The characteristics of extended-spectrum beta-lactamases in Korean isolates of Enterobacteriaceae

Extended-spectrum beta-lactamases (ESBLs) in gram-negative organisms have been implicated as the enzymes responsible for resistance to oxyimino-cephalosporins. The incidence of ESBL-producers in Korean isolates of Escherichia coli and Klebsiella pneumoniae were in the range of 4.8-7.5% and 22.5-22.8%, respectively. The ESBL-producing isolates revealed variable levels of resistance to cefotaxime, ceftazidime and aztreonam. They also showed the elevated MIC values of non-beta-lactam antibiotics. SHV-12 and SHV-2a were the enzymes most frequently found in K. pneumoniae strains, but TEM-52 was the most prevalent in E. coli isolates. About 15% of ESBL-producing isolates of Enterobacteriaceae produced CMY-1 enzyme, which conferred resistance to cephamycins such as cefoxitin as well as oxyimino-cephalosporins. Thus, the most common types of ESBLs in Korea are TEM-52, SHV-12 SHV-2a, and CMY-1.     

Ritscher-Schinzel cranio-cerebello-cardiac (3C) syndrome: report of four new cases and review

Ritscher-Schinzel syndrome, also known as the 3C syndrome, is a rare, autosomal recessive syndrome characterized by craniofacial, cerebellar, and cardiac anomalies. Cardiac manifestations include ventricular septal defect, atrial septal defect, tetralogy of Fallot, double outlet right ventricle, hypoplastic left heart, aortic stenosis, pulmonic stenosis and other valvular anomalies. Central nervous system anomalies include Dandy-Walker malformation, cerebellar vermis hypoplasia and enlargement of the cisterna magna. Craniofacial abnormalities seen are cleft palate, ocular coloboma, prominent occiput, low-set ears, hypertelorism, down-slanting palpebral fissures, depressed nasal bridge and micrognathia. Dandy-Walker malformation, posterior fossa cyst, hydrocephalus and congenital heart defect are common malformations that may occur in isolation or as a part of many syndromes. Accurate genetic diagnosis and counseling require detailed analysis of the external as well as the internal anatomy and knowledge of the relative frequencies of various malformations in syndromes that may have overlapping clinical signs. We have had the opportunity recently to study four cases of the Ritscher-Schinzel syndrome. A review of all reported cases is presented and an attempt made to define the minimum diagnostic criteria for the Ritscher-Schinzel syndrome. Of the nine craniofacial anomalies commonly reported as a part of the Ritscher-Schinzel syndrome, we consider two i.e., cleft palate and ocular coloboma, to be readily and objectively ascertainable. The other seven craniofacial traits, however, are somewhat subjective, require expert interpretation and are sometimes difficult to ascertain in a newborn or stillborn fetus. These are prominent forehead, prominent occiput, hypertelorism, down-slanting palpebral fissures, low-set ears, depressed nasal bridge and micrognathia. At least four of these were present in all cases that had a secure diagnosis of the Ritscher-Schinzel syndrome. Thus, the criteria we propose to establish the diagnosis of the Ritscher-Schinzel syndrome in a chromosomally normal sporadic case are the presence of cardiac malformation other than isolated patent ductus arteriosus, cerebellar malformation, and cleft palate or ocular coloboma or four of the following seven findings: prominent forehead, prominent occiput, hypertelorism, down-slanting palpebral fissures, low-set ears, depressed nasal bridge, and micrognathia.     

Rapid diagnosis of rotavirus gastroenteritis by a commercial latex agglutination test.

