Diagnosis of Chikungunya fever in an Indian population by an indirect enzyme-linked immunosorbent assay protocol based on an antigen detection assay: a prospective cohort study.
A Chikungunya virus (CHIKV) outbreak continues in India. Monitoring of the clinical features of CHIKV infection is an important component of assessing the disease process. Diagnosis is usually made by an immunoglobulin M (IgM)/IgG enzyme-linked immunosorbent assay (ELISA). However, these assays have extremely low sensitivities for the detection of infection in the majority of CHIKV patients during the acute stage of infection (during the 1 to 4 days after infection). In our laboratory, a sensitive ELISA protocol for antigen detection has been developed for the detection of CHIKV infection in the acute stage, and in the present study we assessed the usefulness of this ELISA-based system for the detection of CHIKV infection. We performed a prospective, double-blinded study of 205 Indian patients with suspected CHIKV infection in the Nagpur District. All patients underwent a full clinical assessment, and their serum samples were analyzed for the presence of antigens and of IgM and IgG by an ELISA protocol. In patients with CHIKV infection, the sensitivity of antigen detection was 85%, which was significantly higher (P < 0.001) than that of IgM (17%) or IgG (45%) detection. The sensitivity of IgM (20%) or IgG (25%) detection was significantly lower than that of the antigen assay (95%) for patients with acute infections (i.e., from day 1 to day 5 after infection). Antigen detection not only gives a positive confirmatory result in the early phase of the disease, but it is also useful in the prodromal and subclinical stage and may be useful for field applications for the rapid detection of CHIKV infection.


[Operative technique for the oesophago-jejunostomy after gastrectomy for the cancer of the stomach].
Author's described operative technique for the oesophagojejunostomy after gastrectomy for the cancer of the smonach. We are making antireflux termino-lateral oesophago-jejunostomy with antiperistaltic including proximal parts of the jejunum and distal parts of the duodenum, and with subcolic dextromesenterial propulsive latero-lateral duodeno-jejunostomy.


In Situ Dark Adaptation Enhances the Efficiency of DNA Extraction from Mature Pin Oak (Quercus palustris) Leaves, Facilitating the Identification of Partial Sequences of the 18S rRNA and Isoprene Synthase (IspS) Genes.
Mature oak (Quercus spp.) leaves, although abundantly available during the plants' developmental cycle, are rarely exploited as viable sources of genomic DNA. These leaves are rich in metabolites difficult to remove during standard DNA purification, interfering with downstream molecular genetics applications. The current work assessed whether in situ dark adaptation, to deplete sugar reserves and inhibit secondary metabolite synthesis could compensate for the difficulties encountered when isolating DNA from mature leaves rich in secondary metabolites. We optimized a rapid, commercial kit based method to extract genomic DNA from dark- and light-adapted leaves. We demonstrated that in situ dark adaptation increases the yield and quality of genomic DNA obtained from mature oak leaves, yielding templates of sufficiently high quality for direct downstream applications, such as PCR amplification and gene identification. The quality of templates isolated from dark-adapted pin oak leaves particularly improved the amplification of larger fragments in our experiments. From DNA extracts prepared with our optimized method, we identified for the first time partial segments of the genes encoding 18S rRNA and isoprene synthase (IspS) from pin oak (Quercus palustris), whose full genome has not yet been sequenced.


[Motility of antrum, pylorus, and duodenal bulb: importance of radiologic series analysis in man].
The quantification of gastroduodenal motility uses invasive methods. The aim of our study was to further characterize the contractility of antrum, pylorus and duodenal bulb in two states, using a new, non invasive fluorographic method. Healthy volunteers (mean age = 28) were involved in this study under fasting conditions (n = 20) and after a meal (n = 20). In both conditions, the subjects have swallowed 250 ml of a barium sulfate solution for fluoroscopic gastrographies taken every 2 seconds, during 30 s. Spot films were analysed using a graphic table and locally developed microcomputer program to generate space-time diagrams of antral and duodenal areas and of pylorus diameters. For each subject, the antral CA, duodenal CB contractilities (maximal variation of antral, duodenal areas in p 100) and pylorus contractility CP (closure during the observation time in p 100) were calculated. CA values were high in the two situations, but did not differ (81.1 p 100 vs 82.5 p 100 post-prandial). In contrast, CP was higher under fasting (54.0 p 100) than in post-prandial (15.0 p 100; p less than .001). Two pyloric motor patterns were observed in post-prandial: A--pyloric contractions in relation with the end of antral contraction B--augmented pyloric resistances observed during the end of antral contraction and also associated with duodenal contractions. CB was low in post-prandial (27.0 p 100) compared to fasting CB (50.8 p 100; P less than .001). This method is reproducible and simple to use. It allows quantification of contractility and coordination in the antrum, pylorus and duodenal bulb. It may be useful to assess gastroduodenal motility under pathological conditions.


A Novel Dual-Targeted α-Helical Peptide With Potent Antifungal Activity Against Fluconazole-Resistant Candida albicans Clinical Isolates.
Due to compromised immune system, fungal infection incidences have markedly increased in the last few decades. Pathogenic fungi have developed resistance to the clinically available antifungal agents. Antifungal resistance poses a great challenge to clinical treatment and has stimulated the demand for novel antifungal agents. A promising alternative to the treatment of fungal diseases is the use of antimicrobial peptides (AMPs). However, the antifungal activities of AMPs have not been fully determined. Therefore, this study aimed at designing and screening α-helical peptides with potential antifungal activities. The effects of key physicochemical parameters on antifungal activities were also investigated. A series of lengthened and residue-substituted derivatives of the template peptide KV, a hexapeptide truncated from the α-helical region of porcine myeloid antimicrobial peptide-36, were designed and synthesized. Enhancement of hydrophobicity by introducing aromatic hydrophobic amino acids (tryptophan and phenylalanine) significantly increased the efficacies of the peptides against Candida albicans strains, including fluconazole-resistant isolates. Increased hydrophobicity also elevated the toxic properties of these peptides. RF3 with moderate hydrophobicity exhibited potent anticandidal activities (GM = 6.96 μM) and modest hemolytic activities (HC10 > 64 μM). Additionally, repeated exposure to a subinhibitory concentration of RF3 did not induce resistance development. The antifungal mechanisms of RF3 were due to membrane disruptions and induction of reactive oxygen species production. Such a dual-targeted mechanism was active against drug-resistant fungi. These results show the important role of hydrophobicity and provide new insights into designing and developing antifungal peptides. Meanwhile, the successful design of RF3 highlights the potential utility of AMPs in preventing the spread of drug-resistant fungal infections.


Quantitative comparison between the transplantability of human and murine tumors into the brain of NCr/Sed-nu/nu nude and severe combined immunodeficient mice.
We have demonstrated (A. Taghian et al., Cancer Res., 53: 5012-5017, 1993) that the take rate of human xenografts in the s.c. tissue of severe combined immunodeficient (SCID) mice is significantly higher than that of nude mice. Earlier, this laboratory reported that the transplantability of tumor xenografts was significantly higher for intracranial (i.c.) injection than for s.c. injection in nude mice. The purpose of this study is to assess: (a) the relative i.c. transplantability of human and murine tumors in comparison with s.c. tissue in SCID mice; (b) the relative i.c. transplantability in SCID mice in comparison to nude mice; and (c) the influence of whole-body irradiation on i.c. transplantability of SCID and nude mice. The assay based on the number of cells required to transplant tumors into 50% of recipients (TD50) was used to describe the transplantability assays. Five human and four murine tumor cell lines were used. Concurrent TD50 assays were performed i.c. in whole-body irradiated and nonirradiated SCID and nude mice. Serial 2-10-fold dilutions of cells were injected in a 10-microliters volume into the right parietal lobe 3 mm below the skin. The results showed that in all tumors studied the i.c. TD50S were significantly lower than the s.c. TD50S by a factor of 1.7-1580. The average enhancement ratio (s.c. TD50/i.c. TD50) in nude mice was twice that in SCID mice. No significant difference was found between the i.c. TD50S in SCID and in nude mice, contrary to the significant difference in s.c. TD50S between both strains of mice (A. Taghian et al., Cancer Res., 53: 5012-5017, 1993). Whole-body irradiation did not significantly affect the i.c. TD50 in nude mice; however, it did affect two of three xenografts in SCID mice. In conclusion, despite the significantly lower s.c. TD50S of human xenografts in SCID mice, i.c. TD50S were almost similar to those of NCr/Sed-nu/nu nude mice. This suggests the presence of different immunoreactivities between nude and SCID mice in s.c. transplantability; however, for i.c. transplantability, nude mice behaved equally as well as SCID mice. The significant enhancement ratio in SCID mice is further evidence that this strain of mice displays a residual systemic immunoreactivity, although the immunoreactivity is significantly lower than that of nude mice.


Efficacy study of multimedia rheumatoid arthritis patient education program.
The research goal of improving patient adherence was assessed in this randomized controlled trial of the outcomes of a 15-min multimedia educational program when compared to educational literature for rheumatoid arthritis (RA) patients. One hundred eight RA patients from a Midwestern rheumatology outpatient clinic completed the self-reported Medication Adherence Questionnaire (MAQ), the Brief Illness Perception Questionnaire (BIPQ), and Health Assessment Questionnaire (HAQ) at baseline and 1 month after education. A paired samples t-test was use for data analyses to determine if there was a significant difference in the change between the groups at preintervention and 1-month postintervention. There were no significant differences in the scores between the two groups from pretest to posttest. Results from this study showed that medication adherence, illness perception, and disability were not improved by use of multimedia or the literature within 1 month. Findings from this research study showed that a short multimedia educational program is as effective as printed materials to educate patients with RA about their disease and treatment. However, neither multimedia nor literature affects medication adherence, illness perception, or disability as self-reported by patients with RA.


Peroxidase Activity in Relation to Suberization and Respiration in White Spruce (Picea glauca [Moench] Voss) Seedling Roots.
Peroxidase (EC 22.214.171.124) activity is associated with suberization during endodermal development and metacutization in roots of white spruce (Picea glauca [Moench] Voss) seedlings. Histochemical analysis indicates a relationship between suberization and peroxidase activity, but peroxidase is ubiquitous. Increased peroxidase activity results from the induction of four anodic peroxidase isozymes in addition to quantitative increases in two anodic peroxidase isozymes. Four of these polymerized eugenol. Cold temperatures induce formation of two anodic isozymes and result in suberization. The increased peroxidase activity associated with suberization is correlated to residual respiration. In an attempt to elucidate this relationship, the effect of respiratory inhibitors on respiration and peroxidase activity are compared.


