Abnormalities in the transcription of reprogramming genes related to global epigenetic events of cloned endangered felid embryos.
The present study examined transcription levels of the Oct4, DNMT1, DNMT3a, DNMT3b, HAT1 and HDAC1 genes in cloned felid embryos developing from single one-cell to blastocyst stages. IVF, cloned domestic and leopard cat embryos had low Oct4 and HAT1 levels during the early stages, but transcript expression increased at the eight-cell and blastocyst stages. In contrast, expression in the cloned marble cat embryos was low at all stages. Transcription patterns of HDAC1 were altered in cloned embryos compared with IVF embryos. Transcription levels of DNMT1 decreased markedly throughout development of both IVF and cloned embryos. In IVF embryos, DNMT3a transcripts rarely appeared in the four- to eight-cell stages, but levels increased in the morula to blastocyst stages. In contrast, in cloned embryos, DNMT3a transcript levels were high at the one- to two-cell stages, decreased during subsequent cell division and then increased again at the blastocyst stage. The IVF and cloned embryos showed similar DNMT3b transcription patterns, starting with low levels at the two-cell to morula stages and reaching a maximum at the blastocyst stage. These results suggest that the low level of Oct4 transcripts may be responsible, in part, for the failure of blastocyst production in the cloned marbled cat. However, higher transcription of the DNA methylation genes and lower transcription of the histone acetylation genes were observed in cloned compared with IVF embryos, suggesting that the felids' donor nucleus could not completely reprogramme the nuclear genome and so the re-establishment of embryonic totipotency was not achieved.


Alkyl Chain Growth on a Transition Metal Center: How Does Iron Compare to Ruthenium and Osmium?
Industrial Fischer-Tropsch processes involve the synthesis of hydrocarbons usually on metal surface catalysts. On the other hand, very few homogeneous catalysts are known to perform a Fischer-Tropsch style of reaction. In recent work, we established the catalytic properties of a diruthenium-platinum carbene complex, [(CpRu)₂(μ²-H) (μ²-NHCH₃)(μ³-C)PtCH₃(P(CH₃)₃)₂](CO)n⁺ with n=0, 2 and Cp=η⁵-C₅(CH₃)₅, and showed it to react efficiently by initial hydrogen atom transfer followed by methyl transfer to form an alkyl chain on the Ru-center. In particular, the catalytic efficiency was shown to increase after the addition of two CO molecules. As such, this system could be viewed as a potential homogeneous Fischer-Tropsch catalyst. Herein, we have engineered the catalytic center of the catalyst and investigated the reactivity of trimetal carbene complexes of the same type using iron, ruthenium and osmium at the central metal scaffold. The work shows that the reactivity should increase from diosmium to diruthenium to diiron; however, a non-linear trend is observed due to multiple factors contributing to the individual barrier heights. We identified all individual components of these reaction steps in detail and established the difference in reactivity of the various complexes.


Evaluating droplet digital PCR for the quantification of human genomic DNA: converting copies per nanoliter to nanograms nuclear DNA per microliter.
The highly multiplexed polymerase chain reaction (PCR) assays used for forensic human identification perform best when used with an accurately determined quantity of input DNA. To help ensure the reliable performance of these assays, we are developing a certified reference material (CRM) for calibrating human genomic DNA working standards. To enable sharing information over time and place, CRMs must provide accurate and stable values that are metrologically traceable to a common reference. We have shown that droplet digital PCR (ddPCR) limiting dilution end-point measurements of the concentration of DNA copies per volume of sample can be traceably linked to the International System of Units (SI). Unlike values assigned using conventional relationships between ultraviolet absorbance and DNA mass concentration, entity-based ddPCR measurements are expected to be stable over time. However, the forensic community expects DNA quantity to be stated in terms of mass concentration rather than entity concentration. The transformation can be accomplished given SI-traceable values and uncertainties for the number of nucleotide bases per human haploid genome equivalent (HHGE) and the average molar mass of a nucleotide monomer in the DNA polymer. This report presents the considerations required to establish the metrological traceability of ddPCR-based mass concentration estimates of human nuclear DNA. Graphical abstract The roots of metrological traceability for human nuclear DNA mass concentration results. Values for the factors in blue must be established experimentally. Values for the factors in red have been established from authoritative source materials. HHGE stands for "haploid human genome equivalent"; there are two HHGE per diploid human genome.


White matter hyperintensities: from medical comorbidities to bipolar disorders and back.
White matter hyperintensities (WMHs) are among the most replicated neuroimaging findings in studies of patients with bipolar disorders (BD). Despite the high rates of WMHs, their role and etiology in BD are not well understood. WMHs occur in multiple other conditions frequently co-morbid with BD. From the available studies it seems that WMHs are not a primary risk factor/endophenotype for BD. More likely, these lesions indicate the presence of medical co-morbidities with specific links to BD. Furthermore, the etiology of the WMHs in BD may represent different processes depending on age. In certain forms of BD, such as pediatric BD, WMHs may represent co-morbidity with developmental disorders. High frequency of migraine in BD and high prevalence of WMHs in migraine may suggest that a substantial proportion of WMHs in early adulthood to midlife BD subjects may be related to co-morbidity with migraine. Among elderly subjects with BD, or those with late-onset BD, WMHs are likely related to the presence of cardiovascular/metabolic disorders. With further research WMHs may enhance our knowledge about various pathological pathways involved in BD, help in decreasing the etiological heterogeneity of BD, and become useful as markers of severity or subtype of BD.


Toward the Virtual Benchmarking of Pneumatic Ventricular Assist Devices: Application of a Novel Fluid-Structure Interaction-Based Strategy to the Penn State 12 cc Device.
The pediatric use of pneumatic ventricular assist devices (VADs) as a bridge to heart transplant still suffers for short-term major complications such as bleeding and thromboembolism. Although numerical techniques are increasingly exploited to support the process of device optimization, an effective virtual benchmark is still lacking. Focusing on the 12 cc Penn State pneumatic VAD, we developed a novel fluid-structure interaction (FSI) model able to capture the device functioning, reproducing the mechanical interplay between the diaphragm, the blood chamber, and the pneumatic actuation. The FSI model included the diaphragm mechanical response from uniaxial tensile tests, realistic VAD pressure operative conditions from a dedicated mock loop system, and the behavior of VAD valves. Our FSI-based benchmark effectively captured the complexity of the diaphragm dynamics. During diastole, the initial slow diaphragm retraction in the air chamber was followed by a more rapid phase; asymmetries were noticed in the diaphragm configuration during its systolic inflation in the blood chamber. The FSI model also captured the major features of the device fluid dynamics. In particular, during diastole, a rotational wall washing pattern is promoted by the penetrating inlet jet with a low-velocity region located in the center of the device. Our numerical analysis of the 12 cc Penn State VAD points out the potential of the proposed FSI approach well resembling previous experimental evidences; if further tested and validated, it could be exploited as a virtual benchmark to deepen VAD-related complications and to support the ongoing optimization of pediatric devices.


Bacterial degradation of dissolved organic matter released by Planktothrix agardhii (Cyanobacteria).
Although Planktothrix agardhii often produces toxic blooms in eutrophic water bodies around the world, little is known about the fate of the organic matter released by these abundant Cyanobacteria. Thus, this study focused in estimating the bacterial consumption of the DOC and DON (dissolved organic carbon and dissolved organic nitrogen, respectively) produced by axenic P. agardhii cultures and identifying some of the bacterial OTUs (operational taxonomic units) involved in the process. Both P. agardhii and bacterial inocula were sampled from the eutrophic Barra Bonita Reservoir (SP, Brazil). Two distinct carbon degradation phases were observed: during the first three days, higher degradation coefficients were calculated, which were followed by a slower degradation phase. The maximum value observed for particulate bacterial carbon (POC) was 11.9 mg L-1, which consisted of 62.5% of the total available DOC, and its mineralization coefficient was 0.477 day-1 (t½ = 1.45 days). A similar pattern of degradation was observed for DON, although the coefficients were slightly different. Changes in the OTUs patterns were observed during the different steps of the degradation. The main OTUs were related to the classes Alphaproteobacteria (8 OTUs), Betaproteobacteria (2 OTUs) and Gammaproteobacteria (3 OTUs). The genus Acinetobacter was the only identified organism that occurred during the whole process. Bacterial richness was higher at the slower degradation phase, which could be related to the small amounts of DOM (dissolved organic matter) available, particularly carbon. The kinetics of the bacterial degradation of P. agardhii-originated DOM suggests minimal loss of DOM from the Barra Bonita reservoir.


Three-dimensional aspects of matrix assembly by cells in the developing cornea.
Cell-directed deposition of aligned collagen fibrils during corneal embryogenesis is poorly understood, despite the fact that it is the basis for the formation of a corneal stroma that must be transparent to visible light and biomechanically stable. Previous studies of the structural development of the specialized matrix in the cornea have been restricted to examinations of tissue sections by conventional light or electron microscopy. Here, we use volume scanning electron microscopy, with sequential removal of ultrathin surface tissue sections achieved either by ablation with a focused ion beam or by serial block face diamond knife microtomy, to examine the microanatomy of the cornea in three dimensions and in large tissue volumes. The results show that corneal keratocytes occupy a significantly greater tissue volume than was previously thought, and there is a clear orthogonality in cell and matrix organization, quantifiable by Fourier analysis. Three-dimensional reconstructions reveal actin-associated tubular cell protrusions, reminiscent of filopodia, but extending more than 30 µm into the extracellular space. The highly extended network of these membrane-bound structures mirrors the alignment of collagen bundles and emergent lamellae and, we propose, plays a fundamental role in dictating the orientation of collagen in the developing cornea.


