Predictive features of chronic kidney disease in atypical haemolytic uremic syndrome.
Chronic kidney disease (CKD) is a frequent and serious complication of atypical haemolytic uremic syndrome (aHUS). We aimed to develop a simple accurate model to predict the risk of renal dysfunction in aHUS based on clinical and biological features available at hospital admission. Renal function at 1-year follow-up, based on an estimated glomerular filtration rate < 60mL/min/1.73m2 as assessed by the Modification of Diet in Renal Disease equation, was used as an indicator of significant CKD. Prospectively collected data from a cohort of 156 aHUS patients who did not receive eculizumab were used to identify predictors of CKD. Covariates associated with renal impairment were identified by multivariate analysis. The model performance was assessed and a scoring system for clinical practice was constructed from the regression coefficient. Multivariate analyses identified three predictors of CKD: a high serum creatinine level, a high mean arterial pressure and a mildly decreased platelet count. The prognostic model had a good discriminative ability (area under the curve = .84). The scoring system ranged from 0 to 5, with corresponding risks of CKD ranging from 18% to 100%. This model accurately predicts development of 1-year CKD in patients with aHUS using clinical and biological features available on admission. After further validation, this model may assist in clinical decision making.


Effect of the extract of Thespesia populnea leaves on mice testis.
Male swiss mice were administered with the leaf extract of Thespesia populnea at a daily dose of 400 mg/kg body weight for 15 days and the testis were subjected to structural analysis. The structure of the seminiferous tubule in the testis of treated animal was elongated. Sertoli cells were enlarged in its structure and spermatids became round and disintegrated. It is suggested that the extract of T. populnea treatment leads to pathological changes in the seminiferous tubules, Sertoli cells and spermatids of the testis.


Neurocysticercosis: an update.
Cysticercosis is the commonest parasitic disease of the central nervous system and is endemic not only in developing countries but in industrialized nations with high rates of immigration from endemic areas. Clinical manifestations of neurocysticercosis are non-specific and depend mainly on the number and the topography of the lesions, the host immune response to the parasite, and the sequelae of previous infections. Diagnosis is difficult on clinical grounds, but integration of data from computed tomography and cerebrospinal fluid analysis permits accurate diagnosis of most cases. Therapy for neurocysticercosis is also varied and must be individualized according to the activity of the disease and location of cysticerci. In this paper, the experience of the authors with neurocysticercosis is summarized and current information on several controversial aspects of this disease is reviewed.


Amino acid substitutions in loop BC and helix C affect antigenic properties of helix D in hybrid IFN-alpha21a/alpha2c molecules.
We compared the antigenic properties of human interferon-alpha2c (IFN-alpha2c), IFN-alpha21a, hybrids IFN-alpha21a/alpha2c, and their mutants, using a panel of 27 anti-IFN-alpha1, anti-IFN-alpha2, and anti-IFN-alpha8/1/8 monoclonal antibodies (mAb). After immunoanalysis by ELISA, we found parental IFN-alpha2c and IFN-alpha21a to be antigenically distinct. Lack of reactivity of anti-IFN-alpha1 mAb with IFN-alpha21a indicated an antigenic distinction between subtypes alpha1 and alpha21a. The antigenic properties of hybrid IFNs consisting of the N-terminal portion (1-75) of IFN-alpha21a and the C-terminal portion (76-166) of IFN-alpha2c were analyzed with mAb recognizing defined regions of IFN-alpha2c, IFN-alpha1, and IFN-alpha8/1/8. We found that extending the sequence of IFN-alpha21a up to position 95 in hybrid molecule decreased the immunoreactivity of mAb specific for the antigenic structure formed by residues --112-132-- (helix D) of IFN-alpha2c. Inserting the sequence 76-81 (loop BC) of IFN-alpha2c into the sequence of 1-95 of IFN-alpha21a restored the reactivity of anti-IFN-alpha2c mAb. Some amino acid substitutions at positions 86 and 90 (helix C) of hybrid IFN-alpha21a/alpha2c also affected the immunoreactivity of C-terminal-specific mAb, which recognize helix D, but did not influence the structure of C-terminus of IFN (aa 151-165). Changes in the structure of constructs affected not only their antiproliferative activity but also their antiviral activity on human cells.


Glaucoma medications, glaucoma therapy, and the evolving paradigm.
Therapy for the glaucomas is dynamic, with changes evolving as new medications or modalities are discovered. In comparing the method(s) of treating open-angle glaucoma today, as compared to treatment in the 1980s, clear differences emerge. While topical beta-blockers remain the mainstay for treatment of open-angle glaucoma, other medications and modalities have recently become available that supplement their use. Topical carbonic anhydrase inhibitors (CAIs), introduced in 1995, have become an important addition to the glaucoma armamentarium. They are more useful than their oral counterparts, since they cause fewer systemic side effects, with similar efficacy. Brimonidine, a topical alpha2-adrenergic agonist, and latanoprost, a topical prostaglandin, have become important additions to the glaucoma regimen because of their ability to reduce the intraocular pressure (i.o.p.) with an improved therapeutic index, as compared to older medications. Finally, argon laser trabeculoplasty (ALT) appears to be a safe technique and useful in reduction of IOP. The scheme for how the anti-glaucoma medications and modalities are used for the therapy of open-angle glaucoma will change over time. The evolution will occur as we continue to learn more about the drugs presently being used.


Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression.
Progesterone receptors (PR) are emerging as important breast cancer drivers. Phosphorylation events common to breast cancer cells impact PR transcriptional activity, in part by direct phosphorylation. PR-B but not PR-A isoforms are phosphorylated on Ser294 by mitogen activated protein kinase (MAPK) and cyclin dependent kinase 2 (CDK2). Phospho-Ser294 PRs are resistant to ligand-dependent Lys388 SUMOylation (that is, a repressive modification). Antagonism of PR small ubiquitin-like modifier (SUMO)ylation by mitogenic protein kinases suggests a mechanism for derepression (that is, transcriptional activation) of target genes. As a broad range of PR protein expression is observed clinically, a PR gene signature would provide a valuable marker of PR contribution to early breast cancer progression. Global gene expression patterns were measured in T47D and MCF-7 breast cancer cells expressing either wild-type (SUMOylation-capable) or K388R (SUMOylation-deficient) PRs and subjected to pathway analysis. Gene sets were validated by RT-qPCR. Recruitment of coregulators and histone methylation levels were determined by chromatin immunoprecipitation. Changes in cell proliferation and survival were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and western blotting. Finally, human breast tumor cohort datasets were probed to identify PR-associated gene signatures; metagene analysis was employed to define survival rates in patients whose tumors express a PR gene signature. 'SUMO-sensitive' PR target genes primarily include genes required for proliferative and pro-survival signaling. DeSUMOylated K388R receptors are preferentially recruited to enhancer regions of derepressed genes (that is, MSX2, RGS2, MAP1A, and PDK4) with the steroid receptor coactivator, CREB-(cAMP-response element-binding protein)-binding protein (CBP), and mixed lineage leukemia 2 (MLL2), a histone methyltransferase mediator of nucleosome remodeling. PR SUMOylation blocks these events, suggesting that SUMO modification of PR prevents interactions with mediators of early chromatin remodeling at 'closed' enhancer regions. SUMO-deficient (phospho-Ser294) PR gene signatures are significantly associated with human epidermal growth factor 2 (ERBB2)-positive luminal breast tumors and predictive of early metastasis and shortened survival. Treatment with antiprogestin or MEK inhibitor abrogated expression of SUMO-sensitive PR target-genes and inhibited proliferation in BT-474 (estrogen receptor (ER)+/PR+/ERBB2+) breast cancer cells. We conclude that reversible PR SUMOylation/deSUMOylation profoundly alters target gene selection in breast cancer cells. Phosphorylation-induced PR deSUMOylation favors a permissive chromatin environment via recruitment of CBP and MLL2. Patients whose ER+/PR+ tumors are driven by hyperactive (that is, derepressed) phospho-PRs may benefit from endocrine (antiestrogen) therapies that contain an antiprogestin.


Identification and serotyping of atypical Legionella pneumophila strains isolated from human and environmental sources.
To validate identification methods for Legionella pneumophila strains that cannot be serotyped into the known serogroups and to characterize their antigenic diversity. Fifty L. pneumophila strains that could not be serogrouped, but which had been confirmed as L. pneumophila by mip gene sequencing, were further identified phenotypically. We used (i) MONOFLUO anti-Legionella Staining Reagent (Bio-Rad) (50/50), (ii) an in-house prepared immunoblot assay for the detection of L. pneumophila- specific Mip protein epitope (50/50), (iii) fatty acid analysis using the Microbial Identifications System (MIDI) (47/50) and (iv) Oxoid agglutination tests (44/50). The serological diversity was further characterized by testing with five serogroup-cross-reactive monoclonal antibodies, resulting in nine phenons. The division of L. pneumophila into 15 serogroups does not reflect the serogroup heterogeneity. Results of these tests indicate that there are more serogroups. MONOFLUO anti-Legionella Staining Reagent is the only commercially available tool for identifying atypical strains of L. pneumophila. If necessary for epidemiological purposes, the antigenic heterogeneity of these strains can be analysed by monoclonal antibodies.


Complications in endoscopic-assisted open reduction and internal fixation of mandibular condyle fractures.
Endoscopic-assisted open reduction and internal fixation (EAORIF) of subcondylar fractures is minimally invasive, provides excellent visibility without a large incision, and reduces surgical scarring and the risk of facial nerve injury. This study evaluated the complications associated with EAORIF. Twenty-six patients underwent EAORIF for mandibular condyle fractures. The postoperative follow-up period was longer than 6 months. We analyzed associations between the complication incidence and the number of fixation plates, accompanying mandibular fractures, and age. Eighteen (69.2%) and 6 (23.1%) patients had temporary (<3 months after surgery) and long-term (>6 months after surgery) complications, respectively. Patients older than 30 years had complications more frequently than those younger than 30 years. Complication rates were similar for different numbers of fixation plates and among patients with and without accompanying mandibular fractures. EAORIF is a reliable technique for treating condylar fractures, regardless of patient age, number of fixation plates, or accompanying mandibular fractures. However, improvements are needed to reduce long-term complications.


