Fluoroscopic investigation of Riata® transvenous defibrillator leads.

BACKGROUND: Implantable cardioverter-defibrillator leads from Riata® family (St. Jude Medical Inc., Sylmar, CA, USA) have been recently recalled by Food and Drug Administration for concerns of a unique type of "inside-out" insulation failure leading to conductor externalization. The objective of this study was to evaluate the prevalence and predictors of conductor externalization in patients implanted with Riata 8 French (Fr) and 7 Fr leads. METHODS: Patients implanted with Riata® and Riata ST® who were actively followed up in our institution were scheduled for high resolution 3 view fluoroscopy and device interrogation including high voltage (HV) lead impedance testing. Fluoroscopic images were graded as presence of externalization or no externalization. RESULTS: Of the 90 patients who underwent screening fluoroscopy, majority had dual coil leads (62.5%) and median duration from the implant time to screening was 79.5 months. Twenty four (26.7%) patients exhibited evidence of lead externalization with 10 (41.6%) of these showing electrical abnormalities at the time of screening. No externalization was seen in the 7 Fr leads. Pacing thresholds were significantly elevated in the externalized cohort compared to non-externalized group (1.42 ± 1.23 vs. 0.93 ± 0.53; p = 0.01). Time since lead implant and lead diameter emerged as significant predictors of lead externalization on univariate analysis with only lead diameter being significant on multivariate analysis (odds ratio 30.68; 4.95-∞, p = 0.001). CONCLUSIONS: Prevalence of insulation failure exhibiting as conductor externalization is high (26.7%) among the large diameter 8 Fr Riata® leads with a significant proportion of patients manifesting electrical failure. High resolution 3 view fluoroscopy is a reasonable approach to screen for this unique type of insulation failure.

The evaluation of long-term effects of ionizing radiation through measurement of current sister chromatid exchange (SCE) rates in radiology technologists, compared with previous SCE values.

Ionizing radiation is a strong physical mutagen, causing breakage of phosphodiester bonds in DNA at any stage of the mitotic cycle. Analysis of sister chromatid exchange (SCE) has come into use as a sensitive DNA-damage indicator. We investigated the SCE rates in radiology technologists who are occupationally and chronically exposed to ionizing radiation. The study included 39 radiology technologists and 35 sex- and age-matched healthy controls. There was a statistically significant difference in the SCE frequency between radiology technologists and controls (p<0.0001). Additionally, previous SCE data of 10 radiology technologists were compared with current results regarding radiation exposure time. There was statistically significant difference between previous and current SCE values (p=0.005). The significant increase in the frequency of SCE in radiology technologists emphasizes the importance of radiation-protection procedures in order to minimize radiation exposure and avoid possible genotoxic effects. Comparison of two studies that measured SCE values of radiology technologists after 8 years also suggests that the genotoxic effect is reversible. In conclusion, radiation is still an important mutagenic agent despite improvements in daily working hours and conditions.

Atomic-scale evolution of modulated phases at the ferroelectric-antiferroelectric morphotropic phase boundary controlled by flexoelectric interaction.

Physical and structural origins of morphotropic phase boundaries (MPBs) in ferroics remain elusive despite decades of study. The leading competing theories employ either low-symmetry bridging phases or adaptive phases with nanoscale textures to describe different subsets of the macroscopic data, while the decisive atomic-scale information has so far been missing. Here we report direct atomically resolved mapping of polarization and structure order parameter fields in a Sm-doped BiFeO(3) system and their evolution as the system approaches a MPB. We further show that both the experimental phase diagram and the observed phase evolution can be explained by taking into account the flexoelectric interaction, which renders the effective domain wall energy negative, thus stabilizing modulated phases in the vicinity of the MPB. Our study highlights the importance of local order-parameter mapping at the atomic scale and establishes a hitherto unobserved physical origin of spatially modulated phases existing in the vicinity of the MPB.

Complete nucleotide sequence of Dendrocalamus latiflorus and Bambusa oldhamii chloroplast genomes.

