Payment and Care for Hematopoietic Cell Transplantation Patients: Toward a Specialized Medical Home for Complex Care Patients.
Patient-centered medical home models are fundamental to the advanced alternative payment models defined in the Medicare Access and Children's Health Insurance Plan Reauthorization Act (MACRA). The patient-centered medical home is a model of healthcare delivery supported by alternative payment mechanisms and designed to promote coordinated medical care that is simultaneously patient-centric and population-oriented. This transformative care model requires shifting reimbursement to include a per-patient payment intended to cover services not previously reimbursed such as disease management over time. Payment is linked to quality measures, including proportion of care delivered according to predefined pathways and demonstrated impact on outcomes. Some medical homes also include opportunities for shared savings by reducing overall costs of care. Recent proposals have suggested expanding the medical home model to specialized populations with complex needs because primary care teams may not have the facilities or the requisite expertise for their unique needs. An example of a successful care model that may provide valuable lessons for those creating specialty medical home models already exists in many hematopoietic cell transplantation (HCT) centers that deliver multidisciplinary, coordinated, and highly specialized care. The integration of care delivery in HCT centers has been driven by the specialty care their patients require and by the payment methodology preferred by the commercial payers, which has included bundling of both inpatient and outpatient care in the peritransplant interval. Commercial payers identify qualified HCT centers based on accreditation status and comparative performance, enabled in part by center-level comparative performance data available within a national outcomes database mandated by the Stem Cell Therapeutic and Research Act of 2005. Standardization across centers has been facilitated via voluntary accreditation implemented by Foundation for the Accreditation of Cell Therapy. Payers have built on these community-established programs and use public outcomes and program accreditation as standards necessary for inclusion in specialty care networks and contracts. Although HCT centers have not been described as medical homes, most HCT providers have already developed the structures that address critical requirements of MACRA for medical homes.


Very late-onset friedreich ataxia with laryngeal dystonia.
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN) on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA), after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA), after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances) occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA.


Effects of hepatic ischemia-reperfusion injury on the hepatic mixed function oxidase system in rats.
Hepatic ischemia induced in vivo by ligation of the left hepatic lobe of rats for up to 2 hr had no effect on cytochrome P-450, cytochrome c reductase, or lobe histology; however, cytochrome b5 increased with ischemia duration. Ethylmorphine demethylation decreased 35% after 2 hr of ischemia. Reperfusion of tissue previously made ischemic for up to 2 hr was associated with appreciable necrosis as well as decreases in cytochrome P-450, cytochrome b5, cytochrome c reductase, and ethylmorphine demethylation. Serum alanine transaminase and aspartate transaminase concentrations were increased by reperfusion of previously ischemic tissue. Reperfusion of the previously ischemic lobe for 18 hr was associated with a greater loss of cytochromes P-450 and b5, cytochrome c reductase, and ethylmorphine demethylation than reperfusion for 1 hr. The total decrease in cytochrome P-450 and b5 content was equal to the decrease in total microsomal heme content, although cytochrome P-450 decreased more than cytochrome b5. Ethoxyresorufin deethylation by hepatic microsomes from 3-methylcholanthrene-treated rats was decreased by ischemia-reperfusion; however, pentoxyresorufin dealkylation by hepatic microsomes from phenobarbital-treated rats was not, suggesting specific cytochrome P-450 isozyme loss. In vitro NADPH-dependent lipid peroxidation in hepatic microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats resulted in a selective decrease of ethoxyresorufin but not pentoxyresorufin dealkylation, similar to that observed in livers subjected to ischemia-reperfusion in vivo. These data suggest that cytochrome P-450, ethylmorphine demethylation, and ethoxyresorufin deethylation are more susceptible to ischemia-reperfusion injury than cytochrome b5 or pentoxyresorufin dealkylation.


The Physiological Characteristics of an 83-Year-Old Champion Female Master Runner.
To examine the cardiorespiratory, muscular, and skeletal characteristics of an 83-year-old champion female master athlete (called DL in this study) who had set multiple world running records in the 80-to-84-year-old age group. Measures of maximal oxygen uptake, maximal heart rate, maximal isometric torque for knee extensor muscles, thigh and triceps surae muscle volumes, and bone mineral density (BMD) of the proximal femur region were evaluated. Based on previously published equations, physiological age was determined for maximal oxygen uptake, maximal heart rate, and maximal isometric torque. Muscle volumes for the dominant leg were compared with previously published sex- and age-matched data using z scores. For BMD, T score and z score were calculated. DL had the highest maximal oxygen uptake (42.3 mL·min-1·kg-1) ever observed for a female older than 80 years of age, which gave her a remarkable physiological age (27 y). By contrast, she had a physiological age closer to her biological age for maximal isometric torque (90 y) and maximal heart rate (74 y). The z scores for thigh (0.4) and triceps surae (1.1) muscle volumes revealed that DL's leg muscles were affected almost as much as her sex- and age-matched peers. The T score (-1.7) for BMD showed that DL had osteopenia but no osteoporosis, and the z score (0.7) showed that DL's BMD was similar to that of females of the same age. This single case study shows that the remarkable cardiorespiratory fitness coupled with intensive endurance training observed in a female master athlete was not associated with specific preservation of her muscular and skeletal characteristics.


NQO1 C609T polymorphism associated with esophageal cancer and gastric cardiac carcinoma in North China.
To investigate the association of the NQO1 (C609T) polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in North China. The NQO1 C609T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 317 cancer patients (193 ESCC and 124 GCA) and 165 unrelated healthy controls. The NQO1 C609T C/C, C/T and T/T genotype frequency among healthy controls was 31.5 %, 52.1 % and 16.4 % respectively. The NQO1 T/T genotype frequency among ESCC patients (25.9 %) was significantly higher than that among healthy controls (chi(2)=4.79, P=0.028). The NQO1 T/T genotype significantly increased the risk for developing ESCC compared with the combination of C/C and C/T genotypes, with an age, sex and smoking status adjusted odds ratio (OR) of 1.78 (1.04-2.98). This increased susceptibility was pronounced in ESCC patients with family histories of upper gastrointestinal cancers (UGIC) (adjusted OR=2.20, 95 % CI=1.18-3.98). Similarly, the susceptibility of the NQO1 T/T genotype to GCA development was also observed among patients with family histories of UGIC, with an adjusted odds ratio of 2.55 (95 % CI=1.21-5.23), whereas no difference in NQO1 genotype distribution was shown among patients without family histories of UGIC. Determination of the NQO1 C609T genotype may be used as a stratification marker to predicate the individuals at high risk for developing ESCC and GCA in North China.


Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer.
Fas (APO-1/CD95) is a cell surface receptor that mediates apoptosis when it reacts with Fas ligand (FasL) or Fas antibody. In this study, we analyzed Fas and FasL expression in normal esophageal mucosa and esophageal squamous cell carcinomas. Reverse transcriptase-PCR revealed that Fas, soluble Fas, and FasL were expressed in all eight esophageal squamous carcinoma cell lines analyzed. Furthermore, it was demonstrated that FasL expressed in esophageal carcinoma cells is functional because coculture experiments using FasL-expressing TE-15 esophageal carcinoma cells resulted in apoptosis of Jurkat T leukemia cells, which are sensitive to Fas-mediated apoptosis. Immunohistochemistry of Fas and FasL showed that they are constitutively expressed in normal esophageal mucosa, FasL being predominantly in the basal and suprabasal layers, whereas Fas is in more differentiated layers, i.e., rows of polyhedral cells of the intermediate layers and squamous cells forming the outer layers. In 18 of 19 invasive esophageal squamous cell carcinomas, FasL expression was found in >50% of tumor cells. In contrast, most tumors (15 of 19, 79%) either showed no Fas expression or showed expression in <5% of tumor cells. These alterations were already detected in dysplasia and carcinoma in situ. These results suggest that up-regulation of FasL and down-regulation of Fas expression are early and frequent events associated with the evolution of esophageal squamous cell carcinomas.


Beta2-integrins and acquired glycoprotein IIb/IIIa (GPIIb/IIIa) receptors cooperate in NF-kappaB activation of human neutrophils.
Microparticles from various cells are generated during inflammation. Platelet-derived microparticles (PMPs) harbor receptors that are not genuinely expressed by neutrophils. We tested whether or not functional glycoprotein IIb/IIIa (GPIIb/IIIa) receptors can be acquired by neutrophils via PMPs and whether these receptors participate in pro-inflammatory signaling. Surface expression was analyzed by flow cytometry and confocal microscopy. NF-kappaB activation was analyzed by Western blot experiments, electrophoretic mobility shift assays, and reverse transcription-PCR. Cell adhesion and spreading were estimated by myeloperoxidase assay and light microscopy. We found that PMPs transfer GPIIb/IIIa receptors to isolated and whole blood neutrophils via PMPs. We used specific antibodies in granulocyte macrophage colony-stimulating factor-treated neutrophils and observed that acquired GPIIb/IIIa receptors co-localized with beta2-integrins and cooperated in NF-kappaB activation. We show that Src and Syk non-receptor tyrosine kinases, as well as the actin cytoskeleton, control NF-kappaB activation. In contrast to NF-kappaB, acquisition of GPIIb/IIIa receptors was not necessary to induce adhesion to fibronectin or phosphatidylinositol 3-kinase/Akt signaling. When granulocyte macrophage colony-stimulating factor-stimulated neutrophils were incubated on fibronectin, strong NF-kappaB activation was observed, but only after loading with PMPs. Blocking either beta2-integrins or GPIIb/IIIa receptors abrogated this effect. Therapeutic GPIIb/IIIa inhibitors were similarly effective. The compounds also inhibited NF-kappaB-dependent tumor necrosis factor-alpha mRNA up-regulation. The data implicate GPIIb/IIIa receptors as new therapeutic targets in neutrophil-induced inflammation.


