Effects of Sodium Hyaluronate Eye Drops With or Without Preservatives on Ocular Surface Bacterial Microbiota.
This study aimed to determine the composition and diversity of bacterial communities on the ocular surface before and after the intervention with sodium hyaluronate eye drops (with or without preservatives) using 16S rRNA gene amplicon sequencing. Sixteen healthy adults were randomly divided into two groups and treated with sodium hyaluronate eye drops with or without preservatives for 2 weeks. The individuals used the same artificial tears in both eyes. The microbial samples from the conjunctival sac of each participant were collected at baseline and 2 weeks after intervention. The diversity and taxonomic differences among different groups before and after intervention were compared by sequencing the V3-V4 region of the 16S rRNA gene. The similarity in the binocular microbial community was high in 1 of the 16 volunteers (Bray-Curtis dissimilarity score < 0.3). At the genus level, 11 bacteria were detected in all samples with an average relative abundance of more than 1%. The bacterial community changed significantly after the use of sodium hyaluronate eye drops (with or without preservatives), whether within individuals or between individuals in different groups (P < 0.05, PERMANOVA). Different dosage forms of sodium hyaluronate eye drops significantly decreased the relative abundance of Flavobacterium caeni and Deinococcus antarcticus, respectively (P < 0.05). Healthy people had a rich diversity of the bacterial microbiota on the ocular surface, but the bacterial communities between the eyes were not completely similar. Irrespective of containing benzalkonium chloride (BAC), sodium hyaluronate eye drops can change the bacterial community on the ocular surface.


Copper-catalyzed regio- and enantioselective synthesis of chiral enol acetates and β-substituted aldehydes.
The in situ transformation of α,β-unsaturated aldehydes into α-chloroallylic acetates and subsequent copper-catalyzed regio- and enantioselective (up to 94% ee) allylic alkylation with Grignard reagents provides chiral enol acetates and chiral β-substituted aldehydes in a one-pot protocol.


Light-evoked NMDA receptor-mediated currents are reduced by blocking D-serine synthesis in the salamander retina.
Experiments were carried out in the retina of the tiger salamander (Ambystoma tigrinum) to evaluate the importance of D-serine synthesis on light-evoked N-methyl D-aspartate (NMDA) receptor-mediated components of ganglion cells and contributions to the proximal negative field potential. We blocked the synthesis of D-serine through brief exposures of the retina to phenazine ethosulfate and validated the changes in the tissue levels of D-serine using capillary electrophoresis methods to separate and measure the amino acid enantiomers. Ten minute exposures to phenazine ethosulfate decreased D-serine levels in the retina by about 50% and significantly reduced the NMDA receptor contribution to light responses of the inner retina. This is the first report of a linkage between D-serine synthesis and NMDA receptor activity in the vertebrate retina.


Anger is more influential than joy: sentiment correlation in weibo.
Recent years have witnessed the tremendous growth of the online social media. In China, Weibo, a Twitter-like service, has attracted more than 500 million users in less than five years. Connected by online social ties, different users might share similar affective states. We find that the correlation of anger among users is significantly higher than that of joy. While the correlation of sadness is surprisingly low. Moreover, there is a stronger sentiment correlation between a pair of users if they share more interactions. And users with larger number of friends possess more significant sentiment correlation with their neighborhoods. Our findings could provide insights for modeling sentiment influence and propagation in online social networks.


Malpractice suits in chest radiology: an evaluation of the histories of 8265 radiologists.
The aim of this study was to present rates of claims, causes of error, percentage of cases resulting in a judgment, and average payments made by radiologists in chest-related malpractice cases in a survey of 8265 radiologists. The malpractice histories of 8265 radiologists were evaluated from the credentialing files of One-Call Medical Inc., a preferred provider organization for computed tomography/magnetic resonance imaging in workers' compensation cases. Of the 8265 radiologists, 2680 (32.4%) had at least 1 malpractice suit. Of those who were sued, the rate of claims was 55.1 per 1000 person years. The rate of thorax-related suits was 6.6 claims per 1000 radiology practice years (95% confidence interval, 6.0-7.2). There were 496 suits encompassing 48 different causes. Errors in diagnosis comprised 78.0% of the causes. Failure to diagnose lung cancer was by far the most frequent diagnostic error, representing 211 cases or 42.5%. Of the 496 cases, an outcome was known in 417. Sixty-one percent of these were settled in favor of the plaintiff, with a mean payment of $277,230 (95% confidence interval, 226,967-338,614). Errors in diagnosis, and among them failure to diagnose lung cancer, were by far the most common reasons for initiating a malpractice suit against radiologists related to the thorax and its contents.


Curvatures of the refracted wavefronts and Ronchigrams for a plano arbitrary lens.
In this work we obtain the equations for curvatures of refracted wavefronts for a plano arbitrary lens. The functions H0, H1, and H2 that determine the caustic also determine the curvature of these wavefronts. The analysis performed in these calculations allows us to study the behavior of the Ronchigrams for the case of plane incident wavefronts. We apply this procedure for a plano-spherical lens, and we discover that it is possible to describe the behavior of the Ronchigrams based on the τ function, which labels the refracted wavefronts of the optical system.


Stroke in China, 1986 through 1990.
Incidence of stroke varies markedly in different world populations. In seven Chinese cities, the effect of a program of risk factor modification on the incidence and mortality of stroke was studied and compared with a control population. This article describes the incidence of stroke in the control populations for the years 1986 through 1990. Incidence (first-ever strokes only) for 1986 was obtained by door-to-door interview with heads of households with subsequent verification on examination by a neurologist and review of medical and/or hospital records. In subsequent years, cases were ascertained with a three-tier monitoring system: by community health workers, local medical centers, and the Beijing Neurosurgical Institute. Average annual age-adjusted incidence per 100,000 was 215.6 (261.5 for males, 174.5 for females; P < .001). There was a significant drop in the total number of cases from 137 in 1986 to 106 in 1990, but the age-adjusted rate showed a significant drop for males only (322.3 to 182.5, P < .001). Marked differences in average annual age-adjusted rates existed among the seven cities, from 486.4 for Harbin to 80.9 for Shanghai. This difference in rate among cities was found for both sexes but was more pronounced in males. The stroke incidence rates in China, like those in Japan, are among the higher ones in the world. In recent years, there has been an apparent decline in stroke incidence. Marked differences in rates were found between males and females with decline in incidence occurring almost exclusively in males. There were also marked differences in stroke incidence among the cities studied. These differences may result in part from differences in diet, alcohol and cigarette consumption, or prevalence of hypertension.


A broadband tapered nanocavity for efficient nonclassical light emission.
We present the design of a tapered nanocavity, obtained by sandwiching a photonic wire section between a planar gold reflector and a few-period Bragg mirror integrated into the tapered wire. Thanks to its ultrasmall mode volume (0.71 λ3/n3), this hybrid nanocavity largely enhances the spontaneous emission rate of an embedded quantum dot (Purcell factor: 6), while offering a wide operation bandwidth (full-width half-maximum: 20 nm). In addition, the top tapered section shapes the cavity far-field emission into a very directive output beam, with a Gaussian spatial profile. For realistic taper dimensions, a total outcoupling efficiency to a Gaussian beam of 0.8 is predicted. Envisioned applications include bright sources of non-classical states of light, such as widely tunable sources of indistinguishable single photons and polarization-entangled photon pairs.


A case report of opium body packer; review of the treatment protocols and mechanisms of poisoning.
ABSTRACT Body packers are people who illegally carry drugs, mostly cocaine as well as opium and/or heroin, concealed within their bodies. The packets are inserted in the mouth, rectum, or vagina in order to get across borders without being detected. In this presentation we report a case of an opium body packer and review the available scientific literature by focusing on mechanisms of toxicity and treatment approach. The patient was a 35-year-old man who had lethargy, respiratory depression, tachycardia, normal blood pressure, hyperthermia, and pinpoint pupils on presentation. No past medical history was obtained and the only positive history was his travel from Afghanistan 2 days earlier, which he had given to emergency personnel before arriving at our hospital. Complete blood cells and kidney and liver tests were all in normal range. In the emergency department, the patient was treated with oxygen, naloxone, and hypertonic glucose. One dose of activated charcoal (1 g/kg) was administered orally. After intravenous injection of naloxone (4 mg), the lethargy, respiratory depression, and miosis were resolved. The patient was admitted to the intensive care unit and 90 min after admission, the patient redeveloped respiratory distress and lost consciousness. He was intubated and mechanically ventilated due to the suspicious of body packing. Plain abdominal x-ray showed multiple packets throughout the gastrointestinal tract; 81 packets were removed by surgery and three of them were left due to leaking. After removing the packets, the patient was treated conservatively. He suffered a pulmonary infection (aspiration pneumonia) and he regained consciousness after 4 days. Upon recovery the patient was seen by a psychiatrist prior to going to prison. Surgery is recommended for body packers who have significant signs or symptoms.


Acute pancreatitis in patients with Crohn's disease: clinical features and outcomes.
Acute pancreatitis has occasionally been associated with Crohn's disease (CD), but whether a causal association exists remains unclear. We sought to determine the frequency of etiologies in a consecutive series of patients with CD with acute pancreatitis. A centralized diagnostic index was used to identify all patients with CD with acute pancreatitis that were evaluated at Mayo Clinic Rochester between 1976 and 2001. Both diagnoses were made or confirmed at our institution. Records were abstracted for demographics, presenting symptoms, diagnostic tests, risk factors of pancreatitis, treatment, and follow-up. Forty-eight patients with CD with pancreatitis were identified. The median age at diagnosis of acute pancreatitis was 47 years (range, 31-91 yr). Forty-six (96%) met biochemical criteria for acute pancreatitis. The most sensitive radiographic tests were abdominal computed tomography (70%) and abdominal ultrasound (46%). The etiology of pancreatitis was considered to be gallstones (21%), significant alcohol intake (15%), use of purine analogs (13%), duodenal Crohn's involvement (12%), postendoscopic retrograde cholangiopancreatography complications (10%), postoperative complications (12%), use of other medications (4%) and idiopathic (8%). The median length of hospitalization was 7 days (range, 0-40 d). Ten patients (21%) had recurrence of acute pancreatitis. Three patients (6%) were subsequently diagnosed with pancreatic cancer. A definite etiology could be identified in most patients with CD with acute pancreatitis. Gallstones and alcohol accounted for more than one third of cases, whereas CD, either because of duodenal involvement or medications used for its treatment, accounted for more than one quarter of the cases. A small proportion of patients remained idiopathic.