Although bamboo is one of the most important woody crops in Asia, information on its genome is still very limited. To investigate the relationship among Poaceae members and to understand the mechanism of albino mutant generation in vitro, the complete chloroplast genome of two economically important bamboo species, Dendrocalamus latiflorus Munro and Bambusa oldhamii Munro, was determined employing a strategy that involved polymerase chain reaction (PCR) amplification using 443 novel primers designed to amplify the chloroplast genome of these two species. The lengths of the B. oldhamii and D. latiflorus chloroplast genomes are 139,350 and 139,365 bp, respectively. The organization structure and the gene order of these two bamboos are identical to other members of Poaceae. Highly conserved chloroplast genomes of Poaceae facilitated sequencing by the PCR method. Phylogenetic analysis using both chloroplast genomes confirmed the results obtained from studies on chromosome number and reproductive organ morphology. There are 23 gaps, insertions/deletions > 100 bp, in the chloroplast genomes of 10 genera of Poaceae compared in this study. The phylogenetic distribution of these gaps corresponds to their taxonomic placement. The sequences of these two chloroplast genomes provide useful information for studying bamboo evolution, ecology and biotechnology.

Ligand discovery and virtual screening using the program LIDAEUS.

This paper discusses advances in docking and scoring approaches with examples from the high-throughput virtual screening program LIDAEUS. We describe the discovery of small molecule inhibitors for the immunophilin CypA, the cyclin-dependent kinase CDK2 and the cyclapolin series of potent Polo-like kinase inhibitors. These results are discussed in the context of advances in massively parallel computing and in the development of annotated databases.

A boy with small supernumerary marker chromosome X identified by FISH.

Marker or ring X chromosomes are frequently seen in Ullrich-Turner Syndrome with 46,X,r(X) karyotype, but only 8 children were reported with an extra marker X chromosome in at least some of their cell lines, we describe a 5 years old male patient who is mosaic (17%) for a cell line with an extra ring shaped marker X chromosome in addition to a normal 46,XY cell line. He had mild motor mental retardation, a dysmorphic face, dysplastic ears, high arched palate, cryptorchidism and brachydactyly. G-banding showed 46,XY[83]/47,XY,+r?[17] karyotype. NOR banding revealed no satellite region but its centromere was intact in C-banding. By fluorescent in situ hybridization (FISH) technique, dual X/Y alpha-satellite probes were used to detect the origin of ring shaped marker chromosome and 17% of his cells had two X chromosome signals due to marker X; hybridization with X chromosome inactivation center (XIST) specific probe revealed the absence of the locus on the ring chromosome. In this report, clinical features of our patient are compared with previously reported cases and the cytogenetic and molecular cytogenetic techniques used to detect origin of marker chromosome are discussed.

Transposition of great arteries in an infant born after prenatal diagnosis of trisomy 20 mosaicism.

We report a case of prenatally diagnosed mosaic trisomy 20 in cells cultured from amniotic fluid. Trisomy 20 was present in 7 cells (13 percent) in a total of 52 investigated cells. Following the normal findings of an ultrasound scan, the couple decided to continue the pregnancy. A dysmorphic infant was born at the 38 weeks of gestation with generalized dysmorphic features and multiple cardiac anomalies including transposition of great arteries. Chromosome analysis on both cord blood and placenta at birth revealed a normal 46,XX karyotype. This patient is the first case of a liveborn infant with mosaic trisomy 20 cells detected in amniotic fluid culture with transposition of great arteries, atrioventricular concordance and ventricoarterial discordance.

A case with mosaic partial duplication of 1q: prenatal and postmortem clinical and cytogenetic evaluations.

Partial trisomy 1q including different segments of the long arm is a rare cytogenetic anomaly. Especially the cases with mosaic proximal tandem duplication of 1q included a longer fragment are very rare. Cases who have partial 1q trisomy showed large phenotypic variation due to the differences in size of the duplicated segments of 1q. The clinical phenotype of most cases is characterized by multiple congenital anomalies especially including central nervous system and developmental delay. We describe a prenatally diagnosed case with mild cerebral ventriculomegaly and karyotype with mosaic pure trisomy of chromosome 1q [(46,XX/46,XX,dup(1)(q21qter)]. Phenotypic postmortem examination showed cranial asymmetry, flat and broad nasal bridge, anteverted nostrils, hypertelorism, retrognathia, abnormal pinnae, hypoplasic thumbs, long fingers and toes, mediodorsal curvature of the 4th and 5th toes and posterior prominence of the heel was observed. Autopsy confirmed the ventriculomegaly. Postmortem chromosome preparation from skin culture, cord blood and intracardiac blood confirmed the mosaic pure trisomy of chromosome 1q.

Two complementary recombinant chromosomes 5 in a healthy woman.