Effect of intranigral Mn2+ on striatal and nigral synthesis and levels of dopamine and cofactor.
A single injection of manganese chloride into the rat substantia nigra caused a significant and reversible drop in nigral and striatal dopamine and cofactor content ipsilateral to the lesion. Maximal decrease, in both tissues, was observed 60 days after the lesion, and showed complete recovery at 90 days. In vivo striatal tyrosine hydroxylation and GTP cyclohydrolase activities were also decreased maximally at 60 days and were recovered by 90 days after the lesion. No effects were observed on the side contralateral to the injection.


[Postoperative pulmonary disease associated with haemophilus influenzae and neisseria meningitidis in a diabetic child].
Haemophilus influenzae is a saprophyte that colonizes the nasopharynx in nearly two thirds of children and adults. Neisseria meningitidis is a strict human bacterium which lives in the nasopharynx. It can cause benign nasopharyngitis or asymptomatic colonization. We report the case of a diabetic child with postoperative pneumonia associated with Haemophilus influenzae and Neisseria meningitidis. A 3-year old diabetic patient admitted to the Department of Cardiac Surgery due to delayed surgical treatment. The postoperative course was marked by a worsening of respiratory status caused by abundant secretions requiring patient admission to the intensive care unit. An assessment for the detection of infections was performed, including protected distal sampling which revealed the association of Neisseria meningitidis with Haemophilus influenzae. This case study allowed us to highlight bacterial associations in certain high-risk situations. Each of these two species is responsible for various infections. However their presence in the same infected site is rare.


Increased technetium uptake is not equivalent to muscle necrosis: scintigraphic, morphological and intramuscular pressure analyses of sore muscles after exercise.
A scintigraphic technique employing technetium pyrophosphate uptake was used to identify the area of skeletal muscle damage in the lower leg of four runners 24 h after an ultramarathon footrace (160 km). Most of the race had been run downhill which incorporated an extensive amount of eccentric work. Soreness was diffuse throughout the posterior region of the lower leg. In order to interpret what increased technetium uptake reflects and to express extreme endurance related damages, a biopsy was taken from the 3-D position of abnormal uptake. In addition, intramuscular pressures were determined in the deep posterior compartment. Scintigraphs revealed increased technetium pyrophosphate uptake in the medial portion of the gastrocnemius muscle. For 3698 fibres analysed, 33 fibres (1%) were necrotic, while a few other fibres were either atrophic or irregular shaped. A cluster of necrotic fibres occurred at the fascicular periphery for one subject and fibre type grouping occurred for another. Ultrastructural analysis revealed Z-line streaming near many capillaries and variously altered subsarcolemmal mitochondria including some with paracrystalline inclusions. The majority of the capillaries included thickened and irregular shaped endothelial cells. Intramuscular pressures of the deep posterior compartment were slightly elevated (12-15 mmHg) for three of the four subjects. Increased technetium uptake following extreme endurance running does not just reflect muscle necrosis but also subtle fibre abnormalities. Collectively, these pathological findings are attributed to relative ischaemia occurring during the race and during pre-race training, whereas, intramuscular pressure elevations associated with muscle soreness are attributed to mechanical stress caused by extensive eccentric work during the race.


Interleukin-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species-dependent lipid peroxidation and disrupting iron homeostasis.
Asthma occurs accompanied by the ferroptosis in bronchial epithelial cells, during which Interleukin-6 (IL-6) plays a key role. However, the associations between IL-6, ferroptosis and asthma have not been reported. Bronchial epithelial cells BEAS-2B cells were induced by different concentrations of IL-6 and cell viability was detected by MTT assay. The TBARS production rate was detected by corresponding kit. The expression of oxidative stress-related indexes was detected by ELISA. The Iron Assay Kits detected total iron levels and ferrous ion (Fe2+) levels. Labile iron pool assay was used to detect the cell unstable iron pool. The expression of ferroptosis-related proteins was detected by Western blot. To further examine the mechanism of action, ferroptosis inhibitor Ferrostatin 1 (Fer-1), antioxidant NAC, and the iron supplement Fe were added. We found that IL-6 decreased the activity, promoted lipid peroxidation, disrupted iron homeostasis of BEAS-2B cells, and induced iron death in bronchial epithelial BEAS-2B cells. However, pretreatment with Ferrostatin-1 (Fer-1) and antioxidant NAC partially reversed the effect of IL-6 on lipid peroxidation and ferroptosis in BEAS-2B cells, while Fe augmented the effect. Overall, IL-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species (ROS)-dependent lipid peroxidation and disrupting iron homeostasis.


Lipoprotein lipase immobilization onto polyacrolein microspheres.
A lipoprotein lipase (LPL) was made water insoluble by immobilizing onto the surface of polyacrolein (PAA) microspheres with and without oligoglycines as spacer. The activity of the immobilized LPL was found to remain high toward a small ester substrate, p-nitrophenyl laurate (pNPL). The relative activity of the immobilized LPL without spacer decreased gradually with the decreasing surface concentration of the immobilized LPL on the PAA microsphere. On the contrary, the immobilized LPL with oligoglycine spacers gave an almost constant activity for the substrate hydrolysis within the surface concentration region studied and gave a much higher relative activity than that without any spacer. The Michaelis constant K(m) and the maximum reaction velocity V(m) were estimated for the free and the immobilized LPL. The apparent K(m) was larger for the immobilized LPL than for the free one, while V(m) was smaller for the immobilized LPL. The pH, thermal, and storage stabilities of the immobilized LPL were higher than those of the free one. The initial enzymatic activity of the immobilized LPL maintained almost unchanged without any leakage and inactivation of LPL when the batch enzyme reaction was performed repeatedly, indicating the excellent durability of the immobilized LPL.


The Role of the Endocannabinoid System and Genetic Variation in Adolescent Brain Development.
During adolescence, both rodent and human studies have revealed dynamic changes in the developmental trajectories of corticolimbic structures, which are known to contribute to the regulation of fear and anxiety-related behaviors. The endocannabinoid (eCB) system critically regulates stress responsivity and anxiety throughout the life span. Emerging evidence suggests that during adolescence, changes in eCB signaling contribute to the maturation of local and corticolimbic circuit populations of neurons, such as mediating the balance between excitatory and inhibitory neurotransmission within the prefrontal cortex. This function of the eCB system facilitates efficient communication within and between brain regions and serves a central role in establishing complex and adaptive cognitive and behavioral processing. Although these peri-adolescent changes in eCB signaling promote brain development and plasticity, they also render this period a particularly sensitive one for environmental perturbations to these normative fluctuations in eCB signaling, such as stress, potentially leading to altered developmental trajectories of neural circuits governing emotional behaviors. In this review, we focus on the role of eCB signaling on the regulation of stress and anxiety-related behaviors both during and after adolescence. Moreover, we discuss the functional implications of human genetic variation in the eCB system for the risk for anxiety and consequences of stress across development and into adulthood.


Bone mesenchymal stromal cells exhibit functional inhibition but no chromosomal aberrations in chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasia characterized by the presence of the Philadelphia (Ph) chromosome in hematopoietic cells (HCs). As one of the most important components of the bone marrow microenvironment (BMM), bone mesenchymal stromal cells (BMSCs) are critical in the development of leukemia and essential in the regulation of hematopoiesis. However, little is known regarding the alterations of BMSCs in CML. The current study performed Cell Counting Kit-8 and colony-forming unit fibroblast assays to evaluate the proliferative ability of BMSCs. The percentage of senescent BMSCs was evaluated by a senescence-associated β-galactosidase staining assay. Subsequently, a long-term culture-initiating cell assay was designed to explore the HC-supporting capacity of the BMSCs. Furthermore, cytogenetics were detected by conventional cytogenetic analysis and fluorescence in situ hybridization analysis. The current results revealed that CML-BMSCs exhibited decreased cell proliferation and impaired HC-support capacity, as well as increased susceptibility to senescence. No chromosomal aberrations, including the absence of the Ph chromosome, were noted in all CML-BMSCs. In conclusion, the current study demonstrated functional inhibition of CML-BMSCs; however, no signs of chromosomal aberrations were observed, thereby providing insight into the changes occurring in the CML-BMM.


Somatosensory evoked potentials produced by stimulation of the dorsomedial nerves innervating the tail in dogs.
To record the somatosensory evoked potentials (SEPs) produced by stimulation of tail nerves and determine the effects of acute compression of the cauda equina on SEPs. The subjects were 10 adult Beagles. SEPs were recorded after stimulating the dorsomedial nerves (DMN) innervating the tail. The cauda equina was compressed using a balloon catheter inserted into the vertebral arch. In SEPs, two negative and one positive peak were often observed. The compression of the cauda equina caused significant depression of the positive component. The SEPs produced by stimulation of the DMN reflect the activities of ascending neuronal pathways above the coccygeal spinal segments and may be a useful tool for examining cauda equina syndrome.


Therapeutic efficacy of hyperimmune bovine colostrum treatment against clinical and subclinical Cryptosporidium serpentis infections in captive snakes.
Therapy based on the protective passive immunity of Hyperimmune Bovine Colostrum (HBC) (raised against Cryptosporidium parvum in dairy cows immunized during gestation) was tested for heterologous efficacy in subclinical and clinical infections of 12 captive snakes with C. serpentis. Six gastric HBC treatments of 1% snake weight at 1-week intervals each, have histologically cleared C. serpentis in three subclinically infected snakes, and regressed gastric histopathological changes in one of these snakes. In all snakes, each subsequent HBC treatment significantly decreased the number of oocysts recovered in gastric lavage eluants (P < 0.03). The treatments induced oocyst-negative gastric eluants and stools in all snakes, and improved clinical signs of infection. Clinically infected snakes displayed severe histopathological changes in the gastric region; however, the numbers of developmental stages of C. serpentis were moderate. Considering the severity of pathology, much lower than expected pathogen numbers were observed, and it is believed that clinically infected snakes did not have enough time to repair tissue damage that had occurred over the years of infection. As the HBC treatment was safe and highly efficacious, it is recommended to gastrically administer the HBC therapeutically to snakes that are clinically or subclinically infected with C. serpentis. Hyperimmune bovine colostrum can also be used in snake supportive therapy or prophylaxis.