Esters of Quinoxaline-7-Carboxylate 1,4-di-N-Oxide as Potential Inhibitors of Glycolytic Enzymes of Entamoeba histolytica: In silico Approach.
Esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives are compounds that inhibit the growth of Entamoeba histolytica, the causative agent of amebiasis. Although these compounds cause changes in the redistribution of glycogen deposits within the parasite, it is unknown whether these compounds interact with enzymes of the glycolytic pathway. The aim of this study was to test the binding affinity of these compounds to pyrophosphate- dependent phosphofructokinase (PPi-PFK), triosephosphate isomerase (TIM), and pyruvate phosphate dikinase (PPDK) from E. histolytica as a possible mechanism of action. The molecular docking study of the 7-carboxylate QdNOs derivatives and the proteins was performed using AutoDock/Vina software. Molecular dynamics simulation was performed for 100 ns. Among all the selected compounds, T-072 exhibited the best binding affinity to EhPPi- PFK and EhTIM proteins, while T-006 interacted best with EhPPDK. ADMET analysis revealed that T-072 was non-toxic, while T-006 could become harmful to the host. In addition, molecular dynamics showed that T-072 has stable interaction with EhPPi-PFK and EhTIM. Including all aspects, these data indicated that these compounds might inhibit the activity of key enzymes in energy metabolism leading to parasite death. Furthermore, these compounds may be a good starting point for the future development of new potent antiamebic agents.


The population structure of drug-resistant Mycobacterium tuberculosis clinical isolates from Sichuan in China.
China ranks second next to India among 22 high-burden countries despite decades' effort on tuberculosis (TB) control. The Sichuan province today contains the second-largest number of TB cases among Chinese provinces, where the prevalence of drug-resistant TB, especially MDR-TB, is much higher than the average level in eastern China. In this study, the population structure and the transmission characteristics of drug-resistant TB in Sichuan province were studied by spoligotyping and 24-locus Mycobacterial interspersed repetitive units-variable number tandem DNA repeats (MIRU-VNTR), applied to a total of 306 clinical isolates. Spoligotyping-based analysis showed that Beijing family represented 69.28% of all isolates and constituted the largest group (66.24%) of MDR-TB in Sichuan. The remaining isolates, accounting for 33.76% of MDR isolates, belonged to the ill-defined T family, Manu2, H3, LAM9, and other minor unassigned clades. The discriminatory power evaluated for spoligotyping was poor (HGI=0.595), but high for 24-locus MIRU-VNTRs (HGI=0.999). The number of the most discriminatory loci (h>0.6) was 12, including locus 424, 802, 960, 1644, 1955, 2163b, 2996, 3007, 3192, 3690, 4348 and 4052. It was concluded that 24-locus MIRU-VNTRs could be a more discriminatory tool for differentiating clinical isolates from Sichuan region. The small clustering size obtained from the current population structure analysis suggested that the high prevalence of drug-resistant TB in this region might be attributed partially to the acquired resistance due to inappropriate drug use rather than active transmission of drug-resistant TB (primary resistance).


Urea-induced release of heat-labile enterotoxin from Escherichia coli.
Urea induces the release of heat-labile enterotoxin (LT) from cells of LT-producing Escherichia coli strains. Optimal conditions were defined by using the checkerboard immunoblotting system. LT release was highest when E. coli cells were incubated in 8 M urea, pH 8.0, at 37 degrees C in a water bath for 30 min. Urea was more effective than polymyxin B in inducing the release of LT antigen from E. coli; the activity of LT from urea-treated cells was seven times that of LT from polymyxin B-treated cells. Urea also increased the antigenic and biological reactivities of purified LT. This procedure is potentially applicable for the detection of LT-producing E. coli strains in the clinical laboratory.


Shoulder Anatomy and Normal Variants.
The shoulder joint is functionally and structurally complex and is composed of bone, hyaline cartilage, labrum, ligaments, capsule, tendons and muscles. It links the trunk to the upper limb and plays an important biomechanical role in daily activities. Indications for imaging of the shoulder have considerably increased in the last few years. The article focuses mainly on Magnetic Resonance Imaging (MRI) as well as MR and CT arthrography, diagnostic procedures of choice for assessment of internal derangement of the shoulder. Bony components, rotator cuff tendons and muscles can be assessed on MR imaging without arthrographic technique, whereas the articular structures (including glenohumeral ligaments, capsulolabral structures and hyaline cartilage) require arthrography for more accurate assessment. Appropriate MR imaging protocols and sequences and applied MR anatomy of the shoulder (including normal variants) are proposed to help assist management and treatment of common shoulder pathologies encountered (such as rotator cuff tears, impingement syndromes, and instability as well as less frequent causes of shoulder pain). The most common variants and pitfalls are related to the anterosuperior aspect of the shoulder joint. Basic anatomy as well as recent findings are developed, including a new description of the attachment of supraspinatus and infraspinatus tendons at the superior aspect of the humerus, the rotator cable and the superior glenohumeral ligament complex.


How many elders receive assistance? A cross-national comparison.
To examine models of informal support received by elders in the United States and Sweden and to test whether differences in informal support appear to stem from demographic differences between the nations alone or whether cultural and historical differences must also be considered. Samples with similar functional dependence, age 75 and older in the United States (n = 4,677) and Sweden (n = 1,378), were used to model cross-national differences in the association between country, age, sex, potential availability of kin support, and receipt of informal assistance. Patterns of informal help were higher in the United States than in Sweden but were qualified by higher order interactions among age, sex, and availability of kin support. Cultural differences predating current policies in both countries appear to influence informal support over and above what can be accounted for by demographic differences alone.


[Analysis of surface deposits on intrauterine contraceptive devices].
The surface deposits on stainless steel contraceptive devices removed from the uterus after various periods of insertion were examined and analyzed by means of scanning electron microscopy, X-ray energy dispersive analysis, Augar electron spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy and atomic absorption spectrophotometer for microquantitative analysis. The data obtained were compared with those of copper-bearing IUDs (TCu 200) obtained by the same methods. The wire coils of stainless steel IUDs which had been in situ for 5 years showed on evident changes but the copper wire coils of the same duration showed varying degrees of erosion. The analysis clearly showed that the wire coils of both types of IUDs were encrusted with deposit. Deposition began on copper-bearing IUDs earlier than on stainless steel IUDs (27 days and 3 months after insertion, respectively). This process began earlier than was reported in other literature. The amount of deposits increased with the time of insertion, but there were great individual variations. Through the above mentioned microanalysis, it was found that the principal composition of the deposition both types of IUDs was calcium and existed in the crystal form of calcium carbonate. The substance attaching to the crystals were very likely nitrogenous organic compounds. Regarding the mechanism of the deposit formation, the authors suggest that it may be similar to that of calculus. The influence of the deposits on the complications of IUD insertion, such as uterine bleeding and unwanted pregnancy, is discussed briefly in this article should be studied for further details.


Value of reagent strips in the rapid diagnosis of spontaneous bacterial peritonitis.
Spontaneous bacterial peritonitis is a severe complication in cirrhotic patients with ascites. Early antibiotics are essential to improve the prognosis. An ascites neutrophil count >250/mm3 is an indication for antibiotic therapy. However this procedure requires intensive labor and is not available in all hospitals on emergency setting. The aim of this study was to assess the utility of Human-Test Combina strips for the rapid diagnosis of spontaneous bacterial peritonitis. The interobserver variability in the result reading was also evaluated. A prospective study of 109 consecutive ascitic fluid samples colected from 55 patients was carried out. The results of the reagent strips were compared with the neutrophil count by conventional optical microscopy. Interobserver agreement was tested in 37 cases. The prevalence of infection was 8.3%. Reagent strips had sensitivity, specificity, positive and negative predictive values of 78%, 88%, 37% and 98% for a cut-off level > or =2 and 67%, 98%, 75% and 97% for > or =3, respectively. Concordance between investigators was 100%. Reagent strips are a rapid, simple and easily available method for the diagnosis of spontaneous bacterial peritonitis. A positive result should be an indication to start antibiotics and a negative result can be useful to exclude the possibility of infection.


Efficacy of olanzapine and risperidone for treatment-refractory schizophrenia among long-stay state hospital patients.
The authors studied the efficacy of olanzapine and risperidone among patients with treatment-refractory schizophrenia who had been hospitalized for more than five years and who were not suitable candidates for a clozapine trial. The patients were systematically reassessed and were given olanzapine or risperidone as part of a "second-chance program." The patients in both groups showed significant improvement in scores on the 18-item Brief Psychiatric Rating Scale after three months. Forty-four percent of the patients in the olanzapine group and 43 percent of those in the risperidone group were discharged to supervised residences on the basis of their clinical improvement. There is value in reassessing long-stay patients who have treatment-refractory schizophrenia and giving them systematic trials with new medications that become available.


