Unequal access to cadaveric kidney transplantation in California based on insurance status.
To assess the impact of insurance status on access to kidney transplantation among California dialysis patients. California Medicare and Medicaid dialysis populations. All California ESRD dialysis patients under age 65 eligible for Medicare or Medicaid in 1991 (n = 9,102) took part in this cohort analytic study. Medicare and California Medicaid Program data were matched to the Organ Procurement and Transplantation Network Kidney Wait List files. Only 31.4 percent of California Medicaid dialysis patients were placed on the kidney transplant waiting list compared to 38.8 percent and 45.0 percent of dually eligible Medicate/Medicaid and Medicare patients, respectively. Compared to the Medicaid population, Medicare enrollees were more likely to be placed on the kidney transplant waiting list (adjusted Relative Risk [RR] = 2.10, Confidence Interval [CI] 1.68, 2.62) as were dually eligible patients (RR = 1.54, CI 1.24, 1.91). Once on the waiting list, however, Medicare enrollment did not influence the adjusted median waiting time to acquire a first cadaveric transplant (p > .05). California dialysis patients excluded from Medicare coverage, who are disproportionately minority, female, and poor, are much less likely to enter the U.S. transplant system. We hypothesize that patient concerns with potential subsequent loss of insurance coverage as well as cultural and educational barriers are possible explanatory factors. Once in the system, however, insurance status does not influence receipt of a cadaveric renal transplant.


Serum amyloid A measurements in saliva and serum in growing pigs affected by porcine respiratory and reproductive syndrome in field conditions.
The response of serum amyloid A (SAA) concentrations in serum and saliva during a natural porcine respiratory and reproductive syndrome (PRRS) outbreak was investigated. Basal levels of SAA were reliably determined and significant differences in SAA were found between diseased and healthy pigs in both sample types (serum SAA medians 78.3 vs. 55.74 mg/L, respectively; salivary SAA medians 8.97 vs. 2.52 mg/L, respectively; P<0.001). In serum, an SAA cut-off value of 66.4 mg/L showed 68.9% sensitivity and 68.09% specificity, while in saliva an SAA cut-off value of 5.59 mg/mL showed a sensitivity-specificity pair of 69-66%. Furthermore, it was observed that the growth stage of animals should be accounted to correctly interpret SAA measurements, since more accurate cut-off values could be determined and a particular behaviour of salivary SAA was identified in post-weaning pigs. Salivary and serum SAA measurements can therefore be confirmed as a valuable tool to consistently discriminate between healthy and PRRS-affected pigs.


[Two cases of suspected Bartonella henselae infection from a dog].
A 55-year-old male was admitted to our hospital because of fever and left submaxillary, right axillary, and left inguinal lymphadenopathy. A presumptive diagnosis of rickettsiosis was made and treatment with oral doxycycline was started. Lymphadenopathy was partialy resolved after antibiotics treatment. Ablation of the left inguinal node was done and histopathological examination showed non-Hodgkin's lymphoma. Lymphadenopathy was resolved by chemotherapy. The second patient, a 40-year-old male, developed a tender submandibular node. Excisional biopsy of the node was performed to eliminate lymphoma. Histopathological examination revealed granulomatous lymphadenitis with follicular hyperplasia. The patients had no history of cat contact, but owned a dog. Diagnosis of both cases was confirmed by the detection of IgG antibodies to Bartonella henselae with an enzyme immunoassay. Our findings suggest that dogs are implicated in B. henselae infection and can serve as a reservoir of the organism as well as cats. In the abscence of other bacterial and especially after exposure to dogs, B. henselae should be included as possible cause of lymphadenopathy.


Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.
This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.


New agents in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myeloid leukemia (AML). Therapeutic interventions for MDS other than allogeneic stem cell transplantation have been palliative. Novel and targeted therapeutic agents such as the inhibition of farnesyl transferases and receptor tyrosine kinases, more potent thalidomide analogs, arsenic trioxide, immunomodulating agents, hypomethylating agents, and histone deacetylase inhibitors have shown encouraging results and may offer durable benefit to patients with MDS. Further development of rational therapies and improvements in the outcome of patients with MDS are likely to emerge from an increased understanding of the pathophysiology of these diseases.