53BP1 Mediates ATR-Chk1 Signaling and Protects Replication Forks under Conditions of Replication Stress.
Complete replication of the genome is an essential prerequisite for normal cell division, but a variety of factors can block the replisome, triggering replication stress and potentially causing mutation or cell death. The cellular response to replication stress involves recruitment of proteins to stabilize the replication fork and transmit a stress signal to pause the cell cycle and allow fork restart. We find that the ubiquitously expressed DNA damage response factor 53BP1 is required for the normal response to replication stress. Using primary, ex vivo B cells, we showed that a population of 53BP1-/- cells in early S phase is hypersensitive to short-term exposure to three different agents that induce replication stress. 53BP1 localizes to a subset of replication forks following induced replication stress, and an absence of 53BP1 leads to defective ATR-Chk1-p53 signaling and caspase 3-mediated cell death. Nascent replicated DNA additionally undergoes degradation in 53BP1-/- cells. These results show that 53BP1 plays an important role in protecting replication forks during the cellular response to replication stress, in addition to the previously characterized role of 53BP1 in DNA double-strand break repair.


The value of West Nile virus RNA detection by real-time RT-PCR in urine samples from patients with neuroinvasive forms.
Routine laboratory screening is based on the detection of WNV specific IgM and IgG in blood and cerebrospinal fluid. Confirmation is then classically applied by real time RT-PCR (rRT-PCR) in Cerebrospinal fluid (CSF), which often gives negative results due to too short virorachia and late sampling. rRT-PCR was applied-for the first time for routine diagnosis purpose-on urine samples. During 2018 outbreak in Tunisia, 107 patients presented WNV neurologic symptoms and were positive for WNV serology. Of them, 95 patients were sampled for urine and 35 were sampled for CSF. Qualitative rRT-PCR was performed on both type of samples. WNV RNA was detected in 50.5% of urine samples (48/95) and in 2.8% of CSF samples (1/35). WNV RNA was detectable from day 1 to day 41 from symptom onset, however, positive urine rate was 53.1% during the first 10 days from symptom onset. The proportions of urine-positive and urine-negative samples, based on day of collection, showed no statistical difference (p > 0.005). Cycle threshold (Ct) values ranged from 12 to 39, with no correlation with the day of collection. The lowest Ct value was detected for urine sampled on day 5 after symptom onset. A statistically significant difference was found between age groups of confirmed and non confirmed cases (p < 0.001). Our study reported the use of rRT-PCR on urine samples as a confirmatory diagnostic tool for WNV "probable cases" during an outbreak. Our findings underlined the reliability and the rapidity of this confirmatory tool, even late, and showed its superiority on CSF investigation.


Language and action control: the acquisition of action goals in early childhood.
This study examined the role of verbal labeling in 4-year-old children's acquisition of action-effect learning. The acquisition of action-effect associations was tested by having children first perform a two-choice key-pressing task in which each key press was followed by an effect (i.e., a particular sound) and then respond to the previously perceived effects under either consistent or inconsistent key-sound mappings. During acquisition, the children overtly described the actions, the effects, both the actions and the effects, or, in a control condition, something irrelevant to the actions and effects. Action-effect learning was reliable only if the description related actions to effects, even though some evidence of learning was also obtained in the control condition. In contrast, learning was prevented if only the actions or only the effects were described. The results suggest that verbal labeling plays an important role in integrating and isolating event representations.


Mutations of the 5alpha-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village.
We describe six Turkish patients with 5alpha-steroid reductase type 2 deficiency from unrelated Turkish families and a large pedigree of one of these patients who reside north-west of Anatolia. Patients NA, KS, BD and SY presented for evaluation of bilateral inguinal masses with female phenotypes. Patient ABE had penoscrotal hypospadias with male phenotype. Homozygous mutation of the 5alphaSR2 gene was identified in five of these patients by genomic DNA analysis. These mutations were Leu55Gln in exon 1 (in patients FG, BD and ABE), deltaMet157 in exon 3 (in patient NA), and splice junction abnormality in intron 1 (in patient SY). One individual (patient KS) was found to be a compound heterozygous carrier of two different mutations, Leu55Gln in exon 1 and Arg171Ser in exon 3. Patient FG had a large pedigree with the Leu55Gln mutation in exon 1. The pedigree of this family with marital consanguinity is remarkable, and possibly due to the isolation of this family because of economic and social problems. A further 85 individuals belonging to this family were analyzed for exon 1 Leu55Gln mutations in the 5alphaSR2 gene. Forty-two of these 85 individuals (49.41%) had this alteration; 11 were homozygous (8 genetic male, 3 genetic female) and 31 heterozygous (18 genetic male, genetic female) for this mutation. It was interesting to see asymptomatic homozygous female carriers. In conclusion, according to our results and those of other Turkish patients reported by different investigators, 5aSR2 gene mutation analysis, especially for Leu55Gln in exon 1 and deltaMet157 in exon 3, must be carried out in Turkish patients with male pseudohermaphroditism. Homozygous asymptomatic female carriers must be taken into consideration in this clinical entity, especially in a closed population, because of the risk of transmitting the disease to their offspring.


Inhibitory effect of 5-iodotubercidin on pigmentation.
Melanin pigments are the primary contributors for the skin color. They are produced in melanocytes and then transferred to keratinocytes, eventually giving various colors on skin surface. Although many depigmenting and/or skin-lightening agents have been developed, there is still a growing demand on materials for reducing pigmentation. We attempted to find materials for depigmentation and/or skin-lightening using the small molecule compounds commercially available, and found that 5-iodotubercidin had inhibitory potential on pigmentation. When HM3KO melanoma cells were treated with 5-iodotubercidin, pigmentation was dramatically reduced. The 5-iodotubercidin decreased the protein level for pigmentation-related molecules such as MITF, tyrosinase, and TRP1. In addition, 5-iodotubercidin decreased the phosphorylation of CREB, while increased the phosphorylation of AKT and ERK. These data suggest that 5-iodotubercidin inhibits melanogenesis via the regulation of intracellular signaling related with pigmentation. Finally, 5-iodotubercidin markedly inhibited the melanogenesis of zebrafish embryos, an in vivo evaluation model for pigmentation. Together, these data suggest that 5-iodotubercidin can be developed as a depigmenting and/or skin-lightening agent.


Efficient synthesis of spironaphthopyrano [2,3-d]pyrimidine-5,3'-indolines under solvent-free conditions catalyzed by SBA-Pr-SO3H as a nanoporous acid catalyst.
A green, simple one-pot synthesis of spironaphthopyrano[2,3-d]pyrimidine-5,3'-indoline derivatives by a three-component reaction of isatins, 2-naphthol, and barbituric acids under solvent-free conditions in the presence of SBA-Pr-SO(3)H has been accomplished. Sulfonic acid functionalized SBA-15 (SBA-Pr-SO(3)H) as a heterogeneous nanoporous solid acid catalyst was found to be an efficient and recyclable acid catalyst in this synthesis.


The association of physical illness and self-harm resulting in hospitalisation among older people in a population-based study.
With population ageing, self-harm injuries among older people are increasing. Further examination of the association of physical illness and self-harm among older people is warranted. This research aims to identify the association of physical illness with hospitalisations following self-harm compared to non-self-harm injury among older people. A population-based cohort study of individuals aged 50+ years admitted to hospital either for a self-harm or a non-self-harm injury using linked hospital admission and mortality records during 2003-2012 in New South Wales, Australia was conducted. Logistic regression and survival plots were used to examine the association of 21 physical illnesses and mortality at 12 months by injury intent, respectively. Age-adjusted health outcomes, including length of stay, readmission and mortality were examined by injury intent. There were 12,111 hospitalisations as a result of self-harm and 474,158 hospitalisations as a result of non-self-harm injury. Self-harm compared to non-self-harm hospitalised injury was associated with higher odds of mental health conditions (i.e. depression, schizophrenia, bipolar and anxiety disorders), neurological disorders (excluding dementia), other disorders of the nervous system, diabetes, chronic lower respiratory disease, liver disease, tinnitus and pain. Tinnitus, pain, malignancies and diabetes all had a higher likelihood of occurrence for self-harm compared to non-self-harm hospitalisations even after adjusting for mental health conditions, number of comorbidities and alcohol and drug dependency. Older people who are experiencing chronic health conditions, particularly tinnitus, malignancies, diabetes and chronic pain may be at risk of self-harm. Targeted screening may assist in identifying older people at risk of self-harm.


The effect of bridge exercise method on the strength of rectus abdominis muscle and the muscle activity of paraspinal muscles while doing treadmill walking with high heels.
[Purpose] The purpose of this research is to investigate the effect of the method of bridge exercise on the change of rectus abdominis muscle and the muscle activity of paraspinal muscles while doing treadmill walking with high heels. [Subjects and Methods] The subjects of this research are healthy female students consisting of 10 persons performing bridge exercises in a supine group, 10 persons performing bridge exercises in a prone group, and 10 persons in a control group while in S university in Busan. Bridge exercise in supine position is performed in hook lying position. Bridge exercise in prone position is plank exercise in prostrate position. To measure the strength of rectus abdominis muscle, maintaining times of the posture was used. To measure the muscle activity of paraspinal muscles, EMG (4D-MT & EMD-11, Relive, Korea) was used. [Results] The strength of rectus abdominis muscle of both bridge exercises in the supine group and bridge exercises in the prone group increases significantly after exercise. The muscle activity of paraspinal muscle such as thoracic parts and lumbar parts in bridge exercises in the prone group decreases statistically while walking on a treadmill with high heels. Muscle activity of thoracic parts paraspinal muscle and bridge exercises in the supine group decreased significantly. [Conclusion] According to this study, we noticed that bridge exercise in a prone position is desirable for women who prefer wearing high heels as a back pain prevention exercise method.