Effects of salinity on short-term waterborne zinc uptake, accumulation and sub-lethal toxicity in the green shore crab (Carcinus maenas).
Waterborne zinc (Zn) is known to cause toxicity to freshwater animals primarily by disrupting calcium (Ca) homeostasis during acute exposure, but its effects in marine and estuarine animals are not well characterized. The present study investigated the effects of salinity on short-term Zn accumulation and sub-lethal toxicity in the euryhaline green shore crab, Carcinus maenas. The kinetic and pharmacological properties of short-term branchial Zn uptake were also examined. Green crabs (n=10) were exposed to control (no added Zn) and 50μM (3.25mgL(-1)) of waterborne Zn (∼25% of 96h LC50 in 100 seawater) for 96h at 3 different salinity regimes (100%, 60% and 20% seawater). Exposure to waterborne Zn increased tissue-specific Zn accumulation across different salinities. However, the maximum accumulation occurred in 20% seawater and no difference was recorded between 60% and 100% seawater. Gills appeared to be the primary site of Zn accumulation, since the accumulation was significantly higher in the gills relative to the hepatopancreas, haemolymph and muscle. Waterborne Zn exposure induced a slight increase in haemolymph osmolality and chloride levels irrespective of salinity. In contrast, Zn exposure elicited marked increases in both haemolymph and gill Ca levels, and these changes were more pronounced in 20% seawater relative to that in 60% or 100% seawater. An in vitro gill perfusion technique was used to examine the characteristics of short-term (1-4h) branchial Zn uptake over an exposure concentration range of 3-12μM (200-800μgL(-1)). The rate of short-term branchial Zn uptake did not change significantly after 2h, and no difference was recorded in the rate of uptake between the anterior (respiratory) and posterior (ion transporting) gills. The in vitro branchial Zn uptake occurred in a concentration-dependent manner across different salinities. However, the rate of uptake was consistently higher in 20% seawater relative to 60% or 100% seawater - similar to the trend observed with tissue Zn accumulation during in vivo exposure. The short-term branchial Zn uptake was found to be inhibited by lanthanum (a blocker of voltage-independent Ca channels), suggesting that branchial Zn uptake occurs via the Ca transporting pathways, at least in part. Overall, our findings indicate that acute exposure to waterborne Zn leads to the disruption of Zn and Ca homeostasis in green crab, and these effects are exacerbated at the lower salinity.


A phase IV observational multi-centre, open-label study on efficacy and safety of tolperisone 150 mg in patients with painful muscle spasm associated with degenerative or inflammatory diseases of the musculoskeletal system.
To generate real world clinical data on efficacy and tolerability of tolperisone 150 mg in painful muscle spasms in Indian population. Prospective, open-labelled, non-comparative, multi-centre observational, Post Marketing surveillance study conducted at 174 participating orthopaedic care centres across India Nine hundred and twenty adult patients having painful muscle spasm associated with degenerative or inflammatory conditions were enrolled who received tolperisone 150 mg thrice daily orally for 7 days. Assessment of primary efficacy (muscle spasm) was done by (0-3) Likert scale. Adverse events were monitored for safety and global efficacy assessment was done by clinicians and patients at the end of study period. Significant improvements from baseline (p < 0.0001) in scores for muscle tone, mobility & pain were seen on days 3 & 7. At the end of study there was a significant reduction in scores by more than 80% from baseline. A subgroup analysis revealed no statistical difference in the scores in patients receiving Non-Steroidal AntiInflammatory Drug (NSAID) as compared to those receiving Tolperisone alone suggesting that Tolperisone alone could be offered to patients with painful muscle spasm who are intolerant to NSAIDs or in whom NSAIDs are contraindicated. Tolperisone was well tolerated with no sedation reported by any patient during study period. The incidence of common adverse effects like nausea, gastric irritation was less than 2%. Tolperisone is a safe, effective and non sedative alternative in management of acute painful spasm conditions associated with degenerative or inflammatory diseases of the musculoskeletal system. Key Messages: Tolperisone is a skeletal muscle relaxant without concomitant sedation or withdrawal phenomena. In this open-labelled, non-comparative, prospective study tolperisone was proved to be a safe & effective alternative to skeletal muscle relaxants in the management of acute painful spasm conditions associated with degenerative or inflammatory diseases of the musculoskeletal system.


NRF2 as a regulator of cell metabolism and inflammation in cancer.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.


[Self migrating intracranial bullets].
We report herein two patients in whom bullets migrated into adjacent lateral ventricles in the brain and moved freely as a consequence of gravity. A rewiew ofthe literature suggests that spontaneous migration ofintracerebral bullets is being eased by cerebral softness, specific gravity of the bullet compared with brain tissue. ln patients undergoing the surgical removal of intracerebral or intraventricular bullets, an x-ray is recommended after final positioning.


Effect of inhibitors of enzymes involved in polyamine biosynthesis pathway on pregnancy in mouse and hamster.
The syntheses of polyamines, which play a definitive role in cell proliferation and tissue growth during early embryogenesis, are believed to be principally regulated by two enzymes: ornithine decarboxylase (ODC) and polyamine oxidase (PAO). However, when the level of enzyme ODC goes down, another enzyme known as S-adenosyl methyl decarboxylase (SAMDC) is believed to up-regulate the biosynthetic pathway. In the present study, the effects of inhibitors of enzymes SAMDC and PAO were determined in mated hamster and mouse in peri-and immediate postimplantation stages of pregnancy. It was noticed that, whereas the SAMDC inhibitor (MDL-73815) failed to arrest the pregnancy in the hamster in spite of raising the dose to 100 mg/kg, the PAO inhibitor (MDL-72527DA) was found to be 100% effective at 75 mg/kg in both species. The results confirmed the role of enzyme PAO in promoting early development of the embryo.


[Efficacy and mechanism of new resource medicinal materia Moringa oleifera leaves against hyperlipidemia].
High fat diet induced hyperlipidemia hamster model was used to explore the anti-hyperlipidemia effect of water extract of Moringa oleifera leaves( WEMOL). On this basis,the possible action mechanism was predicted by network pharmacology. Golden hamsters were randomly divided into normal diet group( NFD),high-fat diet group( HFD),simvastatin group,high dose group of WEMOL( HIWEMOL) and low dose group of WEMOL( LOWEMOL). The model was administered simultaneously for 66 days,during which the body weight changes of hamsters were recorded. At the end of the experiment,serum lipid level and serum transaminase level of golden hamsters in each group were detected,and the pathological changes of liver were observed by hematoxylin-eosin( HE) staining. The results showed that WEMOL could significantly decrease the serum total cholesterol( TC),total triglyceride( TG),low density lipoprotein cholesterol( LDL-c) levels,and reduce the lipid deposition in liver tissue,thus improving the hyperlipidemia of golden hamsters. According to the prediction of network pharmacology,219 targets of potential active components of M.oleifera leaves and 185 targets of water-soluble potential active components of M. oleifera leaves for the treatment of hyperlipidemia were obtained separately. The MCODE analysis was performed on the PPI network of 219 targets and 185 targets obtained above and got five and four clusters respectively. The signaling pathway analysis of clusters showed that among the common pathways,nonalcoholic fatty liver,insulin resistance,MAPK signaling pathway,estrogen signaling pathway,cell apoptosis and HIF-1 signaling pathway were associated with hyperlipidemia. In addition,the potential active components of M. oleifera leaves could also inhibit the metabolic inflammation of hyperlipidemia by modulating complement and coagulation cascades signaling pathway,and GSK3 B,F2,AKT1,RELA,SERPINE1 might be the key targets. The water-soluble potential active components of M. oliefera leaves could modulate lipid metabolism by modulating AMPK signaling pathway and JAK-STAT signaling pathway,with PIK3 CB,PIK3 CA,CASP3,AKT1 and BCL2 as the key targets. These results suggested that WEMOL had anti hyperlipidemia effect,and its mechanism might be related to the protein expression regulation of lipid metabolism,nonalcoholic fatty liver disease and atherosclerosis related signaling pathways.


[Contemporary view on the role of bacteriophages in evolution of nosocomial strains and prophylaxis of healthcare associated infections].
One of the actual problems of contemporary healthcare are healthcare associated infections (HAI). An important aspect of study of HAI problem is the study of evolution of hospital strains causing HAI. The knowledge accumulated to date in the field of bacteria genetics gives evidence on the significant role of phages in the mechanism of virulence obtaining by pathogenic and opportunistic microorganisms. The studies of the authors of this article show that bacteriophages may play a significant role in the formation of virulent properties in hospital conditions that in different hospitals with participation of phages form virulent and antibiotic resistant hospital strains of HAI causative agents. At the same time bacteriophages are effective means for HAI therapy and prophylaxis. Under the condition of mass and irrational use of antibiotics, HAI causative agents form multiple resistance to the existing antibacterial preparations. In this regard bacteriophages as antimicrobial agents become especially actual. To date in Russian and foreign literature considerable material has been accumulated that shows high effectiveness of bacteriophages under the conditions of rational use. The aim of this review is to evaluate contemporary achievements in the field of study of bacteriophage role in evolution of hospital strains and therapy and prophylaxis of healthcare associated infections.


Evaluation of three immunofluorescence assays for culture confirmation and typing of herpes simplex virus.
Three pairs of monoclonal antibodies, supplied in kits by Electro-Nucleonics, Inc. (ENI), The Syva Co., and Kallestad Laboratories, Inc. (KL), were evaluated for the laboratory confirmation and typing of herpes simplex virus (HSV). Of 108 coded HSV slide preparation, run in parallel with each monoclonal-antibody set, 103 were equivalent by the immunofluorescence assays. Among the five discordant isolates, three (2.8%) did not type with the KL monoclonal antibodies and two (1.9%) false-positive results occurred with the Syva typing system. All of the HSV clinical isolates tested were correctly typed with the ENI indirect immunofluorescence antigen detection system. Typing confirmation of the five discordant HSV isolates was performed by differential sensitivity to 5-bromo-2'-deoxyuridine and endonuclease cleavage analysis of the viral DNA. Use of the Syva and KL direct immunofluorescence antigen detection systems for the identification of HSV isolates is less time-consuming than use of the ENI indirect antigen detection system; however, sensitivity and specificity may be lost.


A Case of Subcutaneous Phaeohyphomycosis Associated with Leprosy.
Subcutaneous phaeohyphomycosis is an infection caused by melanized fungi and is increasingly reported among immunosuppressive patients. The most commonly cited etiologic agent is Exophiala jeanselmei, followed by Alternaria spp. We present a case of subcutaneous phaeohyphomycosis in a 48-yearold woman, with a history of lepromatous leprosy, using corticosteroid in immunosuppressive doses due to a type 2 repetitive reaction leprosy outbreak. The diagnosis was confirmed by fine-needle aspiration of the secretion, with subsequent direct mycological observations, culture and molecular analysis. The species agent was identified by culture and nucleotide sequences of ribosomal DNA as Exophiala dermatitidis.