Glucocorticoid Exposure Induces Preeclampsia via DampeningLipoxin A4, an Endogenous Anti-Inflammatory and Proresolving Mediator.
The pathogenesis of preeclampsia (PE) involves several pathophysiological processes that may be affected by glucocorticoid (GC). We confirmed previously that GC exposure could result in PE, while PE is linked to a deficiency of lipoxin A4 (LXA4), an endogenous dual anti-inflammatory and proresolving mediator. The present study was to investigate whether GC exposure induces PE via dampening LXA4. In the study, cortisol levels of PE women were higher than those of normal pregnancies, LXA4 levels were downregulated in both PE patients and GC-mediated PE rats, and leukotriene B4 (LTB4) levels were upregulated in both PE patients and GC- mediated PE rats. Moreover, cortisol levels were negatively correlated to LXA4 levels, while positively correlated to LTB4 levels in PE patients. Mechanically, GC downregulated LXA4 via disturbing its biosynthetic enzymes, including ALOX15, ALOX5B and ALOX5, especially activating ALOX5, the key enzyme for class switching between LXA4 and LTB4. Importantly, replenishing LXA4 could ameliorate PE-related symptoms and placental oxidative stress in PE rat model induced by GC. Moreover, LXA4 could inhibit GC-mediated ALOX5 activation and LTB4 increase, and also suppress 11β-HSD2 expression and corticosterone upregulation. The protective actions of LXA4 might be explained by its roles in antagonizing the adverse effects of GC on trophoblast development. Together, our findings indicate that GC exposure could contribute to PE through dampening LXA4, and GC/LXA4 axis may represent a common pathway through which PE occurs.


[Genotype analysis of Giardia duodenalis isolates obtained from humans in west-central Poland].
Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a cosmopolitan flagellate organism belonging to the most common intestinal protozoan parasites of humans and animals. Great genetic heterogeneity has been found within G. duodenalis, where only genotypes representing assemblages A and B have zoonotic potential. Fecal samples (447 specimens) obtained from 232 humans in West-central region of Poland were examined by microscopy and PCR. The total prevalence of Giardia in humans was 1.3%. DNA was extracted from three positive fecal samples and PCR products were obtained after amplification using the beta-giardin primers G7 and G759. Sequence and phylogenetic analyses showed that G. duodenalis isolates from humans belonged to A and B genotypes. Moreover, three subgenotypes, including a cosmopolitan subgenotype A2 and two new subgenotypes A and B were detected.


BiP binding sequences in antibodies.
During the process of folding and assembly of antibody molecules in the endoplasmic reticulum, immunoglobulin heavy and light chains associate transiently with BiP, a resident endoplasmic reticulum protein that is a member of the Hsp70 family of molecular chaperones. BiP is thought to recognize unfolded or unassembled polypeptides by binding extended sequences of approximately seven amino acids that include bulky hydrophobic residues not normally exposed on the surface of native proteins. We used a computer algorithm developed to predict BiP binding sites within protein primary sequences to identify sites within immunoglobulin chains that might mediate their association with BiP. Very few of the sequential heptapeptides in the heavy or light chain sequences were potential BiP binding sites. Analysis of the ability of synthetic heptapeptides corresponding to 24 potential sites in heavy chains to stimulate the ATPase activity of BiP indicated that at least half of them were authentic BiP binding sequences. These sequences were not confined to a single domain of the heavy chain but were distributed within both the VH and CH domains. Interestingly, when the BiP binding sequences were mapped onto the three-dimensional structure of the Fd antibody fragment, the majority involve residues that participate in contact sites between the heavy and light chains. Therefore, we suggest that in vivo BiP chaperones the folding and assembly of antibody molecules by binding to hydrophobic surface regions on the isolated immunoglobulin chains that subsequently participate in interchain contacts.


Developing nurse practitioner associated metrics for outcomes assessment.
As nurse practitioners (NPs) assume an increasing role in providing care to hospitalized patients, measuring the impact of their care on patient outcomes and quality of care measures becomes a necessary component of performance evaluation. Developing metrics that relate to quality of care measures as well as patient outcomes based on the specific practices of an NP can help to specifically identify the impact of NP care in hospital and ambulatory care settings. New opportunities have arisen for highlighting NP outcomes that can be used to structure NP-associated metrics including the Hospital Value-Based Purchasing Program and the Joint Commission's practice evaluation standards. This manuscript discusses the use of NP-associated metrics for assessing the outcomes of NP care on patient care as well as on quality of care measures.


Double mutation in photosystem II reaction centers and elevated CO2 grant thermotolerance to mesophilic cyanobacterium.
Photosynthetic biomass production rapidly declines in mesophilic cyanobacteria grown above their physiological temperatures largely due to the imbalance between degradation and repair of the D1 protein subunit of the heat susceptible Photosystem II reaction centers (PSIIRC). Here we show that simultaneous replacement of two conserved residues in the D1 protein of the mesophilic Synechocystis sp. PCC 6803, by the analogue residues present in the thermophilic Thermosynechococcus elongatus, enables photosynthetic growth, extensive biomass production and markedly enhanced stability and repair rate of PSIIRC for seven days even at 43 °C but only at elevated CO(2) (1%). Under the same conditions, the Synechocystis control strain initially presented very slow growth followed by a decline after 3 days. Change in the thylakoid membrane lipids, namely the saturation of the fatty acids is observed upon incubation for the different strains, but only the double mutant shows a concomitant major change of the enthalpy and entropy for the light activated Q(A)(-)→Q(B) electron transfer, rendering them similar to those of the thermophilic strain. Following these findings, computational chemistry and protein dynamics simulations we propose that the D1 double mutation increases the folding stability of the PSIIRC at elevated temperatures. This, together with the decreased impairment of D1 protein repair under increased CO(2) concentrations result in the observed photothermal tolerance of the photosynthetic machinery in the double mutant.


Mapping quantitative trait loci responsible for resistance to Bakanae disease in rice.
Bakanae or foot rot disease caused by Fusarium fujikuroi [teleomorph: Gibberella fujikuroi (Sawada) Ito] is emerging as a serious disease in rice. The disease causes both quantitative and qualitative losses to the grains under the field conditions. Breeding for resistance to Bakanae disease is a promising strategy to manage this emerging disease. In this study, we used a population of 168 F14 recombinant inbred lines (RILs) derived from two indica rice parents Pusa 1342, a highly resistant variety and Pusa Basmati 1121, a highly susceptible variety to map quantitative trait loci (QTLs) governing resistance against Bakanae disease. The disease reaction of 168 F14 RILs were measured on the seedlings inoculated using Fusarium fujikuroi culture using high-throughput screening protocol under glasshouse conditions. Utilizing inclusive composite interval mapping, three QTLs governing resistance to Bakanae were identified, namely qBK1.1, qBK1.2 and qBK1.3 which accounted 4.76, 24.74 and 6.49 % of phenotypic variation, respectively. The major effect QTL designated qBK1.2 was mapped in 0.26 Mb region between RM5336 and RM10153. A total of 55 annotated genes were identified within the identified QTL region qBK1.2. The novel QTLs identified in this study are useful resource for efficiently breeding rice cultivars resistant to Bakanae disease. This is the first report on identification of QTLs governing resistance against Bakanae in rice using inclusive composite interval mapping strategy in a RIL population.


Structural and molecular characterization of equine sperm-binding fibronectin-II module proteins.
Phospholipid-binding proteins in the male genital tract are characterized by differing numbers Fn-2 modules (B-domain) carrying N-terminal extensions (A-domain) of variable length. In the stallion, three different proteins were identified, SP-1, SP-2, and EQ-12. SP-1 and SP-2 of the AA'BB'- and ABB'-type, respectively, are major proteins of the seminal plasma. Here we report the cDNA sequences of SP-1, and of a new member of the SP-2 family (SPnew) and the partial characterization of their iso- and glycoforms. The phosphorylcholine (PC)-binding ability of the long Fn-2 protein, EQ-12, with four tandemly arranged Fn-2 modules was determined by PC-affinity chromatography. Expression patterns of EQ-12, and the SP-proteins were studied by means of RT-PCR, Northern blot analysis and immunological approaches indicating differential expression along the male reproductive tract. The vast majority of the short SP-1 and SP-2 proteins are produced by the ampulla whereas EQ-12 originates from the epididymis. Indirect immunofluorescence microscopy of sperm isolated from different regions of the epididymis and Western blot analysis indicate that both, the long and the short Fn-2 proteins associate to the sperm surface during post-testicular maturation. Sperm binding of Fn-2 proteins at the post-acrosome and midpiece was at first detected in the corpus epididymis. Enhanced fluorescence intensity after ejaculation point to an increased number of molecules bound to the sperm surface. The function of these proteins is discussed in regard to their structure-function relationships.


Usefulness of Proximal Coronary Wave Speed for Wave Intensity Analysis in Diseased Coronary Vessels.
Background: Wave speed is needed to separate net wave intensity into forward and backward traveling components. However, wave speed in diseased coronary arteries cannot be assessed from hemodynamic measurements obtained distal to a stenosis. Wave speed inherently depends on arterial wall properties which should be similar proximal and distal to a stenosis. Our hypothesis is that proximal wave speed can be used to separate net wave intensity obtained distal to a stenosis. Methods: We assessed coronary wave speed using the sum-of-squares single-point technique (SPc) based on simultaneous intracoronary pressure and flow velocity measurements in human coronary arteries. SPc at resting flow was determined in diseased coronary vessels of 12 patients both proximal and distal to the stenosis. In seven of these vessels, distal measurements were additionally obtained after revascularization by stent placement. SPc was also assessed at two axial locations in 14 reference vessels without a stenosis. Results: (1) No difference in SPc was present between proximal and distal locations in the reference vessels. (2) In diseased vessels with a focal stenosis, SPc at the distal location was paradoxically larger than SPc proximal to the stenosis (28.4 ± 3.7 m/s vs. 18.3 ± 1.8 m/s, p < 0.02), despite the lower distending pressure downstream of the stenosis. The corresponding separated wave energy tended to be underestimated when derived from SPc at the distal compared with the proximal location. (3) After successful revascularization, SPc at the distal location no longer differed from SPc at the proximal location prior to revascularization (21.9 ± 2.0 m/s vs. 20.8 ± 1.9 m/s, p = 0.48). Accordingly, no significant difference in separated wave energy was observed for forward or backward waves. Conclusion: In diseased coronary vessels, SPc assessed from distal hemodynamic signals is erroneously elevated. Our findings suggest that proximal wave speed can be used to separate wave intensity profiles obtained downstream of a stenosis. This approach may extend the application of wave intensity analysis to diseased coronary vessels.