A Narrative Review of Implementing Precision Oncology in Metastatic Castration-Resistant Prostate Cancer in Emerging Countries.
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved considerably with the introduction of newer agents, such as poly-ADP ribose polymerase (PARP) inhibitors targeting DNA damage repair mutations. Combining and sequencing novel and existing therapies appropriately is necessary for optimizing the management of mCRPC and ensuring better treatment outcomes. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection, treatment sequencing patterns, and factors influencing treatment decisions in the management of mCRPC in the era of PARP inhibitors. This article can also serve as a comprehensive guide to clinicians for optimizing genetic testing and counseling and management of patients with mCRPC. Although the PROfound study has validated the concept of PARP sensitivity across multiple genes associated with homologous recombination repair (HRR) in mCRPC and highlighted the importance of genomic testing in this at-risk patient population, it still remains unclear how patients with rarer HRR mutations will respond to PARP inhibitors. Therefore, real-world data obtained through registry-based randomized controlled trials in the future may help produce robust scientific evidence for supporting optimal clinician decision-making in the management of mCRPC.


Interaction between electron-affinic sensitizers.
Measurements of effect of pairs of the sensitizers PNAP, misonidazole and oxygen have shown that if one sensitizer is giving an enhancement ratio (ER) of about 1.6 or less and the other is giving a larger ER, the combination behaves as if only the latter is present. There is only an additive effect of the two if they both give ERs less than 1.6 or greater than 1.6. These results show that at low concentrations sensitizers only act on damage associated with the "fast component" of the oxygen effect. This could result from interaction with two distinct species, or there could be only one critical species formed initially but more than one step by which it could be converted to a lethal form.


Metabolic syndrome, endothelial function and lifestyle modification.
We evaluated (1) endothelial function (FMD, ICAM-1 and VCAM-1) cross-sectionally in subjects with (MS+) and without (MS-) metabolic syndrome who were at increased risk for cardiovascular disease due to either HNBP and/or IGR, and (2) examined in a subgroup of subjects the effects of 24-week lifestyle modification on endothelial function. MS components, FMD by Doppler ultrasound, ICAM-1 and VCAM-1 by fasting blood samples were assessed. All of the endothelial functions were similar between MS- and MS+. Although waist circumference, blood pressure, and fasting glucose showed improvements, endothelial function remained unchanged following the intervention. The results showed that in our subject population, MS does not reduce endothelial function, and our 24-week lifestyle modification programme did not result in an improvement in endothelial function in MS+ despite the improvements in some MS components.


Signet-ring cell adenocarcinoma of the bladder: case series between 1990-2009.
To present a revision on the signet-ring cell bladder adenocarcinomas found in our department. We reviewed all the transurethral resections of the bladder (TURB) performed between 1990 and 2009 finding 9 cases of primary signet ring cell adenocarcinomas (4 pure and 5 mixed). Eight were male and one female, with ages between 39 and 82 years. Definitive treatment was radical cystectomy with Bricker's urinary diversion in four patients, cysctectomy with Mainz's II diversion in one patient and palliative management with TURB in three cases and percutaneous nephrostomy in the remaining case. We used adyuvant chemotherapy in three cases. Only two patients were alive at the time of the study. Mean survival was 327 days for pure tumors and 586 for the mixed ones. Signet-ring cell primary adenocarcinoma of the bladder is an uncommon type of tumor, with worse prognosis than transitional cell cancer. It is important to discard other possible metastatic origins(like stomach, prostate, lung, or ovary) because the management will be different. Radical cystectomy is the treatment of choice, with adyuvant chemotherapy if possible. Five year survival is less than 11%


Prevention, not just treatment.
A tragic burden of disease, disability, and death has resulted from smoking. The role of pulmonary rehabilitation is not only in treatment and rehabilitation of lung disease but in the prevention of lung disease. The skills of the pulmonary rehabilitation specialist should be used in the earlier detection and prevention of lung disease through primary and secondary prevention. The spirometer must gain acceptance in the medical community as the early tool to evaluate lung health, not the chest radiograph or the stethoscope. The lung age formula and sputum pap smears are just a few of the evaluation tools used to detect and motivate susceptible individuals. Prevention is the key to enhancing lung health.


X-linked adrenoleukodystrophy: phenotype distribution and expression of ALDP in Spanish kindreds.
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by an impairment in peroxisomal beta-oxidation of very long straight-chain fatty acids (VLCFAs). Six clinical phenotypes have been delineated: childhood cerebral (CCALD), adolescent cerebral (AdolCALD), adult cerebral (ACALD), adrenomyeloneuropathy (AMN), Addison-only (AO), and presymptomatic (PALD). The distribution of phenotypes varies in different countries. We have diagnosed biochemically 60 X-ALD Spanish patients belonging to 48 kindreds. Their phenotypic distribution was: CCALD plus AdolCALD, 33%; ACALD, 16%; AMN, 27%; AO, 12%; and PALD, 12%. These results contrast with the distribution described in other countries, due to a higher prevalence of the ACALD form. Regarding the expression of the protein product (ALDP), we studied 17 kindreds using immunochemical techniques and found absence of ALDP in 84% of cases. We also studied 13 females from 7 negative ALDP kindreds in order to correlate ALDP expression and the carrier status established by VLCFA measurement. In one case with normal VLCFA levels in serum and fibroblasts, we observed mosaicism in ALDP expression. This fact supports the use of this technique for identifying carriers.


Influence of storage temperature and low-temperature conditioning on the levels of health-promoting compounds in Rio Red grapefruit.
Commercial operations use low-temperature conditioning of citrus fruits to reduce the incidence of chilling injury (CI) during cold storage and quarantine treatments. Rio Red grapefruits (Citrus paradisi Macf) were stored for 12 weeks at 11°C or 5°C; an additional set was temperature conditioned at 16°C for 7 days before storing at 5°C (CD). Every 3 weeks, samples were assessed for chilling injury (CI) and health-promoting compounds such as ascorbic acid, carotenoids, limonoids, flavonoids, and furocoumarins. Low-temperature conditioning significantly reduced CI but did not affect the total soluble solids, acidity, and ripening ratio. After 12 weeks of storage, grapefruits showed no significant differences in lycopene, narirutin, poncirin, furocoumarins, and radical scavenging activity in all the three treatments. Limonin was significantly higher (p < .05) in CD fruits, nomilin was significantly higher in fruits stored at 11°C, whereas fruits stored at 5°C had lower levels of naringin, neohesperidin, and didymin after 12 weeks of storage. Low-temperature conditioning treatment helped fruits to retain similar or higher levels of most of the health-promoting compounds by the end of storage period while maintaining better quality than the nonconditioned fruits.


Multiple sclerosis initially presenting as facial palsy.
A case of multiple sclerosis initially presenting as a facial palsy is presented. A 35-yr-old U.S. Air Force aviator developed a purely right-sided facial palsy with no sensory abnormalities. She had no other neurologic findings except for a barely perceptible loss of coordination in her right upper extremity. Subsequent brain MRI revealed multiple white matter lesions. Further history and laboratory analysis confirmed multiple sclerosis. This case underscores the potential for multiple sclerosis to mimic other more benign conditions and the need for clinicians to carefully examine patients presenting with new neurologic abnormalities. The diagnosis and treatment of multiple sclerosis as well as military aviation policy regarding multiple sclerosis patients is discussed.


Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites.
Natural product search is undergoing resurgence upon the discovery of a huge previously unknown potential for secondary metabolite (SM) production hidden in microbial genomes. This is also the case for filamentous fungi, since their genomes contain a high number of "orphan" SM gene clusters. Recent estimates indicate that only 5% of existing fungal species have been described, thus the potential for the discovery of novel metabolites in fungi is huge. In this context, fungi thriving in harsh environments are of particular interest since they are outstanding producers of unusual chemical structures. At present, there are around 16 genomes from extreme environment-isolated fungi in databases. In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described. Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds. The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs.


Racial/ethnic variation in mental health correlates of substance use among college students.
This study investigated mental health indicators, substance use, and their relationships, by race/ethnicity. A probability sample of 1,053 students at two California universities self-reported their frequency of substance use and rated their experience with indicators of mental health. One-way analysis of variance (ANOVA), chi-square tests, and multivariate censored regression models were estimated to examine which indicators of mental health were associated with each substance use form by race/ethnicity. Results from the one-way ANOVA and chi-square tests showed differences in substance use prevalence and mental health by race/ethnicity. For example, students who identified as White demonstrate a higher prevalence for every form of substance use in comparison to the Asian, Latino, and "All other" categories. Results from the regression showed, among Whites, inattention was associated with prescription stimulant misuse, and psychological distress was associated with marijuana use. Among Latinos, inattention was associated with cocaine and prescription stimulant use. Among Asians, psychological distress was associated with tobacco use and the misuse of prescription painkillers. Findings highlight the need to ensure subpopulations receive needed services.


Ineffective Health Management in Hemodialysis Patients: Diagnostic Accuracy Study.
This study analyzed the accuracy of clinical indicators of ineffective health management in hemodialysis patients. A diagnostic accuracy study was performed in 200 chronic kidney disease patients undergoing hemodialysis during the first half of 2015. Measures of sensitivity and specificity were calculated using latent class analysis. Ineffective health management was present in 66.28% of patients. Accurate clinical indicators included expressed nonadherence to treatment, daily life choices ineffective to achieve health goals, expression of difficulty with prescribed regimens, inappropriate use of medicines, lack of expression of willingness to control the disease, irregular attendance of dialysis sessions, and infection. Hemodialysis may trigger a set of clinical indicators that predict the presence of ineffective health management. This knowledge provides evidence to clinical practices for hemodialysis patients and contributes to the best clinical performance of nurse practitioners.