Association between arthritis score at the onset of the disease and long-term locomotor outcome in adjuvant-induced arthritis in rats.
To investigate the connection between the intensity of initial symptoms of inflammation and locomotor outcome in rheumatoid arthritis, we examined the relationship between long-term locomotor abnormalities and signs of inflammation at the onset of the disease in adjuvant-induced arthritis (AIA) in rats. The arthritis score and hind-paw diameter were followed from immunization to day 195 (~7 months). At this time, locomotion was recorded during forced treadmill walking using 3D motion technology before radiographic scoring of hind limb joint damage. Many locomotor parameters were analyzed including time and length parameters, limbs kinematics, lateral paw position at toe off, maximal hind-paw elevation and posture. Ankle mobility was assessed from range of motion (ROM) of the joint during locomotion. Experiments were run in AIA (n = 18) and age-matched non-AIA rats (n = 8). All AIA rats exhibited signs of inflammation at day 14 with a peak of inflammatory symptoms at day 22 post-immunization. After the first episode of inflammation, 83 % of AIA rats demonstrated recurrent disease (from week 6 to week 23). The frequency of inflammatory episodes (1 to 5) was not linked to the arthritis score at day 22. At day 195 post-immunization, AIA rats showed significantly impaired locomotion and radiographic lesions as compared to control rats. Significant relationships were observed between most locomotion-related parameters and concurrent ROM of ankle, which correlated negatively with the radiographic score. ROM of ankle at day 195 correlated negatively with both the arthritis score and hind-paw diameter measured at day 14, 22 and 30 post-immunization. Decreased ankle mobility can be considered a driver of locomotion impairment in AIA. In this model, the severity of the initial inflammatory symptoms had a good prognostic value for long-term locomotor outcome.


Effect of recombinant Ganoderma lucidum immunoregulatory protein on cyclophosphamide-induced leukopenia in mice.
The aim of the study is to investigate the effect of recombinant Ganoderma lucidum immunoregulatory protein (rLZ-8) on mouse models of cyclophosphamide-induced leukopenia, which we have established with both single-phase and multi-phase administration methods. Treatment with rLZ-8 had a strong effect on both models of cyclophosphamide-induced leukopenia. In particular, it increased the number of neutrophils, lymphocytes and monocytes. rLZ-8 treatment also increased the percentage of CD4(+) T cells and the levels of secreted IL-3 and IL-4, which contributed to the cyclophosphamide-induced immune dysfunction and immune system imbalance. In conclusion, rLZ-8 treatment benefitted mice with cyclophosphamide-induced leukopenia by improving overall immune function and by specifically increasing the number of white blood cells.


The implantable artificial kidney.
The confluence of an increasing prevalence of end-stage renal disease (ESRD), clinical trial data suggestive of benefit from quotidian dialysis, and ongoing cost/benefit reanalysis of healthcare spending have stimulated interest in technological improvements in provision of ESRD care. For the last decade, our group has focused on enabling technologies that would permit a paradigm shift in dialysis care similar to that brought by implantable defibrillators to arrhythmia management. Two significant barriers to wearable or implantable dialysis persist: package size of the dialyzer and water requirements for preparation of dialysate. Decades of independent research into highly efficient membranes and cell-based bioreactors culminated in a team effort to develop an implantable version of the University of Michigan Renal Assist Device. In this review, the rationale for the design of the implantable artificial kidney is described.


Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample. Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.


Stable overexpression of pregnane X receptor in HepG2 cells increases its potential for bioartificial liver application.
To bridge patients with acute liver failure to transplantation or liver regeneration, a bioartificial liver (BAL) is urgently needed. A BAL consists of an extracorporeal bioreactor loaded with a bioactive mass that would preferably be of human origin and display high hepatic functionality, including detoxification. The human hepatoma cell line HepG2 exhibits many hepatic functions, but its detoxification function is low. In this study, we investigated whether stable overexpression of pregnane X receptor (PXR), a master regulator of diverse detoxification functions in the liver [eg, cytochrome P450 3A (CYP3A) activity], would increase the potential of HepG2 for BAL application. Stable overexpression was achieved by lentiviral expression of the human PXR gene, which yielded cell line cBAL119. In monolayer cultures of cBAL119 cells, PXR transcript levels increased 29-fold versus HepG2 cells. Upon activation of PXR by rifampicin, the messenger RNA levels of CYP3A4, CYP3A5, and CYP3A7 increased 49- to 213-fold versus HepG2 cells. According to reporter gene assays with different inducers, the highest increase in CYP3A4 promoter activity (131-fold) was observed upon induction with rifampicin. Inside BALs, the proliferation rates, as measured by the DNA content, were comparable between the 2 cell lines. The rate of testosterone 6beta-hydroxylation, a measure of CYP3A function inside BALs, increased 4-fold in cBAL119 BALs versus HepG2 BALs. Other functions, such as apolipoprotein A1 synthesis, urea synthesis, glucose consumption, and lactate production, remained unchanged or increased. Thus, stable PXR overexpression markedly increases the potential of HepG2 for BAL application.


Principal component model of multispectral data for near real-time skin chromophore mapping.
Multispectral images of skin contain information on the spatial distribution of biological chromophores, such as blood and melanin. From this, parameters such as blood volume and blood oxygenation can be retrieved using reconstruction algorithms. Most such approaches use some form of pixelwise or volumetric reconstruction code. We explore the use of principal component analysis (PCA) of multispectral images to access blood volume and blood oxygenation in near real time. We present data from healthy volunteers under arterial occlusion of the forearm, experiencing ischemia and reactive hyperemia. Using a two-layered analytical skin model, we show reconstruction results of blood volume and oxygenation and compare it to the results obtained from our new spectral analysis based on PCA. We demonstrate that PCA applied to multispectral images gives near equivalent results for skin chromophore mapping and quantification with the advantage of being three orders of magnitude faster than the reconstruction algorithm.


Synthesis and Antitumor Evaluation of Novel 5-Hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one Derivatives.
A series of novel 5-hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one derivatives bearing natural product substructures has been successfully synthesized and their antitumor activity studied. These newly synthesized derivatives were characterized by ¹H-NMR, (13)C-NMR and high resolution mass spectral data, then screened as antitumor agents against the A549, HCC1937, and MDA-MB-468 human tumor cell lines using MTT cell proliferation assays. The results show that some of these compounds can effectively inhibit the growth of these cancerous cells, with compound 5b being the best one (IC50 = 2.6 μM). Flow cytometry data revealed that compound 5b induced apoptosis of HCC1937 cells with increased solution concentration. The structure and activity relationships (SAR) of these compounds is summarized.


[Therapeutic policy in stage I-II laryngeal cancer].
Radio-, chemoradiation (with making use of cysplatin and 5-fluorouracil) therapies were employed together with a surgical method as treatment of 197 patients with T1-2N0M0 laryngeal cancer. Efficiency of the methods each was assessed by recurrence-free source of the disease, survivals, and by functional results as well. The best results in the treatment of T1N0M0 laryngeal cancer have been found out to be secured with the use of the surgical method, as evidenced by the analysis of the clinical material--94.3 percent of patients are free from recurrence and metastases for more than three years versus 81.6 percent with the radiotherapy method. In T2N0M0 laryngeal cancer, 70% of patients are free from recurrence and metastases after radiotherapy treatments. With chemoradiotherapy and surgical treatment these parameters comprised 88.8% and 11.2%; 91.5% and 8.5%. In T2N0M0 glottic cancer the surgical method is considered to be superior to other options.


NFATc1 and TNFalpha expression in giant cell lesions of the jaws.
Activation mutations of SH3BP2 gene have been demonstrated in cherubism and central giant cell lesion (CGCL). In the present study we first attempted to investigate the SH3BP2 gene in peripheral giant cell lesion (PGCL). The effect of SH3BP2 gene mutations on the transcription of the downstream genes nuclear factor of activated T cells (NFATc1) and the cytokine tumor necrosis factor-alpha (TNF-alpha) was also investigated together with the immunolocalization of NFATc1 protein in a set of cases of PGCL, CGCL and cherubism with and without SH3BP2 mutation. Fresh samples of five PGCL, five CGCL and one cherubism cases were included in this study. One of the samples of CGCL presented a somatic heterozygous mutation c.1442A>T in exon 11. The cherubism case showed a heterozygotic substitution c.320C>T in both blood and lesion. These mutations were previously published. All coding and flanking regions of the SH3BP2 gene were sequenced in the cases of PGCL. The real-time polymerase chain reaction (RT-PCR) was performed to analyze the transcription of NFATc1 and TNF-alpha genes. The immunohistochemical analysis of the NFATc1 protein was also performed. No SH3BP2 gene mutation was found in PGCL. The RT-PCR showed increased expression of NFATc1 and decreased transcription of TNF-alpha in all the samples. The immunohistochemical analysis of the NFATc1 protein showed a predominant nuclear staining in the multinucleated giant cells. The development of giant cells lesions of the jaws and cherubism are possibly mediated by overexpression of NFAT in the nucleus of the multinucleated cells.


Differential responses of ammonia/ammonium-oxidizing microorganisms in mangrove sediment to amendment of acetate and leaf litter.
The effects of acetate and leaf litter powder on ammonia/ammonium-oxidizing microorganisms (AOMs) in mangrove sediment were investigated in a laboratory incubation study for a period of 60 days. The results showed that different AOMs responded differently to the addition of acetate and leaf litter. A higher diversity of anaerobic ammonium-oxidizing (anammox) bacteria was observed when acetate or leaf litter was added than the control. However, acetate and leaf litter generally inhibited the growth of anammox bacteria despite that leaf litter promoted their growth in the first 5 days. The inhibitory effects on anammox bacteria were more pronounced by acetate than by leaf litter. Neither acetate nor leaf litter affected ammonia-oxidizing archaea (AOA) community structures, but promoted their growth. For ammonia-oxidizing bacteria (AOB), the addition of acetate or leaf litter resulted in changes of community structures and promoted their growth in the early phase of the incubation. In addition, the promoting effects by leaf litter on AOB growth were more obvious than acetate. These results indicated that organic substances affect AOM community structures and abundances. The study suggests that leaf litter has an important influence on the community structures and abundances of AOMs in mangrove sediment and affects the nitrogen cycle in such ecosystem.


