Aminoalkylaziridines as substrates and inhibitors of lysyl oxidase: specific inactivation of the enzyme by N-(5-aminopentyl)aziridine.
The reaction of lysyl oxidase was assessed with members of a series of aminoalkylaziridines in which the primary amino group and the aziridinyl nitrogen were separated by 3-7 methylene carbons. Among these, N-(5-aminopentyl)aziridine proved to be the poorest substrate by far and to inhibit the enzyme activity. Aminoalkylaziridines with chain lengths shorter or longer than five carbons did not inhibit the enzyme. The resulting inhibition was competitive with productive substrates and became irreversible with time, following pseudo first order kinetics with a KI of 0.22 mM. N-(5-aminopentyl)aziridine appears to act as a bifunctional affinity label covalently interacting with the active site of this enzyme.


[Focal nodular hyperplasia and liver cell adenoma: operation or observation?].
In a 15-year period a total of 146 patients underwent surgery for benign hepatic tumors, including 54 focal nodular hyperplasias (FNH) and 23 hepatic cell adenomas (65 hemangioma and 4 cholangioma). The medical records of these patients were retrospectively analyzed with respect to tumor-related symptoms, surgical procedures and postoperative complications. Regardless of the type of the tumor, 70% of the patients had no or only non-specific symptoms. Most frequently, surgery was indicated due to questionable dignity of the lesion (adenoma 70%, FNH 41%). In hepatic cell adenomas (HCA) also perforation or bleeding of the tumor (17%) and severe symptoms (13%) required urgent operation. In two of three cases local excision of the lesion or segmental hepatic resection were performed, whereas extended resection procedures became necessary only in 20 (FNH) to 34% (HCA). The mean duration of postoperative intensive care treatment was significantly shorter in FNH and HCA than in other benign hepatic tumors (1.0 vs. 2.0 days, p < 0.01). After resection of FNH no fatalities or significant complications were observed. In HCA morbidity was 13% without related mortality (hemangioma: 3% mortality; 11% morbidity). The elective resection of benign hepatic tumors can be achieved with very low mortality and morbidity, and usually provides longterm relief of annoying symptoms. Whenever HCA is suspected surgery should be performed, since severe symptoms and spontaneous hemorrhage (30%) are common in this tumor. Also hepatocellular carcinoma can be excluded only by histologic work-up of the operative specimen. In focal nodular hyperplasia (FNH), complications are rare and malignant transformation does not occur even when observation is employed only. Resection should be restricted to symptomatic or growing tumors with subsequent cholestasis or to cases with uncertain diagnosis.


Home-based palliative care for children--Part 2: The benefits of an established program.
Thirty-four patients have been admitted to our palliative care program since its institution in March 1986. Five were unsuitable and were withdrawn soon after admission. Of the remainder, 22 (75.9%) had central nervous system (CNS) tumors, 5 (17.2%) had myelomeningocoele, 1 (3.45%) had an arteriovenous (AV) malformation, and 1 (3.45%) had a storage disease. Twenty-five (86.2%) have since died and 17 (68%) of these have died at home. In comparison with a similar group of 30 patients studied in a feasibility study prior to the institution of our program, patients admitted to our palliative care program were hospitalized for significantly fewer days during the terminal phase of their illness (p less than 0.05) and a significantly higher proportion died at home (p less than 0.001). Following a survey of the parents of 14 children diagnosed with CNS tumors who died while under our care, we determined that the overall level of satisfaction with the program was high compared to care provided prior to admission to the program (p less than 0.01). Components of the program deemed most satisfactory were (1) being able to care for the child at home (p less than 0.01), (2) having access to a palliative care nurse (p less than 0.05), and (3) having access to a pediatric clinical pharmacologist (p less than 0.05). The most troublesome symptoms occurring in this group of patients were pain, gastrointestinal symptoms, and seizures. Most problems were adequately managed by the parents under the supervision of the team. Eighty percent of the terminal care for these patients was provided at home.(ABSTRACT TRUNCATED AT 250 WORDS)