Antimicrobial efficacy of platinum-doped silver nanoparticles.
Silver nanoparticles (AgNPs) have been proposed to combat oral infection due to their efficient ionic silver (Ag+ ) release. However, concentrations required for antimicrobial efficacy may not be therapeutically viable. In this work, platinum-doped silver nanoparticles (Pt-AgNPs) were explored to evaluate their potential for enhanced Ag+ release, which could lead to enhanced antimicrobial efficacy against S. aureus, P. aeruginosa, and E. coli. AgNPs doped with 0.5, 1, and 2 mol% platinum (Pt0.5 -AgNPs, Pt1 -AgNPs, and Pt2 -AgNPs) were synthesized by a chemical reduction method. Transmission electron microscopy revealed mixed morphologies of spherical, oval, and ribbon-like nanostructures. Surface-enhanced Raman scattering revealed that the surface of Pt-AgNPs was covered with up to 93% Pt. The amount of Ag+ released increased 16.3-fold for Pt2 -AgNPs, compared to AgNPs. The initial lag phase in bacterial growth curve was prolonged for Pt-AgNPs. This is consistent with a Ag+ release profile that exhibited an initial burst followed by sustained release. Doping AgNPs with platinum significantly increased the antimicrobial efficacy against all species. Pt2 -AgNPs exhibited the lowest minimum inhibitory concentrations, followed by Pt1 -AgNPs, Pt0.5 -AgNPs, and AgNPs, respectively. Doping AgNPs with a small amount of platinum promoted the release of Ag+ , based on the sacrificial anodic effect, and subsequently enhanced their antimicrobial efficacy.


Bluetongue virus and epizootic hemorrhagic disease virus survey in cattle of the Galapagos Islands.
Bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) have both been reported in mainland Ecuador, but their occurrence was unknown in the Galapagos Islands, an Ecuadorian province. We aimed to detect BTV or EHDV in cattle from the 3 main cattle-producing Galapagos Islands at a between-herd design prevalence of 20% and a within-herd design prevalence of 15%. Blood samples were collected from 410 cattle in 33 farms and tested for antibodies against BTV and EHDV by competitive ELISAs. All results were negative, suggesting that BTV and EHDV are not present in the Galapagos Islands.


Modern Tumor Marker Discovery in Urology: Surface Enhanced Laser Desorption and Ionization (SELDI).
During the last two decades, biomarker research has benefited from the introduction of new proteomic analytical techniques. In this article, we review the application of surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy in urologic cancer research. After reviewing the literature from MEDLINE on proteomics and urologic oncology, we found that SELDI-TOF is an emerging proteomic technology in biomarker discovery that allows for rapid and sensitive analysis of complex protein mixtures. SELDI-TOF is a novel proteomic technology that has the potential to contribute further to the understanding and clinical exploitation of new, clinically relevant biomarkers.


Preformative, Performative and Narative in Creative Person Centered Psychopharmacotherapy.
Psychopharmacotherapy does not stand alone. The act of prescribing involves much more than solely choosing "best" medication. It seems that somewhere in the process of trying to objectify and scientify our therapy, we have neglected an important and effective dimensions of it. Psychopharmacology should consider much more than just biological dimension of drugs. Psychological, social and behavioral factors that influence drug metabolism, efficacy and side-effects are largely overlooked. Obviously, the subtext of information provided by the medical professional inevitably contains suggestion. Important part of that subtext is consisted in way we think of it, we talk of it and we perform that information. Defining of preformative and performative psychopharmacotherapy was atempted as well as desciption of narrative creative person-centered psychopharmacotherapy. Studies that indicate that medicines (SSRI) do not work on its own but as amplifier of the influence of the living conditions on mood are provided. Undirected susceptibility to change hypothesis which request acknowledging the importance of social, psychological, environmental factors to explain such the mechanisms underlying the recovery from the disease is explained. Understanding the role of medicines (SSRIs) as amplifier of the influence of the living conditions on mood represents a critical step in developing a creative, person-centered psychopharmacotherapy aimed at better matching patients with treatment and avoiding potential harmful consequences.


Biological Sensitivity to the Effects of Childhood Family Adversity on Psychological Well-Being in Young Adulthood.
The theory of biological sensitivity to context may inform our understanding of why some children exposed to family adversity develop mental health problems in emerging adulthood whereas others demonstrate resilience. This study investigated the interactive effects of heart rate (HR) reactivity and childhood family adversity (maltreatment and changes in family structure) on depressive symptoms and positive affect among 150 undergraduate students (18-28 years old; 77% White, non-Hispanic; 61% female). Participants reported on childhood parental divorce or death, and child maltreatment, and current depressive symptoms and positive affect. HR reactivity was assessed in response to a laboratory interpersonal stressor. HR reactivity moderated the effects of child maltreatment on depressive symptoms and positive affect; higher maltreatment was associated with more depressive symptoms and less positive affect, but only among those with average and higher levels of HR reactivity. Results suggest that higher physiological reactivity may confer greater susceptibility to environmental contexts.


Impact of lifetime control on the threshold of quantum dot lasers.
Despite significant improvements in their properties as emitters, colloidal quantum dots have not had much success in emerging as suitable materials for laser applications. Gain in most colloidal systems is short lived, and needs to compete with biexcitonic decay. This has necessitated the use of short pulsed lasers to pump quantum dots to thresholds needed for amplified spontaneous emission or lasing. Continuous wave pumping of gain that is possible in some inorganic phosphors has therefore remained a very distant possibility for quantum dots. Here, we demonstrate that trilayer heterostructures could provide optimal conditions for demonstration of continuous wave lasing in colloidal materials. The design considerations for these materials are discussed in terms of a kinetic model. The electronic structure of the proposed dot architectures is modeled within effective mass theory.


Does remaining teeth and dental prosthesis associate with social isolation? A six-year longitudinal study from the Japan Gerontological Evaluation Study (JAGES).
Social isolation was associated with increased mortality and numerous adverse health outcomes. However, the longitudinal association between oral health and social isolation has not been studied. In this longitudinal prospective cohort study, the association between the number of remaining teeth and dental prosthesis use with social isolation after 6-years follow-up was examined. Functionally independent adults aged 65 years or older, who were not socially isolated in 2010, were followed up until 2016 in the Japan Gerontological Evaluation Study. Data from 26 417 participants were analysed after random forest imputation to address missing data. Logistic regression models were used to calculate the odds ratio (OR) for incident social isolation in 2016 after adjusting for age, sex, educational attainment, income, activities of daily living, living area and having depressive symptoms. The mean age of the participants at baseline was 72.3 (SD = 5.0). A total of 1,127 (4.3%) participants were socially isolated at follow-up. Of these, 338 (3.2%) had ≥20 teeth (with or without using dental prosthesis), 171 (3.9%) had 10-19 teeth and used dental prosthesis, 112 (4.2%) had 10-19 teeth and did not use the dental prosthesis, 338 (5.1%) had 0-9 teeth and used dental prosthesis, and 168 (7.6%) had 0-9 teeth and did not use the dental prosthesis. Fully adjusted logistic regression models showed that the OR of incident social isolation was higher for those with fewer teeth; OR = 1.13 (95%CI = 0.96-1.33) for those with 10-19 teeth and OR = 1.36 (95%CI = 1.17-1.58) for those with 0-9 teeth, compared to those with ≥20 teeth. The OR of incident social isolation was lower for those who used a dental prosthesis [OR = 0.90, 95%CI = 0.80-1.02)] compared to those who did not use a dental prosthesis. The interaction between the number of teeth and dental prosthesis use demonstrated that the latter mitigated the incidence of social isolation for participants with tooth loss. Compared to those with ≥20 teeth (with or without prosthesis use), participants with 0-9 teeth that did not use a dental prosthesis were 79% [OR = 1.79, 95%CI = 1.49-2.19] more likely to be socially isolated, whereas participants with 0-9 teeth that used a dental prosthesis were only 23% [OR = 1.23, 95%CI = 1.05-1.45] more likely to be socially isolated. Tooth loss was the main predictor for social isolation at follow-up, while no dental prostheses use was an additional risk factor. Dental prosthesis use may reduce the risk of social isolation especially in those with severe tooth loss.


Target recognition of beta2-glycoprotein I (beta2GPI)-dependent anticardiolipin antibodies: evidence for involvement of the fourth domain of beta2GPI in antibody binding.
Beta2-glycoprotein I (beta2GPI) is an absolute requirement for the binding of autoimmune anticardiolipin Abs (aCL) to cardiolipin (CL). We evaluated the target recognition of human beta2GPI by IgG derived from two patients with primary and two with secondary antiphospholipid syndrome. The total IgG serum fractions and beta2GPI affinity-purified IgGs were assessed by using various domain-deleted mutants (DM) of human beta2GPI (DMs: I-III, I-IV, II-V, III-V, IV-V, and V) and mouse mAbs against individual beta2GPI domains. The four IgGs bound slightly to CL in the absence of beta2GPI and showed increased binding in the beta2GPI presence. Following affinity purification of the IgGs on a beta2GPI column, reactivity toward CL was absent. DMs containing domain V inhibited the binding of biotinylated beta2GPI to CL. The addition to CL-coated plates of DM V, but not the other DMs, reduced the binding of all four IgGs. The anti-beta2GPI IgGs bound only to complete beta2GPI and DM I-IV coated on the plates. The binding to plate-adsorbed beta2GPI could be inhibited by complete beta2GPI and DM I-IV, the latter being a more efficient inhibitor. Further, the human anti-beta2GPI IgGs could compete with the binding to beta2GPI of Cof-21 mouse mAb (directed at domain IV), but not with the two other mouse mAbs. The results suggest that some "autoimmune:" beta2GPI-dependent anticardiolipin Abs recognize a beta2GPI target that is distinct from the CL-binding site in domain V. The target site for some antiphospholipid syndrome IgGs appear to reside in domain IV of beta2GPI.