Fokker-Planck perspective on stochastic delay systems: exact solutions and data analysis of biological systems.
Stochastic delay systems with additive noise are examined from the perspective of Fokker-Planck equations. For a linear system, the exact stationary probability density is derived by means of a delay Fokker-Planck equation. We show how to determine the delay equation of the linear system from experimental data, and corroborate a fundamental result previously obtained by Küchler and Mensch. We also propose a method to derive delay equations of nonlinear systems from experimental data. To this end, the theory of multivariate Fokker-Planck equations is used. The applicability of this method is demonstrated for stochastic models describing tracking and pointing movements of humans.


Assessing the deamination rate of a covalent aminomutase adduct by burst phase analysis.
Burst-phase kinetic analysis was used to evaluate the deamination rate of the aminated-methylidene imidazolone (NH(2)-MIO) adduct of a Taxus phenylalanine aminomutase. The kinetic parameters were interrogated by a non-natural substrate (S)-styryl-α-alanine that yielded a chromophoric styrylacrylate product upon deamination by the aminomutase. Transient inactivation of the enzyme by the NH(2)-MIO adduct intermediate resulted in an initial burst of product, with reactivation by deamination of the adduct. This study validated the rate constants of a kinetic model demonstrating that the NH(2)-MIO adduct and cinnamate intermediate are sufficiently retained to catalyze the natural α- to β-phenylalanine isomerization.


Nonspherical laser-induced cavitation bubbles.
The generation of arbitrarily shaped nonspherical laser-induced cavitation bubbles is demonstrated with a optical technique. The nonspherical bubbles are formed using laser intensity patterns shaped by a spatial light modulator using linear absorption inside a liquid gap with a thickness of 40 microm. In particular we demonstrate the dynamics of elliptic, toroidal, square, and V-shaped bubbles. The bubble dynamics is recorded with a high-speed camera at framing rates of up to 300,000 frames per second. The observed bubble evolution is compared to predictions from an axisymmetric boundary element simulation which provides good qualitative agreement. Interesting dynamic features that are observed in both the experiment and simulation include the inversion of the major and minor axis for elliptical bubbles, the rotation of the shape for square bubbles, and the formation of a unidirectional jet for V-shaped bubbles. Further we demonstrate that specific bubble shapes can either be formed directly through the intensity distribution of a single laser focus, or indirectly using secondary bubbles that either confine the central bubble or coalesce with the main bubble. The former approach provides the ability to generate in principle any complex bubble geometry.


Addressing the First 90: A Highly Effective Partner Notification Approach Reaches Previously Undiagnosed Sexual Partners in Tanzania.
To meet UNAIDS' 90-90-90 treatment goals, effective approaches to HIV testing services (HTSs) are urgently needed. In 2015, a cross-sectional study was conducted to evaluate effectiveness and feasibility of partner notification for HTS in Tanzania. Men and women newly diagnosed with HIV were enrolled as index clients, listed sexual partners, and given options to notify and link their partners to HTS. Of 653 newly diagnosed individuals, 390 index clients were enrolled, listed 438 sexual partners, of whom 249 (56.8%) were successfully referred. Of 249 partners reaching the facilities, 96% tested for HIV, 148 (61.9%) tested HIV+ (all newly diagnosed), and 104 (70.3%) of partners testing positive were enrolled into HIV care and treatment. Results showed good acceptability, feasibility and effectiveness, as evidenced by high uptake of partner notification among newly diagnosed individuals, over half of listed partners successfully referred, and a very high positivity rate among referred sexual partners.


Intestinal fibrosis is associated with lack of response to Infliximab therapy in Crohn's disease.
Overt fibrostenotic disease is a relative contraindication for anti-TNF therapy in Crohn's disease. We hypothesized that subclinical fibrosis may also contribute to an incomplete response to anti-TNF therapy before the onset of symptomatic stenosis. In a previous trial, patients with ileocecal Crohn's disease were randomized to either immediate ileocecal resection or medical treatment with Infliximab. In case of insufficient response to Infliximab, the latter underwent secondary ileocecal resection. We compared specimens from those patients undergoing immediate resection (Infliximab naïve, n = 20) to those who failed Infliximab therapy (n = 20). Infliximab naïve and Infliximab failure patients had similar severity of inflammation when assessed by CRP levels (median 14 vs 9 mg/L) and histology (Geboes-D'Haens-score, median 10 vs 11 points). On immunohistochemistry, collagen-III and fibronectin depositions were increased in patients previously exposed to Infliximab compared to patients naïve to Infliximab. On mRNA level, procollagen peptidase showed significantly more mucosal mRNA expression in Crohn's disease patients who failed Infliximab. Infliximab responders showed no increase of this marker after 4 weeks of successful Infliximab treatment. Failure to Infliximab therapy is associated with subclinical fibrosis in Crohn's disease.


Microbial colonization dynamics of the postnatal digestive tract of Bos indicus calves.
The rumen and the jejunum of calves have distinct functional roles; the former is in the storage and fermentation of feed, and the latter is in transporting digesta to the ileum. It is unknown how nutrition changes the evolution of the microbiome of these organs after birth. We sequenced and characterized the entire microbiome of the rumen and the jejunum from Bos indicus calves of the Mexican Tropics to study their dynamics at Days 0, 7, 28, and 42 after birth. Operational taxonomic units (OTUs) belonging to 185 and 222 genera from 15 phylum were observed in the organs, respectively. The most abundant OTUs were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. We observed that proteobacterial species were outcompeted after the first week of life by Bacteroidetes and Firmicutes in the rumen and the jejunum, respectively. Moreover, Prevotella species were found to predominate in the rumen (36% of total OTUs), while the jejunum microbiome is composed of small proportions of several genera. Presumably, their high relative abundance assists in specialized functions and is more likely in fermentation since they are anaerobes. In summary, the rumen and the jejunum microbiomes were outcompeted by new microbiomes in a dynamic process that begins at birth.


Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder.
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder and has a high prevalence in children. Recently, mitochondrial oxidative stress has been proposed to be associated with ASD. Besides, SIRT1/PGC-1α signaling plays an important role in combating oxidative stress. In this study, we sought to determine the role of SIRT1/PGC-1α signaling in the ASD lymphoblastoid cell lines (LCLs). In this study, the mRNA and protein expressions of SIRT1/PGC-1α axis genes were assessed in 35 children with ASD and 35 healthy controls (matched for age, gender, and IQ). An immortalized LCL was established by transforming lymphocytes with Epstein-Barr virus. Next, we used ASD LCLs and control LCLs to detect SIRT1/PGC-1α axis genes expression and oxidative damage. Finally, the effect of overexpression of PGC-1α on oxidative injury in the ASD LCLs was determined. SIRT1/PGC-1α axis genes expression was downregulated at RNA and protein levels in ASD patients and LCLs. Besides, the translocation of cytochrome c and DIABLO from mitochondria to the cytosol was found in the ASD LCLs. Moreover, the intracellular reactive oxygen species (ROS) and mitochondrial ROS and cell apoptosis were increased in the ASD LCLs. However, overexpression of PGC-1α upregulated the SIRT1/PGC-1α axis genes expression and reduced cytochrome c and DIABLO release in the ASD LCLs. Also, overexpression of PGC-1α reduced the ROS generation and cell apoptosis in the ASD LCLs. Overexpression of PGC-1α could reduce the oxidative injury in the ASD LCLs, and PGC-1α may act as a target for treatment.


Long Non-coding RNA LINC01119 Promotes Neuropathic Pain by Stabilizing BDNF Transcript.
Neuropathic pain (NP) is caused by primary injury or dysfunction of the peripheral and the central nervous system. Long non-coding RNAs were critical regulators involved in nervous system diseases, however, the precise regulatory mechanism remains unclear. This study aims to uncover the essential role of LINC01119 in NP progression and further clarify the underlying regulatory mechanism at post-transcriptional level. LINC01119 was significantly upregulated in rats of spare nerve injury (SNI) group compared to sham group. Functionally, silencing of LINC01119 significantly alleviated the neuropathic pain-induced hypersensitivity and reduced the increase in IL-6, IL-1β, and TNF-α caused by SNI. Mechanistically, Brain-derived neurotrophic factor (BDNF) was identified as the functional target of LINC01119. Besides, an RNA binding protein, ELAVL1 could directly interact with LINC01119, and this formed LINC01119- ELAVL1 complex binds to BDNF mRNA, strengthening its RNA stability and increasing the expression level of BDNF at both transcript and protein levels. Clinically, serum LINC01119 was verified as a promising diagnostic biomarker for NP patients. LINC01119 induces NP progression via binding with ELAVL1 and increasing BDNF mRNA stability and expression level. Therefore, LINC01119 may serve as a promising diagnostic marker and therapeutic target for NP treatment.


Elk velvet antler in rheumatoid arthritis: phase II trial.
The purpose of this phase II clinical trial was to examine safety of elk velvet antler taken concurrently with rheumatoid arthritis medications and to determine efficacy by dose to enable sample size estimation and dose standardization for a larger study. Forty patients with stage II rheumatoid arthritis were randomly assigned to 1 of 4 arms of 10 patients each. One group received placebo and the other 3 groups received 2, 4, or 6 capsules (215 mg) of elk velvet antler with appropriate placebos to total 6 capsules daily. All subjects continued to take their arthritis medications. Outcome variables were reported adverse events and health status. At 1 month, there were no significant differences between groups in number of adverse events or health status. The greatest improvement was in the 6 elk velvet antler group, the least was in the placebo group. Differences were not statistically significant. It was concluded that elk velvet antler can be taken safely in conjunction with a number of rheumatoid arthritis medications and should be studied further to assess efficacy.