We report a healthy woman with two abortions who is a carrier for a rare heterozygous double recombinant of an inv(5) chromosome, karyotype 46,XX,rec(5)dup(5p) inv(5)(p13q22),rec(5)dup(5q)inv(5)(p13q22). Her father had a 46,XY,inv(5)(p13q22) karyotype; his consanguineous wife had died. Molecular investigation of 11 highly polymorphic markers spanning chromosome 5 revealed biparental inheritance for two markers (D5S406, D5S681) on 5p15.3 and 5q13.1, and an allele constellation not compatible with paternal heterodisomy for marker D5S623 on 5q11.2. Eight markers were not informative. Three mechanisms of formation are proposed: First, fertilization of a normal oocyte by a sperm carrying the two recombinant chromosomes 5, followed by postzygotic recombination between the normal maternal homologue and the rec(5)dup(5p), and by loss of the mitotically recombined maternal homologue, leading to segmental paternal heterodisomy 5q13-->qter (trisomic rescue). Second, postzygotic recombination in a 46,XX,inv(5)(p13q22) zygote resulting in the 46,XX,rec(5)dup(5p)inv(5)(p13q22),rec(5) dup(5q)inv(5)(p13q22) karyotype, followed by absence of the original cell line in lymphocytes. Third and most likely, both parents were inv(5) carriers and complementary recombinations in maternal and paternal meiosis resulted in a zygote with two recombinant chromosomes 5. Our patient refused any further studies but later reported the birth of a phenotypically normal child. This is the first report known to us of complementation by two non-homologous recombinant chromosomes in a phenotypically normal woman, and the first example of a child born to a carrier of complementary recombinant chromosomes.

Correlation of pharmacokinetics with the antitumor activity of Cetuximab in nude mice bearing the GEO human colon carcinoma xenograft.

PURPOSE: The epidermal growth factor receptor (EGFR), a protein tyrosine kinase expressed in many types of human cancers including colon and breast, has been strongly associated with tumor progression. Cetuximab, an IgG1 anti-EGFR chimeric mouse/human monoclonal antibody, has been proven to be effective in the treatment of advanced colon cancer. To date, there has not been a study to systematically evaluate the pharmacokinetics (PK) of Cetuximab in a preclinical model and to further explore any correlation of drug exposure between animal models and cancer patients. In the present study, we characterized the PK of Cetuximab in nude mice at efficacious dose levels and further compared the preclinical optimal dose and active plasma drug concentration with those determined in clinical studies. EXPERIMENTAL DESIGN: The antitumor activity of Cetuximab was evaluated using the GEO human colon carcinoma xenografts implanted subcutaneously in nude mice. The drug was administered ip every 3 days for five total injections (inj) (q3dx5) at dose levels ranging from 1 mg/inj to 0.04 mg/inj. The plasma PK of Cetuximab was determined at dose levels of 1.0, 0.25, and 0.04 mg/inj with a single bolus iv or ip administration in nude mice. The tumoral PK of Cetuximab was determined at dose levels of 0.25, and 0.04 mg/inj with a single bolus ip administration in nude mice bearing GEO tumor xenografts. The plasma and tumoral levels of Cetuximab were quantitated by an ELISA assay. RESULTS: Cetuximab demonstrated a dose-dependent antitumor activity at dose levels of 0.25, 0.1, and 0.04 mg/inj, with a statistically significant tumor growth delay (in reaching a tumor target size of 1 gm) of 18 days (P < 0.001), 12.3 days (P < 0.01), and 10 days (P < 0.01) for 0.25, 0.1, and 0.04 mg/inj, respectively. A separate study employing the same treatment schedule showed that Cetuximab was equally active at dose levels ranging from 0.25 mg/inj to 1 mg/inj. Therefore, dose levels of Cetuximab from 1 mg/inj to 0.04 mg/inj can be considered to be within the efficacious range, while dose levels of 0.25 mg/inj or higher appeared to be optimal for the antitumor activity of Cetuximab in the GEO tumor model. When Cetuximab was given iv to mice, the elimination half life (t(1/2)) was 39.6, 37.8, and 42.2 h for doses of 1.0, 0.25, and 0.04 mg/inj, respectively, suggesting a similar disposition kinetics of Cetuximab within this dose range. The volume of distribution (V(d)) ranged from 0.062 l/kg to 0.070 l/kg, suggesting that Cetuximab is primarily confined to the plasma compartment with limited peripheral tissue distribution. Clearance (CL) was similar and no apparent PK saturation was observed across the dose ranging from 0.04 mg/inj to 1.0 mg/inj. When mice were administered with a single bolus ip administration at doses of 1, 0.25, and 0.04 mg/inj, the maximum plasma concentration (C(max)) was 407.6, 66.4, and 16.5 microg/ml. The area under the curve of plasma drug concentration (AUC) was 19212.4, 3182.4, and 534.5 microg/ml h, for 1.0, 0.25, and 0.04 mg/inj, respectively. The average steady state plasma concentration (C(ss avg)) for the multiple dosing schedule was estimated to be 73.1 microg/ml at 0.25 mg/inj and was considered as an active plasma drug concentration. The maximum tumoral concentration of Cetuximab was 2.6 and 0.53 ng/mg-tumor while the tumoral drug exposure was 112.6 and 18.3 ng/mg h for 0.25 and 0.04 mg/inj, respectively. The EGFR was estimated to be nearly completely occupied by Cetuximab at the optimal dose of 0.25 mg/inj. CONCLUSION: In the present study, we compared the preclinical optimal dose and the corresponding active plasma concentration determined in mice with those being observed in cancer patients, i.e. 65-100 microg/ml. The preclinical optimal dose of 0.25 mg/inj was significantly lower than the current clinical dose. However, the active plasma concentration at 0.25 mg/inj is within the range of the active drug concentrations in cancer patients treated with Cetuximab under the current optimal dosing regimen. It appears that the active plasma drug concentration determined in preclinical model predicts better than the optimal preclinical dose for the clinical development of antibody drugs.