Component proteins in cystic fluid of Taenia solium metacestodes collected surgically from neurocysticercosis patients.
Surgically collected cystic fluid of Taenia solium metacestodes from patients of intracranial cystic lesion were compared in their protein composition with those from naturally infected pigs in Cheju Do, Korea and Ecuador. In non-denaturing discontinuous-polyacrylamide gel electrophoresis (disc-PAGE), no discernible differences were recognized in banding patterns between the cystic fluids from Cheju Do and Ecuador, and between the cystic fluids from pigs and human lesions except wider bands that corresponded to human albumin and gamma-globulin (in 4 of 9 patients). In reducing SDS-PAGE, bands in the cystic fluid from Ecuador showed the same banding pattern with that from Cheju Do but two bands of 21 and 17 kDa were stained darker. Cystic fluids from patients revealed the same protein compositions of the major protein bands of 94, 64, 15, 10 and 7 kDa as in the cystic fluid of pig origin, but human albumin (66 kDa), heavy and light chains of gamma globulin (55 and 22.5 kDa) were contaminated in 4 of 9 cystic fluids. Human CSF proteins seem to have been contaminated during cystic fluid collection. In any cystic fluid from patients, the major protein component was 150 kDa which was subdivided into 15, 10 and 7 kDa in reducing SDS-PAGE.


Predictors for County Level Variations in Initial 4-week COVID-19 Incidence and Case Fatality Risk in the United States.
While studies indicate differences in incidence and case fatality risk of COVID-19, few efforts have shed light on regional variations in the intensity of initial community spread. We conducted a nationwide study using county-level data on COVID-19 from Center for Systems Science and Engineering at Johns Hopkins University. We characterized intensity of initial community COVID-19 attack by calculating the incidence and case fatality risk (CFR) for the first 4-week period of COVID-19 spread in each county. We used multivariate multilevel multinomial logistic regression to estimate the association of county-level characteristics with COVID-19 incidence and CFR. Of 3,143 counties, we included 1,052 with at least 100 reported cases on June 1st. Median incidence was 193.4 per 100,000 population (IQR: 94.2-397.5). Median case fatality risk was 3.6% (IQR: 1.4-7.3). Median age, rural population, population density, lower education, uninsured population, obesity, COPD prevalence were positively associated, while population, female sex, races (Asian, white), higher education, excessive drinking were negatively associated with initial COVID-19 incidence. Median age, female sex, Asian race, population density, higher education, excessive drinking, Intensive Care Unit beds, airborne infection isolation rooms were positively associated, while Hispanic ethnicity, lower education, obesity (paradox), uninsured population were negatively associated with initial COVID-19 CFR.


The Climatological Significance of a Doubling of Earth's Atmospheric Carbon Dioxide Concentration.
The mean global increase in thermal radiation received at the surface of the earth as a consequence of a doubling of the atmospheric carbon dioxide content is calculated to be 2.28 watts per square meter. Multiplying this forcing function by the atmosphere's surface air temperature response function, which has recently been determined by three independent experimental analyses to have a mean global value of 0.113 K per watt per square meter, yields a value of </= 0.26 K for the resultant change in the mean global surface air temperature. This result is about one order of magnitude less than those obtained from most theoretical numerical models, but it is virtually identical to the result of a fourth experimental approach to the problem described by Newell and Dopplick. There thus appears to be a major discrepancy between current theory and experiment relative to the effects of carbon dioxide on climate. Until this discrepancy is resolved, we should not be too quick to limit our options in the selection of future energy alternatives.


Applying Case-Based Reasoning to Tactical Cognitive Sensor Networks for Dynamic Frequency Allocation.
In this paper, a cognitive radio engine platform is proposed for exploiting available frequency channels for a tactical wireless sensor network while aiming to protect incumbent communication devices, known as the primary user (PU), from undesired harmful interference. In the field of tactical communication networks, there is an urgent need to identify available frequencies for opportunistic and dynamic access to channels on which the PU is active. This paper introduces a cognitive engine platform for determining the available channels on the basis of a case-based reasoning technique deployable as a core functionality on a cognitive radio engine to enable dynamic spectrum access (DSA) with high fidelity. To this end, a plausible learning engine to characterize the channel usage pattern is introduced to extract the best channel candidate for the tactical cognitive radio node (TCRN). The performance of the proposed cognitive engine was verified by simulation tests that confirmed the reliability of the functional aspect, which includes the learning engine, as well as the case-based reasoning engine. Moreover, the efficacy of the TCRN with regard to the avoidance of collision with the PU operation, considered the etiquette secondary user (SU), was demonstrated.


[Separation and characteristics of the components of the antibiotic virenomycin].
The composition of virenomycin, a new antitumor antibiotic was studied. Two components V and M were detected with high resolution liquid chromatography and thin layer chromatography on siluphol (Czechoslovakia) and silica gel (Merk, BRD). A preparative method for separation of the antibiotic components with the use of chromatography on columns with silica gel was developed. Biological and physicochemical properties of separate components were studied to show that they significantly differed by their antibacterial action in vitro: virenomycin V was 2 to 4 times more active than virenomycin M against a number of microbes. The physicochemical properties of the components are similar. It was shown with mass spectrometry that the molecular weight of virenomycin is 12 units higher than that of virenomycin M. The PMR spectra showed that this difference is due to the presence of a vinyl group in the chromophore moiety of the virenomycin V molecule and a methyl group at the similar site of the virenomycin M molecule.


Deep venous thrombosis after percutaneous insertion of vena caval filters.
A large multicenter study has recently questioned the overall clinical efficacy of vena caval filters, especially when inserted prophylactically, because of the subsequent development of deep venous thrombosis (DVT) at the insertion site. We examined the incidence of this complication with newer, smaller diameter percutaneous devices. We reviewed our vascular surgery and interventional radiology clinical registries to identify patients in whom a femoral percutaneous vena caval filter had been placed from 1993 to 1998. This list was cross referenced with patients who had undergone lower extremity venous ultrasound scan examinations for the diagnosis of DVT in the vascular laboratory within a 60-day period before and after the insertion of the filter device. A total of 35 patients during this 5-year period had timely follow-up venous duplex scan studies performed. The indications for filter placement were DVT in 16 patients (46%), pulmonary embolus in 13 patients (37%), DVT and pulmonary embolus in three patients (9%), and prophylactically in three patients (9%) at high risk for thromboembolization. Of the patients with documented thromboembolic events, 91% (29 of 32) had contraindications to anticoagulation therapy, and the remaining 9% (3 of 32) represented failure of anticoagulation therapy. A Greenfield filter was used in 13 patients (37%), a Simon Nitinol filter was used in 11 patients (31%), and a VenaTech filter was used in nine patients (26%). The other two patients (6%) had a Bird's Nest filter inserted. At a mean follow-up period of 12 +/- 2 days (median, 6 days), there was a 40% (14 of 35) incidence of proximal DVT in venous segments without evidence of thrombus before filter insertion. The majority (71%; 10 of 14) occurred in the common femoral vein, with three located in the superficial femoral vein and one in the external iliac vein. The lowest incidence of DVT was seen with the Greenfield and Bird's Nest filters as compared with the smaller Simon Nitinol and VenaTech filters (20% vs 55%; P < .05). The highest incidence of thrombosis occurred in patients with pre-insertion pulmonary emboli (50%; 8 of 16) as compared with those patients with DVT (38%; 6 of 16) and prophylactic insertion (0%; 0 of 3). However, the subgroups were too small to attain statistical significance. There is a continuing and significant incidence of new DVT development ipsilateral to the percutaneous femoral insertion site of vena caval filters. The smaller diameter filters are not associated with a lower incidence of femoral thrombosis.


Effect of refined functional carbohydrates from enzymatically hydrolyzed yeast on the presence of Salmonella spp. in the ceca of broiler breeder females.
Broiler breeders hatched from Salmo-nella negative grandparents received either zero or 50 g/MT of refined functional carbohydrates (RFC) in their diets from d of placement to end of lay. There were no other treatments used. Pullets and cockerels were reared separately in an enclosed litter-floor house to 21 wk of age when 28 randomly selected pullets from each diet were transferred to individual cages for an additional 14 d before they were killed, and their ceca were excised aseptically and tested for Salmonella spp. The remaining birds were transferred to a two-thirds slat and one-third litter curtain-sided laying house. There were 8 pens of 60 to 65 females and 8 to 18 males, depending upon flock age and housing type, fed each diet, and there was no effort made to isolate pens from typical daily foot traffic between pens. At 51 wk of age, male progeny broiler chicks were hatched and received either zero or 50 g/MT of RFC to complete a 2 × 2 design with 4 replicate pens of 12 males per interaction. All broilers were tested for cecal Salmonella spp. at 34 d of age. Ceca were collected from 30 breeder hens from each treatment at 64 wk of age and tested for Salmonella spp. Of the ceca sampled at 23 wk from the control pullets, 71.4% were found to contain Salmonella spp., while none of the ceca from the RFC pullets tested positive. Of the ceca sampled from the control hens at 64 wk, 40% were found to contain Salmonella spp., while none of the ceca from the RFC hens tested positive. Salmonella spp. was isolated from broilers in one pen of the control broilers that were also progeny of control breeders out of 4 replicates but not from any pens in which the breeders had been fed RFC. These data demonstrated that RFC reduced natural Salmonella spp. colonization of broiler breeder hen and broiler progeny ceca during a complete production cycle.