Lack of correlation between non-labile iron parameters, total carbonyl and malondialdehyde in major thalassemia.
Thalassemia patients are at high risk of iron-induced toxicity and oxidative stress consequences. The present cross-sectional study is conducted to determine whether or not lipid peroxidation or protein oxidation is correlated with iron parameters in patients with thalassemia major. To prove this hypothesis, malondialdehyde and total carbonyl were correlated with the degree of excess iron concentration in the patients. A total of 118 Arabic Iraqi patients and 30 healthy children were participated in the present study. Results showed a significant increase (p<0.05) in serum total carbonyls, malondialdehyde and the iron indices of patients as compared with the control group. Total iron binding capacity and transferrin concentrations decreased significantly (p<0.05) in patients with thalassemia compared with the control group. The results also showed a lack of a significant correlation between each serum malondialdehyde and total carbonyl with each component of iron status. In conclusion, total carbonyls and malondialdehyde were increased in thalassemia patients indicating the vulnerability of these patients to tissue injury caused by oxidative stress. The formation of total carbonyl and malondialdehyde are independent of excess non-labile iron concentration, indicating that different mechanisms are involved in injury caused by the labile iron and in the formation of oxidation end products.


Synchronous primary endometrial and ovarian cancers: a case report.
Synchronous primary cancers of the endometrium and ovary are relatively uncommon in the general population. The patient, a 49-year-old postmenopausal Greek woman, presented with abdominal pain and a pelvic mass. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, total omentectomy, appendectomy and pelvic lymph node dissection. The histopathology revealed synchronous primary cancers of the endometrium and right ovary. She underwent postoperative chemotherapy. Thirty-nine months after surgery, she remains well without evidence of recurrence.


"Black Esophagus" or Gurvits Syndrome: A Rare Complication of Diabetic Ketoacidosis.
Acute esophageal necrosis (AEN) also known as "black esophagus" or necrotizing esophagitis is a rare syndrome characterized by a striking diffuse patchy or circumferential black appearance of the esophageal mucosa that preferentially affects the distal esophagus and terminates at the gastroesophageal junction. Only 88 patients over a span of 40 years have received this diagnosis, and the prevalence of this disease ranges from 0.001 to 0.2% of cases in literature. It more commonly affects men (4 : 1 ratio) in the sixth decade of life. It is associated with a high mortality rate, approaching 32%. We report a case of AEN presenting in the setting of diabetic ketoacidosis (DKA), affecting both the proximal and distal esophagus.


The Gender Difference in the Association between Early Onset of Drinking and Problem Drinking between the U.S. and Japan.
Using comparable survey data from the GENACIS Project, collected from representative samples of people aged 20 to 70 years old in the U.S. (n=2,598) and Japan (n=1,734), this study examined, across these two diverse societies, the gender difference in the association between the early onset of drinking and the development of drinking problems. The results of this study suggest that there does not appear to be a cross-national causal relationship between the early onset of drinking and problem drinking because of significant country and gender variations in this association and because there is no association found among Japanese females. As hypothesized, the early onset of drinking predicted problem drinking among males more strongly than among females in both countries.


Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate.
Trastuzumab emtansine (T-DM1) provides clinical benefit in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2). However, its efficacy against biliary tract cancers (BTC) has not been evaluated. In this study, the effectiveness of T-DM1 in various BTC cell lines and xenograft models with different levels of HER2 expression was investigated. HER2 expression status in xenografts and patient tissue microarrays was assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Cell-surface HER2 expression levels and cell growth inhibition in response to T-DM1 were examined in 17 BTC cell lines. The antitumor activity of T-DM1 was evaluated in four xenograft mouse models with different levels of HER2 expression. The effects of T-DM1 on HER2 signaling, antibody-dependent cell-mediated cytotoxicity (ADCC), cell cycle, and apoptosis were assessed in vitro. Cell-surface expression of HER2 was observed in both gallbladder carcinoma and cholangiocarcinoma tissues. The anti-proliferative activity of T-DM1 was higher in BTC cell lines and breast cancer cell lines with higher levels of HER2 expression. The HER2 status (IHC score|HER2-to-CEP17 ratio by FISH testing) of each BTC xenograft was 3 +|8.3 for KMCH-1, 2 +|4.7 for Mz-ChA-1, 1 +/0|1.4 for OCUG-1, and 0|1.1 for KKU-100, and T-DM1 showed antitumor activity in proportion to the HER2 status. T-DM1 inhibited HER2 signaling and induced ADCC, mitotic arrest, and apoptosis in KMCH-1 cells. T-DM1 exhibited preclinical activity in HER2-overexpressing BTC. Further evaluation in clinical studies is warranted.


Understanding patient and physician perceptions of male androgenetic alopecia treatments in Asia-Pacific and Latin America.
This survey aimed to explore patient and physician attitudes towards male androgenetic alopecia (AGA), satisfaction with currently available male AGA treatments and investigate the factors affecting treatment choice. The survey was carried out in five countries (Japan, South Korea, Taiwan, Mexico and Brazil) between November and December 2015 using a standard market research methodology. Questionnaires were completed by patients with male AGA or hair loss/thinning and practicing physicians who were responsible for prescribing AGA treatment. In total, 835 patients and 338 physicians completed the questionnaire. Overall, 37.6% of patients reported satisfaction with the treatments they had used. The highest patient satisfaction was reported for 5-alpha-reductase inhibitors (53.9% of patients satisfied). In all countries, physicians were more likely than patients to think that male AGA has a major impact on patient confidence (89.3% vs 70.4%, respectively). There was agreement by physicians and patients that male AGA patients who are involved in their treatment decisions have better outcomes. Patients who were satisfied with AGA treatments were more likely to have the level of involvement they desired in treatment decisions (69.1% of satisfied patients) than dissatisfied patients (56.4% of dissatisfied patients). This survey provides valuable insights into the attitudes of patients and physicians in Asia and Latin America about male AGA and its treatments. The survey identified areas of disconnect between physicians and patients regarding the impact of male AGA, treatment consultations and the importance of treatment attributes. It also highlights the need for physicians to spend sufficient time with patients discussing AGA treatment approaches.


Concurrent chemoradiotherapy incorporating high-dose rate brachytherapy for locally advanced cervical carcinoma: survival outcomes, patterns of failure, and prognostic factors.
This is a retrospective study evaluating the survival outcomes, patterns of failure, and prognostic factors of chemoradiotherapy incorporating high-dose rate brachytherapy in the treatment of locally advanced cervical cancer. A review of 120 consecutive patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stages IB2 to IVA cervical cancer treated with concurrent cisplatin-based chemoradiotherapy between April 1999 and January 2005. Overall (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method. The 5-year OS and DFS rates were, respectively, 65.0% (35.0% IB2, 65.7% IIA-B, 71.0% IIIA-B, and 40.0% IVA) and 57.3% (30.0% IB2, 58.2% IIA-B, 64.0% IIIA-B, and 40.0% IVA). Most patients had squamous cell carcinoma (89.2%) and belonged to FIGO stages IIB (40.8%) and IIIB (30.8%). All but 4 patients completed the planned radiotherapy regimen. There were 48 documented recurrences, of which 13 were locoregional only, 26 were distant only, and 9 were both sites. Five patients (4.2%) experienced late grade 3 to 4 gastrointestinal toxicity. On multivariate analysis, a preradiotherapy hemoglobin level of less than 10 g/dL and tumor size of 4 cm or greater or bulky on computed tomography were independently significant variables for OS, whereas a nadir hemoglobin level of less than 10 g/dL and presence of radiologically enlarged pelvic or paraaortic lymph nodes were independently significant variables for DFS. We conclude that this regimen is efficacious and feasible, but the safety profile about concurrent administration of high-dose rate brachytherapy and chemotherapy should be studied further. Finally, for cervical cancer patients selected for nonsurgical treatment, radiological assessment of tumor size and lymph node status can provide valuable prognostic information over and above FIGO staging alone.


The Case for Mass Treatment of Intestinal Helminths in Endemic Areas.
Two articles published earlier this year in the International Journal of Epidemiology [1,2] have re-ignited the debate over the World Health Organization's long-held recommendation of mass-treatment of intestinal helminths in endemic areas. In this note, we discuss the content and relevance of these articles to the policy debate, and review the broader research literature on the educational and economic impacts of deworming. We conclude that existing evidence still indicates that mass deworming is a cost-effective health investment for governments in low-income countries where worm infections are widespread.


Dopaminergic contribution to the regulation of emotional perception.
Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role in motor and cognitive function. However, the impairment of emotional processes in neurologic and psychiatric pathologies involving the dopaminergic system (Parkinson disease, schizophrenia, autism, Attention Deficit Hyperactivity Disorder, Huntington disease, frontal lobe lesions), as well as the influence that administration of dopaminergic agonists/antagonists exert on the processing of emotion, suggest a role for DA in emotional processes. Moreover, emotional processes are dependent upon a variety of structures, the majority of which form part of the limbic system and are subject to DA innervation. In reviewing the literature, the amygdala emerges as a brain structure critical for emotional processing. It may also be implicated in deficits in emotional recognition found in two major disorders where DA's implication is clear: Parkinson disease and schizophrenia. In addition, the amygdala's response to emotional tasks is likely to be altered by the administration of both agonist and antagonist dopaminergic drugs. Experimental studies reinforce the idea of a dopaminergic contribution to emotional response, as suggested by biochemical, pharmacologic, and lesion experiments. Although the implication of the dopaminergic system in emotional processing appears to be clearly documented, the contribution of specific DA receptor subtypes, or of the DA cotransmitters cholecystokinin and neurotensin, or even glutamate, is, however, still unclear. Altogether, these observations suggest that DA has, undoubtedly, a direct and/or indirect role in the full emotional process.


Methylene Blue Absorption in Sentinel Lymph Node Biopsy for Early Breast Cancer after Neoadjuvant Chemotherapy.
Chemotherapy is claimed to cause lymphatic drainage damage because of the tumor cell's apoptosis process. This event might cause decreased marker (radioactive solution and/or blue dye) absorption on sentinel lymph nodes (SLN). In this study, the researchers used methylene blue only and wished to evaluate the methylene blue absorption of the SLNB procedure on early-stage breast-cancer patients after neoadjuvant chemotherapy (NAC). The method used was the historical cohort study conducted from 2016-2019 in Indonesia. Samples were collected from 117 patients of stage I and II breast cancer with clinically negative axillary lymph nodes, who were then grouped into post-NAC and no-NAC (control group), in which SLNB procedures were conducted on the two groups by using single-method methylene blue. The results of methylene blue absorption were then analyzed by the Chi-square hypothesis test. From the total of 564 early-stage patients who were referred to surgical oncologists, 117 patients were found to meet criteria of inclusion, consisting of the control group (52 patients) and the post-NAC group (65 patents). Of 65 patients who had undergone NAC treatment and SLNB procedure, it was found that 40 patients (61.5%) showed positive blue SLN. Of 52 pre-NAC breast-cancer patients, it was found that 47 patients (90.4%) showed methylene blue absorption on SLN with the p-value of 0.000 (P<0.05, significant). The relative risk value amounted to 0.522. Post-NAC patients had a tendency of decreased absorption of methylene blue. Neoadjuvant chemotherapy can cause the decrease of methylene blue absorption on SLNB procedure.