Haplotype block definition and its application.

We present a simple two-stage procedure to define haplotype blocks and construct a statistic to test whether a polymorphism belongs to a block. Applying this method to the data of Gabriel et al. [2002] yielded longer haplotype blocks than were originally reported with a similar average percentage of common haplotypes in blocks. Furthermore, across regions of the genome and among the four populations that were studied, we found that linkage disequilibrium between a given single nucleotide polymorphism (SNP) and the haplotype block was a monotonic function of distance. This correlation was essentially independent of the minor allele frequency of the putative causal SNP when it fell outside of the block, however it was strongly dependent on the minor allele frequency when the SNP was internal to the block. These results have direct application to the design of candidate gene or region-wide association studies.

Ensuring accurate femoral guide pin placement in anterior cruciate ligament reconstruction.

The correct placement of the femoral tunnel is of critical importance in successfully reconstructing a knee with a deficient anterior cruciate ligament. By inserting the femoral guide pin through the anteromedial portal with the knee fully flexed, and subsequently withdrawing the pin from the anterior thigh until just the end of the pin remains at the insertion site at the posterior aspect of the intercondylar notch, the knee can then be safely extended and a thorough arthroscopic evaluation performed. In addition, the arthroscope can now be introduced into the medial portal to better evaluate the pin placement. Thus, visualization of the pin position and accurate placement based upon the intended tunnel size can be confirmed prior to drilling of the femoral tunnel, and more reproducibility in anterior cruciate ligament reconstructions can be achieved.

Fetal alcohol syndrome with Arnold-Chiari malformation: report of one case.

We report a rare case of fetal alcohol syndrome (FAS) with Arnold-Chiari malformation. The new-born had the typical facial abnormalities associated with FAS and the mother had a history of heavy drinking. CNS malformation, which is rarely seen in FAS, was also presented. The relationship between the developmental defects and maternal alcohol drinking are discussed together with a review of the literature.

Planar LiTaO(3) waveguides fabricated by proton exchange in concentrated and diluted pyrophosphoric acid with annealing.

Annealed proton-exchanged z-cut LiTaO(3) planar waveguides fabricated with pyrophosphoric acid have been characterized. For proton exchange, the extraordinary index increase Δ n(e) ranged from 0.0119 to 0.0141, depending on the exchange temperature. The effective diffusion coefficient D(e) ranged from 0.1325 µm(2)/h at 240°C to 0.545 µm(2)/h at 280 °C. Single-mode propagation losses were α = 0.7 dB/cm. Compared with benzoic acid, pyrophosphoric acid produces waveguides with a higher Δ n(e) and a lower propagation loss. For proton exchange in lithium phosphate-diluted pyrophosphoric acid, a lower Δ n(e) was obtained, but D(e) and propagation losses were not reduced. After proton exchange, the waveguides were annealed. The surface index initially increased, peaked, and then decreased. The waveguide depth d and the surface index n(s) were measured at regular intervals. Figures and empirical formulas relating the waveguide depth d and the surface index increase Δ n(s) to the anneal time, anneal temperatures, and the waveguide depth after proton exchange are given. An example is given in which, the desired waveguide parameters d and Δ n(s), the fabrication conditions could be calculated with the previously derived formulas. Propagation losses decreased to 0.4 dB/cm after prolonged annealing.