Environmental enrichment alleviates the deleterious effects of stress in experimental autoimmune encephalomyelitis.
Clinical observations support the hypothesis that stressful events increase relapse occurrence in multiple sclerosis patients, while stress-reduction strategies can modulate this effect. However, a direct cause-effect relationship between stress level and relapse cannot be firmly established from these data. The purpose of this work was to address whether modulation of stress could interfere with symptom relapse in an animal model of multiple sclerosis with relapsing-remitting course. Mice bred in standard or enriched environment were subjected to repeated acute stress during the remission phase of relapsing-remitting PLP-induced experimental autoimmune encephalomyelitis. We report that repeated acute stress induced a twofold increase in relapse incidence in experimental autoimmune encephalomyelitis. On the other hand, environmental enrichment reduced relapse incidence and severity, and reversed the effects of repeated acute stress. These data provide the platform for further studies on the biological processes that link stress and multiple sclerosis relapses in a suitable animal model.


The Gut Virome Database Reveals Age-Dependent Patterns of Virome Diversity in the Human Gut.
The gut microbiome profoundly affects human health and disease, and their infecting viruses are likely as important, but often missed because of reference database limitations. Here, we (1) built a human Gut Virome Database (GVD) from 2,697 viral particle or microbial metagenomes from 1,986 individuals representing 16 countries, (2) assess its effectiveness, and (3) report a meta-analysis that reveals age-dependent patterns across healthy Westerners. The GVD contains 33,242 unique viral populations (approximately species-level taxa) and improves average viral detection rates over viral RefSeq and IMG/VR nearly 182-fold and 2.6-fold, respectively. GVD meta-analyses show highly personalized viromes, reveal that inter-study variability from technical artifacts is larger than any "disease" effect at the population level, and document how viral diversity changes from human infancy into senescence. Together, this compact foundational resource, these standardization guidelines, and these meta-analysis findings provide a systematic toolkit to help maximize our understanding of viral roles in health and disease.


High-pressure freezing of tissue obtained by fine-needle biopsy.
High-pressure freezing (HPF) permits adequate cryoimmobilization (without detectable ice crystals after freeze-substitution) of biological tissue up to a thickness of about 200 microns. Until now the preparation of tissue prior to freezing has been unsatisfactory: sizing of the tissue to the required dimensions takes minutes, during which structural alterations must occur. We demonstrate that the use of a fine-needle biopsy technique minimizes tissue damage and guarantees sample dimensions close to the optimal thickness for HPF. The tissue cores can be cryoimmobilized within 40 s of excision.


Anti-Biofilm Properties of Saccharomyces cerevisiae CNCM I-3856 and Lacticaseibacillus rhamnosus ATCC 53103 Probiotics against G. vaginalis.
Bacterial vaginosis (BV) is characterized by the presence of a polymicrobial biofilm where Gardnerella vaginalis plays a key role. Previously, we demonstrated that Saccharomyces cerevisiae CNCM (French National Collection of Cultures of Microorganisms) I-3856 is helpful in resolving experimental simulated BV in mice. In this study, we analyzed its capacity to affect G. vaginalis biofilms and to potentiate the activity of standard antimicrobial agents. We also investigated the anti-biofilm activity of Lacticaseibacillus rhamnosus GG (ATCC 53103), a well-known strain for its intestinal healthy benefits. Biofilm biomass was assessed by crystal violet staining, and G. vaginalis viability was assessed by a colony forming unit (CFU) assay. Here, for the first time, we demonstrated that S. cerevisiae CNCM I-3856 as well as L. rhamnosus GG were able (i) to significantly inhibit G. vaginalis biofilm formation, (ii) to markedly reduce G. vaginalis viability among the biomass constituting the biofilm, (iii) to induce disaggregation of preformed biofilm, and (iv) to kill a consistent amount of bacterial cells in a G. vaginalis preformed biofilm. Furthermore, S. cerevisiae CNCM I-3856 strongly potentiates the metronidazole effect on G. vaginalis biofilm viability. These results suggest that S. cerevisiae CNCM I-3856 as well as L. rhamnosus GG could be potential novel therapeutic agents against bacterial vaginosis.


Thoracic endovascular aortic repair and off-pump coronary artery bypass grafting after renal transplantation: a case report.
Twelve years after receiving a renal transplant, a 50-year-old woman developed asthmatic symptoms. Chest CT revealed a descending thoracic aortic aneurysm. She had undergone percutaneous coronary intervention to treat the left anterior descending artery 10 years earlier. Coronary artery angiography revealed restenosis of the left anterior descending artery (99%, #6 in-stent). Because cardiopulmonary bypass may cause problems for transplanted kidney, we performed off-pump coronary artery bypass grafting (left internal thoracic artery to left anterior descending artery) and thoracic endovascular graft placement to treat the aortic aneurysm. Considering that the artery of the transplanted kidney was attached to the right iliac artery, and then the left common femoral artery was selected as the access root for GORE TAG(®) endografts (34 × 200 and 34 × 150 mm) (stentgrafts were deployed for the descending aortic artery). Postoperative angiography showed a patent bypass graft. Postoperative CT confirmed the absence of endoleaks. The postoperative course was uneventful, and she was discharged without complications. Ischemic heart disease and descending thoracic aortic aneurysm in recipients of kidney transplants can be treated using off-pump coronary bypass grafting and thoracic endovascular graft placement. The transplanted kidney was protected without using cardiopulmonary bypass (CPB).


Spatiotemporal Dynamics of the Carbon Budget and the Response to Grazing in Qinghai Grasslands.
Estimating the grassland carbon budget is critically important for ensuring that grassland resources are used sustainably. However, the spatiotemporal dynamics of the carbon budget and the response to grazing have not yet been characterized in Qinghai grasslands. Here, we estimated the gross primary productivity (GPP) and net ecosystem exchange (NEE) in Qinghai grasslands using the improved Biome-BGCMuSo model to characterize the spatiotemporal dynamics of the carbon budget and the response to grazing in this region from 1979 to 2018. The GPP of Qinghai grasslands fluctuated during the study period, with an average annual value of 118.78 gC/m2. The NEE of Qinghai grasslands fluctuated from 1979 to 2018, with an average value of -5.16 gC/m2. After 2,000, GPP increased, and NEE decreased in a fluctuating manner. There were clear regional differences in GPP and NEE. GPP was low in most areas of Qinghai, and GPP was high in eastern and southern Qinghai. The southern, southeastern, and northeastern parts of Qinghai were mainly carbon sinks, and the northwestern part of Qinghai and the region between the southeastern and northeastern parts of Qinghai were mainly carbon sources. Grazing generally decreased GPP and increased NEE in Qinghai grasslands from 1979 to 2018. There was spatial heterogeneity in the effect of grazing on GPP and NEE. Under grazing, GPP and NEE were significantly decreased mainly in eastern Qinghai, and GPP and NEE were significantly increased mainly in southern and eastern Qinghai. NEE was most affected by grazing in eastern Qinghai. The results of this study aid our understanding of the mechanism driving variation in the grassland carbon budget and provide new data that could be used to support local grassland management.


Molecular diagnostics.
Nucleic acid technology has assumed an essential role in various areas of in vitro diagnosis. Its major applications include the genomic characterization of mutations and polymorphisms, amplification of nucleic acids by the polymerase chain reaction, analysis of gene expression patterns at the mRNA level, specific detection of mutant proteins, and engineering of proteins used in ligand binding assay. Manipulating the expression of genes in cells and experimental animals allows detailed analysis of processes leading from genomic alterations to disease manifestations and may ultimately yield refinements in diagnostic strategies. The addition of DNA and RNA to the conventional diagnostic in vitro targets and novel approaches to the study of disease processes and manifestations characterize a diagnostic strategy referred to as "molecular diagnostics." This contribution describes some of essential ways in which molecular diagnostics differs from conventional diagnostic approaches. Applications such as differential diagnosis, prenatal diagnosis, early diagnosis, and diagnosis of disease susceptibility are well established in single-gene disorders, and the diagnostic impact of DNA polymorphisms is steadily increasing in multifactorial diseases. The high sensitivity of the polymerase chain reaction makes possible the detection of single infectious agents or tumor cells. With increasing knowledge of expressed gene sequences the expression pattern of mRNA will reflect the biological state of cells with high precision. Mutant proteins can be analyzed based on their structural or biological properties. Use of the appropriate expression systems makes it possible to design proteins for diagnostic in vitro applications such as ligand binding assays.


Myocardial delayed enhancement in patients with pulmonary hypertension and right ventricular failure: evaluation by cardiac MRI.
In this study, we evaluated patients with pulmonary arterial hypertension (PAH) and impaired right ventricular function. We used cardiac MRI for the detection of myocardial delayed enhancement (MDE) and its possible association with other clinical variables. 20 patients (6 males and 14 females, aged 44.5+/-11 years; 15 New York Heart Association class III, 5 class IV) with known PAH (13 idiopathic, 7 resulting from chronic pulmonary embolism) were evaluated for the detection of MDE. Short-axis cine images of the heart were made for ventricular function assessment using a steady-state free precession sequence. For MDE evaluation, a short-axis phase-sensitive inversion recovery sequence was performed 10 min after intravenous administration of 0.2 mmol kg(-1) gadodiamide. Right ventricle (RV) systolic dysfunction, RV enlargement and RV hypertrophy were present in 20 patients (RV ejection fraction, 21.5+/-7.2%; RV diastolic diameter, 5.97+/-0.79 cm; RV wall thickness, 0.73+/-0.10 cm). 13 of the 20 patients (65%) were positive for MDE (10 anterior, 12 inferior). All 13 positive patients with MDE demonstrated small hyperintense areas at the insertion points of the RV free wall in the interventricular septum. We found no significant correlation between MDE and ejection fraction or other haemodynamic variables. In this study, MDE correlated positively only with the duration of disease. We found that septal MDE can be present in patients with PAH and impaired ventricular function. However, further studies are necessary to investigate this possible association and its prognostic implication.