[Geographic spreading of lung cancer in Azerbaijan].
Lung cancer is the second most common cancer and the leading cause of cancer death for both men and women. The impact of geographic as well as of exogenous factor and factors of risk, life style and environment play an important role in etiology of lung cancer. Geographic spread of lung cancer data in literature is fragmentary. The limited existing literature does not report a consistent story of geographic variation in Azerbaijan for the incidence associated with lung cancer. The aim of this study was to evaluate the impact of geographic variation on spread of lung cancer in Azerbaijan. Frequency of lung cancer in various regions of Azerbaijan; different histological types, sex, age and particular risk factors were investigated. It was revealed that epidermoid cancer was the most common histological type in all regions. The highest rate of epidermoid cancer 230 (55.56%) was revealed in industrial regions and industrial cities (Baku and Sumgait). The lowest rate of lung cancer was found in mountain region 12 (3.76%). Smoking and drinking alcohol increases risk of epidermoid cancer (41.2% of patients smoke and drink alcohol). The highest morbidity (13.55 per 100,000 population) and mortality (0.11) rates from lung cancer were observed in industrial regions. Analyses revealed that different endogenous and exogenous factors are associated with lung cancer.


A Discriminative Cross-Aligned Variational Autoencoder for Zero-Shot Learning.
Zero-shot learning (ZSL) aims to classify unseen samples based on the relationship between the learned visual features and semantic features. Traditional ZSL methods typically capture the underlying multimodal data structures by learning an embedding function between the visual space and the semantic space with the Euclidean metric. However, these models suffer from the hubness problem and domain bias problem, which leads to unsatisfactory performance, especially in the generalized ZSL (GZSL) task. To tackle such a problem, we formulate a discriminative cross-aligned variational autoencoder (DCA-VAE) for ZSL. The proposed model effectively utilizes a modified cross-modal-alignment variational autoencoder (VAE) to transform both visual features and semantic features obtained by the discriminative cosine metric into latent features. The key to our method is that we collect principal discriminative information from visual and semantic features to construct latent features which contain the discriminative multimodal information associated with unseen samples. Finally, the proposed model DCA-VAE is validated on six benchmarks including the large dataset ImageNet, and several experimental results demonstrate the superiority of DCA-VAE over most existing embedding or generative ZSL models on the standard ZSL and the more realistic GZSL tasks.


Insulin-dependent (type I) diabetes mellitus.
Insulin-dependent (type I) diabetes mellitus is a chronic disease characterized by hyperglycemia, impaired metabolism and storage of important nutrients, evidence of autoimmunity, and long-term vascular and neurologic complications. Insulin secretory function is limited. Cell membrane binding is not primarily involved. The goal of treatment is to relieve symptoms and to achieve blood glucose levels as close to normal as possible without severe hypoglycemia. However, even with education and self-monitoring of the blood glucose level, attaining recommended target values (plasma glucose level less than 8.0 mmol/L before main meals for adults) remains difficult. Human insulin offers no advantage in glycemic control but is important in the management and prevention of immune-related clinical problems (e.g., injection-site lipoatrophy, insulin resistance and allergy) associated with the use of beef or pork insulin. Therapy with one or two injections per day of mixed short-acting or intermediate-acting insulin preparations is a compromise between convenience and the potential for achieving target plasma glucose levels. Intensive insulin therapy with multiple daily injections or continuous infusion with an insulin pump improves mean glycated hemoglobin levels; however, it increases rates of severe hypoglycemia and has not been shown to decrease the incidence of clinically significant renal, retinal or neurologic dysfunction. Future prospects include automated techniques of insulin delivery, immunosuppression to preserve endogenous insulin secretion and islet transplantation.


Pretreatment verification of dose calculation and delivery by means of measurements with PLEXITOM™ phantom.
To validate a pretreatment verification method of dose calculation and dose delivery based on measurements with Metaplex PTW phantom. The dose-response relationships for local tumor control and radiosensitive tissue complications are strong. It is widely accepted that an accuracy of dose delivery of about 3.5% (one standard deviation) is required in modern radiotherapy. This goal is difficult to achieve. This paper describes our experience with the control of dose delivery and calculations at the ICRU reference point. The calculations of dose at the ICRU reference point performed with the treatment planning system CMS XiO were checked by measurements carried out in the PLEXITOM™ phantom. All measurements were performed with the ion chamber positioned in the phantom, at the central axis of the beam, at depth equivalent to the radiological depth (at gantry zero position). The source-to-phantom surface distance was always set to keep the source-to-detector distance equal to the reference point depth defined in the ICRU Report 50 (generally, 100 cm). The dose was measured according to IAEA TRS 398 report for measurements in solid phantoms. The measurement results were corrected with the actual accelerator's output factor and for the non-full scatter conditions. Measurements were made for 111 patients and 327 fields. The average differences between measurements and calculations were 0.03% (SD = 1.4%), 0.3% (SD = 1.0%), 0.1% (SD = 1.1%), 0.6% (SD = 1.8%), 0.3% (SD = 1.5%) for all measurements, for total dose, for pelvis, thorax and H&N patients, respectively. Only in 15 cases (4.6%), the difference between the measured and the calculated dose was greater than 3%. For these fields, a detailed analysis was undertaken. The verification method provides an instantaneous verification of dose calculations before the beginning of a patient's treatment. It allows to detect differences smaller than 3.5%.


Preferences of physicians and their patients for end-of-life care.
Both physicians and patients view advance directives as important, yet discussions occur infrequently. We assessed differences and correlations between physicians' and their patients' desires for end-of-life care for themselves. Study physicians (n = 78) were residents and faculty practicing in an inner-city, academic primary care general internal medicine practice. Patients (n = 831) received primary care from these physicians and were either at least 75 or between 50 and 74 years of age, with selected morbid conditions. Physicians and patients completed identical questionnaires that included an assessment of their preferences for six specific treatments if they were terminally ill. There were significant differences between physicians' and patients' preferences for all six treatments (p < .0001), with physicians wanting less treatment than their patients for five of them. Patients desiring more care (p < .01) were more often male (odds ratio [OR] 1.7). African-American (OR 1.6), and older (OR 1.02 per year). There were no such correlates with physicians' preferences. A treatment preference score was calculated from respondents' desires to receive or refuse the six treatments. Physicians' scores were highly correlated with those of their enrolled primary care patients (r = .51, p < .0001). Although patients and physicians as groups differ substantially in their preferences for end-of-life care, there was significant correlation between individual academic physicians' preferences and those of their primary care patients. Reasons for this correlation are unknown.


Blast noise characteristics as a function of distance for temperate and desert climates.
Variability in received sound levels were investigated at distances ranging from 4 m to 16 km from a typical blast source in two locations with different climates and terrain. Four experiments were conducted, two in a temperate climate with a hilly terrain and two in a desert climate with a flat terrain, under a variety of meteorological conditions. Sound levels were recorded in three different directions around the source during the summer and winter seasons in each location. Testing occurred over the course of several days for each experiment during all 24 h of the day, and meteorological data were gathered throughout each experiment. The peak levels (L(Pk)), C-weighted sound exposure levels (CSEL), and spectral characteristics of the received sound pressure levels were analyzed. The results show high variability in L(Pk) and CSEL at distances beyond 2 km from the source for each experiment, which was not clearly explained by the time of day the blasts occurred. Also, as expected, higher frequency energy is attenuated more drastically than the lower frequency energy as the distance from the source increases. These data serve as a reference for long-distance blast sound propagation.


Studies using structural analogs and inbred strain differences to support a role for quinone methide metabolites of butylated hydroxytoluene (BHT) in mouse lung tumor promotion.
Chronic treatment of BALB and GRS mice with BHT (2,6-di-tert-butyl-4-methylphenol) following a single urethane injection increases lung tumor multiplicity, but this does not occur in CXB4 mice. Previous data suggest that promotion requires the conversion of BHT to a tert-butyl-hydroxylated metabolite (BHTOH) in lung and the subsequent oxidation of this species to an electrophilic quinone methide. To obtain additional evidence for the importance of quinone methide formation, structural analogs that form less reactive quinone methides were tested and found to lack promoting activity in BHT-responsive mice. The possibility that promotion-unresponsive strains are unable to form BHTOH was tested by substituting this compound for BHT in the promotion protocol using CXB4 mice. No promotion occurred, and in-vitro work demonstrated that CXB4 mice are, in fact, capable of producing BHTOH and its quinone methide, albeit in smaller quantities. Incubations with BALB lung microsomes and radiolabeled substrates confirmed that more covalent binding to protein occurs with BHTOH than with BHT and, in addition, BHTOH quinone methide is considerably more toxic to mouse lung epithelial cells than BHT quinone methide. These data are consistent with the hypothesis that a two-step oxidation process, i.e. hydroxylation and quinone methide formation, is required for the promotion of mouse lung tumors by BHT.


Image-to-Images Translation for Multi-Task Organ Segmentation and Bone Suppression in Chest X-Ray Radiography.
Chest X-ray radiography is one of the earliest medical imaging technologies and remains one of the most widely-used for diagnosis, screening, and treatment follow up of diseases related to lungs and heart. The literature in this field of research reports many interesting studies dealing with the challenging tasks of bone suppression and organ segmentation but performed separately, limiting any learning that comes with the consolidation of parameters that could optimize both processes. This study, and for the first time, introduces a multitask deep learning model that generates simultaneously the bone-suppressed image and the organ-segmented image, enhancing the accuracy of tasks, minimizing the number of parameters needed by the model and optimizing the processing time, all by exploiting the interplay between the network parameters to benefit the performance of both tasks. The architectural design of this model, which relies on a conditional generative adversarial network, reveals the process on how the wellestablished pix2pix network (image-to-image network) is modified to fit the need for multitasking and extending it to the new image-to-images architecture. The developed source code of this multitask model is shared publicly on Github as the first attempt for providing the two-task pix2pix extension, a supervised/paired/aligned/registered image-to-images translation which would be useful in many multitask applications. Dilated convolutions are also used to improve the results through a more effective receptive field assessment. The comparison with state-of-the-art al-gorithms along with ablation study and a demonstration video1 are provided to evaluate the efficacy and gauge the merits of the proposed approach.