[Comparison of the mid- and long-term outcomes between natural orifice specimen extraction surgery and conventional laparoscopic surgery with abdominal auxiliary incision in the treatment of rectal cancer based on propensity score matching method].
Objective: To compare the mid- and long-term outcomes between natural orifice specimen extraction surgery (NOSES) and conventional laparoscopic surgery with abdominal auxiliary incision in the treatment of rectal cancer. Methods: A propensity score matching study was conducted. Patients with pathological diagnosis of rectal adenocarcinoma, preoperative imaging assessment of T1-3 and body mass index <28 kg/m(2) were included. Those who underwent local resection or abdominoperineal resection, had simultaneous multiple primary cancers, malignant intestinal obstruction or perforation, received neoadjuvant radiotherapy, and were unsuitable for laparoscopic surgery were excluded. From January 2017 to January 2019, 264 patients undergoing laparoscopic rectal cancer surgery at the Department of Colorectal Tumor Surgery, Shengjing Hospital of China Medical University were enrolled in this study, and divided into the NOSES group (52 cases) and the auxiliary incision group (212 cases). Propensity score matching method was used as 1:1 to match the initial data, and 46 pairs were finally obtained. SPSS 26.0 was used for data analysis, and 2-year disease-free survival, intraoperative and perioperative indicators were compared between the two groups. Results: The tumor short diameter in the NOSES group and the auxiliary incision group was (2.9±0.8) cm and (3.1±1.0) cm (t=0.842, P=0.402) respectively. Other baseline data were also comparable between the two groups(all P>0.05). There were no significant differences in operative time, intraoperative blood loss, length of hospital stay and postoperative complication rate between the two groups (all P>0.05). The time to first flatus [2 (1-6) days vs. 3 (1-6) days, Z=-3.035, P=0.002] and to liquid food intake [3 (1-6) days vs. 3 (2-7) days, Z=-2.587, P=0.010] after surgery in the NOSES group were earlier than those that in the auxiliary incision group. Compared with the auxiliary incision group, the postoperative pain score was lower [3 (2-5) vs. 4 (3-7), Z=-5.477, P<0.001], and the aesthetic score was higher [8 (6-9) vs. 7 (5-8), Z=-6.329, P<0.001] in the NOSES group. The distal resection margin in the NOSES group was longer than that in the auxiliary incised group [(3.7±1.2) cm vs. (2.9±1.4) cm, t=3.287, P<0.001]. There were no significant differences in proximal resection margin the number of harvested lymph nodes and positive rate of circumferential resection margin between the two groups (all P>0.05). The 2-year disease-free survival rate in the NOSES group and the auxiliary incision group was 93.5% and 89.1% respectively, and the difference was not statistically significant (P=0.466). Conclusions: NOSES has similar mid- and long-term outcomes to conventional laparoscopic surgery and the advantages of better cosmetic effect, less postoperative pain and faster recovery, which is more in line with the concept of minimally invasive and worthy of clinical promotion.


Diagnostic value and potential clinical significance of duodenal lipoma based on computed tomography imaging data.
To explore the diagnostic value of computed tomography (CT) imaging for duodenal lipoma and the potential clinical significance of the findings. Clinicopathological and CT data from 57 patients, who were diagnosed with duodenal lipoma at the first affiliated Hospital of Zhengzhou University (Zhengzhou, China) between June 2014 and March 2019, were retrospectively reviewed. Data collected included location and size of the tumor, morphological manifestations (shape, density, boundary), concomitant diseases, pathology and gastroscopy results, and follow-up. Follow-up was performed via telephone, and surgical patients were followed-up for recurrence, metastasis and tumor size, and morphological changes. The follow-up period was up to January 2019. Of the 57 patients with duodenal lipoma, contrast-enhanced scanning was performed in 7 cases. The tumor was located in the descending duodenum in 33 cases, the ascending in 4 cases, the horizontal in 16 cases, and the bulb in 4 cases. Mean tumor size was 13.0 ± 5.8 mm. CT morphological features of the tumor were as follows: tumor shape, round, quasi-round, or oval (n = 42); long strip (n = 3); nodular (n = 2); triangular (n = 1); and irregular lobulated (n = 9). Among the 57 patients, tumor density was homogeneous in 52 cases, inhomogeneous in 4 cases, and nodular with calcification in 1 case. The tumor boundary was classified as clear and with no capsule. Diseases concomitant with the tumor were as follows: gastritis (n = 23), gastric adenocarcinoma (n = 1), and gastric lymphoma (n = 1). Esophageal disease was found in 16 cases, including reflux esophagitis (n = 12) and esophageal cancer (n = 4). There were 13 cases of gallbladder and biliary disease, including cholecystolithiasis and cholecystitis (n = 9), common bile duct disease (n = 2), colorectal cancer (n = 4), lung cancer (n = 2), duodenal carcinoma with obstruction (n = 1), and ureteral space narrowing (n = 1). CT was an effective, non-invasive method for diagnosis of duodenal lipoma. CT imaging could clearly discern location, size, shape, and nature of duodenal lipomas. Duodenal lipoma can be associated with digestive tract inflammatory diseases and tumors in different locations, and its diagnosis is potentially valuable for their prevention and treatment.


Endovascular Management of Stroke Patients with Large Vessel Occlusion and Minor Stroke Symptoms.
Endovascular mechanical thrombectomy for stroke patients with large vessel occlusion (LVO) in the anterior circulation has become the standard of care based on several major randomized clinical trials. The successful result reported by these trials constitutes what may be the largest achievement in the history of neurological sciences. However, most of these mechanical thrombectomy trials (except for the multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands, i.e., MR CLEAN and Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial, i.e., EXTEND-IA) excluded stroke patients with minor to mild stroke symptoms with National Institutes of Health Stroke Scale (NIHSS) scores of six to eight or lower. The median NIHSS score for patients who underwent acute endovascular thrombectomy was approximately 15 to 17 in all trials. To date, the evidence is lacking to support the mechanical thrombectomy in patients with acute stroke and LVO with minor to mild severity on NIHSS score. The purpose of this review was to assess the current data, safety and clinical outcomes in stroke patients with minor to mild symptoms who were treated with endovascular thrombectomy.


The subrenal capsule assay for chemosensitivity testing of tumors. A review.
The subrenal capsule assay (SRCA) as an in vivo predictive test is reviewed. The main topics include the technique, the evaluability, the reliability (both histological and clinical aspects) and the usefulness of the SRCA in fresh tumor samples.


Correlation between gene polymorphism and blood concentration of calcineurin inhibitors in renal transplant recipients: An overview of systematic reviews.
To provide an overview of systematic reviews and meta-analyses (SRs/MAs) of the correlation between genetic polymorphisms and blood concentrations of calcineurin inhibitors (CNIs) in recipients of renal transplant. Databases including Medline, EMBase, The Cochrane Library (Issue 7, 2016), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, the China Science and Technology Journal Database, and the Wan Fang Database were searched for SRs/MAs of the correlation between genetic polymorphisms and blood concentrations of CNIs in renal transplant recipients from inception to July 2016. Two reviewers independently screened the literatures and extracted data, then the AMSTAR measurement tool was used to assess the methodological quality of SRs/Mas included in the overview. Fourteen SRs/MAs met the inclusion criteria. The most commonly reported genotype was CYP3A53/3, which was strongly associated with cyclosporine A (CsA) and tacrolimus (FK506). MDR1 C3435T CC was also associated with CNI use, especially with CsA therapy. Other less commonly reported genotypes such as CYP3A41B, MDR1 C1236T CC, and MDR1 G2677T/A GG also affected the blood concentrations of CNIs. Our overview showed that polymorphisms influence the blood concentrations of CNIs, which suggests the necessity to monitor these concentrations in patients with genotypes that affect dose-adjusted trough concentrations (C0/D) or dose-adjusted peak concentrations (C2/D) to regulate the dosage for individual administration. Because of the limited number of included studies, these findings should be verified in more high-quality studies.


Measure of predictability.
Many techniques have been developed to measure the difficulty of forecasting data from an observed time series. This paper introduces a measure which we call the "forecast entropy" designed to measure the predictability of a time series. We use attractors reconstructed from the time series and the distributions in the regular and tangent spaces of the data which comprise the attractor. We then consider these distributions on different scales. We present a formula for calculating the forecast entropy. To provide a standard of predictability, we define an idealized random system whose forecast entropy will be maximal; we then use this measure to rescale the forecast entropy to lie in the range [0,1]. The time series obtained from several chaotic systems as well as from a pseudorandom system are studied using this measure. We present evidence that the forecast entropy can be used as a tool for determining optimal delays and embedding dimensions used for reconstructing better attractors. We also show that the forecast entropy of a random system has completely different characteristics from that of a deterministic one.


Achievement of cellular immunity and discordant xenogeneic tolerance in mice by porcine thymus grafts.
Specific cellular immune tolerance may be essential for successful xenotransplantation in humans. Thymectomized (ATX), T and NK cell-depleted immunocompetent mice grafted with xenogeneic fetal pig thymic and liver tissue (FP THY/LIV) result in efficient mouse thymopoiesis and peripheral repopulation of functional mouse CD4(+) T cell. Very importantly, the reconstituted mouse T cells are specifically tolerant to pig donor antigens. Studies demonstrated that porcine MHCs mediated positive and negative selection of mouse thymocytes in FP THY grafts, whereas mouse MHCs were involved in negative selection in grafts. Therefore, T cell tolerance to xenogeneic donor antigens could be induced by grafting donor thymus tissue. Xenogeneic thymic replacement might have a potential role in the reconstitution of cellular immunity in patients with AIDS or other immunodeficiencies caused by thymus dysfunction.


Fluorescent ROMP Monomers and Copolymers for Biomedical Applications.
The synthesis and characterization of a series of green, blue and red-fluorescent exo-oxanorbornene acid and imide monomers carrying nitrobenzofurazan, coumarin, and Rhodamin B, respectively, as fluorophores is presented. These monomers carry oxanorbornene as polymerizable unit, and were readily copolymerized with bioactive functional oxanorbornene monomers by ring-opening metathesis polymerization (ROMP), as demonstrated by gel permeation chromatography and NMR spectroscopy. Due to the ease of synthesis of these monomers, and their cost-effectiveness compared many to other fluorescent probes, they are useful for biomaterials applications.