The Rotalex test, a commercial latex agglutination test for rotavirus, was compared with direct electron microscopy (EM) and the Rotazyme test I, a commercial enzyme immunoassay, for detection of rotavirus in stools of children and neonates. For initial stool specimens from 265 children (less than 3 years old) with diarrhea, the Rotalex test had a sensitivity of 81.7% and specificity of 99.5% compared with EM results. Positive and negative predictive values were 98 and 94.9%, respectively. The Rotalex test was slightly more sensitive and specific than the Rotazyme test. When daily stool specimens from patients with rotavirus gastroenteritis were examined, the sensitivity of the Rotalex test varied depending on the time of stool collection relative to the onset of symptoms. Sensitivity was 100 (20/20), 96 (23/24), and 54% (7/13) during 1 to 4, 5 to 7, and 8 to 18 days, respectively, after the onset of symptoms. The sensitivity of the Rotazyme test varied similarly with days from onset. We also examined 214 EM-negative stool specimens from asymptomatic newborns. False positivity by the Rotalex test was only 3.3% (7/214) compared with 4.2% (9/215) for the Rotazyme test. The Rotalex test was as sensitive and specific as EM for detection of rotavirus during the acute stage of illness and much faster and cheaper than EM or the Rotazyme test. The test appears to be suitable for routine use in small hospitals, emergency wards, or even the physician's office for rapid diagnosis of rotavirus gastroenteritis.     

Comparative biodistribution of indium- and yttrium-labeled B3 monoclonal antibody conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1 B4M-DTPA) or 2-(p-SCN-Bz)-1,4,7,10-tetraazacyclododecane tetraacetic acid (2B-DOTA)

The biodistribution of indium-111/yttrium-88-labeled B3 monoclonal antibody, a murine IgG1k, was evaluated in non-tumor-bearing mice. B3 was conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M) or 2-(p-SCN-Bz)-1,4,7,10 tetraazacyclododecane tetra-acetic acid (2B-DOTA) and labeled with ¹¹¹In at 1.4–2.4 mCi/mg and ⁸⁸Y at 0.1–0.3 mCi/mg. Non-tumor-bearing nude mice were co-injected i.v. with 5–10 Ci/4–10 g of ¹¹¹In/⁸⁸Y-labeled B3 conjugates and sacrificed at 6 h and daily up to 168 h post-injection. Mice injected with ¹¹¹In/⁸⁸Y (IB4M)-B3 showed a similar biodistribution of the two radiolabels in all tissues except the bones, where significantly higher accretion of ⁸⁸Y than ¹¹¹In was observed, with 2.8% ± 0.2% vs 1.3% ± 0.16% ID/g in the femur at 168 h, respectively (P<0.0001). In contrast, mice receiving the ¹¹¹In/⁸⁸Y-(DOTA)-B3 conjugate showed significantly higher accumulation of ¹¹¹In than ⁸⁸Y in most tissues, including the bones, with 2.0% ± 0.1% vs 1.2% ± 0.09% ID/g in the femur at 168 h, respectively (P<0.0001). Whereas the ratios of the areas underneath the curve (%ID × h/g) in the blood, liver, kidney and bone were 0.96, 1.12, 1.13, and 0.74 for ¹¹¹In/⁸⁸Y-(IB4M)-B3 and 0.84, 1.23, 1.56, and 1.31 for ¹¹¹In/⁸⁸Y (DOTA)-B3, respectively, ratios 1 were observed between ¹¹¹In-(IB4M)-B3 and ⁸⁸Y-(DOTA)-B3. In summary, while neither IB4M nor DOTA was equally stable for ¹¹¹In and ⁸⁸Y, the fate of ⁸⁸Y- (DOTA)-B3 could be closely traced by that of ¹¹¹ In-(IB4M)-B3.     

Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the link model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid E_max PD model. For the 300 mg BID dose, PD parameters were: maximum effect (E_max), 8.1mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC₅₀), 0.87 g·ml^–1; and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple E_max PD model. PD parameters obtained over the dose range were: E_max, 10.3 mmHg; Eo, 2.0 mmHg; and EC₅₀, 0.7 g·ml^–1. These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 g·ml^–1.     

Emergency surgery for generalized peritonitis caused by cytomegalovirus colitis in a patient with AIDS

Cytomegalovirus infection of the colon is a late and severe complication in human immunodeficiency virus patients. Despite availability of medical treatment, occasional life-saving emergency surgery must be performed. The controversial surgical aspects of treatment are discussed based upon an unusual case of aseptic generalized peritonitis without perforation. The feasibility and value of limited resection are emphasized.     