Differential steroid and gonadotropin response by individual tertiary porcine follicles in vitro. Possible physiologic role of atretic follicles.
Since atretic follicles contain significant amounts of androgen and/or progesterone in their follicular fluid, we examined whether they also contribute to ovarian steroid secretion. Steroid secretion by atretic porcine follicles and their responsiveness to FSH was assessed by a perifusion system that allows for separate dynamic incubation of whole follicles in vitro. Identically treated nonatretic follicles of comparable size served as a reference group. The extent of granulosal pyknosis, on which the staging of atresia was based, was inversely related to follicular estradiol (E2) secretion and its responsiveness to FSH. Both basal and FSH-stimulated secretion of testosterone (T), androstenedione (A), and progesterone (P) were maintained by follicles in all stages of atresia. Secretion of A by late atretic follicles was greater than that in earlier stages or by nonatretic follicles. Atretic follicles may therefore release comparable or larger amounts of androgen and P into their intraovarian environment than do nonatretic follicles. We examined whether steroids secreted by atretic follicles in vitro could be utilized by nonatretic follicles. A static incubation system was used that allows for simultaneous incubation of a number of individual follicles. When nonatretic follicles were exposed to A, T, or P in physiologic concentrations (10(-7)-10(-5) M), their secretion of E2 increased 2-8-fold. Doses of FSH or LH that stimulated follicular steroid in vitro had no additional stimulatory effect when combined with A or P treatment, respectively. In conclusion, atretic follicles may contribute significantly to intraovarian levels of androgen and P.(ABSTRACT TRUNCATED AT 250 WORDS)


Total pupillary capture with a foldable silicone intraocular lens.
We report a case of total pupillary capture on the 1st postoperative day in a patient who had undergone phacoemulsification and placement of a silicone foldable posterior chamber intraocular lens. Anterior displacement of the lens optic resulted in 2.25 diopters of induced myopia. Dilation of the pupil corrected the lens capture and reversed the induced myopia, yielding a refraction of plano. Higher rates of pupillary capture have been associated with sulcus fixation and nonangulated flexible (polypropylene) haptics. Contraction of the capsular bag on the flexible polypropylene haptics of this silicone lens is thought to force the optic anteriorly, increasing the probability of lens capture by the iris.


A case of simultaneous onset of highly active systemic lupus erythematosus and IgG4-related renal disease.
The patient was a 73-year-old woman who had hair loss, purpura, and numbness of the soles for past 1 year. Three months prior, she was diagnosed with interstitial lung disease (ILD) and was admitted to our department. She was diagnosed with systemic lupus erythematosus (SLE) based on positive antinuclear antibodies 1280× (speckled type), hair loss, low white blood cell count, positive anti-cardiolipin and anti-ds-DNA antibodies, and lupus retinopathy. In addition, the patient was also diagnosed with immunoglobulin G (IgG)4-related disease (IgG4RD) based on high serum IgG4 levels, ILD, urine occult blood, protein, and cast, and renal histological findings showed endocapillary proliferative glomerulonephritis, increased IgG4 positive plasma cells, and characteristic storiform fibrosis. High-dose glucocorticoid therapy, hydroxychloroquine, and belimumab were administered, which improved the SLE symptoms of lupus retinopathy and peripheral neuropathy, as well as the IgG4RD symptoms of ILD and urinary findings. Herein, we report a rare case of simultaneous onset of IgG4-related nephropathy with active glomerular lesions and SLE, in which renal histology, including fluorescent antibodies, was crucial for diagnosis.


Variation in transport explains polymorphism of histidine and urocanate utilization in a natural Pseudomonas population.
Phenotypic variation is a fundamental requirement for evolution by natural selection. While evidence of phenotypic variation in natural populations abounds, its genetic basis is rarely understood. Here we report variation in the ability of plant-colonizing Pseudomonas to utilize histidine, and its derivative, urocanate, as sole sources of carbon and nitrogen. From a population of 164 phyllosphere-colonizing Pseudomonas strains, 77% were able to utilize both histidine and urocanate (His(+) , Uro(+) ) as growth substrates, whereas the remainder could utilize histidine, but not urocanate (His(+) , Uro(-) ), or vice versa (His(-) , Uro(+) ). An in silico analysis of the hut locus, which determines capacity to utilize both histidine and urocanate, from genome-sequenced Pseudomonas strains, showed significant variation in the number of putative transporters. To identify transporter genes specific for histidine and urocanate, we focused on a single genotype of Pseudomonas fluorescens, strain SBW25, which is capable of utilizing both substrates. Site-directed mutagenesis, combined with [(3) H]histidine transport assays, shows that hutT(u) encodes a urocanate-specific transporter; hutT(h) encodes the major high-affinity histidine transporter; and hutXWV encodes an ABC-type transporter that plays a minor role in histidine uptake. Introduction of cloned copies of hutT(h) and hutT(u) from SBW25 into strains incapable of utilizing either histidine, or urocanate, complemented the defect, demonstrating a lack of functional transporters in these strains. Taken together our data show that variation in transport systems, and not in metabolic genes, explains a naturally occurring phenotypic polymorphism.


Epistaxis presenting as sentinel feature of metastatic renal cell carcinoma: A case report and review of literature.
About 30% of all newly diagnosed renal cell carcinoma (RCC) patients present with synchronous metastatic disease. Usual organs of involvement are lung (75%), soft tissues (36%), bone (20%), liver (18%), cutaneous sites (8%), and central nervous system (8%). Metastases to the paranasal sinuses (PNS) are relatively common and may be a part of synchronous multiorgan involvement or present in follow-up after radical nephrectomy (metachronous); but primary presentation as isolated paranasal mass before the diagnosis of RCC is extremely rare. Here, we report a case of 74-year-old female presented with epistaxis and nasal obstruction. On evaluation by magnetic resonance imaging (MRI), a heterogeneously enhancing mass was found involving left PNS. Biopsy from mass revealed clear cell RCC. Later on, contrast-enhanced computed tomography (CECT) of chest, abdomen, and pelvis showed enhancing mass from the upper pole of the left kidney with no evidence of metastasis elsewhere. The patient was started on pazopanib 800 mg once a day. At 6 months follow-up scan, there was a partial response at both primary as well as metastatic site.


Compulsory treatment of anorexia nervosa.
Compulsory treatment in anorexia is a controversial subject brought to the fore of public awareness with each new case reported in the media. The attitudes towards involuntary hospitalization for anorexia swing like a pendulum from recognizing the necessity for compulsory treatment in life-threatening situations to advocating the patient's rights for autonomy over his/her body and thus the right to refuse treatment. In view of the fact that the existing legislation in Israel (Law of Patient's Rights, 1996; Law of Guardianship 1962; and the Law for the Treatment of the Mentally Ill, 1991) does not provide an adequate solution to emergency situations in which anorexia is life threatening, the authors suggest that the Law for the Treatment of the Mentally Ill (1996), which enables compulsory treatment, can be interpreted to include life-endangering conditions.


Transforming growth factor-beta 1 enhances glomerular collagen synthesis in diabetic rats.
In vitro glomerular collagen synthesis and its response to various concentrations of transforming growth factor-beta 1 were studied in normal and diabetic rats. TGF-beta 1 increased collagen synthesis in normal glomeruli in a dose-dependent manner up to 5 ng/ml. Concentrations > 5 ng/ml showed a gradual decline in collagen synthesis. Basal collagen synthesis was increased in diabetic glomeruli, but addition of TGF-beta 1 had no effect. Antibody to TGF-beta 1 prevented this increase in collagen synthesis. Both circulating TGF-beta 1 concentration and its glomerular expression of mRNA were higher in diabetic than in normal rats. Although addition of TGF-beta 1 did not increase synthesis in vitro, the absence of an effect is consistent with downregulation of its receptors attributable to the high circulating levels. This study clearly indicates a regulatory role of TGF-beta 1 in renal glomerular collagen synthesis in the normal rat, and suggests a possible causal role for enhanced collagen synthesis in the diabetic rat.


Treatment of Liver Cancer.
Primary liver cancer, mostly hepatocellular carcinoma, remains a difficult-to-treat cancer. Incidence of liver cancer varies geographically and parallels with the geographic prevalence of viral hepatitis. A number of staging systems have been developed, reflecting the heterogeneity of primary liver cancer, regional preferences, and regional variations in resectability or transplant eligibility. Multimodality treatments are available for this heterogeneous malignancy, and there are variations in the management recommendations for liver cancers across specialties and geographic regions. Novel treatment strategies have merged with the advance of new treatment modalities. This work focuses on reviewing the incidence, staging, and treatment of liver cancer.


Ancient medicine: the patient's perspective.
A number of previously unpublished therapeutic recipes from cuneiform tablets in Berlin (Pergamon Museum) and London (British Museum) list symptoms describing urinary tract disfunction. In addition to presenting extracts from this material, the present article discusses the roles of physician as apothecary or exorcist in ancient texts from Babylonia. This involves technical medical knowledge vs. ""bed-side manner"", taking into account the psychological effects of drug therapy and diagnosis.


Nε-Fatty acylation of Rho GTPases by a MARTX toxin effector.
The multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are a family of large toxins that are extensively distributed in bacterial pathogens. MARTX toxins are autocatalytically cleaved to multiple effector domains, which are released into host cells to modulate the host signaling pathways. The Rho guanosine triphosphatase (GTPase) inactivation domain (RID), a conserved effector domain of MARTX toxins, is implicated in cell rounding by disrupting the host actin cytoskeleton. We found that the RID is an Nε-fatty acyltransferase that covalently modifies the lysine residues in the C-terminal polybasic region of Rho GTPases. The resulting fatty acylation inhibited Rho GTPases and disrupted Rho GTPase-mediated signaling in the host. Thus, RID can mediate the lysine Nε-fatty acylation of mammalian proteins and represents a family of toxins that harbor N-fatty acyltransferase activities in bacterial pathogens.


Building Containerized Workflows Using the BioDepot-Workflow-Builder.
We present the BioDepot-workflow-builder (Bwb), a software tool that allows users to create and execute reproducible bioinformatics workflows using a drag-and-drop interface. Graphical widgets represent Docker containers executing a modular task. Widgets are linked graphically to build bioinformatics workflows that can be reproducibly deployed across different local and cloud platforms. Each widget contains a form-based user interface to facilitate parameter entry and a console to display intermediate results. Bwb provides tools for rapid customization of widgets, containers, and workflows. Saved workflows can be shared using Bwb's native format or exported as shell scripts.