Knowledge gaps in stroke care: results of a survey of family physicians in Pakistan.
Family physicians play a pivotal role in stroke prevention (primary and secondary) and early management of stroke in developing countries. The objective of this study was to evaluate whether Pakistani family physicians' approach to stroke prevention and management was in accordance with established international guidelines. This was a cross-sectional survey of randomly selected family physicians in Pakistan, conducted in 2007. A total of 588 family physicians participated in the study. The data reveal that 88% of the physicians are aware of at least one of the 5 major symptoms of stroke, but only 46% are able to correctly idenitfy all 5 symptoms; 93% of the physicians check blood pressure in their adult patients regularly, and 63% use a cutoff of 140/90 mm Hg to start antihypertensive therapy in routine clinical practice; 90% ask their patients about cigarette smoking or tobacco use, but only 64% regularly advise their patients to quit smoking; 75% do not routinely check cholesterol levels in their patients; 36% treat patients with stroke by themselves, whereas 64% prefer to refer these patients to a specialist or hospital; 57% use intravenous or sublingual antihypertensive medications in patients with acute stroke with blood pressure >160/100 mm Hg; and 95% use antiplatelet agents for stroke prevention, with 70% using aspirin and 28% using clopidogrel as first-line antiplatelet therapy. These data indicate a substantial gap between international guidelines and Pakistani family physicians' management of stroke patients. There is an urgent need for stroke-related continuing medical education to propagate stroke management guidelines.


Stepwise haplotype analysis: are LD patterns repeatable?
A variety of techniques exist to describe and depict patterns of pairwise linkage disequilibrium (LD). In the current paper, a new log-linear framework is proposed for the summarisation of local interactions among single nucleotide polymorphisms (SNPs). Our approach provides a straightforward means of capturing the diversity of higher-order LD relationships for small numbers of loci by investigating inter-marker interactions. Our method was applied to a dataset of 76 SNP markers spanning a genomic interval of length 2.8 megabases. The analysis of three short sub-regions is described in detail here. Model and graphical representations of contiguous markers in medium to high LD are presented. In the regions studied, evidence for sub-structure was detected, supporting the view that the genomic reality is complex. Interestingly, a critical evaluation of the method by bootstrapping showed that while some LD relationships were captured in a highly repeatable fashion, the majority were not. Large numbers of small interactions, both direct and indirect, mean that many models can adequately summarise the data at hand. Our results suggest that repeatability should be further investigated in the application of LD-based approaches.


Treatment for Rotator Cuff Tear Is Influenced by Demographics and Characteristics of the Area Where Patients Live.
Atraumatic rotator cuff tear is a common orthopaedic complaint for people >60 years of age. Lack of evidence or consensus on appropriate treatment for this type of injury creates the potential for substantial discretion in treatment decisions. To our knowledge, no study has assessed the implications of this discretion on treatment patterns across the United States. All Medicare beneficiaries in the United States with a new magnetic resonance imaging (MRI)-confirmed atraumatic rotator cuff tear were identified with use of 2010 to 2012 Medicare administrative data and were categorized according to initial treatment (surgery, physical therapy, or watchful waiting). Treatment was modeled as a function of the clinical and demographic characteristics of each patient. Variation in treatment rates across hospital referral regions and the presence of area treatment signatures, representing the extent that treatment rates varied across hospital referral regions after controlling for patient characteristics, were assessed. Correlations between measures of area treatment signatures and measures of physician access in hospital referral regions were examined. Among patients who were identified as having a new, symptomatic, MRI-confirmed atraumatic rotator cuff tear (n = 32,203), 19.8% were managed with initial surgery; 41.3%, with initial physical therapy; and 38.8%, with watchful waiting. Patients who were older, had more comorbidity, or were female, of non-white race, or dual-eligible for Medicaid were less likely to receive surgery (p < 0.0001). Black, dual-eligible females had 0.42-times (95% confidence interval [CI], 0.34 to 0.50) lower odds of surgery and 2.36-times (95% CI, 2.02 to 2.70) greater odds of watchful waiting. Covariate-adjusted odds of surgery varied dramatically across hospital referral regions; unadjusted surgery and physical therapy rates varied from 0% to 73% and from 6% to 74%, respectively. On average, patients in high-surgery areas were 62% more likely to receive surgery than the average patient with identical measured characteristics, and patients in low-surgery areas were half as likely to receive surgery than the average comparable patient. The supply of orthopaedic surgeons and the supply of physical therapists were associated with greater use of initial surgery and physical therapy, respectively. Patient characteristics had a significant influence on treatment for atraumatic rotator cuff tear but did not explain the wide-ranging variation in treatment rates across areas. Local-area physician supply and specialty mix were correlated with treatment, independent of the patient's measured characteristics.


A review of the evidence for suboptimal compliance of healthcare practitioners to standard/universal infection control precautions.
The review examines from international research: the extent to which practitioners comply with infection control precautions; the pertinent issues that are considered influential in compliance; what strategies have been evaluated to instigate positive behaviour changes amongst practitioners and the effect of these interventions. Internationally, standard/universal precautions (UP) are regarded as fundamental in the prevention and control of infection, and effective in protecting practitioners and patients. However, adherence has been problematic and the practice of standard/UPs is globally suboptimal. Literature review where relevant evidence was identified using several electronic databases, from 1994 to 2006, with number of key terms utilized. Data were extracted by using key headings, which facilitated analysis. Thirty-seven studies were appraised. Twenty-four related to measuring practitioner compliance and 13 studies that evaluated the effect of a research intervention on compliance. In addition, other studies were included which examined the specific reasons for suboptimal compliance, or discussed infection control precautions generally. Compliance to infection control precautions is internationally suboptimal. The evidence confirms that compliance to specific aspects of standard/UPs varies, and practitioners are selective in their application of recommended practice. Compliance does improve following a structured intervention; however, research fails to indicate for how long the intervention affects practitioner compliance, or whether compliance after a period of time returns to the norm. Several reasons for non-compliance are discussed, and recommendations for future research are suggested. Relevance to clinical practice. Suboptimal compliance has significant implications for staff safety, patient protection and the care environment. Infection control teams and researchers need to consider the reasons for non-compliance and provide a supportive environment that is conducive to the routine, long-term application of standard precautions.


Decreased proteasome activity is associated with increased severity of liver pathology and oxidative stress in experimental alcoholic liver disease.
Because of its role in degrading the bulk of intracellular proteins and eliminating damaged proteins, the proteasome is important in maintaining cell viability. Previously, we showed a 35-40% decrease in proteasome peptidase activity when ethanol was administered to rats by intragastric infusion. We hypothesized that this reduction was caused by ethanol-elicited oxidative stress, the degree of which varies depending on the method of ethanol administration. This study examined the relationship of proteasome activity and content with ethanol-induced oxidative stress and the degree of liver injury. Rats were given ethanol or isocaloric dextrose-containing liquid diets by intragastric infusion for 1 month. The diets contained medium-chain triglycerides (MCT), palm oil (PO), corn oil (CO), or fish oil (FO) as the principal source of fat. Rats given ethanol and MCT exhibited no significant liver pathology, whereas cumulative pathology scores in ethanol-fed rats given PO, CO, or FO were 2.5, 5.4 and 7.0, respectively, indicating that ethanol and FO caused the greatest liver damage. The severity of liver pathology in the last three groups of animals correlated with levels of lipid peroxides and serum 8-isoprostanes. Alpha smooth muscle actin, an indicator of stellate cell activation, was increased relative to controls in the livers of all ethanol-fed rats except FO-fed animals, in which both control and ethanol-fed rats had similar levels of this protein. In livers of CO and FO ethanol-fed rats, proteasome chymotrypsin-like activity was decreased by 55-60%, but there was no quantitative alteration in 20S proteasome subunit content. In contrast, ethanol affected neither proteasome activity nor its content in MCT- and PO-treated animals. Our findings indicate that the severity of liver injury and ethanol-induced oxidative stress is associated with a reduction in proteasome catalysis.


[Clinicopathologic and immunohistochemical study on 22 cases of small cell carcinoma of the esophagus].
Primary small cell carcinoma of the esophagus (ESCC) is extremely rare. Twenty-two cases similar to the small cell carcinoma of the lung in histological features were diagnosed in this hospital during the past 30 years. Clinically, this tumor was highly malignant, rapidly growing and poor in prognosis. In our series, 18 of the 22 patients had died and 11 of them did so in about six months postoperatively. Histologically, 11 were of pure small cell type, 5 intermediate cell type and 6 combined small cell type. Neurosecretory granules were observed by electron microscopy in two cases. The results of immunohistochemical study with ABC method were as follow: EMA + 17/18, Keratin + 1/18, NSE + 9/18, S-100 protein + 1/18, but Chromogranin and Vimentin were negative. All the findings suggest that a small cell carcinoma of the esophagus may well be squamous, glandular, or neurosecretory differentiation, therefore supporting the opinion that this tumor is of total potential stem cell origin and that it may derive from the endoderm.