[Children with ADHD].
An ever increasing number of hyperactive and impulsive children receive the diagnosis Attention-Deficit Hyperactivity Disorder (ADHD). The relatively high prevalence, negative prognosis, and assumed inheritable nature of this behavioral disorder make ADHD one of the most prominent child diagnoses to date. This article discusses the behavioral characteristics, etiology, diagnostics and treatment of ADHD in school-age children. Finally, some suggestions for managing ADHD in the dental practice are given.


Low-overhead accrual failure detector.
Failure detectors are one of the fundamental components for building a distributed system with high availability. In order to maintain the efficiency and scalability of failure detection in a complicated large-scale distributed system, accrual failure detectors that can adapt to multiple applications have been studied extensively. In this paper, an new accrual failure detector--LA-FD with low system overhead has been proposed specifically for current mobile network equipment on the Internet whose processing power, memory space and power supply are all constrained. It does not rely on the probability distribution of message transmission time, or on the maintenance of a history message window. By simple calculation, LA-FD provides adaptive failure detection service with high accuracy to multiple upper applications. The related experiments and results have also been presented.


Representation of tones in noise in the responses of auditory nerve fibers in cats. I. Comparison with detection thresholds.
Rate and temporal responses evoked by 1-kHz or 8-kHz tones in continuous broadband noise are described for large populations of auditory nerve fibers in anesthetized cats. The signal-to-noise ratios (S/Ns) of the tone and noise stimuli were above behavioral detection thresholds. Stimulus combinations were presented (1) over a range of moderate to high noise intensities at a constant S/N and (2) using high intensity noise and varying S/N. Responses of low (less than 1 spike/sec) and medium (1 to 19 spikes/sec) spontaneous rate (SR) fibers were compared with those of high SR (greater than 19 spikes/sec) fibers. Low and medium SR fibers with best frequencies in the region of the test tone frequency exhibited tone-evoked rate changes at all sound levels tested. High SR fibers, in contrast, exhibited much weaker tone-evoked rate changes at the lowest noise level tested. In the presence of high intensity noise, high SR fibers did not exhibit tone-evoked rate changes due to saturation by the noise. Fibers with best frequencies in the region of 1 kHz also exhibited strong phase-locking to the 1 kHz tone which increased as the tone level increased but which did not differ for the various SR groups. Results suggest that information in the rate responses of low and medium SR fibers can account for the encoding of information about tones in noise by the nervous system.


Detection of trace drugs of abuse in baby formula using solid-phase microextraction direct analysis in real-time mass spectrometry (SPME-DART-MS).
The intentional or unintentional adulteration of baby formula with drugs of abuse is one of the many increasingly complex samples forensic chemists may have to analyze. This sample type presents a challenge because of a complex matrix that can mask the detection of trace drug residues. To enable screening of baby formula for trace levels of drugs, the use of solid-phase microextraction (SPME) coupled with direct analysis in real-time mass spectrometry (DART-MS) was investigated. A suite of five drugs was used as adulterants and spiked into baby formula. Samples were then extracted using SPME fibers which were analyzed by DART-MS. Development of a proof-of-concept method was completed by investigating the effects of the DART gas stream temperature and the linear speed of the sample holder. Optimal values of 350°C and 0.2 mm/s were found. Once the method was established, representative responses and sensitivities for the five drugs were measured and found to be in the range of single ng/mL to hundreds ng/mL. Additional studies found that the presence of the baby formula matrix increased analyte signal (relative to methanolic solutions) by greater than 200%. Comparison of the SPME-DART-MS method to a traditional DART-MS method for trace drug detection found at least a factor of 13 improvement in signal for the drugs investigated. This work demonstrates that SPME-DART-MS is a viable technique for the screening of complex matrices, such as baby formula, for trace drug residues and that development of a comprehensive method is warranted.