Sudden Death Due to Acute Epiglottitis in Adults: A Retrospective Review of 11 Postmortem Cases.
We report a retrospective review of fatal acute epiglottitis cases in adults in the province of Ontario, Canada, between 2001 and 2014. Information on demographics, clinical history, gross, microscopic, and laboratory findings were collected and analyzed. Eleven cases, predominantly male (73%), with a mean age of 50 years were identified. Common presenting symptoms included sore throat, dysphagia, and low-grade fever. The predominant postmortem findings included hyperemia and edema of the epiglottis and aryepiglottic folds. Histological features included vascular congestion, stromal edema, and acute inflammation. Five cases (45%) were positive for growth of various bacterial organisms on blood and/or tissue cultures. Acute epiglottitis should be in the differential diagnosis in fatalities presenting with symptoms of upper respiratory tract infection, followed by an episode of acute shortness of breath. History, thorough postmortem examination with close attention to the head and neck structures, histological examination of tissues, and sampling for microbiology will assist in differentiating epiglottitis from other cases of laryngeal swelling leading to death.


Sending unhealthy environments up in smoke.
Tobacco use is recognized as the leading cause of preventable death and disease in the United States. It is the foremost reason for the four primary causes of death--heart disease, cancer, emphysema and stroke. Tobacco costs the United States more than $197 billion per year in direct medical and indirect costs (i.e., loss of productivity). Within Michigan, more than 14,500 people die each year from tobacco-related illnesses with monetary losses for the state exceeding more than $6 billion. Additionally, there are no good estimates on the number of Michigan people who suffer from tobacco-related health problems and continue to survive.


LncRNA DCST1-AS1 inhibits PDLCs' proliferation in periodontitis and may bind with miR-21 precursor to upregulate PLAP-1.
This study aimed to investigate the potential interactions among long noncoding RNA domain containing 1-antisense (lncRNA DCST1-AS1), miR-21, and periodontal ligament-associated protein-1 (PLAP-1) in periodontitis. It has been verified that miR-21 can target PLAP-1 to regulate the osteogenic differentiation of periodontal ligament cells (PDLCs). Differential expression of DCST1-AS1 and miR-21 in PDLCs derived from periodontitis patients and healthy controls was determined by qPCR and unpaired t test. QPCR and Western blots were conducted to evaluate the effects of overexpression of DCST1-AS1 and miR-21 on the expression of PLAP-1. CCK-8 assay was applied to evaluate the effect of DCST1-ASI, miR-21, or PLAP-1 on PDLCs' proliferation. Western blotting was conducted to detect the expression levels of CKD family (CDK4, CDK6, and CCND1). DCST1-AS1 was downregulated in PDLCs derived from periodontitis patients, and its expression was inversely correlated with the expression of miR-2 but positively correlated with PLAP-1. Bioinformatics analysis showed that DCST1-AS1 might bind with miR-21 precursor but not mature miR-21. Transfection experiments showed that overexpression of DCST1-AS1 led to decreased expression levels of miR-21 and significantly increased the expression levels of PLAP-1 at both mRNA and protein levels, while overexpression of miR-21 resulted in a dramatic lower level of PLAP-1. CCK-8 assay indicated that overexpression of DCST1-AS1 or PLAP-1 prohibited PDLCs' proliferation. However, elevation of miR-21 had a contrary effect on the proliferation of PDLCs. And increased expression levels of DCST1-AS1 could significantly inhibit the expression of CDK4, CDK6, and CCND-1, while overexpression of miR-21 inversed the effects of DCST1-AS1. Therefore, the expression levels of DCST1-AS1 are much lower in periodontitis patients compared to that in healthy controls, and overexpression of DCST1-AS1 can significantly elevate the expression of PLAP-1 by inhibiting miR-21 in PDLCs.


Gene expression profile by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the liver of wild-type (AhR+/+) and aryl hydrocarbon receptor-deficient (AhR-/-) mice.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants that cause various biological effects on mammals. The purpose of our study was to identify the genes involved in hepatotoxicity and hepatocarcinogenesis caused by TCDD. C57BL/6 (AhR+/+, wild type) and B6.129-AhR<tm1Bra>/J (AhR-/-, knock out) mice were injected i.p. with a single treatment of TCDD at the dose of 100 microg/kg body weight. Relative liver weight was significantly increased at 72 hr after TCDD treatment without an apparent histopathological change in AhR+/+ mice (p<0.05). TCDD treatment also significantly increased activity of serum alanine aminotransferase in AhR-/- mice (p<0.05). The liver was analyzed for gene expression profiles 72 hr later. As compared with AhR-/- mice, the expression of 51 genes (>3-fold) was changed in AhR+/+ mice; 28 genes were induced, while 23 genes were repressed. Most of the genes were associated with chemotaxis, inflammation, carcinogenesis, acute-phase response, immune responses, cell metabolism, cell proliferation, signal transduction, and tumor suppression. This study suggests that the microarray analysis of genes in the liver of AhR+/+ and AhR-/- mice may help to clarify the mechanism of AhR-mediated hepatotoxicity and hepatocarcinogenesis by TCDD.


Ophthalmomyiasis Caused by Sheep Nasal Botfly (Oestrus ovis).
Ophthalmomyiasis is a parasitic eye infection. Ayoung male went on a picnic with his family. After sudden blow of wind, he had a feeling of something struck in the eye, which quickly became swollen with severe itching and lacrimation. Atotal of 19 larvae in their instar stage were removed with fine forceps under topical anesthesia and slides were prepared for their identification, which came out to be Oestrus ovisbelonging to Oestridae family. Recently, cases are being reported from rural and urban areas of Sindh. Doctors in ER (Emergency Room) and ophthalmologists should be aware that whenever next time they see a patient with red eye conjunctivitis, ophthalmomyiasis should always be on their list of differentials.


Impact of the insect biting nuisance on a British youth expedition to Alaska.
The morbidity and nuisance factor associated with bites from mosquitoes and other insects are one of the many hazards faced by travelers, including those to the Arctic. A predeparture literature review suggested that insect bites were such a large problem in the area to be visited that they would probably have a significant impact on expedition activities. Therefore, we set out to assess the extent of the insect biting nuisance, focussing particularly on interference with expedition activities, in order to make recommendations for future expeditions to this area. The number of bites and their effects was examined on a 6-week British youth expedition to Alaska in July/August 1999. A weekly "Insect Biting Nuisance Questionnaire" was distributed to each expedition member (total 72) to record the number of bites received over the previous week, a subjective grading of severity and itchiness, the extent of interference with expedition activities, any complications from the bites, and details about prevention and treatment. The questionnaire response rate was 64%, which was a representative sample. The median number of bites per person over the entire 6-week period was 33, with females and younger expeditioners tending to receive more bites. Multivariate analysis suggested that younger age was associated with more severe and itchier bites. Sleep was disturbed by itching on only 4% (68/1918) of nights. Generally, the bites were thought not to interfere with expedition activities (median score for interference 0; range 0-10). The number of bites and their impact on expedition activities were both lower than expected. Thus, it is recommended that expeditions and independent travelers to this area do not need to increase time spent in the field to compensate for expedition man days lost due to problems associated with the insect biting nuisance.


Two-dimensional exterior sound field reproduction using two rigid circular loudspeaker arrays.
In exterior sound field reproduction using loudspeaker arrays, such as a single circular array, there is a trade-off between the reproduction accuracy and the filter gain of the loudspeaker array. With the aim of reproducing complex sound fields with a lower filter gain, an asymmetrical array geometry with reflections between two or more rigid arrays is introduced. This paper proposes a sound field reproduction method using two rigid circular loudspeaker arrays in a circular harmonic domain. Transfer functions that consider the multiple scattering between two rigid baffles can be represented in the circular harmonic domain. By repeatedly transforming the expansion coefficient between two coordinate systems, the circular harmonic expansion was applied to the reproduced sound field in a mixed coordinate system. Then, the driving function of the loudspeaker arrays was derived through a mode expansion. Numerical simulations were conducted to verify the accuracy of the reproduced sound field.


Induction of a reversible block in murine CFU-C differentiation by exposure to nitrous oxide.
Patients subjected to prolonged exposure to nitrous oxide (N2O) often develop megaloblastic bone marrow changes. This toxicity is due to the N2O-mediated inactivation of cobalamin-dependent enzymes with resultant perturbations in cell metabolism. The effect of N2O on the behavior of murine colony-forming units-cytokine (CFU-C) in vitro was studied by incubating granulocyte/macrophage colony-stimulating factor (GM-CSF)-stimulated bone marrow cultures for 7 days in an atmosphere of either 5% CO2 in air or 50% N2O/5% CO2 in air. Exposure of bone marrow cells in agarose to N2O resulted in an approximately 50% reduction in colony formation when compared with cultures incubated in air. In contrast, when residual CFU-C numbers were determined in bone marrow liquid cultures after 7 days of incubation in the presence of GM-CSF, exposure to N2O was found to dramatically enhance CFU-C recovery. Since these liquid cultures contain a strong differentiation inducer, and are unable to support CFU-C generation, the enhancement of CFU-C recovery in N2O-exposed cultures appears to be related to its ability to induce a reversible block in CFU-C differentiation. The reversible block in CFU-C maturation seen in vitro parallels clinical observations where a rapid hematologic recovery is seen in N2O-exposed patients treated with hydroxycobalamin. These observations would suggest that N2O is not markedly cytotoxic to CFU-C and that its action is, at least in part, cytostatic in nature.


Omission of in vivo T-cell depletion promotes rapid expansion of naïve CD4+ cord blood lymphocytes and restores adaptive immunity within 2 months after unrelated cord blood transplant.
Umbilical cord blood transplant (UCBT) is associated with impaired early immune reconstitution. This might be explained by a lower T-cell dose infused, the naivety of cord blood T-cells and the use of in vivo T-cell depletion. We studied the pattern of early immune reconstitution and the clinical outcome of children undergoing unrelated UCBT when in vivo T-cell depletion was omitted. Thirty children affected by malignancies (46%) or immunodeficiencies (54%) underwent an unrelated UCBT. Prospective assessment of immune reconstitution and clinical outcome was performed. We observed an unprecedented CD4(+) T-cell reconstitution, with a median cell count at 30 and 60 d post UCBT of 0.3 × 10(9) /l and 0.56 × 10(9) /l, respectively. Early T-cell expansion was thymic-independent, with a rapid shift from naïve to central memory phenotype and early regulatory T-cell recovery. Viral infections were frequent (63%) but resolved rapidly in most cases and virus-specific T-lymphocytes were detected within 2 months post-UCBT. Acute graft-versus-host disease (GvHD) was frequent (grade II = 34%, grade III-IV = 16%) but steroid responsive, and the incidence of chronic GvHD was low (14%). The omission of in vivo T-cell depletion promotes a unique thymic-independent CD4(+) T-cell reconstitution after unrelated UCBT in children. We postulate that this relates to the specific immunological and ontological qualities of fetal-derived lymphocytes.


ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment.
Activating transcription factor 4 (ATF4) is a critical transcription factor for bone remodeling; however, its role in bone angiogenesis has not been established. Here we show that ablation of the Atf4 gene expression in mice severely impaired skeletal vasculature and reduced microvascular density of the bone associated with dramatically decreased expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in osteoblasts located on bone surfaces. Results from in vivo studies revealed that hypoxia/reoxygenation induction of HIF-1α and VEGF expression leading to bone angiogenesis, a key adaptive response to hypoxic conditions, was severely compromised in mice lacking the Atf4 gene. Loss of ATF4 completely prevented endothelial sprouting from embryonic metatarsals, which was restored by addition of recombinant human VEGF protein. In vitro studies revealed that ATF4 promotion of HIF-1α and VEGF expression in osteoblasts was highly dependent upon the presence of hypoxia. ATF4 interacted with HIF-1α in hypoxic osteoblasts, and loss of ATF4 increased HIF-1α ubiquitination and reduced its protein stability without affecting HIF-1α mRNA stability and protein translation. Loss of ATF4 increased the binding of HIF-1α to prolyl hydroxylases, the enzymes that hydroxylate HIF-1a protein and promote its proteasomal degradation via the pVHL pathway. Furthermore, parathyroid hormone-related protein (PTHrP) and receptor activator of NF-κB ligand (RANKL), both well-known activators of osteoclasts, increased release of VEGF from the bone matrix and promoted angiogenesis through the protein kinase C- and ATF4-dependent activation of osteoclast differentiation and bone resorption. Thus, ATF4 is a new key regulator of the HIF/VEGF axis in osteoblasts in response to hypoxia and of VEGF release from bone matrix, two critical steps for bone angiogenesis.


Malignant rhabdoid tumours of the small intestine with multiple organ involvement: Case report.
Malignant rhabdoid tumours (MRTs) were first described as an infrequent variant of Wilms' tumour and have been reported in several organs. The small intestine is a rare site for MRTs. A 70-year-old man presented with appetite loss and melena. Haemorrhagic small intestinal tumours, swollen mesenteric and paraaortic lymph nodes, a tumour in the left kidney, and multiple tumours in the lung were found. He underwent partial resection of two haemorrhagic small intestinal tumours classified as MRTs based on the results of a pathological examination. However, melena appeared again on postoperative day 6. We performed another operation and resected approximately 180 cm of the small intestine that contained multiple tumours. All lesions were classified as MRTs. Unfortunately, melena appeared again 4 days after the second operation. He did not want invasive therapy and died from massive melena 2 months after the initial surgery. MRTs of the small intestine are uncommon and have an extremely poor prognosis. Although curative resection is an important treatment, cases of metastasis at diagnosis and postoperative early recurrence have been observed, as was the case for the patient described herein. In these cases, effective systemic therapy is necessary. Recently, tumour suppressor genes were shown to be involved in the occurrence of MRT, and new therapies for MRT have been studied. We herein conclude effective systemic therapy is necessary for MRTs with multiple organ involvement. The development of new drugs for this disease is ongoing.


Frequencies of tetramer+ T cells specific for the wild-type sequence p53(264-272) peptide in the circulation of patients with head and neck cancer.
Immunization with wild-type sequence (wt) p53 epitopes represents a novel therapeutic strategy for cancer patients with tumors accumulating mutant p53. To evaluate usefulness of p53-derived peptides as future cancer vaccines, frequencies of wt p53(264-272) peptide-specific CD8+ T cells were determined in the peripheral circulation of patients with squamous cell carcinoma of the head and neck (SCCHN). T cells of 30 HLA-A2.1+ patients and 31 HLA-A2.1+ healthy individuals were evaluated by multicolor flow cytometry analysis using peptide-HLA-A2.1 complexes (tetramers). T cells specific for an influenza matrix peptide (a model recall antigen) or an HIV reverse transcriptase peptide (a model novel antigen) were studied in parallel. Patients with SCCHN had a significantly higher mean frequency of CD8+ T cells specific for wt p53(264-272) than normal donors (P = 0.0041). Surprisingly, the frequency of epitope-specific T cells in the circulation of patients did not correlate with p53 accumulation in the tumor. In patients whose tumors had normal p53 expression or had p53 gene mutations preventing presentation of this epitope, high frequencies of wt p53(264-272)-specific CD8+ T cells were found, of which many were memory T cells. In contrast, patients whose tumors accumulated p53 had low frequencies of wt p53(264-272)-specific CD8+ T cells, which predominantly had a naive phenotype and were unable to proliferate ex vivo in response to the epitope, as reported by us previously (T. K. Hoffmann, J. Immunol., 165: 5938-5944, 2000). This seemingly contradictory relationship between the high frequency of epitope-specific T cells and wt p53 expression in the tumor suggests that other factors may contribute to the observed anti-p53 responses. Human papillomavirus-16 E6/E7 expression is common in SCCHN, and E6 is known to promote presentation of wt p53 epitopes. Although human papillomavirus-16 E6/E7 expression was detected in 46% of the tumors, it did not correlate with the frequency of wt p53(264-272)-specific CD8+ T cells or with p53 expression in the tumor. These findings emphasize the complexity of interactions between the tumor and the host immune system, and, thus, have particularly important implications for future p53-based immunization strategies.


Localized muscle vibration in the treatment of motor impairment and spasticity in post-stroke patients: a systematic review.
During the last decades, many studies have been carried out to understand the possible positive effects of vibration therapy in post-stroke rehabilitation. In particular, the use of localized muscle vibration (LMV) seems to have promising results. The aim of this systematic review was to describe the use of LMV in post-stroke patients to improve motor recovery, reducing spasticity and disability in both upper and lower limb. A search was conducted on PubMed, Scopus, Pedro and REHABDATA electronic database. Only randomized controlled trials have been included, excluding no-localized vibratory treatments and other pathological conditions. Fourteen studies met the inclusion criteria and were included in this review. Collectively, the studies involved 425 stroke patients. Most studies included chronic stroke patients (ten) and treated only the upper limb (eleven). There is evidence that LMV therapy is effective in reducing spasticity and improving motor recovery, especially when associated with conventional physical therapy. LMV may be a feasible and safe tool to be integrated into traditional and conventional neurorehabilitation programs for post-stroke patients to reduce spasticity. Analysis of the available clinical trials do not allow us to indicate vibration therapy as effective in functional motor recovery, despite some studies showed encouraging results. Further studies, with larger size of homogeneous patients and with a shared methodology are needed to produce more reliable data, especially on the lower limb.


Cardiovascular, neuromuscular, and metabolic alterations with age leading to frailty.
As members of our society live longer, a greater percentage of the population will be older. These demographic changes will stress our social and medical delivery system, unless interventions can alter the course leading to frailty. Maximal aerobic power decreases with age, due to a decrease in cardiac output, and is exacerbated by cardiovascular disease. Asymptomatic aging does not reduce cardiovascular function to an extent that would lead to loss of function. Metabolism, endurance, and contraction velocity and muscle strength remain relatively high until 40, 50, and 60 years of age, respectively. After age 60, there are dramatic decreases (approximately 10% per year) which lead to loss of function and independence. The loss of muscle function leads to an increase in the likelihood of falls (approximately 4-fold). Exercise programs utilizing "aerobic" exercise activities do not lead to an increase in muscle function, whereas programs designed specifically for muscle can increase function and, presumably, reduce the risk of falls and injuries.


Access to cardiac rehabilitation and the role of language barriers in the provision of cardiac rehabilitation to migrants.
Cardiac rehabilitation (CR) has proven health benefits and, according to international guidelines, CR must be offered to all eligible patients. Studies have reported lower uptake of CR among migrants, and migrants are known to face several barriers in their access to healthcare, of which language is the most common. The aim of this study is to examine the provision of CR core components for migrants; and the role of language barriers in the provision of CR in Danish hospitals and municipalities. This is a descriptive study based on repeated nationwide surveys conducted in 2013 and 2015 by the Danish Cardiac Rehabilitation Database. The surveys collected information on provision and organization of CR in hospitals (n = 35) and municipalities (n = 98) in Denmark. The survey in 2015 had additional items related to migrants, such as provision of interpreter services and multilingual information material. Not all CR core components were provided by hospitals to non-Danish speaking patients. There was no improvement from 2013 to 2015. Hospitals had full coverage (19/19) of interpreter services compared to 84% (26/31) of municipalities. Provision of multilingual information material was low in hospitals 32% (6/19) and in municipalities 3% (1/31). This study found language-related barriers in migrants' access to CR, in the form of inadequate provision of CR core components for non-Danish speaking patients at some Danish hospitals and suboptimal provision of interpreter services in municipalities. The findings call for increased attention to language barriers and further studies are needed to map the extent of the problem.


Resilience in the Face of Adversity: Family Processes and the Immigrant Paradox in Youth Externalizing Problems.
Despite increased exposure to social adversity, immigrant youth have fewer externalizing problems compared to non-immigrants. Explanations for this apparent advantage remain unclear. This study examined the extent to which socio-economic characteristics and family processes account for group differences in externalizing problems between immigrant and non-immigrant youth. Data come from a population-based cross-sectional study of 1,449 youth and their primary caregiver in Hamilton, Ontario. Computer-assisted structured interviews were administered separately to primary caregivers and youth, which included assessments of externalizing problems and measures of family obligation, parental monitoring, value of education and socio-economic characteristics. First- and second-generation immigrant youth had lower levels of externalizing problems compared to non-immigrants. The magnitude of group differences was larger for parent (d = 0.37-0.55) versus youth reports of externalizing behaviours (d = 0.15-0.29). Family socio-economic and process characteristics partially accounted for group differences, which remained significant in the parent-reported model but rendered non-significant in the youth-reported model. Results suggesting the potential protective effects of positive family processes for immigrant youth could be extended to non-immigrant youth to inform the development of parenting and family skills interventions. Promoting familial sources of resilience is a potential avenue for reversing downward trends in mental health seen across successive generations of immigrant youth, while also reducing risk of behavioural difficulties among non-immigrant youth.


Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens.
Daclatasvir (DCV) is a pan-genotypic non-structural protein 5A (NS5A) inhibitor that is approved for treatment of hepatitis C virus (HCV) genotype (GT)1 and GT3 in the USA and GT1, GT3 and GT4 in Europe. We set out to examine the impact of daclatasvir-based regimens on the sustained virologic response (SVR) in patients with GT2 infection with respect to GT2 subtype and NS5A polymorphisms at amino acid positions associated with daclatasvir resistance. Analyses were performed on 283 GT2 NS5A sequences from five daclatasvir regimen-based clinical trials (ClinicalTrials.gov: NCT-01257204, NCT-01359644, NCT-02032875, NCT-02032888 and NCT-01616524) and 143 NS5A sequences from the Los Alamos HCV database. Susceptibility analyses of substitutions at amino acid positions associated with daclatasvir resistance and patient-derived NS5A sequences were performed using an in vitro HCV replication assay. Of 13 GT2 subtypes identified from 426 NS5A sequences, the most prevalent were GT2a (32%), GT2b (48%) and GT2c (10%). The most prevalent NS5A polymorphism was L31M (GT2a = 88%; GT2b = 59%; GT2c = 10%). Substitutions identified in 96% of GT2 NS5A sequences exhibited daclatasvir EC50 values ranging from 0.005 to 20 nM when tested in vitro. A similar range in daclatasvir EC50 values was observed for 16 diverse GT2 patient-derived NS5A sequences (EC50 = 0.005-60 nM). Depending on the daclatasvir-based regimen studied (daclatasvir/interferon-based or daclatasvir/sofosbuvir-based), SVR rates ranged from 90% to 100% in GT2 patients with the most prevalent baseline NS5A-L31M polymorphism, compared with from 96% to 100% without this polymorphism. High SVR rates were achieved in patients infected with GT2 treated with daclatasvir-based regimens irrespective of GT2 subtype or baseline NS5A polymorphisms.


Clinical role of F-18 fluorodeoxyglucose positron emission tomography imaging in patients with lung cancer and suspected malignant pleural effusion.
The goals of this study were to determine the sensitivity, specificity, and predictive accuracy of F-18 fluorodeoxyglucose positron emission tomography (PET-FDG) imaging in detecting metastatic disease involvement of pleura and/or presence of malignant pleural effusion in patients with proven lung cancer. We wanted to compare efficacy of PET-FDG imaging to CT scanning in differentiating benign pleural effusion from malignant effusion and/or pleural involvement in patients with lung cancer. We studied 35 patients with biopsy-proven lung cancer and abnormal findings on CT scanning for presence of pleural effusion (n = 34) and/or pleural thickening or nodular involvement (n = 4). The results of positron emission tomography and CT scanning were compared to pleural cytology (n = 31), histologic findings of pleural biopsy (n = 3), and/or clinical follow-up (n = 3) for at least 1 year for presence or absence of malignant pleural effusion. PET-FDG imaging correctly detected the presence of malignant pleural effusion and malignant pleural involvement in 16 of 18 patients and excluded malignant effusion or pleural metastatic involvement in 16 of 17 patients (sensitivity, specificity, and accuracy of 88.8%, 94.1%, and 91.4% respectively). PET-FDG imaging is a highly accurate and reliable noninvasive test to differentiate malignant from benign pleural effusion and/or pleural involvement in patients with lung cancer and findings of suspected malignant pleural effusion on CT scanning.


Method Validation and Characterization of Red Pigment in Beta vulgaris Peels and Pomaces by HPLC-UV and UHPLC-MS/MS.
Color pigments from plant, animal, or mineral sources can be identified, separated, and quantified for various purposes. It is expected that pigments from Beta vulgaris L. peels and pomaces could be used to develop natural dyes that can find applications in areas such as food or textile dyeing industries. This work aimed at identifying and quantifying the pigment in the B. vulgaris L. peels and pomaces extracts as well as validating the method by high-performance liquid chromatography combined with ultraviolet spectroscopy (HPLC-UV) and ultra-high-performance liquid chromatography coupled with triple quadrupole (TSQ) mass spectrometry (UHPLC-MS/MS). Column chromatography was used to isolate compounds after methanolic solvent extraction. Identification and quantification of the pigments in the extract were achieved using reverse-phase HPLC with a UV detector (538 nm). The UHPLC-MS/MS was used for further confirmation of colored compounds in the extract. Method validation included the use of betanin standard (betanidin 5-β-D-glucopyranoside), determination of repeatability (precision), calibration curve linearity, and sensitivity (LOD and LOQ) tests. Betanin was detected in the sample at retention times of 7.699 and 7.71 minutes, respectively, which closely matched the tR (7.60 min) of the standard, according to HPLC-UV and LC-MS/MS data. The average betanin concentration was 3.81 0.31 mg/g of dry weight, according to the HPLC-UV analysis. The LC-MS/MS data revealed the existence of several compounds, including betanin (4.31 ± 2.15 mg/g), isobetanin (1.85 ± 2.20 mg/g), 2, 17-bidecarboxy-neobetanin (0.71 ± 0.02 mg/g), betanidin (0.71 ± 0.03 mg/g), 2-O-glucosyl-betanin (0.40 ± 0.10 mg/g), and isobetanidin (0.36 ± 1.26 mg/g), among other compounds whose yields were too low. In conclusion, the peels and pomaces of B. vulgaris L. can be a useful source for the extraction of a red dye for use in coloring, such as the dyeing of textile substrates.


Combination pharmacotherapy with delayed countershock vs standard advanced cardiac life support after prolonged ventricular fibrillation.
To test the hypothesis that combination pharmacotherapy with delayed countershock would produce higher rates of return of spontaneous circulation (ROSC) and one-hour survival when compared with standard Advanced Cardiac Life Support (ACLS) therapy. A prospective, block-randomized, blinded, laboratory experiment was conducted in an established swine model of prolonged ventricular fibrillation (VF). Fifty-six female domestic swine were anesthetized, instrumented, and shocked into VF with a bipolar pacing catheter. The VF was untreated for 8 minutes, then basic CPR was done mechanically for 1 minute. At 9 minutes of VF, the animals were randomized to treatment with one of seven therapies: group 1, combination pharmacotherapy with epinephrine (0.20 mg/kg), lidocaine (1.0 mg/kg), bretylium (5.0 mg/kg), propranolol (1.0 mg), and U-74389G (3.0 mg/kg); group 2, epinephrine (0.20 mg/kg); group 3, lidocaine (1.0 mg/kg) and bretylium (5.0 mg/kg); group 4, propranolol (1.0 mg); group 5, U-74389G (3.0 mg/kg); group 6, normal saline solution (volume equal to that for group 1); and group 7, standard ACLS (first countershock at 9 minutes of VF). Initial countershocks for groups 1-6 were given after 11 minutes of VF. Data were analyzed with two-tailed Fisher's exact test, with alpha set at 0.05. Return of spontaneous circulation occurred in group 1 = 8/8 (100%); group 2 = 7/8 (88%); group 3 = 3/8 (38%); group 4 = 3/8 (38%); group 5 = 5/8 (63%); group 6 = 4/8 (50%); and group 7 = 3/8 (38%). One-hour survival occurred in group 1 = 8/8 (100%); group 2 = 5/8 (63%); group 3 = 2/8 (25%); group 4 = 2/8 (25%); group 5 = 3/8 (38%); group 6 = 2/8 (25%); and group 7 = 1/8 (13%). Combination pharmacotherapy with delayed countershock (group 1) produced significantly higher rates of ROSC (p = 0.03) and one-hour survival (p = 0.001) when compared with standard ACLS in this porcine model of prolonged VF.


Recommended immunization schedule for children and adolescents: Immunization Guideline (8th edition) released by the Korean Pediatric Society in 2015.
This report includes the recommended immunization schedule table for children and adolescents based on the 8th (2015) and revised 7th (2012) Immunization Guidelines released by the Committee on Infectious Diseases of the Korean Pediatric Society (KPS). Notable revised recommendations include: reorganization of the immunization table with a list of vaccines on the vertical axis and the corresponding age on the horizontal axis; reflecting the inclusion of Haemophilus influenzae type b vaccine, pneumococcal conjugate vaccine, and hepatitis A vaccine into the National Immunization Program since 2012; addition of general recommendations for 2 new Japanese encephalitis (JE) vaccines and their interchangeability with existing JE vaccines; addition of general recommendations for quadrivalent meningococcal conjugate vaccines and scope of the recommended targets for vaccination; and emphasizing catch-up immunization of Tdap vaccine. Detailed recommendations for each vaccine may be obtained from the full KPS 8th Immunization Guidelines.


Acetyl-L-carnitine attenuates okadaic acid induced tau hyperphosphorylation and spatial memory impairment in rats.
Tau hyperphosphorylation and memory deficit are characteristic alterations of Alzheimer's disease (AD). Protein phosphatases (PP) 2A plays a crucial role in AD-like lesions. Inhibition of PP2A through hippocampal injection of okadaic acid (OA) induces tau hyperphosphorylation and memory impairment of rats. By using this model, we explored in the present study the effects of acetyl-L-carnitine (ALCAR), a constituent of the inner mitochondrial membrane, on the memory retention, tau phosphorylation, and oxidative stress in rats. We found that pre-treatment of ALCAR (50 mg/d . rat, per os) for two weeks efficiently improved the OA-induced spatial memory retention impairment of the rats. ALCAR antagonized tau hyperphosphorylation at multiple AD sites and it abated the OA-induced PP2A inhibition and oxidative stress. Our study provides the first in vivo evidence that ALCAR can attenuate AD-like PP2A inhibition, tau hyperphosphorylation, and spatial memory deficit of the rats. It suggests that ALCAR may hold potential in AD treatment.


Cytotoxic Fusicoccane-Type Diterpenoids from Streptomyces violascens Isolated from Ailuropoda melanoleuca Feces.
Six new fusicoccane-type diterpenoids (2-7) were isolated from the fermentation broth of Streptomyces violascens, which was isolated from Ailuropoda melanoleuca (giant panda) feces. The structures of these new compounds were elucidated by a detailed spectroscopic data and X-ray crystallographic analysis. Compounds 5-7 demonstrated cytotoxicity against five human cancer cell lines, with IC50 values ranging from 3.5 ± 0.7 to 14.1 ± 0.8 μM. Cell adhesion, migration, and invasion assays showed that 6 inhibited the migration and invasion of human hepatocellular carcinoma SMMC7721 cells in a dose-dependent manner. Through further investigation, it was revealed that 6 inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), in addition to down-regulating the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels to influence the migration and invasion of cancer cells.