Unprompted recall and reporting of hidden objects by a chimpanzee (Pan troglodytes) after extended delays.
The ability to recall features of environments not present to the senses is important in human thinking, planning, and communication, but to date there are almost no data on recall capabilities in nonverbal animals. In this study, the author used symbol knowledge as a tool to study chimpanzee memory. An 11-year-old female chimpanzee (Pan troglodytes) that had already learned a large number of arbitrarily designated geometric forms (lexigrams) watched as an experimenter hid an object in the woods outside her outdoor enclosure. The type and location of the object varied across trials. After an imposed delay of up to 16 h, the chimpanzee could interact indoors with a person who did not know that an object had been hidden, let alone the type or location of the object. A keyboard in the indoor cage displayed 256 lexigrams. From Trial 1, the chimpanzee seemed to do whatever it took to catch the person's attention and then touched the lexigram corresponding to the type of object hidden, pointed outdoors, went outdoors (if followed), and continued to point manually toward the object and vocalize until the person found the object. The subject indicated nonfood objects as well as more than 20 food types.


AGE-Rich Bread Crust Extract Boosts Oxidative Stress Interception via Stimulation of the NRF2 Pathway.
Advanced glycation end products (AGEs) result from a non-enzymatic reaction of proteins with reactive carbohydrates. Heat-processed food, such as bread, contains high amounts of AGEs. The activation of the NF-κB signaling pathway by bread crust extract (BCE) is well understood. However, it is largely unknown whether NRF2, the master regulator of oxidative stress resistance in mammalian cells, is affected by BCE. We have investigated the molecular mechanisms by which BCE induces antioxidant gene expression in cellular models. Our data showed that soluble extracts from bread crust are capable of stimulating the NRF2 signaling pathway. Furthermore, NRF2 pathway activation was confirmed by microarray and reporter-cell analyses. QRT-PCR measurements and Western blot analyses indicated an induction of antioxidative genes such as HMOX1, GCLM and NQO1 upon BCE treatment. Moreover, BCE pretreated cells had a survival advantage compared to control cells when exposed to oxidative stress. BCE induces phosphorylation of AKT and ERK kinase in EA.hy926 cells. By mass spectrometry, several new, potentially active modifications in BCE were identified. Our findings indicate that BCE activates NRF2-dependent antioxidant gene expression, thus provoking a protection mechanism against oxidative stress-mediated tissue injury. Hence, BCE can be considered as functional food with antioxidative and cardioprotective potential.


Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors.
E1-deleted adenoviral vectors are increasingly being utilized for in vivo gene transfer. The potential use of these vectors is limited by transient expression of the transgene and a markedly reduced rate of transduction following readministration, presumably due to a host immune response to the vector. We hypothesized that CD4+ lymphocytes are necessary to generate an immune response to these vectors and that administration of a depleting anti-CD4 antibody (GK1.5) might prolong transgene expression in vivo. We found that pretreatment of mice with a single injection (transient depletion) or weekly injections of GK1.5 (persistent depletion), markedly prolonged expression of an adenovirus-encoded tumor necrosis factor (TNF) inhibitor or luciferase gene compared to controls. Moreover, mice treated with GK1.5 showed no antiadenoviral antibody response to repeat administration of the vector and a second adenoviral transgene could be expressed in these animals. However, control mice developed a significant neutralizing antibody response that prevented transgene expression with administration of a second adenovirus. These findings demonstrate that manipulation of the host immune response may expand potential applications of gene transfer utilizing adenoviral vectors.


Glycine oxidase based high-throughput solid-phase assay for substrate profiling and directed evolution of (R)- and (S)-selective amine transaminases.
Transaminases represent one of the most important enzymes of the biocatalytic toolbox for chiral amine synthesis as they allow asymmetric synthesis with quantitative yields and high enantioselectivity. In order to enable substrate profiling of transaminases for acceptance of different amines, a glycine oxidase and horseradish peroxidase coupled assay was developed. Transaminase activity is detected upon transfer of an amine group from an amino donor substrate to glyoxylate, generating glycine, which is subsequently oxidized by glycine oxidase, releasing hydrogen peroxide in turn. Horseradish peroxidase uses the hydrogen peroxide to produce benzoquinone, which forms a red quinone imine dye by a subsequent condensation reaction. As glycine does not carry a chiral center, both (R)- and (S)-selective transaminases accepting glyoxylate as amino acceptor are amenable to screening. The principle has been transferred to establish a high-throughput solid-phase assay which dramatically decreases the screening effort in directed evolution of transaminases, as only active variants are selected for further analysis.


Complex study of the physiological role of cadmium. III. Cadmium loading trials on broiler chickens.
Cadmium (Cd) loading trials were conducted on a total of 110 (3 x 10 and 4 x 20) broiler chickens prereared for 21 days. The control chickens received no cadmium, while chickens in the six treatment groups were given different doses of Cd as an aqueous solution of CdSO4 administered either into the crop or mixed in the feed. The chickens were kept in a climatized animal house and treated usually for 3-5 weeks (maximum 68 days), with the exception of group Cd-75 chickens which were treated up to 239 days of age. The chickens' health status, body mass and feed consumption were monitored throughout the trial. On days 14-20 and on day 42 of the trial 2 chickens per group, then at the end of trial a total of 25 chickens were killed in anaesthesia. These birds, together with chickens that died or were killed during the trial, were subjected to detailed gross pathological examination. From 11 organs (kidney, liver, spleen, testicle, brain, myocardium, skeletal muscle, lungs, digestive tract, pancreas, tubular bones) of these chickens samples were taken for assay for a total of 16 elements, as well as for light and electron microscopic examination. With the exception of groups Cd-30 and Cd-600, no abnormal clinical signs were observed in the first two weeks of the trial. Chickens of group Cd-30 died before day 8-12 of the trial among signs of complete anorexia, rapid emaciation, huddling and diarrhoea, while chickens of group Cd-600 died before day 28, showing similar clinical signs. The body mass of chickens fed a Cd-supplemented diet either remained constant or decreased substantially, in a degree proportional to the Cd load. The only exception was group Cd-2.5, in which the average body mass of birds at the end of week 8 slightly exceeded that of the controls. Four out of the 10 cockerel chicks fed a diet containing 75 ppm Cd up to 239 days of age died of intercurrent diseases; the remaining six grew well and reached a body mass of 3.8-4.3 kg. Feed conversion efficiency was satisfactory in the control group and in group Cd-2.5 (2.1 and 2.4 kg, respectively) and could not be evaluated in a realistic manner in the other groups. At necropsy, the cockerel chicks of groups Cd-30 and Cd-600 showed severe emaciation, liver and kidney degeneration, myocardial hypertrophy and cardiac dilatation.(ABSTRACT TRUNCATED AT 400 WORDS)


Isolation and Characterization of an Elicitor of Necrosis Isolated from Intercellular Fluids of Compatible Interactions of Cladosporium fulvum (Syn. Fulvia fulva) and Tomato.
Intercellular fluids of compatible race-cultivar interactions of Cladosporium fulvum and tomato contain specific elicitors of necrosis. These elicitors which are of fungal origin induce chlorosis and necrosis in resistant but not in susceptible plants. With the tomato cultivar Sonatine (carrying resistance gene Cf9, resistant to the fungal races 0, 4, 5, 2, 2.4, and 2.4.5 but susceptible to race 220.127.116.11) as the test plant for assaying necrosis-inducing activity, we isolated and partially characterized an elicitor of necrosis on this cultivar. The elicitor bound to CM-Sephadex but not to DEAE-Sephadex; it was stable to heat (10 minutes at 100 degrees C), HCl (0.01 normal), NaOH (0.01 normal), and NaIO(4) (0.02 molar), sensitive to pronase and protease (from Bacillus polymyxa) but not to other proteases such as alpha-chymotrypsin and trypsin. After electrophoresis of partially purified elicitor preparations under low pH conditions, the necrosis-inducing activity was association with a peptide with an apparent molecular weight of 5500. Races 0, 4, 5, 2.4, and 2.4.5 but not race 18.104.22.168 produced this elicitor in high yields. The elicitor is probably a product of avirulence gene A9 which is present in all races except in race 18.104.22.168 and induces necrosis in cultivars carrying resistance gene Cf9.


Analysis of the multimeric state of proteins by matrix assisted laser desorption/ionization mass spectrometry after cross-linking with glutaraldehyde.
We have undertaken a systematic study on the suitability of matrix-assisted laser desorption/ionization mass spectrometry to analyze and determine the multimericity of several proteins after cross-linking with glutaraldehyde. Using both commercially available proteins and others of viral origin currently being characterized in our laboratory, we studied the range of concentrations of cross-linker and protein for optimal analysis. Under the conditions developed during this study, we confirmed the multimeric states of three phage PRD1 structural proteins with monomeric masses ranging from 13.5 to 63 kDa. In addition, we addressed the question of the general applicability of the method by using it successfully to confirm the stoichiometry of the heptameric chaperonin GroEL, a bacterial protein with a mass well over 450 kDa.


Paradoxical changes of coronary computed tomography derived fractional flow reserve.
A total of 1335 outpatients with suspected coronary artery disease and who underwent computed tomography derived fractional flow reserve (FFRCT ) analysis were examined. Only four patients showed reverse increase of FFRCT from the proximal to the distal vessel and all of them had a large ramus artery (RAM). Of all parameters (vessel length, lumen volume, plaque volume, and left ventricular mass), only the bifurcation angle was significantly higher in reverse increase of FFRCT with RAM group (106.0 ± 15.8°) than normal FFRCT with RAM group (82.6 ± 21.7°) and normal FFRCT without RAM group (66.9 ± 21.1°).


Perceptions of Japanese patients and their family about medical treatment decisions.
Internationally, nurses and physicians are increasingly expected to undertake roles in communication and patient advocacy, including in Japan, where the reigning principle underlying medical ethics is in transition from paternalism to respect for patient autonomy. The study reports the results of a survey in two Japanese teaching hospitals that clarified the perspectives of 128 patients and 41 family members regarding their current and desired involvement in health decision-making. The commonest process that was desired by patients and their family was for patients to make decisions after consultation with both the physician and their family. The decision-making preferences for competent patients varied among the participants, who believed that families have a crucial role to play in health-care decision-making, even when patients are competent to make their own decisions. The findings will inform health professionals about contemporary Japanese health-care decision-making and the ethical issues involved in this process, as well as assist the future development of a culturally relevant model to support patients' preferences for ethical decision-making.