Autocrine growth factor in defined serum-free medium of human salivary gland adenocarcinoma cell line HSG.
Human salivary gland adenocarcinoma cell line HSG secretes an epidermal growth factor (EGF)-like molecule and contains EGF receptors. Growth of HSG cells is inhibited by glucocorticoid. We have identified that the growth inhibition by glucocorticoid is induced by the reduced secretion of the EGF-like molecule and that addition of anti-human EGF antibody to the culture specifically inhibits the growth of HSG cells, suggesting that autocrine secretion is involved in the growth of HSG cells. To prove that autocrine secretion functions in glucocorticoid-regulated growth of the HSG cell line, we purified the EGF-like molecule from serum-free, defined medium conditioned by the HSG cells and examined the growth-stimulatory effect of the purified molecule. The cultivation of HSG cells in serum-free defined medium, which contains insulin (10 micrograms/ml) and transferrin (10 micrograms/ml) only as proteinaceous components, resulted in establishment of a new cell line (HSG-SF) which had different morphological features from the parental HSG cell line. HSG-SF cells were found to have basically the same responsiveness to glucocorticoid as parental HSG cells. Parental HSG cells secreted high molecular weight EGF-like molecules (Mr 46,000 and 57,000), which were recognized by specific antibody to low molecular weight human EGF (Mr 6,201). From conditioned, serum-free medium of HSG-SF cells, an EGF-like molecule (Mr 46,000) was purified by using an anti-human EGF antibody-coupled Sepharose CL-4B column. This EGF-like molecule induced a maximal increase (36%) in incorporation of [3H]thymidine into DNA of parental HSG cells as well as low molecular weight human EGF. These observations demonstrate that growth of the HSG cell line is regulated by autocrine secretion.


Familial hemiplegic migraine with irreversible brain damage.
Familial hemiplegic migraine (FHM) is an autosomal dominant syndrome characterized by recurrent episodes of varying degrees of hemiparesis associated with migraine. The aura including hemiparesis may be prolonged and in severe attacks may often be associated with confusion or coma. We describe a case of FHM whose aura was atypically prolonged and resulted in irreversible brain deficit which on magnetic resonance imaging (MRI) was suggestive of cortical hyperperfusion. A subsequent MRI showed left brain atrophy.


Eggerthella lenta Bloodstream Infections Are Associated With Increased Mortality Following Empiric Piperacillin-Tazobactam (TZP) Monotherapy: A Population-based Cohort Study.
Eggerthella lenta is a anaerobic gram-positive bacilli associated with polymicrobial intraabdominal infections. Recently, E. lenta was recognized as an important cause of anaerobic bloodstream infections (BSIs) associated with high mortality. Eggerthella lenta has been reported to have high minimal inhibitory concentrations (MICs) to piperacillin-tazobactam (TZP), a broad-spectrum antibiotic with anaerobic coverage commonly used in multiple centers for empiric treatment of abdominal sepsis. We describe a retrospective population-based analysis of invasive E. lenta infections from 2009 through 2015. A logistic regression analysis for 30-day mortality risk factors was conducted. We identified 107 E. lenta infections, 95 (89%) were BSIs, 11 (10%) skin and soft tissue infections, and 1 intraabdominal abscess. Polymicrobial infections were found in 40%; 72% of isolates were from a gastrointestinal source, most commonly appendicitis (33%) of which two-thirds were perforated. TZP MIC50 and MIC90 for E. lenta isolates were 32 μg/mL and 64 μg/mL, respectively. The overall 30-day mortality for BSI was 23% and was independently associated with empiric TZP monotherapy (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.2-16; P = .02) and intensive care unit stay (OR, 6.2; 95% CI, 1.4-27.3; P = .01). Thirty-day mortality rates were significantly influenced by the use of different TZP MIC breakpoints. Our results demonstrate the increased recognition of E. lenta as an anaerobic opportunistic pathogen and highlight the need for improved empiric antimicrobial guidelines and TZP MIC breakpoints with better correlation to clinical outcomes to guide appropriate management of invasive E. lenta infections.


Sensorimotor integration in Complex Regional Pain Syndrome: a transcranial magnetic stimulation study.
There is evidence that patients with Complex Regional Pain Syndrome (CRPS) have altered central sensorimotor processing. Sensory input can influence motor output either through indirect pathways or through direct connections from the sensory to motor cortex. The purpose of this study was to investigate sensorimotor interaction via direct connections in patients with CRPS and to compare the results with normal subjects'. Direct short-latency sensory-motor interaction was evaluated in eight patients with CRPS1 affecting a hand. Modulation of EMG responses to transcranial magnetic stimulation (TMS) induced by concomitant median nerve stimulation was measured, the so-called, short-latency afferent inhibition (SAI). Results were compared with eight normal subjects who were age and sex matched with the patients. As expected, all the normal subjects' EMG responses to TMS with median nerve stimulation were smaller than responses to TMS alone. In seven of the eight CRPS patients EMG responses to TMS were suppressed when paired with median nerve stimulation. Only one CRPS patient's results showed no suppression of EMG responses. These results suggest that the disease mechanisms of CRPS1 do not typically affect the direct neural circuit between sensory and motor cortex and that normal sensorimotor interaction is occurring via this route.