Selective activity of BS-RNase against anaplastic thyroid cancer.
Anaplastic thyroid carcinoma is an aggressive solid tumor that fails to adequately respond to any known chemotherapeutic regimen. The development of effective chemotherapy agents would provide the best chance for long-term survival of patients. The cytotoxic effects of bovine seminal ribonuclease (BS-RNase) against thyroid carcinoma cell lines with different degrees of differentiation in comparison to non-malignant cells, including human foreskin fibroblasts (HFF) and retinal pigment epithelial cells (RPE), were tested using the MTT dye reduction assay. Induction of apoptosis was demonstrated by annexin V assay and expression of proteins related to apoptosis was investigated by flow cytometry. The antitumoral in vivo effects of BS-RNase were assessed on established xenografts of anaplastic thyroid carcinoma cell line 8505C in nude mice using subcutaneous injections of BS-RNase (12.5 mg/kg once a day, on 20 consecutive days). All the tumor cell lines exhibited marked sensitivity against BS-RNase in comparison to HFF and RPE cells. The greatest growth inhibition was seen in the 8505C line, while IC50 values for papillary (B-CPAP) and poorly-differentiated thyroid carcinoma cells were about 6-fold higher. The cytotoxic action of BS-RNase was associated with induction of apoptosis. Expressions of Fas and Fas-ligand were not influenced by BS-RNase completely, while the down-regulation of Bcl-2 in treated cells was observed. In vivo treatment induced significant tumor regression after the course of 20 consecutive days. No apparent toxic effects of BS-RNase toward non-malignant cells were observed during the in vivo treatment. After cessation of therapy (day 20) tumor volume continued to decrease and the tumor was no longer detectable after 30 days of treatment induction in all animals. BS-RNase may have beneficial effects for treatment of aggressive anaplastic thyroid cancer.


Secondary acute myeloid leukemia in a child treated for retinoblastoma: A case report with review of literature.
The most devastating late adverse effect of childhood cancer treatment is development of second malignancies. Retinoblastoma is the most common ocular malignancy of childhood and has a very good cure rate. Children with hereditary retinoblastoma have an increased risk of developing second malignancies due to the genetic cancer predisposition status and the additional risk factors are exposure to chemotherapy (alkylating agents and topoisomerase II inhibitors) and external beam radiotherapy during treatment. The common chemotherapy regimen of retinoblastoma consisting of etoposide, an epipodophyllotoxin is associated with risk of secondary AML (s-AML). We report a case of child with bilateral retinoblastoma who developed secondary AML after being treated for retinoblastoma.


Management of status epilepticus.
Status epilepticus (SE) is defined as a condition characterized by an epileptic seizure that is so frequently repeated or so prolonged as to create a fixed and lasting condition. Any type of epileptic seizure can develop into SE. Status epilepticus can be classified as generalized convulsive, non-convulsive and simple partial. Generalized convulsive SE includes tonic clonic seizures with either a partial or a generalized onset. Generalized tonic clonic status is defined when consecutive seizures occur without recovery of consciousness between them. Generalized tonic clonic SE is a medical emergency associated with a high morbidity and mortality if untreated. The most common etiology of SE is non-compliance to antiepileptic drugs. Other causes include alcohol withdrawal, cerebrovascular lesions, drug intoxication, central nervous system infections, neoplasms and acute metabolic derangements. The metabolic-biochemical complication of SE includes respiratory and metabolic acidosis, anoxia, hyperazotemia, hyperkalemia, hypoglycemia, hyponatremia and autonomic and endocrine dysfunctions. Prognosis of SE depends on the duration and etiology of SE. Vigorous treatment of SE is recommended. Effective medical treatment of SE includes Benzodiazepines, Phenytoin, Barbiturates and several other new antiepileptic drugs. In this presentation, we discuss the updated management of SE and propose a protocol for management of convulsive SE.


Severe mitral or aortic valve regurgitation, or both, requiring valve replacement for infective endocarditis complicating hypertrophic cardiomyopathy.
Certain clinical and morphologic findings are described in 11 patients with hypertrophic cardiomyopathy complicated by infective endocarditis that produced severe mitral or aortic valve regurgitation, or both, necessitating valve replacement. All 11 patients had changes in the operatively excised valve or valves characteristic of healed infective endocarditis. The infection involved only the mitral valve in seven patients, only the aortic valve in three patients and both valves in one patient. Study of the operatively excised mitral valves indicated that the healed vegetations were located most commonly on the left ventricular aspects of the anterior mitral leaflet, indicating that vegetation had formed at contact points of this leaflet with mural endocardium of the left ventricular outflow tract. In all 11 patients, the infective endocarditis either worsened preexisting valve regurgitation or initiated valve regurgitation and led to worsened signs and symptoms of cardiac dysfunction, necessitating valve replacement. Functional class improved in the nine patients who survived 7 to 101 months after valve replacement. Hypertrophic cardiomyopathy appears to be a factor predisposing to infective endocarditis. Patients with hypertrophic cardiomyopathy should receive prophylactic antibiotic therapy during procedures that predispose to infective endocarditis.


The fragment spin difference scheme for triplet-triplet energy transfer coupling.
To calculate the electronic couplings in both inter- and intramolecular triplet energy transfer (TET), we have developed the "fragment spin difference" (FSD) scheme. The FSD was a generalization from the "fragment charge difference" (FCD) method of Voityuk et al. [J. Chem. Phys. 117, 5607 (2002)] for electron transfer (ET) coupling. In FSD, the spin population difference was used in place of the charge difference in FCD. FSD is derived from the eigenstate energies and populations, and therefore the FSD couplings contain all contributions in the Hamiltonian as well as the potential overlap effect. In the present work, two series of molecules, all-trans-polyene oligomers and polycyclic aromatic hydrocarbons, were tested for intermolecular TET study. The TET coupling results are largely similar to those from the previously developed direct coupling scheme, with FSD being easier and more flexible in use. On the other hand, the Dexter's exchange integral value, a quantity that is often used as an approximate for the TET coupling, varies in a large range as compared to the corresponding TET coupling. To test the FSD for intramolecular TET, we have calculated the TET couplings between zinc(II)-porphyrin and free-base porphyrin separated by different numbers of p-phenyleneethynylene bridge units. Our estimated rate constants are consistent with experimentally measured TET rates. The FSD method can be used for both intermolecular and intramolecular TET, regardless of their symmetry. This general applicability is an improvement over most existing methodologies.


Angiosarcoma arising within a Malignant Endovascular Papillary Angioendothelioma (Dabska tumor).
We report an angiosarcoma arising within a malignant endovascular papillary angioendothelioma (Dabska tumor) in soft tissue of the upper thigh/buttock of a 42-year-old woman. Although neoplastic progression within a vascular tumor of an existing low-grade lesion into DT has been described so far, we seem to be the first to report transformation of DT into an angiosarcoma.


Self-monitoring of blood glucose versus self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes receiving structured education: a cluster randomized controlled trial.
To compare the effectiveness and acceptability of self-monitoring of blood glucose with self-monitoring of urine glucose in adults with newly diagnosed Type 2 diabetes. We conducted a multi-site cluster randomized controlled trial with practice-level randomization. Participants attended a structured group education programme, which included a module on self-monitoring using blood glucose or urine glucose monitoring. HbA1c and other biomedical measures as well as psychosocial data were collected at 6, 12 and 18 months. A total of 292 participants with Type 2 diabetes were recruited from 75 practices. HbA1c levels were significantly lower at 18 months than at baseline in both the blood monitoring group [mean (se) -12 (2) mmol/mol; -1.1 (0.2) %] and the urine monitoring group [mean (se) -13 (2) mmol/mol; -1.2 (0.2)%], with no difference between groups [mean difference adjusted for cluster effect and baseline value = -1 mmol/mol (95% CI -3, 2); -0.1% (95% CI -0.3, 0.2)]. Similar improvements were observed for the other biomedical outcomes, with no differences between groups. Both groups showed improvements in total treatment satisfaction, generic well-being, and diabetes-specific well-being, and had a less threatening view of diabetes, with no differences between groups at 18 months. Approximately one in five participants in the urine monitoring arm switched to blood monitoring, while those in the blood monitoring arm rarely switched (18 vs 1% at 18 months; P < 0.001). Participants with newly diagnosed Type 2 diabetes who attended structured education showed similar improvements in HbA1c levels at 18 months, regardless of whether they were assigned to blood or urine self-monitoring.


Utilization of CRISPR-Mediated Tools for Studying Functional Genomics in Hematological Malignancies: An Overview on the Current Perspectives, Challenges, and Clinical Implications.
Hematological malignancies (HM) are a group of neoplastic diseases that are usually heterogenous in nature due to the complex underlying genetic aberrations in which collaborating mutations enable cells to evade checkpoints that normally safeguard it against DNA damage and other disruptions of healthy cell growth. Research regarding chromosomal structural rearrangements and alterations, gene mutations, and functionality are currently being carried out to understand the genomics of these abnormalities. It is also becoming more evident that cross talk between the functional changes in transcription and proteins gives the characteristics of the disease although specific mutations may induce unique phenotypes. Functional genomics is vital in this aspect as it measures the complete genetic change in cancerous cells and seeks to integrate the dynamic changes in these networks to elucidate various cancer phenotypes. The advent of CRISPR technology has indeed provided a superfluity of benefits to mankind, as this versatile technology enables DNA editing in the genome. The CRISPR-Cas9 system is a precise genome editing tool, and it has revolutionized methodologies in the field of hematology. Currently, there are various CRISPR systems that are used to perform robust site-specific gene editing to study HM. Furthermore, experimental approaches that are based on CRISPR technology have created promising tools for developing effective hematological therapeutics. Therefore, this review will focus on diverse applications of CRISPR-based gene-editing tools in HM and its potential future trajectory. Collectively, this review will demonstrate the key roles of different CRISPR systems that are being used in HM, and the literature will be a representation of a critical step toward further understanding the biology of HM and the development of potential therapeutic approaches.