Modeling a Pandemic (COVID-19) Management Strategy for Urban Slums Using Social Geometry Framework.
The purpose of this paper is to utilize social geometry framework to model a pandemic (COVID-19) management strategy in densely populated informal settlements in Kenya. Our central claim is that the containment strategy that was instituted to control spread of COVID-19 failed to recognize the socio-cultural and livelihood complexities of the urban slum residents. This unmitigated strategy predisposed the residents to risks of heightened transmission of the pandemic. Drawing on social geometry approach in the analysis of human relations, we reveal some insights offered by our experiences in theorizing about public health intervention (PHI) and in doing so develop an alternative analytical framework ('social pendulum') to support the development of a PHI strategy that is compatible with the swing-like lifestyle of residents in the informal settlements. Our conclusion revisits the reliability and validity criteria for the new framework and offers some direction for further research.


High Diagnostic Value of a New Real-Time Pneumocystis PCR from Bronchoalveolar Lavage in a Real-Life Clinical Setting.
To diagnose Pneumocystis jirovecii pneumonia (PCP), PCR testing in bronchoalveolar lavage (BAL) fluid has recently become an alternative to immunofluorescence testing (IFT); however, its diagnostic accuracy is less clear. To analyze the diagnostic value of a new semiquantitative real-time PCR (RT-PCR) in BAL in a real-life clinical setting. Retrospective analysis of all RT-PCR results [semiquantitative: negative, weakly positive, and strongly positive; measured in cycle thresholds (Ct)] in BAL in the period between 2010 and 2014. The diagnosis of PCP was defined by clinical, radiological, and laboratory signs and by treatment initiation. Any positive PCR was compared with subsequent IFT. Of 128 patient samples, 32 had PCP. There is a relevant correlation of high significance between positive PCR Ct and IFT (r = -0.7781, p < 0.001), which amounts to about 60% of the variance. Sensitivity, specificity, and positive predictive values (PPV) of any positive RT-PCR were 100, 80, and 63%, respectively. No patient with negative RT-PCR had PCP. Specificity and PPV are 100% in strongly positive RT-PCR, whereas they decrease to 80 and 21% in weakly positive RT-PCR. A negative RT-PCR (Ct >45) rules out PCP. A strongly positive PCR (Ct <31.5) confirms PCP. In these cases, the diagnostic value of the new method is at least equal to the IFT. A weakly positive PCR probably represents pneumocystis colonization and can occur under PCP treatment.


Cost effective interprofessional training: an evaluation of a training unit in Denmark.
In 2004, the first Danish undergraduate interprofessional training unit (ITU) was established at the Regional Hospital Holstebro, inspired by experiences from Sweden. In this unit, medical, nursing, occupational therapy and physiotherapy students are given responsibility, under supervision by trained and motivated personnel, for rehabilitation and care of patients in a subunit of an orthopaedic department. The aim of this study was to see whether the ITU was cost effective in treating patients compared with a conventional orthopaedic ward. One-hundred and thirty-four patients admitted for primary hip or knee replacement surgery were included in the study. All costs were recorded in the ITU and in the conventional ward. Follow-up was done by a quality of life questionnaire three months after the operation. Comparison was done by univariable and multivariable testing of costs and effect. In both, the ITU was more cost effective than the conventional ward. No difference was found in complications and patient-reported quality of life. In conclusion, clinical training can be given to students in an ITU without reducing productivity in a hospital environment if pedagogic principles, clinical tutors and patient logistics all adapt to the challenge of the teaching environment.


Effects of Fabrication Methods on the Performance of Luminescent Solar Concentrators Based on Doped Polymer Optical Fibers.
In this work, we detail two types of fabrication processes of four polymer optical fibers doped with lumogen dyes. The fiber preforms have been manufactured with two different methods: extrusion and casting. We have compared the performance of the two types of fibers as luminescent solar concentrators by calculating their optical efficiencies and concentration factors. The obtained results show better performance for those fibers manufactured by the casting process. We have also studied the photostability of the two types of fibers doped with the dye lumogen red under solar light radiation. A high thermal stability of the doped fibers has been observed.


A new magnetic adsorbent of eggshell-zeolitic imidazolate framework for highly efficient removal of norfloxacin.
Many effluents contain various antibiotics commonly, where the simultaneous removal of them is a big challenge. In this study, the magnetic biocomposite (eggshell-zeolitic imidazolate framework) was designed and synthesized by green and facile method. Zeolitic imidazolate framework-8 (ZIF-8) particles were stabilized on the surface of magnetic eggshell (Fe3O4-ES), generating a new Fe3O4-ES/ZIF-8 adsorbent, which was also fully characterized using FTIR, XRD, SEM and BET techniques. Thereafter, norfloxacin (NOR) adsorption processes were investigated through different influencing factors (dosage, concentration, pH and temperature). The Langmuir adsorption isotherm could confirm a maximum removal efficiency of 80.13% for NOR. Kinetic studies illustrated that the pseudo-first-order model was in line with the experimental data of the simultaneous removal of NOR. Moreover, the magnetic nature of the adsorbent caused an easy separation from the aqueous solution.


Dodecagonal photonic quasi-crystal fiber with high birefringence.
A photonic quasi-crystal fiber (PQF) with high birefringence is proposed. A dodecagonal Stampfli quasi-periodic lattice of air holes constitutes the cladding of the PQF. The PQF maintains the properties of high birefringence and single-mode operation regime in a wide wavelength range from 1.2 to 2.0 μm by optimizing the size of the air holes around the core of the PQF. A birefringence with 3.86×10-2 can be obtained at 1.31 and 1.55 μm optical telecommunication windows. The birefringence is of the order of 10-2, which is two orders of magnitude larger than that of the conventional polarization-maintaining fibers and hardly affected by the incident wavelength. The proposed PQF also maintains a high nonlinear coefficient and low confinement loss. Our structure and simulation results are expected to provide a valuable reference and basic data to relative fabrication and experiments.


Glass Substrate Dust Removal Using 233 fs Laser-Generated Shockwave.
Eliminating dust is gaining importance as a critical requirement in the display panel manufacturing process. The pixel resolution of display panels is increasing rapidly, which means that even small dust particles on the order of a few micrometers can affect them. Conventional surface cleaning methods such as ultrasonic cleaning (USC), CO2 cleaning, and wet cleaning may not be sufficiently efficient, economical, or environment friendly. In this study, a laser shockwave cleaning (LSC) method with a 233 fs pulsed laser was developed, which is different from the laser ablation cleaning method. To minimize thermal damage to the glass substrate, the effect of the number of pulses and the gap distance between the focused laser beam and the glass substrate were studied. The optimum number of pulses and gap distance to prevent damage to the glass substrate was inferred as 500 and 20 μm, respectively. With the optimal pulse number and gap distance, cleaning efficiency was tested at a 95% removal ratio regardless of the density of the particles. The effective cleaning area was measured using the removal ratio map and compared with the theoretical value.


[Diphtheria in Denmark 1956-1989. Occurrence of Corynebacterium diphtheriae and other diphtheria toxigenic bacteria].
The public immunization program against diphtheria, established in 1941, has almost eradicated the disease in Denmark, and 1956 became the first year without any notified cases. Since then, toxigenic strains have only been isolated five times--three cases of clinical diphtheria due to Corynebacterium diphtheriae biovar. mitis and two cases of tonsillitis/pharyngitis due to Corynebacterium ulcerans. The source of the infection was not identified in any of the cases. The first case of diphtheria in 1968 was imported from abroad. The following two cases in 1983 and 1985 were due to strains of the same phage type and peptide profile as the strains isolated during the epidemic in Sweden in 1984-1986. This indicates that the Danish cases and the Swedish epidemic derived from the same source. The diphtheria immunity of the Danish population is decreasing, and the level of protection is approaching the Swedish level. The impact is that a situation like that in Sweden may be anticipated with diphtheria epidemic in the lowest socio-economical groups--the skid row dwellers, alcoholics and drug abusers--if the immunization program against diphtheria is not intensified.


Release of beryllium from beryllium-containing materials in artificial skin surface film liquids.
Skin exposure to soluble beryllium compounds causes systemic sensitization in humans. Penetration of poorly soluble particles through intact skin has been proposed as a mechanism for beryllium sensitization; however, this mechanism is controversial. The purpose of this study was to investigate the hypothesis that particulate beryllium compounds in contact with skin surface release ions via dissolution in sweat. Dissolution of 11 particulate beryllium materials (hydroxide, metal, oxides and copper-beryllium fume), 3 copper-beryllium alloy reference materials (chips and solid block), and 4 copper-beryllium alloy tools was measured over 7 days in artificial sweat buffered to pH 5.3 and pH 6.5. All test materials released beryllium ions in artificial sweat. Particulate from a reduction furnace that contained both crystalline and amorphous beryllium was the most soluble compound-40% dissolved in 8 h. Rates of beryllium release from all other particulate and reference materials were faster at pH 5.3 than at pH 6.5 (P < 0.05). At pH 5.3, values of the chemical dissolution rate constant, k [g (cm² day)⁻¹] differed significantly for hydroxide, metal, and oxide -1.7 ± 0.0 × 10⁻⁷, 1.7 ± 0.6 × 10⁻⁸, and 1.0 ± 0.5 × 10⁻⁹, respectively (P < 0.05). Up to 30 μg of beryllium was released from the alloy tools within 1 h. Dissolution rates in artificial sweat were equal to or faster than values previously determined for these materials in lung models. Poorly soluble beryllium materials undergo dissolution in artificial sweat, suggesting that skin exposure is a biologically plausible pathway for development of sensitization. Skin surface acidity, which is regulated by sweat chemistry and bacterial hydrolysis of sebum lipids varies by anatomical region and may be an exposure-modifying factor for beryllium particle dissolution.