Augmentation of pulse wave velocity precedes vascular structural changes of the aorta in rats treated with N(omega)-nitro-L-arginine methyl ester.
We examined the relationship between structural changes of the aorta and pulse wave velocity (PWV), and the effects of antihypertensive treatments on PWV in N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated rats. Twelve-week-old Wistar-Kyoto (WKY) rats were divided into the following groups, all of which received drug treatment in their drinking water: an untreated control group (n = 36), an L-NAME-treated group (0.7 mg/ml) (n = 32), an L-NAME and angiotensin converting enzyme (ACE) inhibitor (ACEI)-treated group (imidapril: 0.4 mg/ml) (n = 8), and an L-NAME and hydralazine-treated group (0.2 mg/ml) (n = 10). PWV was measured at the same blood pressure (BP) level as in the control group and the wall-to-lumen ratio of the thoracic aorta was evaluated in all groups. In the L-NAME group, PWV increased compared with the value in the control group, at the same time that BP was increasing. After the third day of treatment, PWV was higher in the L-NAME group than in the control group after adjusting BP to the control level, while the wall-to-lumen ratios were equal between the two groups. After the first week of treatment, not only the adjusted PWV, but also the wall-to-lumen ratios were greater in the L-NAME group than in the control group. With administration of antihypertensive agents, both PWV and the thickening of the aortic wall were reduced, but there was no significant difference between the ACEI and hydralazine-treated groups. In conclusion, in a rat model of nitric oxide (NO) synthesis inhibition, the increase in PWV preceded the vascular structural changes, while antihypertensive treatment reduced both changes. There was no significant difference between treatments with ACEI and hydralazine in this model.


Congenital anerythremic erythroleukemia presenting as hepatic failure.
We report an atypical case of congenital erythroleukemia in a child born with hepatosplenomegaly and abnormal liver tests. The initial peripheral blood cell count showed anemia and hyperleukocytosis with erythroblastosis that disappeared 1 week later. During the next 5 weeks, no blasts were found in the blood, and less than 5% were found on 2 successive bone marrow aspirates. The infant died of hepatic failure. The suspected diagnosis on a premortem liver biopsy was confirmed by an autopsy that showed a blastic infiltration in many organs. These cells expressed only erythroid markers glycophorin A and C. Rearrangement of the myeloid lymphoid leukemia gene was not found by fluorescence in situ hybridization. The main differential diagnoses include metabolic diseases, Langerhans histiocytosis, Pepper syndrome, transient myeloproliferative disorder, and leukemoid reactions. Although some of these can be excluded by the pathologist, others require a multidisciplinary confrontation: clinical, biologic, genetic, and pathologic examinations.


C2H2 Zinc Finger Proteins: The Largest but Poorly Explored Family of Higher Eukaryotic Transcription Factors.
The emergence of whole-genome assays has initiated numerous genome-wide studies of transcription factor localizations at genomic regulatory elements (enhancers, promoters, silencers, and insulators), as well as facilitated the uncovering of some of the key principles of chromosomal organization. However, the proteins involved in the formation and maintenance of the chromosomal architecture and the organization of regulatory domains remain insufficiently studied. This review attempts to collate the available data on the abundant but still poorly understood family of proteins with clusters of the C2H2 zinc finger domains. One of the best known proteins of this family is a well conserved protein known as CTCF, which plays a key role in the establishment of the chromosomal architecture in vertebrates. The distinctive features of C2H2 zinc finger proteins include strong and specific binding to a long and unique DNA recognition target sequence and rapid expansion within various animal taxa during evolution. The reviewed data support a proposed model according to which many of the C2H2 proteins have functions that are similar to those of the CTCF in the organization of the chromatin architecture.


Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients.
Respiratory syncytial virus infection of the upper airways may progress to fatal pneumonia in hematopoietic cell transplant recipients. The safety and efficacy of aerosolized ribavirin in preventing disease progression is unknown. In a multicenter prospective trial, hematopoietic cell transplant recipients with respiratory syncytial virus infection of the upper airways were randomized to receive ribavirin (2 g 3 times daily) or supportive care for 10 days. The primary end point was progression to radiographically proven pneumonia. Secondary end points included virologically proven respiratory syncytial virus pneumonia, viral load changes, and safety. Fourteen patients were randomized to 1 of 2 treatment arms. The trial was discontinued after 5 years because of slow accrual. Pneumonia at 1 month after randomization occurred in 1 of 9 patients who received ribavirin and in 2 of 5 patients who received supportive care (P=.51); virologically proven respiratory syncytial virus pneumonia occurred in 0 of 9 and 2 of 5 patients, respectively (P=.11). At 10 days after randomization, the average viral load decreased by 0.75 log10 copies/mL in ribavirin recipients, compared with a viral load increase of 1.26 log10 copies/mL in untreated patients (P=.07). No discontinuations of ribavirin therapy because of adverse effects occurred during 84 drug administrations. Rates of adverse events were similar in both groups. Preemptive aerosolized ribavirin treatment appeared to be safe, and trends of decreasing viral load over time were observed. However, proof of efficacy remains elusive in hematopoietic cell transplant recipients.


A rare cause of ileus: late jejunal stricture following blunt abdominal trauma.
Small intestinal stricture forming in the late phase following nonpenetrating abdominal trauma is rare cause of ileus. It has often been suggested that it is result of localized feeding deficiency on the intestinal wall related to minor trauma in the mesentery. Laparoscopy has been increasingly used for diagnosis and treatment. Diagnosis should be supported by pathological analyses in case of intestinal stenosis related to blunt abdominal traumas.


[Frequency-domain analysis methods for single ion channel currents].
The frequency domain of single channel currents is analyzed by the power distribution function (PDF) constructed by the discrete wavelet transform (DWT) and power spectral density (PSD). The result shows that the power distribution function based on DWT is an effective frequency-domain analysis method for single channel currents.


A centred, elongated "ferric tetrahedron" with an S= 15/2 spin ground state.
The reaction of anhydrous FeCl(3) with 1H-benzotriazole-1-methanol (Bta-CH(2)OH) in MeOH produces the pentanuclear complex [Fe(5)O(2)(OMe)(2)(Bta)(4)(BtaH)(MeOH)(5)Cl(5)], containing a distorted tetrahedron of four Fe ions centred on a fifth. The central Fe is antiferromagnetically coupled to the peripheral Fe ions resulting in an S= 15/2 spin ground state.


Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells.
The adaptor protein Shc contains a phosphotyrosine binding (PTB) domain and a Src homology 2 (SH2) domain, both of which are known to interact with phosphorylated tyrosines. We have shown previously that tyrosine 1148 of the activated epidermal growth factor (EGF) receptor is a major binding site for Shc while tyrosine 1173 is a secondary binding site in intact cells. In the present study, we investigated the interaction between the PTB and SH2 domains of Shc and the activated human EGF receptor. Mutant 52-kDa Shc with an arginine-to-lysine substitution at residue 175 in the PTB domain (Shc R175K) or 397 in the SH2 domain (Shc R397K) was coexpressed in Chinese hamster ovary cells overexpressing the wild-type or mutant EGF receptors that retained only one of the autophosphorylation sites at tyrosine 1148 (QM1148) or 1173 (QM1173). Shc R397K was coprecipitated with the QM1148 and QM1173 receptors, was tyrosine-phosphorylated, and associated with Grb2 and Sos. In contrast, coprecipitation of Shc R175K with the mutant receptors was barely detectable. In cells expressing the QM1173 receptor, Shc R175K was tyrosine-phosphorylated and associated with Grb2, while association of Sos was barely detectable. In cells expressing the QM1148 receptor, tyrosine phosphorylation of Shc R175K was markedly reduced. When both Shc R175K and 46-kDa Shc R397K were coexpressed with the mutant receptors, p46 Shc R397K was dominantly tyrosine-phosphorylated. In cells expressing the wild-type receptor, Shc R397K, but not Shc R175K, translocated to the membrane in an EGF-dependent manner. In addition, Ras activity stimulated by the immunoprecipitates of Shc R397K was significantly higher than that by the immunoprecipitates of Shc R175K. The present results indicate that tyrosine 1148 of the activated EGF receptor mainly interacts with the Shc PTB domain in intact cells. Tyrosine 1173 interacts with both the PTB and SH2 domains, although the interaction with the PTB domain is dominant. In addition, Shc bound to the activated EGF receptor via the PTB domain dominantly interacts with Grb2-Sos complex and plays a major role in the Ras-signaling pathway.


Aripiprazole Improves Depressive Symptoms and Immunological Response to Antiretroviral Therapy in an HIV-Infected Subject with Resistant Depression.
Aripiprazole is the first medication approved by the FDA as an add-on treatment for MDD. The impact of aripiprazole on the response to HIV is unknown. The patient we report on was diagnosed HIV-positive in 1997 and has been treated with antiretroviral therapy since then. In 2008, we diagnosed resistant major depression, hypochondria, and panic disorder. On that occasion, blood tests showed a significantly reduced CD4 count and a positive viral load. We treated this patient with aripiprazole and citalopram. Mood, somatic symptoms, and occupational functioning progressively improved. The last blood examination showed an increase in the CD4 count and a negative viral load. On the basis of the present case study and the review of the literature concerning the effects of psychotropic agents on viral replication, we suggest that the use of aripiprazole in HIV-infected subjects warrants further research.