Investigation of the functional role of tryptophan-22 in Escherichia coli dihydrofolate reductase by site-directed mutagenesis.
We have applied site-directed mutagenesis methods to change the conserved tryptophan-22 in the substrate binding site of Escherichia coli dihydrofolate reductase to phenylalanine (W22F) and histidine (W22H). The crystal structure of the W22F mutant in a binary complex with the inhibitor methotrexate has been refined at 1.9-A resolution. The W22F difference Fourier map and least-squares refinement show that structural effects of the mutation are confined to the immediate vicinity of position 22 and include an unanticipated 0.4-A movement of the methionine-20 side chain. A conserved bound water-403, suspected to play a role in the protonation of substrate DHF, has not been displaced by the mutation despite the loss of a hydrogen bond with tryptophan-22. Steady-state kinetics, stopped-flow kinetics, and primary isotope effects indicate that both mutations increase the rate of product tetrahydrofolate release, the rate-limiting step in the case of the wild-type enzyme, while slowing the rate of hydride transfer to the point where it now becomes at least partially rate determining. Steady-state kinetics show that below pH 6.8, kcat is elevated by up to 5-fold in the W22F mutant as compared with the wild-type enzyme, although kcat/Km(dihydrofolate) is lower throughout the observed pH range. For the W22H mutant, both kcat and kcat/Km(dihydrofolate) are substantially lower than the corresponding wild-type values. While both mutations weaken dihydrofolate binding, cofactor NADPH binding is not significantly altered. Fitting of the kinetic pH profiles to a general protonation scheme suggests that the proton affinity of dihydrofolate may be enhanced upon binding to the enzyme. We suggest that the function of tryptophan-22 may be to properly position the side chain of methionine-20 with respect to N5 of the substrate dihydrofolate.


Evidence for DNA damage checkpoint activation in barrett esophagus.
Barrett esophagus is an epithelial metaplasia that predisposes to adenocarcinoma. Better markers of cancer risk are urgently needed to identify those patients who are likely to benefit most from emerging methods of endoscopic ablation. Disease progression is associated with genomic DNA changes (segmental gains, losses, or loss of heterozygosity). Although these changes are not easily assayed directly, we hypothesized that the underlying DNA damage should activate a DNA damage response (DDR), detectable by immunohistochemical (IHC) assays of checkpoint proteins and the resulting replicative phase cell cycle delays. Surgical specimens and endoscopic biopsies (N = 28) were subjected to IHC for the cell cycle markers cyclin A and phosphorylated histone H3 (P-H3), the DDR markers gammaH2AX and phosphorylated ATM/ATR substrates (P-ATM/ATRsub), and the DNA damage-responsive tumor suppressors p16 and p53. Correlations were made with histologic diagnoses. The fractions of cells that stained for cyclin A, P-H3, and gammaH2AX increased in parallel in dysplastic tissue, consistent with checkpoint-mediated cell cycle delays. Foci of nuclear gammaH2AX and P-ATM/ATRsub were demonstrated by standard and confocal immunofluorescence. Staining for p16 was more prevalent in early-stage disease with lower staining for gammaH2AX and P-H3. Staining for p53 was moderately increased in some early-stage disease and strongly increased in some advanced disease, consistent with checkpoint-mediated induction and mutational inactivation of p53, respectively. We suggest that IHC for DDR-associated markers may help stratify risk of disease progression in Barrett.


High-throughput target trial emulation for Alzheimer's disease drug repurposing with real-world data.
Target trial emulation is the process of mimicking target randomized trials using real-world data, where effective confounding control for unbiased treatment effect estimation remains a main challenge. Although various approaches have been proposed for this challenge, a systematic evaluation is still lacking. Here we emulated trials for thousands of medications from two large-scale real-world data warehouses, covering over 10 years of clinical records for over 170 million patients, aiming to identify new indications of approved drugs for Alzheimer's disease. We assessed different propensity score models under the inverse probability of treatment weighting framework and suggested a model selection strategy for improved baseline covariate balancing. We also found that the deep learning-based propensity score model did not necessarily outperform logistic regression-based methods in covariate balancing. Finally, we highlighted five top-ranked drugs (pantoprazole, gabapentin, atorvastatin, fluticasone, and omeprazole) originally intended for other indications with potential benefits for Alzheimer's patients.


Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin.
An emerging paradigm holds that loss of negative signalling to receptor tyrosine kinases (RTKs) is permissive for their oncogenic activity. Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells. Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis. Although mutational inactivation of the RALT gene was not detected in human breast carcinomas, RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines. Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin. Thus, loss of RALT expression cooperates with ERBB2 gene amplification to drive full oncogenic signalling by the ErbB-2 receptor. Moreover, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents.