CD161+ CD4+ T Cells Harbor Clonally Expanded Replication-Competent HIV-1 in Antiretroviral Therapy-Suppressed Individuals.
The presence of an extremely stable latent reservoir of HIV-1 is the major obstacle to eradication, despite effective antiretroviral therapy (ART). Recent studies have shown that clonal expansion of latently infected cells without viral reactivation is an important phenomenon that maintains the long-term stability of the reservoir, yet its underlying mechanism remains unclear. Here we report that a subset of CD4+ T cells, characterized by CD161 expression on the surface, is highly permissive for HIV-1 infection. These cells possess a significantly higher survival and proliferative capacity than their CD161-negative counterparts. More importantly, we found that these cells harbor HIV-1 DNA and replication-competent latent viruses at a significantly higher frequency. By using massive single-genome proviral sequencing from ART-suppressed individuals, we confirm that CD161+ CD4+ T cells contain remarkably more identical proviral sequences, indicating clonal expansion of the viral genome in these cells. Taking the results together, our study identifies infected CD161+ CD4+ T cells to be a critical force driving the clonal expansion of the HIV-1 latent reservoir, providing a novel mechanism for the long-term stability of HIV-1 latency.IMPORTANCE The latent reservoir continues to be the major obstacle to curing HIV-1 infection. The clonal expansion of latently infected cells adds another layer maintaining the long-term stability of the reservoir, but its mechanism remains unclear. Here, we report that CD161+ CD4+ T cells serve as an important compartment of the HIV-1 latent reservoir and contain a significant amount of clonally expanded proviruses. In our study, we describe a feasible strategy that may reduce the size of the latent reservoir to a certain extent by counterbalancing the repopulation and dissemination of latently infected cells.


The distribution of Yin-Deficient symptoms and their relationship on survival rate in cancer patients with Yin-Deficiency.
Yin-Deficiency (YD), representing a status of the human body under lack of nutrition and fluid in traditional Chinese medicine, is commonly seen in late stage of cancer patients. It is not known whether the severity of YD related symptoms/signs can predict the survival rate of cancer patients. This study evaluated the distribution of Yin-deficiency symptoms/signs (YDS) in cancer patients with YD, and investigated whether the severity of YDS can predict the survival rate of cancer patients with YD. From 5 January 2007 to 5 May 2007, we selected 43 cancer patients with diagnosis of YD from hospitalized patients and outpatients. The severity of YD was evaluated by a questionnaire. We further estimated the cumulative probabilities of the survival rates over 4 months since the start of study by the Kaplan-Meier product-limit method, and compared the differences among groups with various severities in each symptom/sign with the use of the log-rank test. The results revealed that, the 3 most common YDS were sleeplessness with annoyance, less or non-coated tongue with or without redness and dry mouth. In the survival rate analysis, only 2 parameters, rapidly small pulse (p = 0.002) and less-or non-coated tongue with paleness (p = 0.017), were found to be related to the decrease of cancer patients with YD. This suggests that, both rapidly small pulse and less-or non-coated tongue without redness may be used as predictors for the estimation of survival rate in cancer patients with YD.


Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.
Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.


A Review on the Sex Differences in Organ and System Pathology with Alcohol Drinking.
Hazardous consequences of alcohol consumption adversely influence overall health, specifically physical and mental health. Differences in alcohol consumption and manifestations in pathology have been observed between males and females, however research on understanding these differences is limited. Negative consequences of alcohol consumption have now been studied including sex as a significant factor. Some studies have shown differences in the severity of consequences of alcohol consumption between the sexes, both in the mental consequences and changes/ injury in various organ systems. Over time, reports in females on both the dynamics of drinking and on the hazardous consequences of alcohol consumption have grown, primarily because of more awareness, better observation, and the inclusion of sex as a factor in scientific investigations. This paper reviews role of sex differences in pathophysiological and behavioral consequences of alcohol drinking.


Differential regulation of leucocyte L-selectin (CD62L) expression in normal lymphoid and inflamed extralymphoid tissues.
To study tissue expression of L-selectin, a leucocyte cell surface molecule that is considered to be involved in adhesion to certain endothelia, particularly in peripheral lymph nodes and during inflammation, and is shed upon leucocyte activation. Leucocytes were examined by immunohistochemistry and double immunofluorescence staining in various lymphoid sites and normal and inflamed extralymphoid tissues. L-selectin was present on mantle zone B lymphocytes in different lymphoid sites, including in intestinal lymphoid tissue, but was absent on germinal centre B cells. Splenic white pulp B cells also expressed L-selectin. The proportion of T lymphocytes expressing L-selectin depended on the site under study, being greatest in peripheral lymph nodes (mean 48% of T cells positive), and lower in mucosal lymphoid sites and spleen (9 and 11% positive, respectively). Non-lymphocytic L-selectin staining was observed on follicular dendritic cells in tonsils and on macrophages in thymus. L-selectin positive leucocytes were rare in normal extralymphoid tissues, and relatively few were seen in most inflammatory settings. However, in rejecting renal transplants, a higher proportion (30%) of leucocytes expressed L-selectin. Overall, the results indicate how the degree of L-selectin expression by leucocytes in particular tissues may reflect a requirement for L-selectin expression for entry into those tissues and the activation state of leucocytes once localised there.


Interstitial Silica and pH in Marine Sediments: Some Effects of Sampling Procedures.
The temperature at which the interstitial water was squeezed from a marine sediment had a profound effect on the measured interstitial silica concentrations which showed an average increase of 51 percent after the sediment was exposed to a temperature 20 degrees C higher than the in situ temperature. Similar effects were not found for interstitial phosphate or alkalinity, but the pH was slightly higher in the water squeezed at the higher temperature. These tempreature-induced changes were completed in a few hours. The use of filter paper can significantly lower the pH of expressed pore waters. Until some important questions about temperature effects are answered, all future data on the pH and silica concentration of pore waters of marine sediments should be obtained from samples extracted at in situ temperatures.


Hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor and erythropoietin in the absence of matrix metalloproteinase-9.
The use of mobilized hematopoietic progenitor cells (HPC) has largely replaced the use of bone marrow HPC for autologous and allogeneic transplantation; however, the mechanisms of HPC mobilization remain unclear. A better understanding of these mechanisms, may allow the development of improved (potentially more rapid and/or higher yield) HPC mobilization strategies, especially for patients who mobilize poorly using current mobilization protocols. Clinically, granulocyte colony-stimulating factor (G-CSF) is widely used to induce HPC mobilization, and evidence suggests that metalloproteinase enzymes released by activated granulocytes play an important role in the G-CSF-induced HPC mobilization. These enzymes may act to disrupt putative cell-cell and/or cell-extracellular matrix interactions within the hematopoietic microenvironment thereby releasing HPC into the blood. Matrix metalloproteinase-9 (MMP-9) appears to be important for G-CSF-induced mobilization. Using an MMP-9 knock-out (KO) mouse model, we investigated the role of MMP-9 in G-CSF and erythropoietin (EPO)-based HPC mobilization at clinically relevant cytokine doses. There were few hematologic or hematopoietic differences between the wild-type and MMP-9KO mice during steady-state hematopoiesis. When treated subcutaneously with EPO (500 U/kg per day) and G-CSF (15 microg/kg per day) for 5 days and assayed on day 6, similarly increased extramedullary hematopoiesis and numbers of HPC in the spleen and blood were observed for both the wild-type and MMP-9KO mice. These data demonstrate that MMP-9 is not required for EPO + G-CSF mobilization and that alternative mobilization mechanisms must be active at clinically relevant cytokine concentrations.


Racial and ethnic disparities in a national cohort of ampullary cancer patients.
Racial and ethnic variations have been described in the different malignancies, but no such data exists for ampullary cancer. The aim of this study was to present an updated report on the epidemiology, treatment patterns, and survival of a national cohort of ampullary cancer patients. Patients diagnosed with ampullary cancer between 2004 and 2014 were identified in the National Cancer Database. Overall survival was estimated and compared between racial/ethnic groups using the log-rank test. A total of 14 879 patients were identified; 78% of the patients were White, 9% Hispanic, 8% Black, and 5% Asian. We noted significant differences in disease presentation, socioeconomic status, and outcomes. Blacks had the lowest median overall survival at 18.9 months followed by Whites at 23.9 months, Hispanics at 32.7 months, and Asians at 37.4 months. On a multivariate Cox proportional-hazards model, being Black was associated with worse survival compared to being White while being Asian and Hispanic were associated with better survival. Overall survival of ampullary cancer patients was independently associated with race and ethnicity. Further studies are needed to clarify whether these disparities are primarily due to socioeconomic status or biologic factors.


Aerogels for Biomedical, Energy and Sensing Applications.
The term aerogel is used for unique solid-state structures composed of three-dimensional (3D) interconnected networks filled with a huge amount of air. These air-filled pores enhance the physicochemical properties and the structural characteristics in macroscale as well as integrate typical characteristics of aerogels, e.g., low density, high porosity and some specific properties of their constituents. These characteristics equip aerogels for highly sensitive and highly selective sensing and energy materials, e.g., biosensors, gas sensors, pressure and strain sensors, supercapacitors, catalysts and ion batteries, etc. In recent years, considerable research efforts are devoted towards the applications of aerogels and promising results have been achieved and reported. In this thematic issue, ground-breaking and recent advances in the field of biomedical, energy and sensing are presented and discussed in detail. In addition, some other perspectives and recent challenges for the synthesis of high performance and low-cost aerogels and their applications are also summarized.


Stretchable thin-film transistors with molybdenum disulfide channels and graphene electrodes.
Two-dimensional (2D) materials including graphene and transition metal dichalcogenides (TMDCs) have attracted great interest as new electronic materials, given their superior properties such as optical transparency, mechanical flexibility, and stretchability, especially for application in next-generation displays. In particular, the integration of graphene and TMDCs enables the implementation of 2D materials-based thin-film transistors (TFTs) in stretchable displays, given that TFTs are the fundamental element of various modern devices. In the present study, we demonstrate chemical-vapor-deposited molybdenum disulfide and graphene-based TFTs on a polymer substrate and investigate the electrical characteristics of TFTs under mechanical deformation to determine the stretchability of our devices. Furthermore, the mechanisms leading to TFT performance degradation are investigated, as they relate to the change in the contact resistance that is closely associated with the relative deformation of 2D materials under mechanical stress. Therefore, the synergetic integration of 2D materials with versatile electrical properties provides an important strategy for creating 2D materials-based stretchable TFTs, thus extending the excellent potential of 2D materials as innovative materials for stretchable active-matrix displays.