Nonequilibrium stationary state of a truncated stochastic nonlinear Schrödinger equation: formulation and mean-field approximation.
We investigate the stationary state of a model system evolving according to a modified focusing truncated nonlinear Schrödinger equation used to describe the envelope of Langmuir waves in a plasma. We restrict the system to have a finite number of normal modes each of which is in contact with a Langevin heat bath at temperature T . Arbitrarily large realizations of the field are prevented by restricting each mode to a maximum amplitude. We consider a simple modeling of wave breaking in which each mode is set equal to zero when it reaches its maximum amplitude. Without wave breaking the stationary state is given by a Gibbs measure. With wave breaking the system attains a nonequilibrium stationary state which is the unique invariant measure of the time evolution. A mean-field analysis shows that the system exhibits a transition from a regime of low-field values at small |lambda| , to a regime of higher-field values at large |lambda| , where lambda<0 specifies the strength of the nonlinearity in the focusing case. Field values at large |lambda| are significantly smaller with wave breaking than without wave breaking.


Growth, Distribution, and Photosynthesis of Chlamydomonas Reinhardtii in 3D Hydrogels.
Engineered living materials (ELMs) are a novel class of functional materials that typically feature spatial confinement of living components within an inert polymer matrix to recreate biological functions. Understanding the growth and spatial configuration of cellular populations within a matrix is crucial to predicting and improving their responsive potential and functionality. Here, this work investigates the growth, spatial distribution, and photosynthetic productivity of eukaryotic microalga Chlamydomonas reinhardtii (C. reinhardtii) in three-dimensionally shaped hydrogels in dependence of geometry and size. The embedded C. reinhardtii cells photosynthesize and form confined cell clusters, which grow faster when located close to the ELM periphery due to favorable gas exchange and light conditions. Taking advantage of location-specific growth patterns, this work successfully designs and prints photosynthetic ELMs with increased CO2 capturing rate, featuring high surface to volume ratio. This strategy to control cell growth for higher productivity of ELMs resembles the already established adaptations found in multicellular plant leaves.


Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment.
Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new-onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood phenotypic analysis. Four blood lymphocyte populations were significantly altered in AIHn patients at diagnosis compared with healthy subjects. Levels of mucosal-associated invariant T cells (MAIT), Type 1/Type 17 helper (Th1/ Th17) cells, clusters of differentiation (CD4) T cells, and invariant natural killer T cells were decreased, whereas MAIT granzyme B+ (GrB) cells were increased. A trend toward an increase of CD8+CD161+GrB+ cells was also observed. These alterations were not restored with standard immunosuppressive treatments. In the liver of AIHn patients, CD4, forkhead box P3 (Foxp3), and MAIT cell markers were enriched in the portal tract, and CD8, CD161, and GrB markers were enriched in the hepatic lobule. During remission, the hepatic lobule was clear of infiltrating T cells, but residual CD4 and MAIT cells were found in the portal tract, where Foxp3 was decreased, as previously described. In vitro, MAIT cells were functionally altered in AIH patients. Ex vivo MAIT cell activity (GrB) was linked to severe fibrosis. Conclusion: Our work proposes a global view of the lymphocyte alterations from diagnosis to remission phase in AIH patients. The absence of blood immune homeostasis restoration and the persistence of a CD4 infiltrate in the liver under standard immunosuppression could form the basis of the high risk of relapse observed in AIH. (Hepatology Communications 2018; 00:000-000).


Highly water repellent but highly adhesive surface with segregation of poly(ethylene oxide) side chains.
Polymer surfaces were modified using methacrylate terpolymers containing both perfluoroalkyl (Rf) groups and poly(ethylene oxide) (PEO) as side chains in the same molecule. The structure and properties of the modified surfaces were evaluated using X-ray photoelectron spectroscopy and by measuring the dynamic contact angles and 90° peel strength. It was found that not only Rf groups but also PEO side chains were segregated on the surface being against the order of the surface free energy. The terpolymer modified surface is hydrophobic in air because Rf groups are predominant, but it becomes hydrophilic in water because the surface is covered with PEO side chains. This response to the environment is rapid and reversible. The modified surface showed high water repellency because of the surface Rf groups and high adhesive strength because of the side chains.


Genetics of apolipoprotein H (beta2-glycoprotein I) polymorphism in India.
Human apolipoprotein H (beta(2)-glycoprotein I, apoH, protein; APOH, gene) is a single-chain glycoprotein that has been implicated in several metabolic pathways, including lipid metabolism, coagulation and production of antiphospholipid antibodies and many disease phenotypes. The structural, molecular and genetic bases of APOH have been studied in detail but population studies, especially from the Indian subcontinent, are limited. This study seeks to enlarge our understanding of APOH genetic diversity in human populations from different regions and social groups of India. Also, we examine the level and extent of genetic variation at this locus in world populations and its utility as a population genetic marker. Blood samples from 1381 unrelated and randomly selected individuals were screened for APOH genetic polymorphism. Eleven populations from North India (Brahmins, Banias, Jat Sikhs, Khatris, Scheduled Castes, Lobanas and Rajputs), West India (Brahmin and Patels) and Central India (Brahmins and Baiga tribe) were studied for APOH polymorphism using isoelectric focusing. Allele frequencies were calculated by the gene counting method. The results were statistically evaluated using chi-square statistics for regional and ethnic variation. Genetic distances were computed on Indian populations to determine the population affinities. Correspondence analysis was used to assess ethnic variation in world populations. An interesting and wide genetic variation at this locus was observed in Indian populations. The frequency distribution of three observed alleles ranged from 0.034 to 0.091 for APOH*1, 0.852 to 0.917 for APOH*2 and 0.027 to 0.075 for APOH*3. The world's highest APOH*2 allele frequency was observed in the Patel (0.917) caste group from West India. Overall, the observed variation at this locus in Indian populations is comparable to many Caucasian populations. An analysis of world populations showed that APOH is a useful genetic marker for population and anthropological studies.


Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function.
Cardiovascular disease is the leading cause of death in people with type 2 diabetes and is linked to insulin resistance even in the absence of diabetes. Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. By contrast, mice lacking the IGF-1 receptor or the IGF-1 receptor plus one Ir allele appear normal. Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function.


Does shade improve light interception efficiency? A comparison among seedlings from shade-tolerant and -intolerant temperate deciduous tree species.
Here, we tested two hypotheses: shading increases light interception efficiency (LIE) of broadleaved tree seedlings, and shade-tolerant species exhibit larger LIEs than do shade-intolerant ones. The impact of seedling size was taken into account to detect potential size-independent effects on LIE. LIE was defined as the ratio of mean light intercepted by leaves to light intercepted by a horizontal surface of equal area. Seedlings from five species differing in shade tolerance (Acer saccharum, Betula alleghaniensis, A. pseudoplatanus, B. pendula, Fagus sylvatica) were grown under neutral shading nets providing 36, 16 and 4% of external irradiance. Seedlings (1- and 2-year-old) were three-dimensionally digitized, allowing calculation of LIE. Shading induced dramatic reduction in total leaf area, which was lowest in shade-tolerant species in all irradiance regimes. Irradiance reduced LIE through increasing leaf overlap with increasing leaf area. There was very little evidence of significant size-independent plasticity of LIE. No relationship was found between the known shade tolerance of species and LIE at equivalent size and irradiance.


Severe interstitial pneumonitis associated with the administration of taxanes.
Interstitial pneumonitis has sporadically been reported as a toxic effect of taxanes such as docetaxel and paclitaxel. This report describes 2 patients who developed interstitial pneumonitis after receiving chemotherapy including taxanes, and both cases grew serious enough to require respiratory support. The first case was a 57-year-old man with gastric cancer treated with docetaxel biweekly and S-1 for 2 weeks as adjuvant chemotherapy. After 4 courses of docetaxel, he presented acute dyspnea. The second case was a 66-year-old woman with breast cancer and postoperative pleural recurrence treated with weekly paclitaxel as fourth-line chemotherapy. She developed a dry cough, high fever, and dyspnea after 1 course of paclitaxel. In both cases, computed tomography (CT) showed extensive bilateral areas of ground-glass attenuation. They developed progressive interstitial infiltrates and respiratory failure that required mechanical ventilation. Taxane-induced interstitial pneumonitis was diagnosed to exclude other causes. From previous reports, intubation is associated with the survival of patients with taxane-induced interstitial pneumonitis. However, corticosteroid therapy was dramatically effective and resolved the interstitial pneumonitis in both our patients. Clinicians should be aware of this occasional complication during the course of chemotherapy with taxanes and initiate treatment, including respiratory support, as soon as possible.


Lentogenic field isolates of Newcastle disease virus isolated in Canada and Hungary are identical with the vaccine type used in the region.
Lentogenic field isolates of Newcastle disease virus were examined by restriction enzyme analysis of RT-PCR products generated from the matrix protein gene that discriminates between strains LaSota and B-1, the two most widely used lentogenic vaccine viruses. Isolates were derived from regions where, exclusively or predominantly, only one type of vaccine was employed. Viruses collected in Hungary for two decades were exclusively of LaSota-type while the Canadian collection predominantly included B-1, which corresponded to the vaccine types used in the regions. Isolation of vaccine type lentogenic viruses from unvaccinated flocks supports the occurrence of area spread of these lentogenic viruses.


Methotrexate improves perivascular adipose tissue/endothelial dysfunction via activation of AMPK/eNOS pathway.
Adipose and endothelial dysfunction is associated with cardiovascular disease. Perivascular adipose tissue (PVAT) directly surrounds vessels and influences vessel function via a paracrine effect, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) modulates the metabolic pathway, thus, the present study hypothesized that activation of AMPK in PVAT may regulate endothelial function in pathological settings. The present study investigated the effect of methotrexate (MTX) on adipocytokine expression in PVAT with an emphasis on the regulation of endothelial function. The effects of MTX and the mechanisms involved were investigated using a relaxation assay and western blot analysis. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the mRNA and protein expression levels. ELISA assay was used to quantify the level of TNF‑α and IL‑6. Palmitic acid (PA) stimulation induced inflammation and dysregulation of adipocytokine expression in PVAT. MTX treatment inhibited nuclear factor‑κB p65 phosphorylation and downregulated expression of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin-6, whereas adiponectin expression increased. MTX increased AMPK phosphorylation under basal and inflammatory conditions in PVAT, whereas knockdown of AMPK via small interfering RNA diminished its modulatory effect, indicating that MTX inhibits inflammation in an AMPK‑dependent manner. The present study prepared conditioned medium from PA‑stimulated PVAT to induce endothelial dysfunction and observed that pre‑treatment of PVAT with MTX effectively restored the loss of acetylcholine‑induced vasodilation and increased endothelial nitric oxide synthase phosphorylation in the rat aorta. The results of the present study demonstrated that MTX ameliorated inflammation-associated adipocytokine dysregulation and thus prevented endothelial dysfunction. These data provide further pharmacological evidence regarding the beneficial effects of MTX in cardiovascular diseases.