Immunostaining with antibodies to desmoglein provides the diagnosis of drug-induced pemphigus and allows prediction of outcome.
No tool is available to diagnose drug-induced pemphigus (DIP) and to predict its outcome after the withdrawal of the culprit drugs. This retrospective pemphigus case series study compared cutaneous/mucosal immunostaining of a monoclonal antibody directed toward desmogleins 1 and 3 (32-2B) in 37 patients with DIP and 56 patients with idiopathic pemphigus. There was a significant difference between the groups in terms of pruritus, superficial form, mucosal involvement, and circulating antibodies. 32-2B staining disclosed a patchy pattern in 47 (84%) of idiopathic pemphigus cases and in 11 (30%) of DIP cases (P<.0001). A normal pattern, used as a diagnostic test for DIP, had 70.3% sensitivity (95% confidence interval [CI], 53.0-84.1), 83.9% specificity (95% CI, 71.7-92.4), a 32.7% positive predictive value, and a 97.9% negative predictive value. Of 17 patients with DIP with a normal pattern of 32-2B, 14 recovered, whereas only 2 of 9 patients with DIP with a patchy pattern recovered (P<.005).32-2B immunolabeling is useful for diagnosing DIP and is an indicator of a good prognosis.


1D to 3D and Chiral to Noncentrosymmetric Metal-Organic Complexes Controlled by the Amount of DEF Solvent: Photoluminescent and NLO Properties.
A mixture of 2D and 1D metal-organic complexes, [ZnL(H2O)2·G1·DEF·2H2O]n (1a: G1 = naphthalene-2,7-disulfonate; DEF = N,N-diethylformamide) and [ZnL(H2O)3·G1·DEF·2H2O]n (2), has been prepared from a hydrogenated Schiff base L and Zn(II) in a DEF-contained solvent system under mild conditions. The yields of 1a and 2 are equivalent; however, they can be tuned by varying the amount of DEF solvent. Increasing the use of DEF tends to form pure 1a, while decreasing it generates 2. Without DEF, another novel 3D four-connected CdSO4 (cds) framework [ZnL(H2O)2·G1·2H2O]n (3) composed of alternated right-handed and left-handed helical chains has been constructed. The amount of DEF solvent has a significant impact on the diverse coordination architectures of 1-3, which is rare in the preparation of metal-organic complexes. The photoluminescence of complexes 1-3 along with naphthalene-2,7-disulfonate has been investigated in the solid state. The luminescent emission of G1 was enhanced greatly after being confined into metal-organic networks. In addition, complexes 1-3 display second-harmonic generation efficiencies, which are approximately 0.58, 0.42, 0.32, and 0.52 times as much as that of potassium dihydrogen phosphate.


Effects of haemostatic agents on bond strength - An In Vitro study.
To evaluate and compare the effect of contamination with haemostatic agents like Tranexamic Acid (TA) and Ethamsylate, on the shear bond strength. There are about 100 extracted human premolars randomly segregated into four groups each consisting of 25 samples. Group I was bonded with Transbond, Group II was bonded with Transbond after blood contamination, while groups III and IV were bonded with Transbond after contamination with Tranexamic acid and the shear bond strength was measured. The data were compared by One- way ANOVA and Tukey (HSD) tests. Group I had the highest shear bond strength (SBS) while Group II, where the teeth were contaminated with blood showed the least SBS values ANOVA indicated significant differences between the four groups (P < .05). Tukey HSD revealed that contamination with TA (Group III) had a statistically higher SBS that contamination with Ethamsylate (Group IV) (P < .05). Since tranexamic acid and ethamsylate reduces the bleeding when used during surgery, these haemostatic agents may be considered in bonding situations where blood contamination is anticipated.


Overlap syndromes.
Many connective tissue diseases share common signs and symptoms, which frequently makes the diagnosis of a specific rheumatic disease difficult. Rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis (DM), mixed connective tissue disease, and Sjögren's syndrome can present with similar clinical features, particularly during the first 12 months of symptoms. Overall, a rheumatic disease can appears in conjunction with features of one or more other connective tissue diseases, for example, patients can have a combination of rheumatoid arthritis and systemic lupus erythematosus ("rhupus"), or systemic sclerosis and polymyositis, defining an "overlap syndrome", where the diseases comply with the diagnosis criterias. Finally, when a person has symptoms of various connective tissue diseases without meeting the full criteria for any one of them, it is often called Undifferentiated Connective Tissue Disease.


Selective selC-independent selenocysteine incorporation into formate dehydrogenases.
The formate dehydrogenases (Fdh) Fdh-O, Fdh-N, and Fdh-H, are the only proteins in Escherichia coli that incorporate selenocysteine at a specific position by decoding a UGA codon. However, an excess of selenium can lead to toxicity through misincorporation of selenocysteine into proteins. To determine whether selenocysteine substitutes for cysteine, we grew Escherichia coli in the presence of excess sodium selenite. The respiratory Fdh-N and Fdh-O enzymes, along with nitrate reductase (Nar) were co-purified from wild type strain MC4100 after anaerobic growth with nitrate and either 2 µM or 100 µM selenite. Mass spectrometric analysis of the catalytic subunits of both Fdhs identified the UGA-specified selenocysteine residue and revealed incorporation of additional, 'non-specific' selenocysteinyl residues, which always replaced particular cysteinyl residues. Although variable, their incorporation was not random and was independent of the selenite concentration used. Notably, these cysteines are likely to be non-essential for catalysis and they do not coordinate the iron-sulfur cluster. The remaining cysteinyl residues that could be identified were never substituted by selenocysteine. Selenomethionine was never observed in our analyses. Non-random substitution of particular cysteinyl residues was also noted in the electron-transferring subunit of both Fdhs as well as in the subunits of the Nar enzyme. Nar isolated from an E. coli selC mutant also showed a similar selenocysteine incorporation pattern to the wild-type indicating that non-specific selenocysteine incorporation was independent of the specific selenocysteine pathway. Thus, selenide replaces sulfide in the biosynthesis of cysteine and misacylated selenocysteyl-tRNA(Cys) decodes either UGU or UGC codons, which usually specify cysteine. Nevertheless, not every UGU or UGC codon was decoded as selenocysteine. Together, our results suggest that a degree of misincorporation of selenocysteine into enzymes through replacement of particular, non-essential cysteines, is tolerated and this might act as a buffering system to cope with excessive intracellular selenium.


Norms and customs: causally important or causally impotent?
In this article, I argue that norms and customs, despite frequently being described as being causes of behavior in the social sciences and ordinary conversation, cannot really cause behavior. Terms like "norms" and the like seem to refer to philosophically disreputable disjunctive properties. More problematically, even if they do not, or even if there can be disjunctive properties after all, I argue that norms and customs still cannot cause behavior. The social sciences would be better off without referring to properties like norms and customs as if they could be causal.


[The effect of interventional therapy in multimodality treatment on multi-drug resistant pulmonary tuberculosis].
To evaluate the effect of interventional therapy with antituberculous drug instillation to the lesions in the treatment of multi-drug resistant pulmonary tuberculosis (MDR-PTB) on conventional therapy. Sixty-one cases of MDR TB were included from January 2001 to October 2002 in five hospitals. Pasiniazide, rifapentine levofloxacin, ethambutol, ethionamide, amikacin and clarithromycin were used as the basic chemotherapy regimen. In addition, M. vaccac and interventional therapy were used, and chemotherapy was continued for a total of 18 months. The sputum negative conversion rate (including sputum smear and culture) was 50.8% (31/61) after 3 months of interventional therapy. The rate increased to 83.6% (51/61) after 18 months of therapy. Chest X-ray showed that, the foci were markedly absorbed in 50.8% (31/61), and the effective rate was 93.4% (57/61) after 3 months of therapy. The foci were markedly absorbed in 78.7% (48/61) after 18 months of treatment. The effective rate was 96.7%. The rate of cavity closure was 21.3% (13/61) after 3 months of interventional therapy and it increased to 49.2% (30/61) after 18 months of treatment. The rate of symptom disappearance was 73.2%-94.4%, including fever, hemoptysis and dyspnea. For the treatment of MDR-TB, interventional therapy is effective in improving sputum negative conversion, lesion absorption and cavity closure.


RNAi-Mediated Screen of Primary AML Cells Nominates MDM4 as a Therapeutic Target in NK-AML with DNMT3A Mutations.
DNA-methyltransferase 3A (DNMT3A) mutations belong to the most frequent genetic aberrations found in adult acute myeloid leukemia (AML). Recent evidence suggests that these mutations arise early in leukemogenesis, marking leukemic progenitors and stem cells, and persist through consolidation chemotherapy, providing a pool for AML relapse. Currently, there are no therapeutic approaches directed specifically against this cell population. To unravel therapeutically actionable targets in mutant DNMT3A-driven AML cells, we have performed a focused RNAi screen in a panel of 30 primary AML samples, all carrying a DNMT3A R882 mutation. As one of the strongest hits, we identified MDM4 as a gene essential for proliferation of primary DNMT3AWT/R882X AML cells. We analyzed a publicly available RNA-Seq dataset of primary normal karyotype (NK) AML samples and found a trend towards MDM4 transcript overexpression particularly in DNMT3A-mutant samples. Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of DNMT3AWT/R882X primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing DNMT3A R882X mutations.


LogiKEy workbench: Deontic logics, logic combinations and expressive ethical and legal reasoning (Isabelle/HOL dataset).
The LogiKEy workbench and dataset for ethical and legal reasoning is presented. This workbench simultaneously supports development, experimentation, assessment and deployment of formal logics and ethical and legal theories at different conceptual layers. More concretely, it comprises, in form of a dataset (Isabelle/HOL theory files), formal encodings of multiple deontic logics, logic combinations, deontic paradoxes and normative theories in the higher-order proof assistant system Isabelle/HOL. The data were acquired through application of the LogiKEy methodology, which supports experimentation with different normative theories, in different application scenarios, and which is not tied to specific logics or logic combinations. Our workbench consolidates related research contributions of the authors and it may serve as a starting point for further studies and experiments in flexible and expressive ethical and legal reasoning. It may also support hands-on teaching of non-trivial logic formalisms in lecture courses and tutorials. The LogiKEy methodology and framework is discussed in more detail in the companion research article titled "Designing Normative Theories for Ethical and Legal Reasoning: LogiKEy Framework, Methodology, and Tool Support" [5].


Inefficient transmissibility of NS-truncated H3N8 equine influenza virus in dogs.
H3N8 equine influenza virus (EIV) causes respiratory diseases in the horse population, and it has been demonstrated that EIV can transmit into dogs owing to its availability on receptors of canine respiratory epithelial cells. Recently, we isolated H3N8 EIV from an EIV-vaccinated horse that showed symptoms of respiratory disease, and which has a partially truncated nonstructural gene (NS). However, it is not clear that the NS-truncated EIV has an ability to cross the host species barrier from horses to dogs as well. Here, we experimentally infected the NS-truncated H3N8 EIV into dogs, and monitored their clinical signs and viral load in respiratory organs to determine the virus's transmissibility.