Localization and characterization of substance P binding sites in rat and rabbit eyes.
Specific and high-affinity binding sites for Substance P (SP) were found in eyes from albino rabbits and rats using an in vitro autoradiographic method with 125I-Bolton Hunter SP (BHSP). autoradiograms were generated by apposing 10-20 microns-thick cryostat eye sections to 3H-Hyperfilm or liquid emulsion and quantified by means of image-analysis procedures. Kinetic studies showed that equilibrium was reached after a 75-min incubation at room temperature. In rat retina, specific binding corresponding to approximately 90% of total binding, was reversible, of high affinity (dissociation constant [Kd], 0.13 +/- 0.02 nM). Half-time for dissociation of 125I-BHSP was about 15 min. Unlabeled SP and the two neurokinins (NK) A and B competed in a concentration-dependent manner for retinal sites labeled by 125I-BHSP with the following order of potencies: SP greater than NKA greater than NKB, in agreement with a pharmacologic profile of a SP receptor site. In both species, specific binding was found in the iris sphincter muscle, choroid, and retina. In rats, detectable amounts of SP-binding sites were also expressed in the corneal epithelium and iridial stroma. Quantitative analysis of the autoradiograms revealed that the highest densities of 125I-BHSP binding sites were localized in the iris sphincter muscle in rabbits and the inner retina in rats.


A GSH/CB Dual-Controlled Self-Assembled Nanomedicine for High-Efficacy Doxorubicin-Resistant Breast Cancer Therapy.
Chemoresistance is a major therapeutic obstacle in the treatment of breast cancer. Therefore, how to overcome chemoresistance is a problem to be solved. Here, a glutathione (GSH)/cathepsin B (CB) dual-controlled nanomedicine formed by cyclic disulfide-bridged peptide (cyclic-1a) as a potent anticancer agent is reported. Under the sequential treatment of GSH and CB, cyclic-1a can efficiently self-assemble into nanofibers. In vitro studies show that cyclic-1a promotes the apoptosis of MCF-7/DOX cells by inducing the cleavages of caspase-3 and PARP. In vivo studies confirm that cyclic-1a significantly inhibits the progression of MCF-7/DOX cells-derived xenograft in nude mice, with no obvious adverse reactions. This study provides a paradigm of GSH/CB dual-controlled nanomedicine for high-efficacy and low-toxic DOX-resistant breast cancer therapy.


Evaluation of a Product Containing Xyloglucan and Pea Protein on Skin Barrier Permeability.
The skin acts as a mechanical and protective barrier against viral, fungal, and bacterial infections. Skin conditions such as atopic dermatitis and psoriasis are characterized by alterations of the skin barrier, often caused by injury and by bacterial infections. In the last years, non-pharmacological interventions have gained great importance in epidermis-related diseases. Xyloglucan (XG) is a polysaccharide that possesses a "mucin-like" molecular structure that confers mucoadhesive properties, allowing XG-containing formulations to act as a protective barrier for the management of different diseases. Moreover, there is also increasing interest in the use of proteins due to their film-forming features. This study aimed to evaluate the barrier-protective properties of a product containing XG and pea protein (PP) in an in vitro model, assessing its effects on the membrane permeability of keratinocytes infected by Staphylococcus aureus. HaCaT keratinocytes were pretreated with XG and PP for 3 h and then infected with S. aureus cells (106 bacteria/well) at a multiplicity of infection of 10 for 1 h. The number of bacterial colonies and membrane integrity were measured, respectively. We observed that pretreatment with XG and PP in human HaCaT keratinocytes infected with S. aureus significantly increased trans-epithelial electrical resistance (a marker of skin barrier function) measurement, reduced lucifer yellow (a marker of membrane integrity) permeation across the monolayer, and released lactate dehydrogenase (a marker of tissue damage). Moreover, XG and PP pretreatment was able to reduce bacterial adherence, avoiding S. aureus infection. In summary, we demonstrated that the product containing XG and PP was able to maintain barrier permeability preserving its integrity, and therefore, it can be considered as an interesting approach for the management of epidermis-related diseases.


The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes.
Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment. Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression. constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 μg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats. Dysregulated circadian light exposure significantly compromises the efficacy of morphine's antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.


Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
The aims of this article are to review the current understanding of hyperkalemia associated with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy. This includes reviewing the pathophysiology of how these agents affect potassium handling within the kidney, risk factors for developing hyperkalemia, incidence, clinical signs and symptoms, and providing a practical approach to treatment of the patient who is either at risk of, or experiencing, hyperkalemia. ACEi and ARB are effective therapeutic agents used in a variety of clinical scenarios. However, related to their effects on the renin-angiotensin-aldosterone system, their use can be associated with hyperkalemia, particularly in patients who have chronic renal insufficiency. Published incidence estimates of hyperkalemia associated with ACEi or ARB vary, but up to 10% of patients may experience at least mild hyperkalemia. Important considerations when initiating ACEi or ARB therapy include obtaining an estimate of glomerular filtration rate and a baseline serum potassium concentration, as well as assessing whether the patient has excessive potassium intake from diet, supplements, or drugs that can also increase serum potassium. Serum potassium monitoring shortly after initiation of therapy can assist in preventing hyperkalemia. If hyperkalemia does develop, prompt recognition of cardiac dysrhythmias and effective treatment to antagonize the cardiac effects of potassium, redistribute potassium into cells, and remove excess potassium from the body is important.Understanding the mechanism of action of ACEi and ARB coupled with judicious drug use and clinical vigilance can minimize the risk to the patient of developing hyperkalemia. Should hyperkalemia occur, prompt recognition and management can optimize clinical outcome.


Diurnal Changes in Metabolite Levels and Crassulacean Acid Metabolism in Kalanchoë daigremontiana Leaves.
Diurnal changes in levels of selected metabolites associated with glycolysis, the C(3) cycle, C(4)-organic acids, and storage carbohydrates were analyzed in active Kalanchoë daigremontiana Crassulacean acid metabolism leaves. Three metabolic transition periods occurred each day. During the first two hours of light, nearly all of the metabolite pools underwent transient changes. Beginning at daylight, stomata opened transiently and closed again within 30 minutes; malate synthesis continued for about 1 hour into the light; C(3) photosynthesis began within 30 minutes; and net quantities of starch and glucan began to accumulate after 2 hours, continuing linearly throughout the rest of the day.THE SECOND TRANSITION OCCURRED IN MIDAFTERNOON: stomata reopened; malate decarboxylation nearly terminated; and the assimilation of ambient CO(2) occurred primarily via the C(3) cycle. The third transition occurred at dark: stomata transiently closed before opening again; the C(3) cycle stopped; malate synthesis started in about 1 hour; starch and glucan degradation began within 1 hour; and the bulk of carbon flow was through glycolysis leading to the synthesis and accumulation of malate throughout the night. At night, the levels of metabolites involved in acidification and glycolysis (except for phosphoenolpyruvate) generally accumulated. Phosphoenolpyruvate levels peaked near midday and were minimal at night. The ribulose 1,5-bisphosphate pool was depleted at night, while sedoheptulose 1,7-bisphosphate, fructose 1,6-bisphosphate, glucose 6-phosphate, and fructose 6-phosphate accumulated.


Investigation of CTLA-4 and CD28 gene polymorphisms in a group of Turkish patients with colorectal cancer.
Colorectal cancer (CRC), also called colon cancer or bowel cancer, includes cancerous growths in the colon, rectum and appendix. The immune system is an important defence mechanism against cancer and is often dysfunctional in patients with malignancies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and CD28 genes encode receptors that provide negative and positive signals, respectively. Polymorphisms in these genes can affect their functions. In this study, we aimed to investigate the association of cancer with the frequencies and roles of CTLA-4/+49A > G (exon 1) and -318C > T (promoter), and CD28/IVS3 + 17T > C (intron 3 position + 17). These polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 218 Turkish subjects (56 patients with CRC and 162 healthy controls). No statistically significant differences in the genotype distributions of CTLA-4/+49GG (1.8% vs. 6.8%, odds ratio (OR) = 0.250, P = 0.305) and CTLA-4/-318TT (0% vs. 0.6%, OR = 1.006, P = 1.000), and CD28/IVS3 + 17CC (8.9% vs. 3.7%, OR = 0.2411, P = 0.155) between patients with CRC and healthy controls, were observed. We also found that there were no significant differences in the frequencies of CTLA-4/+49G (18.8% vs. 20.1%, OR = 0.920, P = 0.891) and CTLA-4/-318T (7.1% vs. 4.3%, OR = 1.653, P = 0.314), and CD28/IVS3 + 17C alleles (25.9% vs. 19.1%, OR = 1.353, P = 0.139) between two study groups. Present results suggested that CTLA-4 and CD28 gene polymorphisms did not play an important role in Turkish patients with CRC.


The challenge of inhibiting Abeta polymerization.
The discovery of small molecules that inhibit beta-peptide and other amyloid fibril formation has been impeded by featureless structure-activity-relationships, low apparent efficacy of inhibition, and by the perception that protein-protein interactions are too diffuse to be proper medicinal chemistry targets. Atomic resolution structural information on the critical target species are lacking. Despite these difficulties, substoichiometric inhibitors of fibrillogenesis have been reported. By carefully defining assay systems and considering a spectrum of data from different types of measurements, medicinal chemistry can improve molecular structures and their measured effectiveness can be better understood. Compounds with good pharmacokinetic and toxicologic profiles that persist in the target tissue at useful concentrations may be as useful as would extremely high affinity inhibitors with less favorable biological properties.


Nitric oxide synthase activity is required for development of functional nodules in soybean.
The effects of a nitric oxide synthase inhibitor (N(ω)-nitro-L-arginine) on soybean growth parameters and nodule functioning were investigated, along with soybean nodule cell viability and cysteine endopeptidase activity. N(ω)-nitro-L-arginine reduced soybean growth parameters, inhibited nodule nitrogenase activity, and caused a decrease in nodule cell viability. The negative effects of N(ω)-nitro-L-arginine were reversed by the nitric oxide donor 2,2'-(hydroxynitrosohydrazono)bis-ethanimine. Cysteine endopeptidase activity was higher in plants treated with N(ω)-nitro-L-arginine than untreated plants (controls), but decreased to levels similar to the controls when plants were exposed to a combination of N(ω)-nitro-L-arginine and 2,2'-(hydroxynitrosohydrazono)bis-ethanimine. These results suggest that nitric oxide, resulting from nitric oxide synthase activity, is required for development of functional soybean nodules.