Development of novel and polymorphic microsatellite DNA loci from Haliotis ovina.
Twelve microsatellite loci were developed from Haliotis ovina by the magnetic bead hybridization method. Genetic variability was assessed using 30 individuals from 3 wild populations. The number of alleles per locus ranged from 2 to 5, and the polymorphism information content ranged from 0.1228 to 0.6542. Observed and expected heterozygosities ranged from 0.0000 to 0.7778 and 0.1288 to 0.6310, respectively. These loci should provide useful information for genetic studies such as genetic diversity, pedigree analysis, construction of genetic linkage maps, and marker-assisted selection breeding in H. ovina.


A zinc binding site in viral serine proteinases.
The NS3 protein of hepatitis C virus contains a chymotrypsin-like serine proteinase domain. We built a homology model of this domain which predicts the presence of a tetradentate metal binding site formed by three cysteines and one histidine. These residues are strictly conserved in all known hepatitis C viral genotypes as well as in other recently discovered related hepatitis viruses. We show that the hepatitis C virus enzyme does indeed contain a Zn2+ ion with S3N ligation and that the metal is required for structural integrity and activity of the enzyme. Strikingly, the residues forming the metal binding site are also conserved in the chymotrypsin-like 2A cysteine proteinases of picornaviruses. Remarkably, in these highly variable viral genomes the metal binding site is more conserved than the catalytic residues and thus allows us to define a novel class of zinc binding chymotrypsin-like proteinases and to identify a new attractive target for antiviral therapy.


Deep vein thrombosis of the common iliac vein caused by neurogenic heterotopic ossification in the anterior lower lumbar spine of a patient with complete paraplegia due to radiation-induced myelopathy.
Context: Deep vein thrombosis (DVT), a frequent complication of spinal cord injury, is occasionally caused by neurogenic heterotopic ossification (NHO). In most cases of NHO, the hip joint is affected. Herein, we present a case of paraplegia following radiation-induced myelopathy that presented with left leg swelling due to DVT in the common iliac vein (CIV) caused by venous compression by NHO on the anterior lower lumbar spine.Findings: A 28-year-old man with complete paraplegia due to radiation-induced myelopathy presented with left lower extremity swelling 6 years after the onset of paraplegia. DVT in the left CIV was observed on computed tomography venography. The left CIV was significantly compressed between the NHO at the anterior longitudinal ligament of the lumbar spine and the right common iliac artery, suggestive of May-Thurner syndrome. Slightly distal to that compressed area, the left CIV was significantly compressed by the large NHO at the anterior longitudinal ligament of the lumbar spine.Conclusions: We believe that such compression of the left CIV would have contributed to the development of DVT. This case shows that DVT might be caused by NHO at the anterior aspect of the lumbar vertebral body, and this may help clinicians identify the main cause of DVT in the leg.


The development of DMA for the detection of amorphous content in pharmaceutical powdered materials.
The aim of this short study was to develop a novel method of sample presentation that will allow currently available DMA apparatus designed for the testing of self-supporting materials to detect amorphous content in controlled mixtures of amorphous and crystalline powders. The preparation of amorphous lactose was carried out by spraying drying, using a Büchi mini spray drier. Controlled mixtures of amorphous and crystalline lactose were produced to give eight samples ranging between 2% and 75% (w/w) amorphous content. These powdered mixtures were loaded into the DMA using a novel powder-pocket device, which consisted of folded sheet of stainless steel. The pocket was clamped directly into the DMA using a single cantilever configuration, and subjected to oscillating displacement, forcing horizontal shearing of the powder between the two plates of the pocket. Typical experimental parameters were a dynamic displacement of 0.05 mm with a frequency of 1 Hz and a heating rate of 5 degrees C/min, from 25 degrees C to 250 degrees C. Over the glass transition region of amorphous lactose, the storage modulus decreased rapidly and a peak was observed in the tandelta signal, which are typical DMA responses for self-supporting glassy materials over their glass transition region. In both the storage modulus and tandelta signals, contributions from both plasticized and non-plasticized amorphous lactose were demonstrated. Such an observation was caused by the powder pocket restricting the loss of the 2.5% (w/w) water present in the spray-dried lactose within the time scale of the first heating cycle. The tandelta peak for the non-plasticized amorphous lactose showed Arrhenius behaviour as function of oscillation frequency. The relationship between the increase in the tandelta peak with increasing frequency allowed the determination of an activation energy that was comparable to the literature values for similar compounds. The height of the tandelta peak for the non-plasticized material was directly proportional to the amount of amorphous lactose present in the mixtures. The glass transition response was still detectable in mixtures containing as little as 2% (w/w) amorphous content, however the theoretical limit of detection was higher than that determined for the same mixtures using solution calorimetry. The results demonstrate that the novel powder pocket allows the use of conventional DMA instruments for the analysis of pharmaceutical powders, however the technique requires more development to further reduce its theoretical limit of detection.