Carminic Acid Based Red Dye from Scale Insects Detected in Red Ruby-Crowned Kinglet Feathers by Surface-Enhanced Raman Scattering.
In most birds, red feather color is linked to diet and attributed to carotenoids contained in plants and fruits. In the red crown feathers of the Ruby-crowned Kinglet (Regulus calendula), a new biopigment was identified based on carminic acid, the main coloring compound of cochineal (Dactylopius coccus) and other scale insects. This has revealed a potential new class of carminic acid-based biopigments, not previously identified in feathers. In this research, red crown feathers of a Ruby-crowned Kinglet were analyzed by surface-enhanced Raman scattering (SERS) employing synthesized silver star-shaped colloids as the nanoplasmonic platform. Results indicated peaks at 450, 670, 1290-1312, 1355, 1410, 1570, 1620 cm-1 in the feather SERS spectra characteristic of carminic acid. SERS has proven to be an extremely sensitive, non-destructive technique for the identification of different feather biopigments, even at trace quantities and in the presence of other predominant coloring substances.


Mineral Reactions in Shale Gas Reservoirs: Barite Scale Formation from Reusing Produced Water As Hydraulic Fracturing Fluid.
Hydraulic fracturing for gas production is now ubiquitous in shale plays, but relatively little is known about shale-hydraulic fracturing fluid (HFF) reactions within the reservoir. To investigate reactions during the shut-in period of hydraulic fracturing, experiments were conducted flowing different HFFs through fractured Marcellus shale cores at reservoir temperature and pressure (66 °C, 20 MPa) for one week. Results indicate HFFs with hydrochloric acid cause substantial dissolution of carbonate minerals, as expected, increasing effective fracture volume (fracture volume + near-fracture matrix porosity) by 56-65%. HFFs with reused produced water composition cause precipitation of secondary minerals, particularly barite, decreasing effective fracture volume by 1-3%. Barite precipitation occurs despite the presence of antiscalants in experiments with and without shale contact and is driven in part by addition of dissolved sulfate from the decomposition of persulfate breakers in HFF at reservoir conditions. The overall effect of mineral changes on the reservoir has yet to be quantified, but the significant amount of barite scale formed by HFFs with reused produced water composition could reduce effective fracture volume. Further study is required to extrapolate experimental results to reservoir-scale and to explore the effect that mineral changes from HFF interaction with shale might have on gas production.


Neuroprotective effect of BDNF in young and aged 6-OHDA treated rat model of Parkinson disease.
Brain derived neurotrophic factor (BDNF) has been shown to exert trophic effects on dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in young rat. Since the degeneration of substantia nigra dopaminergic neurons that occurs in Parkinson's disease is more often than not confined to elderly individuals, it is of interest to determine whether the effects of BDNF against 6 hydroxydopamine (6-OHDA) in young rats can be extended to aged animals. 6-hydroxydopamine was stereotaxically injected into the striatum of young (3-months) and aged (24-months) rats, which were treated two hours earlier with BDNF. 6-OHDA results in almost complete destruction of substantia nigra pars compacta dopaminergic neurons. BDNF injection significantly changed apomorphine induced rotations from 132 +/- 15 to 181 +/- 10, staircase test from 73 +/- 2% to 61 +/- 3%, initiation time from 7 +/- 2 to 12 +/- 1 sec, and disengage time from 80 +/- 7 to 90 +/- 5 sec in young and aged animals, respectively. It is concluded that BDNF causes the limited behavior recovery of striatal DA systems from 6-OHDA toxicity in aged animals.


Brain dysfunctions during facial discrimination in schizophrenia: selective association to affect decoding.
Schizophrenia patients exhibit impaired facial affect perception, yet the exact nature of this impairment remains unclear. We investigated neural activity related to processing facial emotional and non-emotional information and complex images in 12 schizophrenia patients and 15 healthy controls using functional magnetic resonance imaging. All subjects performed a facial information processing task with three conditions: matching facial emotion, matching facial identity, and matching complex visual patterns. Patients and controls showed comparable behavioral performance in all task conditions. The neural activation patterns in schizophrenia patients and healthy controls were distinctly different while processing affect-related facial information but not other non-emotional facial features. During emotion matching, orbital frontal cortex and left amydala activations were found in controls but not in patients. When comparing emotion versus identity matching, controls activated the fusiform and middle temporal gyri, left superior temporal gyrus, and right inferior and middle frontal gyrus, whereas schizophrenia patients only activated the middle and inferior frontal gyri, the frontal operculi and the right insular cortex. Our findings suggest that schizophrenia patients and healthy controls may utilize different neural networks when processing facial emotional information.


Hypochlorous Acid Versus Saline Nasal Irrigation in Allergic Rhinitis: A Multicenter, Randomized, Double-Blind, Placebo-controlled Study.
Low concentrations of hypochlorous acid (HOCl) have proven antipruritic, anti-inflammatory, and antimicrobial effects without toxicity, although the mechanism has not been fully elucidated. The aim of this study was to evaluate the effectiveness of HOCl nasal irrigation to reduce allergic rhinitis (AR) symptoms compared with saline nasal irrigation. This was multicenter, randomized, double-blind, placebo-controlled study. Initially, 139 patients with perennial AR were enrolled; however, 25 did not successfully complete the study. Patients were randomly assigned to the nasal irrigation with low-concentration HOCl (n = 55) or normal saline (n = 59) treatment groups for the 4-week study period. Participants completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at every visit (baseline, Weeks 2 and 4), and Total Nasal Symptom Score (TNSS) was determined before and after nasal irrigation every morning and evening. We found that RQLQ scores significantly decreased after 4 weeks in the HOCl and placebo groups, but the decrement of the RQLQ score was similar between the 2 groups. Additionally, TNSS improved in both groups between baseline and Week 4, whereas there were no significant differences in the change of TNSS between the 2 groups. The HOCl group did not show any clinical side effects related to nasal irrigation. Allergic symptoms significantly decreased with low-concentration HOCl nasal irrigation, without significant adverse events. However, HOCl showed no additional improvement in symptoms compared with saline nasal irrigation for patients with perennial AR.


Cells, stem cells, and cancer stem cells.
The stem cell field owes a great deal to the previous work conducted by embryologists and researchers devoted to reproductive medicine. The time is coming when this emerging field will pay off in the reproductive sciences by offering new avenues of understanding gametogenesis and early embryonic development. Human embryonic stem cells are pluripotent cells that proliferate in vitro while maintaining an undifferentiated state, and they are capable of differentiating into most cell types under appropriate conditions. Embryo-friendly approaches have been developed as new methods of obtaining human embryonic stem cells without destroying the embryo. Somatic stem cells have been identified and isolated from numerous adult organs and tissues to create a multipotent and autologous source of cells with established medical indications. Cell reprogramming is now a scientific fact, and induced pluripotent cells, a new pluripotent cell type, have been generated by the overexpression of specific genes from a myriad of differentiated adult cell types. Cancer is now considered a stem cell disease. Cancer stem cells share numerous features with normal stem cells including hallmarks properties such as self-renewal and undifferentiation. Therefore, the actual focus of ovarian cancer research on the cancer stem cell model should generate efficient and personalized treatment designs to improve treatment efficiency.


Assessment of dependency levels of older people in the community and measurement of nursing workload.
This paper is a report of a study to explore the relationship between the dependency levels of older people who are part of the community nurse's caseload and the volume and nature of nursing input required. International healthcare policy has consistently emphasized the reorientation of health services from hospital to community care. It is necessary to determine ways to use nursing resources appropriately to meet service needs of an increasing older population. This quantitative study was conducted in one region of Ireland, which included a city and sparsely populated rural areas. Over a 4-week period in 2004, a volunteer sample of 44 nurses assessed all older people (1482) on their community caseload using the Community Client Need Classification System. In addition, participants recorded the amount of care time spent with each individual client by all members of the community nursing team. The vast majority of clients were seen in their own homes (85%, n = 1259). On the 5-point Community Client Need Classification System, the majority (39%, n = 571) were assessed at level 2 (low level of need) and 4% (n = 61) at level 5 (high level of need). As client need level increased, the consumption of community nursing time also increased. The tool was successful in discriminating between care needs levels of older people and may be useful in predicting the type and amount of human resources required by individuals who need community nursing services. Lack of information on demographic variables may limit the transferability of these findings.


Water quality and health in the new millennium: the role of the World Health Organization Guidelines for Drinking-Water Quality.
In this report the role of the WHO Guidelines for Drinking Water Quality in promoting safe drinking water for the world's population is briefly described. The guidelines are being revised in a third edition to emphasize an integrated approach to water quality assessment and management from source to consumer. The forthcoming guidelines will: be risk-based and quantitative, emphasize quality protection and prevention of contamination, be proactive and participatory, and address the needs of those in developing countries who have no access to piped community water supplies. The guidelines emphasize the maintenance of microbial quality to prevent waterborne infectious disease as an essential goal. In addition, they address protection from chemical toxicants and other contaminants of public health concern. The forthcoming 3rd edition of the WHO GDWQ intend to be responsive to the under-served in developing countries by inclusion of non-piped supplies and addressing practical systems for their collection, treatment and storage at household level to provide safe water. Beyond the inclusion of these and possibly additional household water collection, treatment and storage systems, what is needed is to achieve their widespread use is an education and dissemination campaign that promotes and explains them and their benefits. Such a communication and marketing campaign is best done by including as many different sectors and stakeholders as possible in the process. It will be important to acknowledge that safe water is one of essential components or needs for healthy living, along with adequate sanitation and proper nutrition. Together, these are the essential health needs to be met in the developing and the developed world. All three contribute to reduced disease and increased health, and the lack of one can degrade the beneficial impact of the others. The importance of safe water, sanitation and nutrition to human health and well-being can be stated no better than it was by United Nations Secretary General Kofi Annan in his statement on "Freedom from Want" in the Millennium Report, 03/04/00. "How can we call human beings free and equal in dignity when over a billion of them are struggling to survive on less than one dollar a day, without safe drinking water, and when half of all humanity lacks adequate sanitation? Some of us are worrying about whether the stock market will crash, or struggling to master our latest computer, while more than half our fellow men and women have much more basic worries, such as where their children's next meal is coming from."