Oral analgesic efficacy of suprofen compared to aspirin, aspirin plus codeine, and placebo in patients with postoperative dental pain.
The purpose of this study was to evaluate the analgesic efficacy and safety of single oral doses of suprofen 200 and 400 mg, compared with aspirin 650 plus codeine 60 mg, aspirin 650 mg, and placebo in the relief of moderate to severe pain resulting from the surgical removal of impacted third molars. 157 patients completed a randomized, double-blind, single-dose, stratified, parallel-groups trial, and were observed for at least 4 h. Based upon each of the summary efficacy measures, sum pain intensity difference (SPID), percent SPID, TOTPAR and a global evaluation, all four active treatments were approximately equally effective and all were statistically superior to placebo. In addition, suprofen at both dose levels was significantly more effective than placebo beginning at the 0.5-hour observation for mean pain intensity, whereas the two aspirin treatments were not superior to placebo until the 1-hour observation. Side effects were minimal; there was one in the suprofen 200 mg, three in the aspirin 650 mg, and one in the placebo treatment group. Thus, it appears that suprofen at 200 and 400 mg is a safe and effective oral analgesic for the relief of moderate or severe postoperative dental pain, and it is possible that compared to aspirin 650 mg and aspirin 650 mg plus codeine 60 mg, it has a more rapid onset of action.


Bisphenol A Analogues Inhibit Human and Rat 11β-Hydroxysteroid Dehydrogenase 1 Depending on Its Lipophilicity.
Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11β-HSD1 were investigated. The potencies of inhibition on human 11β-HSD1 were bisphenol H (IC50, 0.75 µM) > bisphenol G (IC50, 5.06 µM) > diallyl bisphenol A (IC50, 13.36 µM) > dimethyl bisphenol A (IC50, 30.18 µM) > bisphenol A dimethyl ether (IC50, 33.08 µM) > tetramethyl bisphenol A (>100 µM). The inhibitory strength of these chemicals on rat 11β-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 µM. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11β-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC50 values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC50 values with ΔG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11β-HSD isoforms.


Thymopentin treatment in genital warts of long duration.
The immunomodulatory effect of thymopentin as therapy in genital warts of long duration and the proliferative responses of the patient's peripheral blood mononuclear cells were investigated in this pilot study. The observations in 6 patients suggest that subcutaneous injections of thymopentin (50 mg) beneficially influence the systems of therapy-resistant genital warts. The small number of patients and controls used in the assessment of the proliferation responses allows only a descriptive analysis of the results, but definitive trends can be observed in the Con A- and PHA-induced proliferation tests. These clinical observations, the theoretical considerations, and the low rate of side effects of thymopentin reported also by other investigators all emphasize the importance of further well-controlled double-blind studies on the treatment of genital warts with thymopentin.


A gene for familial juvenile polyposis maps to chromosome 18q21.1.
Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.


Circular RNA Sirtuin1 represses pulmonary artery smooth muscle cell proliferation, migration and autophagy to ameliorate pulmonary hypertension via targeting microRNA-145-5p/protein kinase-B3 axis.
Recently, several studies have been clarified that circular RNA (circRNA) was a vital regulatory gene of pulmonary hypertension (PH). Nevertheless, the action of circRNA in PH was not yet explored. This study was to figure out the biological function and potential molecular mechanism of circSirtuin1 (SIRT1) in PH. Construction of the PH rat model and hypoxia pulmonary artery smooth muscle cells (PASMC) model was performed, and test of circSIRT1/microRNA (miR)-145-5p/protein kinase-B3 (Akt3) was conducted. The influence of the circSIRT1/miR-145-5p/Akt3 axis on the histopathology, hemodynamics with autophagy of the pulmonary artery in rats was examined. Additionally, the impact of circSIRT1/miR-145-5p/Akt3 on the proliferation, migration and apoptosis with autophagy of PASMC under hypoxic environment was also determined. The targeting of circSIRT1/miR-145-5p/Akt3 was testified. The results manifested that circSIRT1 and Akt3 were elevated in PH, while miR-145-5p was declined. Knockdown of circSIRT1 ameliorated rat PH, suppressed PASMC proliferation, migration with autophagy in hypoxic environment. CircSIRT1 competitively combined with miR-145-5p to mediate Akt3. To sum up, circSIRT1/miR-145-5p/Akt3 was supposed to perform as a prospective molecular target for the treatment of PH.


Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients.
In patients with type 1 diabetes and reduced awareness of hypoglycemia, the glycemic thresholds for activation of counterregulatory hormone and symptom responses to hypoglycemia are impaired, in part due to recurrent episodes of hypoglycemia. Islet transplantation can ameliorate occurrences of hypoglycemia in these patients. The objective of the study was to determine whether the avoidance of hypoglycemia achieved through islet transplantation results in improved glycemic thresholds for counterregulatory responses. The study was conducted at a general clinical research center. Seven islet transplant recipients, six type 1 diabetic, and eight nondiabetic control subjects participated in the study. We performed a stepped hyperinsulinemic hypoglycemic clamp and, in 12 subjects, a paired hyperinsulinemic euglycemic clamp to calculate the glycemic thresholds for and magnitude of counterregulatory responses. The glycemic thresholds for all counterregulatory hormone and symptom responses in the islet transplant group were comparable with normal and higher than in the type 1 diabetes group (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of the glucagon and epinephrine responses in the islet transplant group, although greater than in the type 1 diabetes group (P < 0.05 for both), remained less than normal (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of GH secretion in the islet transplant group was comparable with normal and greater than in the type 1 diabetes group (P < 0.05). The glycemic thresholds for activation of counterregulatory hormone and symptom responses appear normal after islet transplantation; however, the magnitudes of the glucagon and epinephrine responses remain impaired.


Proper sequence of endocrine therapies in advanced breast cancer.
Tamoxifen (TAM) is widely used as therapy in early breast cancer and first-line endocrine therapy in metastatic disease. Despite this therapy, many patients relapse and an important question is: What is the preferred sequence of endocrine therapies in metastatic breast cancer (MBC). While treatment with oophorectomy, aminoglutethimide or progestins have been a logical choice after failure to Tamoxifen recent research has extended the options for endocrine therapy of MBC. New selective aromatase inhibitors (AI) are now in clinical use. The first commercially available of these inhibitors is LENTARON. The active ingredient of LENTARON is a steroidal compound 4-OH-androstenedione: Formestane. It is presented as a depot formulation and applied as an i.m. injection of 250 mg every second week. Previous findings from phase II trials have indicated similar activity as other endocrine treatment modalities. Clinical investigations in properly conducted phase III trials have revealed that the efficacy of LENTARON matches the results which can be obtained with TAM and Megace in trials of first and second-line endocrine therapy. Fifty-four and 51% of MBC patients, respectively, did benefit from therapy with LENTARON in these phase III trials by achieving objective responses or stable disease. Moreover, similar overall survival was seen. The systemic tolerability of LENTARON is comparable to that of TAM, and LENTARON seems less systemically toxic than Megace. Local side effects occured in approximately 7% of the patients giving rise mainly to pain or inflammation at the injection site. In elderly patients, LENTARON therapy assures compliance and no interference with other oral medications has been observed. In conclusion, since the endocrine treatment modalities are comparable in terms of efficacy the optimal sequence of these treatments is based upon differences in tolerability. Patients previously treated with Tamoxifen and with a high probability of a further endocrine response could preferably be treated with a selective AI like LENTARON as second-line endocrine therapy followed by a progestin upon progression in responders.


Efficacy of Pulsed Radiofrequency to Cervical Nerve Root for Postherpetic Neuralgia in Upper Extremity.
Postherpetic neuralgia (PHN) seriously affects a patient's quality of life, and it is urgent to find a method that can effectively alleviate the PHN of the upper extremity. To observe the Efficacy of pulsed radiofrequency (PRF) to cervical nerve root for PHN in upper extremity under CT guidance. Retrospective comparative study. Shengjing Hospital of China Medical University. Fifty patients with PHN in upper extremity were enrolled in Pain Management. Patients were randomized into two groups: cervical nerve root block (A group, n = 25) and cervical nerve root PRF (B group, n = 25). At each observation time, the general characteristics, visual analog scale (VAS), quality of life scores assessment (SF-36), the total efficacy rate, dosage of antiepileptic and narcotic analgesics, and the incidence of complications were followed up. Compared with the preoperative, the postoperative VAS decreased, the physical component summary (PCS) and the mental component summary (MCS) increased in both groups (P < 0.05). The differences between group B and group A were statistically significant after 1 month, which could be maintained for 1 year (P < 0.05). The total efficacy rate of group A and group B was 52.0% and 80.0% at 1 Year, respectively. The total efficacy rate of group B was higher than that of group A (P < 0.05). The dosage of antiepileptic and narcotic analgesics in group B decreased significantly, and the decline was significant compared with group A (P < 0.05). The incidence of complications between the two groups were similar (P > 0.05). CT-guided PRF to cervical nerve root for the treatment of PHN in the upper extremity is safe and effective. PRF can replicate the location of pain, precise positioning, reduce trauma, and increased pain relief rate.


Geographical trends of PFAS in cod livers along the Norwegian coast.
The level of perfluorinated alkyl substances (PFAS) was determined in North East Arctic cod (Gadus morhua) liver samples from 15 Norwegian fjords and harbors. Five harbors in the eastern part of Norway, six harbors in the western part and four harbours in the northern part. A total of 200 samples were analyzed for 16 PFAS. Determination of PFAS were carried out by LC-MS/MS following sample clean up by solid phase extraction and ultracentrifugation. The predominating PFAS was PFOS, which was found to be higher than the level of quantification (1.5 μg kg-1 wet weight) in 72% of the samples. The highest level of PFOS found was 21.8 μg kg-1 wet weight in a sample from Kragerø in the eastern part of Norway. A significantly higher level of PFOS was found in the eastern fjords and harbors compared to fjords and harbors in the western and northern part of Norway. Within the northern fjords and harbors elevated PFOS levels were found in Narvik, which may indicate a local source there. Variations in PFOS of the cod livers thus reflect differences in levels of pollution between the areas.