Phylogenetic analysis of gram-positive bacteria based on grpE, encoded by the dnaK operon.
The dnaK operon in gram-positive bacteria includes grpE, dnaJ and, in some members, hrcA as well. Both DnaK and DnaJ have been utilized for constructing phylogenetic relationships among various organisms. Multiple copies exist for dnaK and dnaJ genes in some bacterial genera, as opposed to a single gene copy for grpE and for hrcA, according to the currently available data. Here, we present a partial protein-based phylogenetic tree for gram-positive bacteria, derived by using the amino acid sequence identity of GrpE; the results are compared with the phylogenetic trees generated from 5S rRNA, 16S rRNA, dnaK and dnaJ sequences. Our results indicate three main groupings: two are within low-G+C DNA gram-positive bacteria comprising Bacillus species and Staphylococcus aureus on the one hand and Streptococcus species/Lactococcus lactis/Enterococcus faecalis/Lactobacillus sakei on the other hand; the Mycobacterium species and Streptomyces coelicolor, belonging to the high-G+C DNA gram-positive bacteria, form the third cluster. This hierarchical arrangement is in close agreement with that obtained with 16S rRNA and DnaK sequences but not DnaJ-based phylogeny.


Health-related quality of life among adults with multiple chronic conditions in the United States, Behavioral Risk Factor Surveillance System, 2007.
Little is known about health-related quality of life (HRQOL) among people with multiple chronic conditions. We examined the association between the number of chronic conditions and self-reported HRQOL outcomes among adults in the United States. We used data from the Behavioral Risk Factor Surveillance System (BRFSS) in 2007 (n = 430,912) to compare 4 HRQOL measures for people with any of 8 chronic conditions. We also assessed the frequency of self-reported physical and mental distress and the number of days activity was limited because of chronic conditions. We estimated prevalence and adjusted odds ratios (AORs) and 95% confidence intervals (CIs) by using survey logistic regression analyses. People with 3 or more chronic conditions had the highest risk of reporting fair or poor health compared with respondents with no chronic conditions (AOR, 8.7; 95% CI, 8.0-9.4). People with cardiovascular conditions or diabetes had higher risk of reporting poor HRQOL outcomes than those with other chronic conditions. The odds ratios for frequent physical distress were consistently higher than those for frequent mental distress and frequent activity limitations for all conditions. Strategies that help clinicians to manage their patients' chronic conditions may contribute to improved HRQOL among adults. Our findings may help to inform these strategies.


Supplementing Oregano Essential Oil in a Reduced-Protein Diet Improves Growth Performance and Nutrient Digestibility by Modulating Intestinal Bacteria, Intestinal Morphology, and Antioxidative Capacity of Growing-Finishing Pigs.
This study investigated the effects of supplementing oregano essential oil (OEO) to a reduced-protein diet on growth performance, nutrient digestibility, intestinal bacteria, intestinal morphology, and antioxidative capacity of growing-finishing pigs. Forty-eight barrows were randomly allotted to four treatments including normal-protein diet (NPD), reduced-protein, amino acid-supplemented diet (RPD), the same RPD supplemented with chlortetracycline (RPA), and RPD supplemented with OEO (RPO). The data showed that dietary OEO supplementation increased the average daily gain of pigs compared with NPD and RPD. The gain:feed in RPO- and NPD-fed pigs was higher than those in RPD- and RPA-fed pigs. Increased average daily feed intake and 10th-rib backfat thickness were detected in RPA-fed pigs. Pigs fed the RPO had higher apparent total tract digestibility (ATTD) of crude protein than those fed the other diets. The RPD and RPA treatments showed reduced counts of Lactobacillus spp. in ileal digesta of pigs. The RPA and RPO treatments also showed lower Escherichia coli counts in ileal digesta than the NPD and RPD treatments. Dietary OEO supplementation increased villous height of the jejunum and the ileal and plasma total antioxidative capacity of pigs. In conclusion, dietary OEO supplementation could improve the growth performance and nutrient digestibility of pigs by modulating intestinal bacteria, intestinal morphology, and antioxidative capacity.