Rerouting of the biceps brachii for paralytic supination contracture of the forearm in tetraplegia due to trauma.

Six tetraplegic patients (eight forearms) who had a supination contracture were evaluated after lengthening and rerouting of the biceps brachii. Preoperatively, the mean range of supination and pronation of the forearm was 85 and 14 degrees, respectively. Pronation increased a mean of 75 degrees without affecting the strength of flexion or the flexion-extension arc of motion of the elbow. The forearms that had a satisfactory result had a mean active range of supination of 69 degrees, while those that had a poor result had no active supination. The mean duration of follow-up was twenty-seven months (range, twelve to seventy-two months). The result was considered satisfactory for six limbs and unsatisfactory for two. Functional gains were made in the patients' ability to feed and groom themselves, in their ability to tend to personal hygiene, and in writing and typing skills when the dominant extremity was treated. The results were less predictable for the non-dominant extremity. The maximum gain in the range of motion occurred at three months and the maximum functional gain, by six months.

[ELISA for detection of SC5b-9 levels in plasma and its clinical significance in SLE disease].

Using IgG from rabbit antiserum to human MAC neoantigens and SC5b-9, we established a sandwich ELISA for detecting SC5b-9 levels in human plasma. SC5b-9 was measured in 51 normal plasma samples and 40 plasma samples from patients with SLE. We found that SC5b-9 levels in 96.1% of the controls and in 78.9% of the patients with inactive SLE were below 450 ng/ml, while SC5b-9 levels in 81.0% of the patients with active SLE were above 450 ng/ml. This shows that SC5b-9 levels may be useful for diagnosing patients with clinically active SLE.

[Activation of human serum complement with inulin and purification of SC5b-9].

During a study of the effect of inulin on human complement, we found that complements were partially activated after incubation with inulin for one hour and completely activated after incubation for three hours at 37 degrees C. SC5b-9 was purified by DEAE-Sephacel chromatography, linear sucrose density gradients centrifugation and anti-IgM-protein A affinity chromatography. Purified SC5b-9, as assayed by immunoelectrophoresis, was a single fraction and had C5b, C6, C7/C8 alpha gamma, C8 beta, C9, C92, and S-protein bands appearing in the 10% SDS-PAGE.

Identification of occupational cancer risks using a population-based cancer registry.

The study of Xuan Wei fuel use and lung cancer mortality and also the interim case-control study suggested an association between domestic smoky coal use and Xuan Wei lung cancer. The collaborative studies of physical characterization, chemical analysis, and toxicology further substantiated this linkage. The Xuan Wei residents who used smoky coal inhaled extremely high concentrations of mostly submicron-sized particles, which can be inhaled and deposited effectively deep in the lung. These fine particles were composed mostly of organic compounds (72%), including mutagenic and carcinogenic organic compounds, especially in the aromatic and polar fractions. These residents were exposed to polycyclic aromatic compounds, such as benzo[a]pyrene, at comparable or higher levels than those measured in coke oven plants and other occupational environments (International Agency for Research on Cancer 1984). In comparison with wood and smokeless coal combustion emissions, the organic extracts of smoky coal emission particles showed much higher activity of genotoxicity and carcinogenicity. These results all point to a strong etiological link between the complex organic mixtures from smoky coal emissions and Xuan Wei lung cancer. This study and studies reported by other investigators (de Koning et al. 1984) suggested little association between indoor open-fire wood smoke and lung cancer. The less efficient lung deposition of the larger particles from wood combustion, as well as the lower concentrations of biologically active organic compounds, may contribute to the low rate of lung cancer in the wood-burning communes. As to the smokeless coal emissions, the lower particulate concentration and the lower organic content of the particles emitted may also contribute to the low lung cancer rate in the commune using this fuel. In conclusion, the complex organic mixtures from combustion emissions are genotoxic and carcinogenic in animal and in vitro assays. The magnitude of the cancer risks from the complex organic mixtures in man depends on the degree of the exposure, the types of the compounds contained in the mixtures, and the concentrations of these biologically active compounds present in the combustion emissions.