Challenges in Palliative Care Research on Family Caregivers: Who Volunteers for Interviews?
Background: Interviews are a common method of data collection in palliative care research because they facilitate the gathering of rich, experiential data that are important for theory and practice. What is less clear is the extent to which those interviewed are representative of the larger group. Objective: The aim of this study was to determine if family caregivers who volunteer to be interviewed were similar or different to those who do not. Design: This study used data from the Caregiving and Bereavement study, a prospective, longitudinal mixed-methods study of family caregivers' general health, quality of life, and grief. Setting/Subjects: The 16 caregivers who volunteered to be interviewed were compared to the 20 who did not. Measurements: Comparisons were made in terms of the caregivers' demographic characteristics as well as measures of their quality of life, general health, general grief, and caregiver prolonged grief (i.e., before death). Results: Compared to caregivers who did not volunteer for an interview, those who volunteered were significantly older and reported less caregiver prolonged grief. Logistic regression showed that for each 1-unit increase in the caregiver prolonged grief score, individuals were 13% less likely to agree to an interview. Conclusions: Research findings based upon family caregivers who volunteer for research interviews might not provide a full picture of their experiences and needs. Researchers are encouraged to consider strategies that sample broadly and promote the participation of the full range of family caregivers in research to address the neglected areas of pre- and postdeath bereavement care.


Rapid Assessment of Fish Freshness for Multiple Supply-Chain Nodes Using Multi-Mode Spectroscopy and Fusion-Based Artificial Intelligence.
This study is directed towards developing a fast, non-destructive, and easy-to-use handheld multimode spectroscopic system for fish quality assessment. We apply data fusion of visible near infra-red (VIS-NIR) and short wave infra-red (SWIR) reflectance and fluorescence (FL) spectroscopy data features to classify fish from fresh to spoiled condition. Farmed Atlantic and wild coho and chinook salmon and sablefish fillets were measured. Three hundred measurement points on each of four fillets were taken every two days over 14 days for a total of 8400 measurements for each spectral mode. Multiple machine learning techniques including principal component analysis, self-organized maps, linear and quadratic discriminant analyses, k-nearest neighbors, random forest, support vector machine, and linear regression, as well as ensemble and majority voting methods, were used to explore spectroscopy data measured on fillets and to train classification models to predict freshness. Our results show that multi-mode spectroscopy achieves 95% accuracy, improving the accuracies of the FL, VIS-NIR and SWIR single-mode spectroscopies by 26, 10 and 9%, respectively. We conclude that multi-mode spectroscopy and data fusion analysis has the potential to accurately assess freshness and predict shelf life for fish fillets and recommend this study be expanded to a larger number of species in the future.


[Regulatory mechanisms of skeletal tissues by amino acid signaling].
In this review, we would outline the possible signaling system for three types of amino acids including glutamate (Glu), γ-aminobutyric acid (GABA) and D-serine (D-Ser) to play a role as an extracellular signal mediator in mechanisms underlying maintenance of the cellular homeostasis in skeletal tissues. Although Glu and GABA has been thought to be an excitatory/inhibitory amino acid neurotransmitter in the mammalian central nervous system, our molecular biological analyses give rise to a novel function for Glu and GABA as an autocrine and/or paracrine factor in three types of distinct cell types including osteoblasts, osteoclasts and chondrocytes in bone tissues. Moreover, D-Ser plays a pivotal role in osteoclastogenesis through a mechanism related to the incorporation of serine enantiomers in osteoclasts after the synthesis and subsequent release from adjacent osteoblasts. Accordingly, bone formation and maintenance seems to be under control by amino acid signaling in skeletal tissues as seen with neurotransmission in the brain.


Operationalizing outcome measures of human papillomavirus vaccination among adolescents.
When examining vaccination coverage, researchers must make decisions about how to define outcome measures based on many factors, including the timing of doses. Different operationalizations of the same outcome can often lead to different findings and can affect the ability to make comparisons across studies. This methodological article aimed to illustrate the implications of two options for operationalizing human papillomavirus (HPV) vaccination based on timing: initiation of the first dose at any age vs before the 13th birthday (on time). Cross-sectional observational design. The 2014 National Immunization Survey for Teens (N = 16,439 adolescents aged 13-17 years) was analyzed using multivariate logistic regression for each outcome measure and effect modification by gender. Age was positively associated with initiation at any age but negatively associated with on-time initiation. Gender modified the effect of race/ethnicity for both measures of initiation, but the pattern across groups was different for the two outcomes. Gender modified the effect of provider recommendation for initiation at any age, while gender modified the effects of age and region for on-time initiation. Decisions of how to operationalize outcomes of HPV vaccine initiation among adolescents can lead to different conclusions about the role of age and gender differences for several predictive variables. To inform the development of public health efforts that promote on-time HPV vaccination among male and female adolescents, researchers should consider the importance of dose timing when operationalizing outcome measures. We recommend including on-time receipt of the HPV vaccine as an outcome measure.


Environmental catalysts advance focused on lattice oxygen for the decomposition of harmful organic compounds.
The recent industrial growth has made our lives more comfortable; however, it has led to an increase in the concentration of harmful compounds, such as carbon monoxide, volatile organic compounds (e.g., toluene), and phenolic compounds (e.g., phenol and cresol), in the environment. Catalytic oxidation using environmental catalysts is an important method for the removal of harmful compounds. To date, novel environmental catalysts have been developed from unique concepts based on solid-state ionics. In particular, the oxygen supply ability of a promoter can supply active oxygen from inside the lattice to the catalytically active site. Our catalysts exhibited high activity for the oxidation of harmful chemicals under moderate conditions in both the gaseous and liquid phases compared to conventional catalysts. This short review article describes our concepts of material design and our novel catalysts (ceria-zirconia (CeO2-ZrO2), apatite-type lanthanum silicate (La10Si6O27), and lanthanum oxyfluoride (LaOF) based catalysts).


Risk factors for stereotypic behaviour in captive ungulates.
Behavioural needs are highly motivated actions critical to a species survival and reproduction. Prolonged restriction of these behaviours can lead to stereotypic behaviours (SB) in captive animals, and this is particularly common in ungulate species. While risk factors for SB have been suggested for some ungulates, no study has integrated these findings to identify which aspects of ungulates' wild behavioural biology and captive husbandry are potential drivers for SB across this clade. We collated SB data from 15 236 individuals across 38 ungulate species from 95 sources, and determined species wild/free-ranging behaviour from 559 additional studies. Bayesian-phylogenetic statistical methods showed that ungulate behavioural needs relating to foraging and mating are particularly affected by captive environments, with promiscuous and browsing species showing the greatest prevalence of SB. Concentrate-only diets and lack of ad libitum feed substrates were also associated with high SB prevalence. This study identifies which ungulates are better suited to captive environments and which species require targeted husbandry, enrichment and breeding protocols in order to meet their behavioural needs. Our approach of applying Bayesian-phylogenetic inference to factors influencing SB within a clade can be used to identify other intrinsic and extrinsic risk factors of reduced animal health and welfare.


Identification of neurotoxicology (NT)/developmental neurotoxicology (DNT) adverse outcome pathways and key event linkages with in vitro DNT screening assays.
There is a need to assess compounds reliably and quickly for neurotoxicity (NT) and developmental neurotoxicity (DNT). Adverse outcome pathways (AOPs) enable the mapping of molecular events to an apical endpoint in a chemical agnostic manner and have begun to be applied in NT and DNT testing frameworks. We assessed the status of NT/DNT AOPs in the AOP-Wiki (ca. 2/1/23; https://aopwiki.org/), to characterize the state of AOP development, identify strengths and knowledge gaps, elucidate areas for improvement, and describe areas for future focus. AOPs in the Wiki database were assessed for inclusion of NT/DNT molecular events and endpoints, AOP development and endorsement, as well as the linkages of key neurodevelopmental processes with in vitro new approach methods (NAMs). This review found that 41 AOPs have been proposed detailing NT/DNT, of which eight were endorsed by working parties in OECD. Further, this review determined that learning and memory is included as an adverse outcome in eight NT/DNT AOPS, often without distinction regarding the varying forms of learning and memory, regional specification, temporal dynamics, or acquisition mechanisms involved. There is also an overlap with key events (KEs) and in vitro NAMs, which synaptogenesis appeared as a common process. Overall, progress on NT/DNT AOPs could be expanded, adding in modes of action that are missing, improvement in defining apical endpoints, as well as utilizing NAMs further to develop AOPs and identify gaps in current knowledge.


Follow-up of residual disease using metaphase-FISH in patients with acute lymphoblastic leukemia in remission.
Metaphase-FISH (fluorescence in situ hybridization) was used to detect cells with a chromosomal trisomy and/or translocation in 25 patients with acute lymphoblastic leukemia (ALL) in remission. Twelve patients were treated with chemotherapy alone and 13 patients received bone marrow transplantation after initial chemotherapy. Patients were followed up for 8-56 months (median 18 months). In this study, a total of 82 bone marrow samples were analyzed. Metaphase-FISH identified chromosome morphology, even banding, in cells from which FISH signals were studied. Thus, it is as reliable as standard karyotype analysis and does not cause false positive results. Furthermore, more than 1000 cells can be analyzed in 3-6 h which equals the time it takes to analyze 20 metaphases by standard karyotype. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. All six patients, who had more than 1% of abnormal cells detected at any sampling or whose consecutive follow-up samples showed an increasing frequency (up to 1%) of abnormal cells, relapsed. Absence or occurrence of low numbers of abnormal cells at a frequency of 0.05-0.8% followed by their disappearance was in agreement with continuing complete clinical and hematologic remission (CR) in 16 (84%) of 19 patients. Our results indicate that metaphase-FISH is a reliable technique for quantifying residual leukemic cells. The technique is available in standard cytogenetic laboratories and can be applied to routine follow-up of ALL patients who have a suitable chromosomal aberration.