Comparison of Surgical Parameters and Results between Curved Varus Osteotomy and Rotational Osteotomy for Osteonecrosis of the Femoral Head.
Various osteotomies have been introduced to treat osteonecrosis of the femoral head. The purpose of this study was to compare surgical parameters, postoperative limb length discrepancy, and minimum 5-year clinical and radiological results between transtrochanteric curved varus osteotomy (TCVO) and transtrochanteric rotational osteotomy (TRO) for osteonecrosis of the femoral head. From 2004 to 2009, 103 consecutive TROs (97 patients) followed by 72 consecutive TCVOs (64 patients) were performed for the treatment of osteonecrosis of the femoral head. Of these, 85 patients (91 hips) in the TRO group and 58 patients (65 hips) in the TCVO group completed minimum 5-year clinical and radiological follow-up. The Kaplan-Meier product-limit method was used to estimate survival. The TCVO group had shorter operation time (p < 0.05) and less estimated blood loss (p = 0.026). Postoperative collapse developed in 26 hips (28.6%) in the TRO group and 7 hips (10.8%) in the TCVO group (p = 0.007). Osteophyte formation was observed in 34 hips (37.4%) in the TRO group and 13 hips (20%) in the TCVO group (p = 0.020). Fifteen hips (16.5%) in the TRO group and 7 hips (10.8%) in the TCVO group underwent conversion total hip arthroplasty (THA). The survival rate at 9 years with radiographic collapse as the endpoint was 68.7% (95% confidence interval [CI], 58.1% to 79.3%) in the TRO group, and 84.7% (95% CI, 71.5% to 97.9%) in the TCVO group. With conversion to THA as the endpoint, the survival rate was 82.2% (95% CI, 73.1% to 91.3%) in the TRO group and 89.2% (95% CI, 81.7% to 96.7%) in the TCVO group. The comparison indicates that TCVO was better than TRO in terms of surgical parameters including operation time and estimated blood loss while the 9-year survival rates were similar.


Facile Synthesis of Trisubstituted Carbazoles by Acid-Catalyzed Ring-Opening Annulation of 2-Amidodihydrofurans with Indoles.
A mild and convenient synthesis of carbazoles by TfOTMS (trimethylsilyl trifluoromethanesulfonate)-catalyzed ring-opening annulation of 2-amidodihydrofurans is presented with a high degree of chemoselectivity and regioselectivity. This procedure was also scaled up to a gram-scale synthesis. The reaction could involve an iminonium intermediate through a series of C-O, C-N bond cleavages, C-C bond formations, and a 1,2-migration process.


Algal dermatitis in cichlids.
Three varieties of a popular African cichlid aquarium species, Pseudotropheus zebra, from 2 tropical fish farms in east central Florida were submitted for diagnostic evaluation because of the development of multifocal green lesions. The percentage of infected fish in these populations varied from 5 to 60%. Fish were otherwise clinically normal. Microscopic examination of fresh and fixed lesions confirmed algal dermatitis, with light invasion of several internal organs in each group. A different alga was identified from each farm. Fish from farm A were infected with Chlorochytrium spp, whereas fish from farm B were infected with Scenedesmus spp. Because of the numbers of fish involved, bath treatments to remove the algae from affected fish from farm B were attempted, with different dosages of several common algaecides including copper sulfate pentahydrate, diuron, and sodium chloride. However, none of these treatments were successful, possibly because of the location of the algae under the scales and within the dermis, and also because of the sequestering effect of the granulomatous response. To our knowledge, this is the first report of algal dermatitis in ornamental cichlids, as well as the first report of Scenedesmus spp infection in any fish.


Clinical background of patients with psoriasiform skin lesions due to tumor necrosis factor antagonist administration at a single center.
Paradoxical reaction (PR) occurs when a drug elicits a reaction contrary to what was expected. To clarify the clinical features and genetic background of individuals susceptible to PR, we analyzed the clinical course of patients in whom psoriatic eruptions worsened or newly developed during tumor necrosis factor (TNF) antagonist administration and the role of focal infections and genetic variations. Of 125 patients who received TNF antagonist therapy for psoriasis, acrodermatitis continua of Hallopeau (ACH), generalized pustular psoriasis (GPP), or palmoplantar pustular psoriasis (PPP), eight patients with PR were surveyed at our hospital Dermatology Department between 2010 and 2021. A survey was also done on six patients who received TNF antagonist therapy for Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, and hidradenitis suppurativa and were referred to our department due to PR. Additionally, Sanger sequencing analysis was performed for all exons and flanking introns of IL36RN (interleukin 36 receptor antagonist), CARD14 (caspase recruitment domain-containing protein 14), and AP1S3 (adaptor-related protein complex 1 subunit sigma 3). The clinical assessment of the 14 patients demonstrated an average age at PR onset of 48.4 years, a male : female ratio of 5:9, and a mean administration period until onset of 9.2 months. The clinical types of PR were plaque psoriasis, PPP, GPP, pustulosis, acne, ACH, hair loss, and exacerbation of arthralgia. Histopathology revealed psoriasiform dermatitis in three patients. One patient continued TNF antagonist therapy. All of the patients with psoriasis and GPP had dental infections, suggesting that focal infection may be a risk factor of the development of PR following TNF antagonist therapy. Gene analysis demonstrated CARD14 gene variants associated with RA, CD, AS, or PPP in four patients. In addition, all of the patients with ACH and PPP experienced PR, suggesting that these diseases may predispose patients to PR to TNF antagonist therapy.


Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura.
Pregnancy may precipitate acute episodes of thrombotic thrombocytopenic purpura (TTP), but pregnancy outcomes in women who have recovered from acquired TTP are not well documented. We analyzed pregnancy outcomes following recovery from TTP associated with acquired, severe ADAMTS13 deficiency (ADAMTS13 activity <10%) in women enrolled in the Oklahoma TTP-HUS Registry from 1995 to 2012. We also systematically searched for published reports on outcomes of pregnancies following recovery from TTP associated with acquired, severe ADAMTS13 deficiency. Ten women in the Oklahoma Registry had 16 subsequent pregnancies from 1999 to 2013. Two women had recurrent TTP, which occurred 9 and 29 days postpartum. Five of 16 pregnancies (31%, 95% confidence interval, 11%-59%) in 3 women were complicated by preeclampsia, a frequency greater than US population estimates (2.1%-3.2%). Thirteen (81%) pregnancies resulted in normal children. The literature search identified 382 articles. Only 6 articles reported pregnancies in women who had recovered from TTP associated with acquired, severe ADAMTS13 deficiency, describing 10 pregnancies in 8 women. TTP recurred in 6 pregnancies. With prospective complete follow-up, recurrent TTP complicating subsequent pregnancies in Oklahoma patients is uncommon, but the occurrence of preeclampsia may be increased. Most pregnancies following recovery from TTP in Oklahoma patients result in normal children.


Replication of the Self-Concept and Identity Measure (SCIM) Among a Treatment-Seeking Sample.
Identity distress occurs within a variety of psychiatric conditions. Reliable tools for assessing identity-related functioning among clinical populations are greatly needed. The Self- Concept and Identity Measure (SCIM) is a brief self-report scale designed to assess healthy and disturbed identity dimensions. This measure has been validated within normative but not treatment seeking samples. The present study used an a priori confirmatory approach to replicate the SCIM's factor structure among disadvantaged women enrolled in treatment for chemical dependence (N = 216). The original three-factor structure and item loadings generally replicated within this diagnostically diverse, significantly impaired sample. Higher SCIM scores were also associated with other problems, such as emotion dysregulation and depression. Results support the SCIM's use and scoring with clinical populations.


[Function and prognostic value of tumor suppressor gene LKB1 in human breast carcinoma].
To study the function and prognostic value of the recently identified tumor suppressor gene LKB1 in human breast cancer. Estrogen receptor-positive human breast cancer cells of MCF-7 line and estrogen receptor-negative human breast cancer cells of the lines MDA-MB-435 and MDA-MB-231 were cultured and tested for the LKB1 expression. Plasmid pcDNA4 TOPO HisMAX/LKB1 expressing LKB1 was constructed and transfected into the MDA-MB-435 cells. PCR and Western blotting were used to detect the expressions of LKB1 mRNA and protein. Flow cytometry was used to determine the cell cycle. PCR and Western blotting were used to detect the expressions of LKB1 mRNA and protein in 121 human breast cancer samples. The association with relapse free survival (RFS) and overall survival (OS) was assessed by univariate analysis (log-rank test and Kaplan-Meier method). Human breast cells of MCF-7 line expressed LKB1 and the cells of MDA-MB-435 and MDA-MB-231 lines did not. Flow cytometry showed that 40.9% of the MDA-MB-435 transfected with pcDNA4 TOPO HisMAX/LKB1 was at the G(1) stage, a proportion significantly higher than that of the control (18.3%). The expressions of cyclin D1 and cyclin E were significantly down-regulated and the expression of p21(WAF1/CIP1) was significantly up-regualed. LKB1 was lowly expressed in 43 out of the 121 cases of breast cancer (35.4%) and highly expressed in 78 cases (64.6%). Low expression of LKB1 was correlated with pathological grade (P = 0.013), cancer size (P = 0.001), status of estrogen receptor (P = 0.048), and status of lymph nodes metastasis (P = 0.003). Univariate analysis showed that low expression of LKB1 was significantly correlated with shorter RFS (P = 0.048) and low OS (P = 0.003). Reintroducing LKB1 into breast cell of the lines lacking LKB1 expression restores LKB1 activity and induces growth suppression by G(1) cell cycle block. The LKB1 mediated G(1) cell cycle arrest is caused by up-regulation of the expression of p21(WAF1/CIP1) in MDA-MB-435 breast cancer cells.