted to a hospital for evaluation of intermittent fever, dysphagia, hoarseness, and general chest discomfort. Great vessel mycotic aneurysm was suspected when antibiotic trials failed and chest X-ray showed paraaortic mass with pleural effusion mimicking mediastinitis. Although the correct diagnosis of mycotic aneurysm of innominate artery was made thereafter and vigorous treatment was initiated immediately, this patient succumbed to overwhelming sepsis, probably due to a 2-week delay in another hospital. This case is reported to remind readers of the possibility of this unusual location of mycotic aneurysm. A high index of suspicion should be maintained to make an earlier diagnosis and obtain better prognosis. Computed tomography and 3D magnetic resonance angiography also significantly improve the diagnosis when mycotic aneurysm location is unusual and presentation is equivocal.     

Dimension and related anatomical distance of Koch's triangle in patients with atrioventricular nodal reentrant tachycardia

INTRODUCTION: The dimension of Koch's triangle in patients with AV nodal reentrant tachycardia has not been well described. Understanding the dimension and anatomical distance related to Koch's triangle might be useful in avoiding accidental AV block during ablation of the slow pathway. The purposes of this study were to define the dimension of Koch's triangle and its related anatomical distance and correlate these parameters with the successful ablation sites in patients with AV nodal reentrant tachycardia. METHODS AND RESULTS: We studied 218 patients with AV nodal reentrant tachycardia. The distance between the presumed proximal His-bundle area and the base of the coronary sinus orifice (DHis-OS) measured in the right anterior oblique view was used to define the dimension of Koch's triangle. The distance of the proximal His-bundle recording site from the successful ablation site (DHis-Ab) and the distance as a fraction of the entire length of Koch's triangle (DHis-Ab/DHis-Os) were determined. The mean DHis-Os and DHis-Ab were 25.9 +/- 7.9 and 13.4 +/- 3.8 mm, respectively. DHis-Os negatively correlated with patient age (r = -0.41, P < 0.0001) and body mass index (r = -0.18, P = 0.004). Among the patients with successful ablation sites in the medial area, DHis-Os was longer (27.2 +/- 6.6 vs 24.6 +/- 8.4 mm, P < 0.005), DHis-Ab was similar (12.9 +/- 3.1 vs 13.9 +/- 4.0, P > 0.05) and DHis-Ab/DHis-Os was smaller (0.48 +/- 0.04 vs 0.74 +/- 0.11, P < 0.05). Furthermore, the patients with successful ablation sites in the medial location needed more radiofrequency pulse numbers than those in the posterior location (6 +/- 4 vs 4 +/- 3, P < 0.05). CONCLUSION: The site of successful slow pathway ablation was consistently about 13 mm from the site recording the proximal His-bundle deflection in patients with AV nodal reentrant tachycardia despite marked variability in the dimensions of Koch's triangle; therefore, patients with large triangles required ablation in the medial region rather than the posterior region. Care should be taken when delivering radiofrequency energy to the posteroseptal area in patients with shorter DHis-Os to avoid injury to AV node.