Controlled redistribution of vibrational population by few-cycle strong-field laser pulses.
The use of strong-field (i.e. intensities in excess of 10(13) Wcm(-2)) few-cycle ultrafast (durations of 10 femtoseconds or less) laser pulses to create, manipulate and image vibrational wavepackets is investigated. Quasi-classical modelling of the initial superposition through tunnel ionization, wavepacket modification by nonadiabatically altering the nuclear environment via the transition dipole and the Stark effect, and measuring the control outcome by fragmenting the molecule is detailed. The influence of the laser intensity on strong-field ultrafast wavepacket control is discussed in detail: by modifying the distribution of laser intensities imaged, we show that focal conditions can be created that give preference to this three-pulse technique above processes induced by the pulses alone. An experimental demonstration is presented, and the nuclear dynamics inferred by the quasi-classical model discussed. Finally, we present the results of a systematic investigation of a dual-control pulse scheme, indicating that single vibrational states should be observable with high fidelity, and the populated state defined by varying the arrival time of the two control pulses. The relevance of such strong-field coherent control methods to the manipulation of electron localization and attosecond science is discussed.


Childhood traumatic events and types of auditory verbal hallucinations in first-episode schizophrenia patients.
Evidence is accumulating that childhood trauma might be associated with higher severity of positive symptoms in patients with psychosis and higher incidence of psychotic experiences in non-clinical populations. However, it remains unknown whether the history of childhood trauma might be associated with particular types of auditory verbal hallucinations (AVH). We assessed childhood trauma using the Early Trauma Inventory Self-Report - Short Form (ETISR-SF) in 94 first-episode schizophrenia (FES) patients. Lifetime psychopathology was evaluated using the Operational Criteria for Psychotic Illness (OPCRIT) checklist, while symptoms on the day of assessment were examined using the Positive and Negative Syndrome Scale (PANSS). Based on ETISR-SF, patients were divided into those with and without the history of childhood trauma: FES(+) and FES(-) patients. FES(+) patients had significantly higher total number of AVH types and Schneiderian first-rank AVH as well as significantly higher PANSS P3 item score (hallucinatory behavior) in comparison with FES(-) patients. They experienced significantly more frequently third person AVH and abusive/accusatory/persecutory voices. These differences remained significant after controlling for education, PANSS depression factor score and chlorpromazine equivalent. Linear regression analysis revealed that the total number of AVH types was predicted by sexual abuse score after controlling for above mentioned confounders. This effect was significant only in females. Our results indicate that the history of childhood trauma, especially sexual abuse, is associated with higher number AVH in females but not in males. Third person AVH and abusive/accusatory/persecutory voices, representing Schneiderian first-rank symptoms, might be particularly related to childhood traumatic events.


An EMS approach to psychiatric emergencies.
Psychiatric patients present challenges not only to EMS, but in the ED as well. As we have tried to indicate in the case report, the presentation is not always clear-cut. There may not be a definite solution, and each case can be different. As an EMT or paramedic, how should you approach these issues? First, always make sure the scene is safe for you and your team. If you have doubts, contact law enforcement. With regard to patient care, err on the side of safety and what is in the best interest of the patient (which may include restraints). Follow established procedures and guidelines, and always document well. If you have any questions on scene, contact medical control, and document doing so. If there is a question, let the physician decide on competency issues.


Characterization of a heat-stable protease of Pseudomonas fluorescens P26.
A heat-stable, extracellular proteolytic enzyme was isolated from Pseudomonas fluorescens P26. Brain heart infusion broth (Fisher Scientific Co.), pH 7.5, and incubation at 21 C provided the optimal conditions for bacterial growth for enzyme production. The organism had a D value of 2.6 min at 62.8 C (145 F). The enzyme, however, was quite heat-stable, requiring 15 hr at 62.8 C, 8 hr at 71.4 C, and 9 min at 121 C for complete inactivation. Milk, whey, and casein each had a protective effect on the enzyme against heat inactivation. Purification was accomplished by growth of organisms in broth, centrifugation, sterilization by filtration, ammonium sulfate precipitation (55% saturation), dialysis (against six changes of water), and protein separation by passage through a Sephadex G-100 column. Ultracentrifugation revealed a single band with a sedimentation coefficient of 1.51 which suggested a molecular weight of approximately 23,000. As little as 0.2 unit of the purified enzyme caused detectable flavor defects during 30 days of storage at 4 C, and the Hull test for liberation of tyrosine compared favorably in sensitivity with the sensory method in milk.


Establishing a competitive advantage through quality management.
The successful dentist of the future will establish a sustainable competitive advantage in the marketplace by recognising that patients undergoing dental treatment cannot see the result before purchase, and that they therefore look for signs of service quality to reduce uncertainty. Thus the successful dentist will implement a quality programme that recognises not only that quality is defined by meeting patients' needs and expectations, but also that quality service is fundamental to successful business strategy. Finally, the successful dentist of the future will realise that the pursuit of quality is a never-ending process which requires leadership by example.


Ecological implications of limb apraxia: evidence from mealtime behavior.
Humans learn skilled acts in order to effectively interact with their environment. A loss of the ability to perform skilled acts is termed apraxia. Apraxia has been thought to be of theoretical interest, but the ecological implications of apraxia are controversial and have not been fully studied. We examined ten patients with unilateral left hemisphere cerebral infarctions (eight of whom were apraxic) and compared their mealtime eating behavior to a group of neurologically normal, age-matched controls. The stroke patients were less efficient in completing the meal. They made more action errors and were less organized in the sequencing of mealtime activities. Because the patients made more errors while using tools than when performing nontool actions, their deficit could not be accounted for by an elemental motor deficit. A positive relationship was found between mealtime action errors and the severity of apraxia. These findings suggest that limb apraxia may adversely influence activities of daily living.


Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants.
Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058). These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.


Atomistic molecular dynamics simulations of bioactive engrailed 1 interference peptides (EN1-iPeps).
The neural-specific transcription factor Engrailed 1 - is overexpressed in basal-like breast tumours. Synthetic interference peptides - comprising a cell-penetrating peptide/nuclear localisation sequence and the Engrailed 1-specific sequence from the N-terminus have been engineered to produce a strong apoptotic response in tumour cells overexpressing EN1, with no toxicity to normal or non Engrailed 1-expressing cells. Here scaled molecular dynamics simulations were used to study the conformational dynamics of these interference peptides in aqueous solution to characterise their structure and dynamics. Transitions from disordered to α-helical conformation, stabilised by hydrogen bonds and proline-aromatic interactions, were observed throughout the simulations. The backbone of the wild-type peptide folds to a similar conformation as that found in ternary complexes of anterior Hox proteins with conserved hexapeptide motifs important for recognition of pre-B-cell leukemia Homeobox 1, indicating that the motif may possess an intrinsic preference for helical structure. The predicted NMR chemical shifts of these peptides are consistent with the Hox hexapeptides in solution and Engrailed 2 NMR data. These findings highlight the importance of aromatic residues in determining the structure of Engrailed 1 interference peptides, shedding light on the rational design strategy of molecules that could be adopted to inhibit other transcription factors overexpressed in other cancer types, potentially including other transcription factor families that require highly conserved and cooperative protein-protein partnerships for biological activity.


Induction of CD8+ Immune Memory and Enhanced Inflammation in a Skin Inflammation Model through Pre-Immunization with Inactivated Pathogens.
Laboratory mice live in specific pathogen-free (SPF) conditions, resulting in an immature immune system comparable to that of new-borns rather than adult humans or mice from pet shops. This condition may compromise their translational value. Reintroducing pathogens would lead to the uncontrolled spread of infections and associated diseases, so research facilities should seek safer alternatives. We immunized laboratory mice with a cocktail of pathogens, which were inactivated by ultraviolet irradiation and mixed with the adjuvant Addavax. This immunization resulted in a higher percentage of CD8+ effector memory T cells compared to untreated mice, although the response was not as robust as in pet shop mice. In a model of skin inflammation, pre-immunization led to an increased skin inflammatory response compared to non-immunized mice. All immunized mice seroconverted to the pathogens in the mixture, while none of the non-immunized mice housed together seroconverted to the pathogens applied to the pre-immunized mice. In conclusion, pre-immunization of mice impacts the immune system, which includes increasing the levels of CD8+ effector memory T cells.