Regularly alternating spin-1/2 anisotropic XY chains: the ground-state and thermodynamic properties.
Using the Jordan-Wigner transformation and continued fractions we calculate rigorously the thermodynamic quantities for the spin-1/2 transverse Ising chain with periodically varying intersite interactions and/or on-site fields. We consider in detail the properties of the chains having a period of the transverse field modulation equal to 3. The regularly alternating transverse Ising chain exhibits several quantum phase transition points, where the number of transition points for a given period of alternation strongly depends on the specific set of the Hamiltonian parameters. The critical behavior in most cases is the same as for the uniform chain. However, for certain sets of the Hamiltonian parameters the critical behavior may be changed and weak singularities in the ground-state quantities appear. Due to the regular alternation of the Hamiltonian parameters the transverse Ising chain may exhibit plateaulike steps in the zero-temperature dependence of the transverse magnetization vs transverse field and many-peak temperature profiles of the specific heat. We compare the ground-state properties of regularly alternating transverse Ising and transverse XX chains and of regularly alternating quantum and classical chains. Making use of the corresponding unitary transformations we extend the elaborated approach to the study of thermodynamics of regularly alternating spin-1/2 anisotropic XY chains without field. We use the exact expression for the ground-state energy of such a chain of period 2 to discuss how the exchange interaction anisotropy destroys the spin-Peierls dimerized phase.


Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs.
Recent investigations have suggested that anticancer therapeutics may be enhanced by co-targeting the primary anticancer target and the corresponding drug escape pathways. Whether this strategy confers statistically significant clinical advantage has not been systematically investigated. This question was probed by the evaluation of the clinical status and the multiple targets of 23 approved and 136 clinical trial multi-target anticancer drugs with particular focus on those co-targeting EGFR, HER2, Abl, VEGFR2, mTOR, PI3K, Alk, MEK, KIT, and DNA topoisomerase, and some of the 14, 7, 13, 20, 6, 5, 7, 2, 4 and 10 cancer drug escape pathways respectively. Most of the approved (73.9%) and phase III (75.0%), the majority of the Phase II (62.8%) and I (53.6%), and the minority of the discontinued (35.3%) multi-target drugs were found to co-target cancer drug escape pathways. This suggests that co-targeting anticancer targets and drug escape pathways confer significant clinical advantage and such strategy can be more extensively explored.


DENATURATION AND RENATURATION OF MALIC DEHYDROGENASE IN A CELL-FREE EXTRACT FROM A MARINE PSYCHROPHILE.
Burton, Sheril D. (Oregon State University, Corvallis), and Richard Y. Morita. Denaturation and renaturation of malic dehydrogenase in a cell-free extract from a marine psychrophile. J. Bacteriol. 86:1019-1024. 1963.-Malic dehydrogenase from a marine psychrophilic vibrio (PS 207) was found to be heat-sensitive at 30 C, the maximal growth temperature for the organism. Initial denaturation was reversible, with maximal renaturation occurring when the denatured enzyme was slowly cooled in the presence of mercaptoethanol, reduced nicotinamide adenine dinucleotide, and malate. No renaturation occurred when these compounds were added after slow cooling, or when the renaturation mixture was rapidly cooled. Mercaptoethylamine, cysteine, glutathione, or mercaptoacetic acid could not replace mercaptoethanol. The kinetics of denaturation and renaturation suggest the presence of several malic isozymes each with different heat labilities, or that these processes are occurring in several distinct steps.


[Entomophthoromycosis. Review].
A review of the published reports on entomophthoromycosis (rhynoentomophthoromycosis and basidiobolomycosis) is presented. Geographic distribution, clinical, pathologic, mycologic and therapeutic aspects are emphasized. Primary and secondary visceral involvement are discussed. Data concerning 33 Latin American cases are analysed: 21 cases of rhynoentomophthoromycosis and 11 of basidiobolomycosis. Of these cases, 84% were described in Brazil and of the seven reported cases with primary visceral involvement reported in the world literature six were from Brazil. The importance of an early diagnosis of these infections is asserted specially in view of the resulting deformities and even death.


[Treatment for locally advanced bladder cancer in elderly patients].
As the life expectancy of Japanese population has been increasing, how best to treat invasive bladder cancer in elderly patients has become a new problem. Generally standard treatment for locally advanced invasive bladder cancer is thought to be radical cystectomy, but that for elderly patients is still controversial due to frequent presence of comorbid diseases. Here, we debate the merits and demerits of radical cystectomy and bladder preservation for elderly patients with locally advanced invasive bladder cancer. First, we presented the treatment outcome of 1131 patients with invasive bladder cancer who underwent radical cystectomy in Japan, to clarify the characteristics of invasive bladder cancer of elderly patients and to determine whether age had an impact on the clinical or functional results. Furthermore, to clarify the indication of the bladder preservation for elderly patients, we reviewed the results of recent trials. Several new trials of chemoradiotherapy have shown high response rates with low local morbidity but high systemic morbidity requiring dose reductions or treatment delay. This regimen may prove to be effective for inoperable patients and may be proposed as conservative treatment for patients with complete responses to the initial course of chemoradiation. Although chemoradiation shows promise, more trials are needed to clarify the morbidity and mortality rates of chemoradiation for elderly patients.


Oncofetal fibronectins in oral carcinomas: correlation of two different types.
Different isoforms of fibronectin are derived from a single gene by alternative processing of the primary RNA transcript or by posttranslational modifications. We have previously demonstrated that an oncofetal fibronectin (FN) isoform derived by O-glycosylation is highly associated with malignancy in breast and oral tumors. Another oncofetal FN isoform containing the ED-B sequence is derived by alternative splicing, and FN containing ED-B has been found to be a stromal marker of malignancies in various tissues. Here we report a comparative study by immunohistology of the distribution of the ED-B-containing isoform and the oncofetal FN isoform derived by O-glycosylation, in oral squamous cell carcinomas, premalignant lesions, and normal oral mucosa. A selective expression of the ED-B-containing isoform was demonstrated in close relation to the invading carcinoma (38/38), whereas there was virtually no staining in submucosa underlying premalignant lesions (1/11) and normal epithelium (0/5). The ED-B-containing FN showed close co-distribution and staining pattern with the oncofetal isoform derived by O-glycosylation. These results demonstrate that accumulation of FN adjacent to oral carcinomas includes both the ED-B-containing isoform and the isoform derived by O-glycosylation. Although both the change in primary structure and glycosylation of FN create conformational and immunologically detectable changes, the functional consequences in association with invasive carcinoma are poorly understood at present. Diagnostic implications especially of borderline lesions as well as evaluation of tumor aggressiveness may, however, be important.


The impact of goal-oriented task design on neurofeedback learning for brain-computer interface control.
Neurofeedback training teaches individuals to modulate brain activity by providing real-time feedback and can be used for brain-computer interface control. The present study aimed to optimize training by maximizing engagement through goal-oriented task design. Participants were shown either a visual display or a robot, where each was manipulated using motor imagery (MI)-related electroencephalography signals. Those with the robot were instructed to quickly navigate grid spaces, as the potential for goal-oriented design to strengthen learning was central to our investigation. Both groups were hypothesized to show increased magnitude of these signals across 10 sessions, with the greatest gains being seen in those navigating the robot due to increased engagement. Participants demonstrated the predicted increase in magnitude, with no differentiation between hemispheres. Participants navigating the robot showed stronger left-hand MI increases than those with the computer display. This is likely due to success being reliant on maintaining strong MI-related signals. While older participants showed stronger signals in early sessions, this trend later reversed, suggesting greater natural proficiency but reduced flexibility. These results demonstrate capacity for modulating neurofeedback using MI over a series of training sessions, using tasks of varied design. Importantly, the more goal-oriented robot control task resulted in greater improvements.


Visualising virulence factors: Trichophyton benhamiaes subtilisins demonstrated in a guinea pig skin ex vivo model.
Dermatophytoses rank among the most frequent communicable diseases in humans, and the zoonotic transmission is increasing. The zoophilic dermatophyte Trichophyton (T.) benhamiae is nowadays one of the main causes of tinea faciei et corporis in children. However, scientific data on molecular pathomechanisms and specific virulence factors enabling this ubiquitous occurrence are scarce. To study tissue invasion and the expression of important virulence factors of T. benhamiae, isolates that were recovered from two groups of hosts (humans vs. guinea pigs (GP)) using an ex vivo skin model. After confirmation of species identity by ITS sequencing, CFU suspensions of dermatophyte isolates (n = 20) were applied to the skin infection model and cultured. Employing specific immunofluorescence staining techniques, the expression of subtilisin 3 and 6 and metallocarboxypeptidase A was analysed. The general mode of invasion was explored. Results were compared with biopsies of naturally infected GP. All isolates were successfully recovered and proliferated well after application to the infection model. Progressive invasion of hyphae through all skin structures and destruction of explants were observed with early events being comparable to natural infection. An increasing expression of the examined virulence factors towards the end of culture was noticed but no difference between the two groups of isolates. For the first time, important in vivo markers of dermatophytosis were visualised immunohistochemically in an ex vivo skin infection model and in skin biopsies of GP naturally infected with T. benhamiae. More research on the underlying pathomechanisms of dermatophyte infection is urgently needed.


Simulations of Kikuchi patterns due to thermal diffuse scattering on MgO crystals.
Inelastic scattering of fast transmission electrons from a perfect crystal is investigated using the Bloch wave theory. A comprehensive expression for the scattering of electrons is given, which includes both elastic and inelastic multiple scatterings. This expression is an extended form of Fujimoto's expression for elastic scattering (J. Phys. Soc. Japan 14:1558 (1959)). For the approximation of single inelastic scattering, the expression becomes equivalent to the formula of Rez et al. (Phil. Mag. 35: 81 (1977)). When thermal diffuse scattering (TDS) is considered using the Einstein model or the scattering factor for TDS given by Hall and Hirsch (Proc. R. Soc. A 286: 158 (1965)), Rossouw and Bursill's expression (Acta Cryst. A 41: 320 (1985)) is derived. This expression has been used in computer simulations of TDS intensity distribution (Kikuchi pattern). It is shown that the simulations for magnesium oxide (MgO) using 357 beams agree quite well with the experimental ones.