Immuno-Modulatory Properties of a Quinolin-2-(1H)-on-3-Carboxamide Derivative: Relevance in Multiple Sclerosis.
We have recently released the structure of a class of quinolin-2-(1H)-on-3-carboxamide derivatives and among them; the drug A2 has the highest CB2 receptor selectivity. In this work we assessed the immuno-modulatory properties of A2 in lymphocytes isolated from peripheral blood of multiple sclerosis patients and healthy donors. Cell proliferative response was measured by 3H-thymidine incorporation, cell viability and apoptosis by trypan blue, annexin V staining and western blot. Cell activation was investigated by flow cytometry and molecular pathways by western blot. A2 exerted anti-proliferative effects with down-regulation of TNF-α, IL-10 and Rantes in both cell types. No relevant changes were observed in cell viability between the two cell types. In cells from healthy subjects, A2 did not induce apoptosis, inhibited the cell cycle and similarly down-regulated in CD4+T cells the markers CD69, CD25, CD49d and CD54. Indeed, A2 also inhibited the phosphorylation of Akt, NF-kB, IKKα/β, ERK and blocked the expression of Cox-2 and CB2 receptor. Published patents also describe CB2 receptor agonists like purine derivatives. Differently, in cells from patients, A2 did not affect CD49d, while potently blocked CD54 expression. A2 inhibitory effects of Akt and Cox-2 expression were confirmed, whereas unchanged level of the CB2 receptor was observed in these cells. We reported similar effects of A2 in both cell types; however, a different mechanism of action might be suggested in cells from patients concerning cell activation and CB2 receptor expression. Overall, these data suggest an anti-inflammatory profile of A2 with potential implication in multiple sclerosis.


Diagnosis and management of malignant sublingual gland tumors: a narrative review.
In this article we review the literature on the malignant sublingual gland tumors from a surgical perspective. Sublingual gland tumors occur with a very low incidence and most are malignant tumors. The extent of treatment, clinical outcomes and prognosis of malignant sublingual gland tumors have not been well defined, due to the rarity of this disease. A database search using Web of Science (https://webofknowledge.com/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/) was conducted. The following keywords were used in the search: "sublingual gland tumor", AND "malignancy". Although the sublingual glands are among the major salivary glands, they share common anatomical characteristics with minor salivary gland tumors. Therefore, the tumors from the sublingual gland may have different clinical behaviors from the other major salivary gland tumors. The sublingual glands are small without a true surrounding capsule of the glands; the extra-parenchymal extension is very common in sublingual gland tumors. Furthermore, the sublingual glands are located in close proximity to the lingual nerve, the submandibular gland-duct system and the mandible. Thus, the surgical approach to the malignant sublingual gland tumor should include the adequate management of neighboring structures. In addition, adjuvant radiation therapy provides a survival benefit for patients with malignant sublingual gland tumors, which have adverse features. This article summarizes the clinical characteristics and unique features of malignant sublingual gland tumors based on previous reports, and provides clinical information regarding the sublingual gland tumors to increase awareness of primary physicians as well as patients.


Tubacin kills Epstein-Barr virus (EBV)-Burkitt lymphoma cells by inducing reactive oxygen species and EBV lymphoblastoid cells by inducing apoptosis.
Tubacin is a small molecule inhibitor of histone deacetylase 6 and blocks aggresome activity. We found that Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) cells were generally killed by lower doses of tubacin than EBV-transformed lymphoblastoid cells (LCLs) or EBV-negative BL cells. Tubacin induced apoptosis of LCLs, which was inhibited by pretreatment with a pancaspase inhibitor but not by butylated hydroxyanisole, which inhibits reactive oxygen species. In contrast, tubacin killed EBV-positive BL cells in a caspase-3-independent pathway that involved reactive oxygen species and was blocked by butylated hydroxyanisole. Previously, we showed that bortezomib, a proteasome inhibitor, induces apoptosis of EBV LCLs and that LCLs are killed by lower doses of bortezomib than EBV-positive BL cells. Here we found that the combination of bortezomib and tubacin acted in synergy to kill EBV-positive BL cells and LCLs. Tubacin or the combination of bortezomib and tubacin did not induce EBV lytic replication. These findings suggest that the combination of a proteasome inhibitor and an HDAC6 inhibitor may represent a useful strategy for the treatment of certain EBV-associated B cell lymphomas.


Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial.
Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased. Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.


Reproductive effects of deltamethrin on male offspring of rats exposed during pregnancy and lactation.
The effects of low doses of deltamethrin administered to female rats on the reproductive system of male offspring were examined. The dams (n=10-12/group) were treated daily by oral gavage with 0, 1.0, 2.0, and 4.0 mg deltamethrin/kg from day 1 of pregnancy to day 21 of lactation. Maternal and reproductive outcome data and male sexual development landmarks were assessed. Fertility, sexual behavior, and a large number of reproductive endpoints, such as organ weights, sperm evaluations, testosterone concentration, and testicular histology were examined on adult male offsprings. No signs of maternal toxicity were detected at the dose levels tested. Significantly adverse effects were only seen on testicular and epididymal absolute weights and the diameter of seminiferous tubules in the group treated with the highest dose of deltamethrin (4.0 mg/kg). The results indicate that in utero and lactational exposure to deltamethrin may induce subtle changes in reproductive behavior and physiology of male offspring rats at dose levels that do not cause maternal toxicity.


Tumor suppressor pathways shape EGFR-driven lung tumor progression and response to treatment.
In vivo modeling combined with CRISPR/Cas9-mediated somatic genome editing has contributed to elucidating the functional importance of specific genetic alterations in human tumors. Our recent work uncovered tumor suppressor pathways that affect EGFR-driven lung tumor growth and sensitivity to tyrosine kinase inhibitors and reflect the mutational landscape and treatment outcomes in the human disease.


Incorporation into human enamel of fluoride slowly released from a sealant in vivo.
Fluoride incorporation into human enamel from an experimental sealant resin in vivo was investigated. The sealant consisted of a newly synthesized methacryloyl fluoride-methyl methacrylate (MF-MMA) copolymer resin, which contains acidic fluoride covalently bonded to carbonyl groups and releases fluoride ions slowly by hydrolysis in an aqueous environment. This experimental sealant was applied to the enamel of permanent pre-molars and the control sealant without MF-MMA copolymer to that of the contralateral teeth. Fluoride concentration was determined by an enamel biopsy procedure with acid-etching four weeks after the sealant application. As much as 3500 ppm fluoride was found to be deposited at 10 microns depth in the enamel under the MF-MMA copolymer sealant. The increase in fluoride concentration was significant even at 60 microns. Of the fluoride incorporated into the enamel, from 70 to 80% was present as a tightly bound form. This resin sealant is expected to protect the enamel from caries attack even after detachment of the sealant.


Characteristics of trauma centers and trauma surgeons.
We surveyed directors of trauma at 408 trauma centers (as indicated by the state chairmen of the American College of Surgeons' Committee on Trauma [ACSCOT]). Of the 408 trauma directors 290 (71%) responded with information relative to their hospitals and the 1537 general surgeons taking trauma call. Altogether, 75% of the surgeons worked on an identified trauma service, 80% belonged to a cadre of surgeons identified as expert, 52% were viewed as full time, 25% provided in-house staff coverage, and 76% had completed an ATLS course. Six percent of the entire group were 60 to 73 years old and demonstrated a commitment to trauma equal to that of their younger cohorts. As a group, the older surgeons took less call, but when community or the institutional call needs were identified, the older surgeons met the challenge.


D-Amino Acids and D-Amino Acid-Containing Peptides: Potential Disease Biomarkers and Therapeutic Targets?
In nature, amino acids are found in two forms, L and D enantiomers, except for glycine which does not have a chiral center. The change of one form to the other will lead to a change in the primary structure of proteins and hence may affect the function and biological activity of proteins. Indeed, several D-amino acid-containing peptides (DAACPs) were isolated from patients with cataracts, Alzheimer's and other diseases. Additionally, significant levels of free D-amino acids were found in several diseases, reflecting the disease conditions. Studying the molecular mechanisms of the DAACPs formation and the alteration in D-amino acids metabolism will certainly assist in understanding these diseases and finding new biomarkers and drug targets. In this review, the presence of DAACPs and free D-amino acids and their links with disease development and progress are summarized. Similarly, we highlight some recent advances in analytical techniques that led to improvement in the discovery and analysis of DAACPs and D-amino acids.


Fine-needle aspiration of low-grade adenosquamous carcinomas of the breast: a report of three new cases.
To describe cytology patterns in low-grade adenosquamous carcinomas (LGASCs) of the breast. Low-grade adenosquamous carcinomas of the breast are a recently described rare variant of primary metaplastic carcinomas characterized by clinical indolence, slow evolution and excellent survival. To date, only 7 cases of LGASC were studied cytologically, and it was demonstrated that LGASC identification was difficult because its cellular components exhibited unspecific and nonsuspicious features. They consisted of irregularly clustered cells without prominent cytonuclear atypia, mitosis or necrosis. The presence of metaplastic cells or keratin debris was helpful in accurate tumor typing. We report here 3 additional cases of LGASC that were initially studied by fine-needle aspiration. We have also encountered diagnostic difficulties and misdiagnosed tumors, since 2 cases were underdiagnosed as 'suspicious' and only 1 was accurately diagnosed as malignancy. The review of our cases and the literature confirms that, despite its putative metaplastic origin, LGASC is an entity which is difficult to diagnose using classical cytological methods. Moreover, core-needle biopsy as well as frozen sections may also misdiagnose LGASC as a benign breast lesion.