Management of Multiple Nitrogen Sources during Wine Fermentation by Saccharomyces cerevisiae.
During fermentative growth in natural and industrial environments, Saccharomyces cerevisiae must redistribute the available nitrogen from multiple exogenous sources to amino acids in order to suitably fulfill anabolic requirements. To exhaustively explore the management of this complex resource, we developed an advanced strategy based on the reconciliation of data from a set of stable isotope tracer experiments with labeled nitrogen sources. Thus, quantifying the partitioning of the N compounds through the metabolism network during fermentation, we demonstrated that, contrary to the generally accepted view, only a limited fraction of most of the consumed amino acids is directly incorporated into proteins. Moreover, substantial catabolism of these molecules allows for efficient redistribution of nitrogen, supporting the operative de novo synthesis of proteinogenic amino acids. In contrast, catabolism of consumed amino acids plays a minor role in the formation of volatile compounds. Another important feature is that the α-keto acid precursors required for the de novo syntheses originate mainly from the catabolism of sugars, with a limited contribution from the anabolism of consumed amino acids. This work provides a comprehensive view of the intracellular fate of consumed nitrogen sources and the metabolic origin of proteinogenic amino acids, highlighting a strategy of distribution of metabolic fluxes implemented by yeast as a means of adapting to environments with changing and scarce nitrogen resources.IMPORTANCE A current challenge for the wine industry, in view of the extensive competition in the worldwide market, is to meet consumer expectations regarding the sensory profile of the product while ensuring an efficient fermentation process. Understanding the intracellular fate of the nitrogen sources available in grape juice is essential to the achievement of these objectives, since nitrogen utilization affects both the fermentative activity of yeasts and the formation of flavor compounds. However, little is known about how the metabolism operates when nitrogen is provided as a composite mixture, as in grape must. Here we quantitatively describe the distribution through the yeast metabolic network of the N moieties and C backbones of these nitrogen sources. Knowledge about the management of a complex resource, which is devoted to improvement of the use of the scarce N nutrient for growth, will be useful for better control of the fermentation process and the sensory quality of wines.


Autogenous tooth transplantation: a reevaluation.
This paper discusses whether autogenous tooth transplantation can survive as an option in the future dental armamentaria. Clinically, successful transplants must show a radiolucent space between the roots and surrounding bone. There must be no evidence of ankylosis, no permanent root resorption, and no inflammation. Histologically, the criterion of success is a normal and functional periodontal ligament between the root surfaces of transplants and the bone or gingival connective tissues. Case reports are presented to illustrate replantation or transplantation of teeth. Possible donor teeth are those with the proper amount of viable periodontal ligament, single-rooted teeth, third molars, and malpositioned or impacted teeth. The transplantation procedure involves extraction of the donor tooth, measurement of the root form and amount of periodontal ligament, preservation of donor tooth, preparation of recipient socket, positioning of donor tooth, suturing, and temporary splinting.


Recurrence risk factors in detachable balloon embolization of traumatic direct carotid cavernous fistulas in 188 patients.
To investigate the effects of detachable balloons in embolizing traumatic carotid cavernous fistulas (TCCFs) and the risk factors for recurrence after balloon embolization. 188 patients with TCCFs were enrolled, and clinical, treatment, and follow-up data were analyzed for possible risk factors for recurrence after embolization. Among 188 patients, 182 (96.8%) had successful balloon embolization; 6 patients failed. One balloon was used in 94 cases and multiple (two or more) balloons were used in 62 patients. 26 patients had occlusion of the parent artery whereas the remainder had parent artery preservation. Periprocedural complications occurred in 3 patients (1.6%) including cerebral embolism in 1 and abducent nerve paralysis in the other 2. Immediately following embolization, headache appeared in 92 patients and was relieved after 3-5 days with medications. A total of 165 patients (87.8%) had follow-up (6 months to 16 years, mean 5 years). 23 (13.9%) patients with internal carotid artery preservation had recurrence 1-33 days (mean 11 days) after the first embolization and were retreated to complete occlusion. Factors affecting recurrence were multiple balloons and residual fistula (p<0.05). Logistic regression confirmed the independent factors affecting recurrence were multiple balloons (≥2 balloons, OR 7.80, 95% CI 2.28 to 26.73; p=0.001) and residual fistula immediately following embolization (OR 10.46, 95% CI 2.99 to 36.5; p=0.000). The recurrence rate is high in the first month after embolization with detachable balloons, and multiple balloons and residual fistula are two independent factors affecting recurrence following balloon embolization.


Inhibition of Japanese encephalitis virus infection by nitric oxide: antiviral effect of nitric oxide on RNA virus replication.
The antiviral effects of nitric oxide (NO) on Japanese encephalitis virus (JEV), a member of the family Flaviviridae, were investigated in this study. In vitro, inhibition of replication of JEV in gamma interferon-activated RAW 264.7 murine macrophages was correlated to cellular NO production. When cocultured with infected murine neuroblastoma N18 cells, gamma interferon-activated RAW 264.7 cells also efficiently hindered JEV replication in contiguous bystanders, and this anti-JEV effect could be reversed by an NO synthase (NOS) inhibitor, N-monomethyl-L-arginine acetate. In vivo, the mortality rate increased as the NOS activity of JEV-infected mice was inhibited by its competitive inhibitor, N-nitro-L-arginine methyl ester. Moreover, when an organic donor, S-nitro-N-acetylpenicillamine (SNAP), was used, the NO-mediated antiviral effect was also observed in primarily JEV-infected N18, human neuronal NT-2, and BHK-21 cells, as well as in persistently JEV-infected C2-2 cells. These data reaffirm that NO has an effective and broad-spectrum antimicrobial activity against diversified intracellular pathogens. Interestingly, the antiviral effect of NO was not enhanced by treatment of N18 cells with SNAP prior to JEV infection, a measure which has been shown to greatly increase the antiviral effect of NO in infection by vesicular stomatitis virus. From biochemical analysis of the impact of NO on JEV replication in cell culture, NO was found to profoundly inhibit viral RNA synthesis, viral protein accumulation, and virus release from infected cells. The results herein thus suggest that NO may play a crucial role in the innate immunity of the host to restrict the initial stage of JEV infection in the central nervous system.


Oral gentamicin gut decontamination for prevention of KPC-producing Klebsiella pneumoniae infections: relevance of concomitant systemic antibiotic therapy.
Gut colonization represents the main source for KPC-producing Klebsiella pneumoniae (KPC-Kp) epidemic dissemination. Oral gentamicin, 80 mg four times daily, was administered to 50 consecutive patients with gut colonization by gentamicin-susceptible KPC-Kp in cases of planned surgery, major medical intervention, or need for patient transfer. The overall decontamination rate was 68% (34/50). The median duration of gentamicin treatment was 9 days (interquartile range, 7 to 15 days) in decontaminated patients compared to 24 days (interquartile range, 20 to 30 days) in those with persistent colonization (P<0.001). In the six-month period of follow-up, KPC-Kp infections were documented in 5/34 (15%) successfully decontaminated patients compared to 12/16 (73%) persistent carriers (P<0.001). The decontamination rate was 96% (22/23) in patients receiving oral gentamicin only, compared to 44% (12/27) of those treated with oral gentamicin and concomitant systemic antibiotic therapy (CSAT) (P<0.001). The multivariate analysis confirmed CSAT and KPC-Kp infection as the variables associated with gut decontamination. In the follow-up period, KPC-Kp infections were documented in 2/23 (9%) of patients treated with oral gentamicin only and in 15/27 (56%) of those also receiving CSAT (P=0.003). No difference in overall death rate between different groups was documented. Gentamicin-resistant KPC-Kp strains were isolated from stools of 4/16 persistent carriers. Peak gentamicin blood levels were below 1 mg/liter in 12/14 tested patients. Oral gentamicin was shown to be potentially useful for gut decontamination and prevention of infection due to KPC-Kp, especially in patients not receiving CSAT. The risk of emergence of gentamicin-resistant KPC-Kp should be considered.


Rumen development process in goats as affected by supplemental feeding v. grazing: age-related anatomic development, functional achievement and microbial colonisation.
The aim of the present study was to describe age-related changes in anatomic, functional and microbial variables during the rumen development process, as affected by the feeding system (supplemental feeding v. grazing), in goats. Goats were slaughtered at seven time points that were selected to reflect the non-rumination (0, 7 and 14 d), transition (28 and 42 d) and rumination (56 and 70 d) phases of rumen development. Total volatile fatty acid (TVFA) concentration (P= 0·002), liquid-associated bacterial and archaeal copy numbers (P< 0·01) were greater for supplemental feeding v. grazing, while rumen pH (P< 0·001), acetate molar proportion (P= 0·003) and solid-associated microbial copy numbers (P< 0·05) were less. Rumen papillae length (P= 0·097) and extracellular (P= 0·093) and total (P= 0·073) protease activity potentials in supplemented goats tended to be greater than those in grazing goats. Furthermore, from 0 to 70 d, irrespective of the feeding system, rumen weight, rumen wall thickness, rumen papillae length and area, TVFA concentration, xylanase, carboxymethylcellulase activity potentials, and microbial copy numbers increased (P< 0·01) with age, while the greatest amylase and protease activity potentials occurred at 28 d. Most anatomic and functional variables evolved progressively from 14 to 42 d, while microbial colonisation was fastest from birth to 28 d. These outcomes suggest that the supplemental feeding system is more effective in promoting rumen development than the grazing system; in addition, for both the feeding systems, microbial colonisation in the rumen is achieved at 1 month, functional achievement at 2 months, and anatomic development after 2 months.


Ultrastructure of chordoma. A case report.
A 50-year-old male developed a sacro-coccygeal chordoma. Prior to the surgery, he had experienced back-pain, numbness of the right thigh and difficulty in voiding and defecation. Total excision of the mass was done and all symptoms were relieved. The light microscopic examination revealed a chordoma. The ultrastructural study was performed with particular interest in physaliferous cells. The fine structure disclosed the prominent associations of mitochondria and rough endoplasmic reticulum. The mitochondria showed irregularities in sizes and shapes but did not attenuate as much as previously reported. The vacuoles that were observed by light microscopy in physaliferous cells were both extra-cellular and intra-cellular and contained finely granular material of acid mucopolysaccharides probably of chondroitin type. The presence of both subplasmalemmal linear densities (SLD) and pinocytic vesicles was consistent with the histogenetic conviction that the tumor arose from mesodermal derivatives.