Neovascularization of nucleus pulposus. A diagnostic feature of intervertebral disc prolapse

STUDY DESIGN: Seventy-five surgically excised prolapsed intervertebral discs were histopathologically evaluated. Fifteen prospective normal cadaveric discs were used as control specimens. OBJECTIVE: To compare the morphologic features between the prolapsed and normal discs. SUMMARY OF BACKGROUND DATA: The histologic criteria were edge neovascularization of the fibrocartilage, chondrocyte cloning, fibrillation with fraying, and granular change. METHODS: Sections stained with hematoxylin and eosin, Van Gieson's, and toluidine blue were studied. The presence or absence of edge neovascularization was noted. The other criteria were graded based on a semiquantitative scoring system. RESULTS: Edge neovascularization was observed in 56% of the discs in the test group and in none of the control specimens. Fibrillation with fraying was the most significant finding in the test group (P < 0.001). Although the mean grades were higher in the test group, they did not predict the presence of edge neovascularization. CONCLUSIONS: Edge neovascularization was the most significant finding to confirm disc prolapse. Fibrillation with fraying, was observed more frequently in prolapsed intervertebral discs and the grades of fibrillation with fraying, chondrocyte cloning, and granular change were significantly higher in the test group. Pathologists can usually agree on the presence or absence of a particular histologic characteristic but are rarely consistent when they estimate the degree. Simple, reproducible agreed-on criteria are needed before semiquantitative evaluations become reliable.     

Three-Dimensional Echocardiographic Reconstruction of the Left Ventricle by a Transesophageal Tomographic Technique: In Vitro and In Vivo Validation of its Volume Measurement

Accurate determination of left ventricular (LV) volume has important therapeutic and prognostic implications in patients with cardiac disease. Volume estimations by two-dimensional techniques are not very accurate due to geometric assumptions. OBJECTIVES: To validate LV volume determinations by a new transesophageal three-dimensional echocardiographic technique. We performed three-dimensional reconstruction of the LV using an echo-computed tomographic (CT) technique based on serial pullback parallel slice imaging technique in both in vitro and in vivo settings. Fourteen latex balloons with various sizes (30-235 mL) and shapes (conical, pear shaped, round, elliptical, and aneurysms in various locations) filled with known volumes of water were imaged in a water bath. From the static three-dimensional image, the LV long axis was defined and the LV was sectioned perpendicular to this axis into 2-mm slices. The volume of each slice was calculated with the observer blinded to the actual volume as the product of the slice thickness and the manually traced perimeter of the slice and the LV volume as the sum of the volumes of the slices (Simpson's method). The calculated LV volume closely correlated with the actual volume (r = 0.99, P < 0.0001, calculated volume = 1.06x - 11.3, Deltavolume = -5.7 +/- 10.0 cc). Using the same system, transesophageal echocardiographic (TEE) images of the LV were obtained in 15 patients gated to respiration and ECG. Satisfactory dynamic three-dimensional reconstruction of the LV was possible in ten patients. The three-dimensional LV volumes (systolic and diastolic) using Simpson's method correlated well with those obtained from biplane or multiplane TEE images using the area length method (r = 0.89, p < 0.0001, y = 12.7 + 0.84x, Deltavolume = 1.3 +/- 18.1 cc). The LV major-axis diameters by the two methods showed very close correlations as well (r = 0.86, P < 0.0001, y = 19 + 0.74x, Deltadiameter = 1.0 +/- 7.2 mm). We conclude that three-dimensional LV volume calculation by the echo-CT technique is intrinsically sound, is independent of LV geometry, and with some limitations, is applicable in vivo. (ECHOCARDIOGRAPHY, Volume 13, November 1996)     

Characterization of AUCs from Sparsely Sampled Populations in Toxicology Studies

Purpose. The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. Methods. Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13–16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed critical time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each critical point. The data were subsequently modeled using PCNONLIN, and the parameters (k_a, k_e, and V_d) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally, Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. Results. The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was ~10%, with a precision (%CV) of ~15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. Conclusions. Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.