Retrospective evaluation of craniofacial growth of Japanese children with isolated cleft palate: from palatoplasty to adolescence.
The purposes of this study were to analyze the craniofacial growth in women with an isolated cleft palate, to compare their matured craniofacial form with that of women with normal occlusion, and to survey the factors that influenced the matured craniofacial morphology of the adults with cleft palate during their growth process. Eighteen women with nonsyndromic isolated cleft palate were chosen from patients who received a palatoplasty at the Kyushu University Hospital, Fukuoka, Japan. Their lateral cephalometric radiographs were taken longitudinally from palatoplasty to adolescence. Fifty women with normal occlusion were chosen as controls. From their lateral cephalographs, linear and angular variables were calculated using the x,y coordinates of 20 skeletal landmarks. Maxillary length was shorter and the nasomaxillary complex was positioned more posteriorly in relation to the anterior cranial base of the adults with isolated cleft palate, compared with the controls. The mandible was shorter and was rotated inferiorly and posteriorly. However, remarkable deviation from the average craniofacial growth pattern was not recognized from palatoplasty to adolescence. The factors that influenced the craniofacial growth in the subjects with cleft palate were the forward growth of the A point from 2 to 5 years of age, the downward growth of the Ba point, the anterior upper facial height N-Ans in puberty, and the vertical position of the point Ba at the time of palatoplasty. This study provided evidence of the growth tendency and the factors influencing the intermaxillary relationship in subjects with isolated cleft palate. These are significant for orthodontic treatment planning.


Rhodium-Catalyzed Synthesis of 2-Aroylpyrimidines via Cascade Heteropolyene Rearrangement.
A one-step synthesis of cytotoxic 2-aroylpyrimidines by the denitrogenative reaction of 1-tosyl-1,2,3-triazoles with isoxazoles under rhodium catalysis has been developed. According to the density functional theory calculations and control experiments, the disclosed reaction proceeds via the rearrangement of an oxadiazatetraene intermediate involving a cascade of intramolecular aza-Diels-Alder and retro-aza-Diels-Alder reactions. The presence of a substituent at C4 of the isoxazole is a prerequisite for the formation of the pyrimidines.


Trypsin digestion of proteins on intact immobilized pH gradient strips for surface matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis.
Isolelectric focusing (IEF) of proteins on immobilized pH gradient (IPG) strips is an integral part of two-dimensional (2D) electrophoresis-based proteomics. Proteins can be effectively analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) on the intact strip itself, leading to the creation of a virtual 2D map giving pI and MW information, bypassing the second dimension SDS-PAGE. Further, trypsin digestion of proteins on the strip can significantly aid the identification of IPG-separated proteins. However, the small size of the peptides leads to diffusion along and outside the gel matrix. In this study, we describe a simple spray-based procedure to perform 'on-strip' trypsin digestion of proteins embedded in IPG strips. Examination of intact myoglobin and its tryptic peptides shows that post-digestion diffusion of tryptic peptides is significantly minimized using this approach.


The Modified Bristol Stool Form Scale: A Reliable and Valid Tool to Score Stool Consistency in Dutch (Non)Toilet-trained Toddlers.
The aim of the study was to assess whether the modified Bristol Stool Form Scale (m-BSFS) is reliable, valid and user-friendly to use by parents, grandparents, and day childcare employees to evaluate stool consistency in toilet and nontoilet-trained toddlers in the Netherlands. Translation to Dutch and validity of the m-BSFS (scoring 32 general stool pictures) for 1 to 3 year old toddlers (n = 89) was evaluated by parents, grandparents, and day childcare employees. A subgroup of participants scored an additional 7 pictures of stools in a diaper to validate the m-BSFS for non-toilet-trained toddlers (n = 16). To determine inter-rater reliability, 2-way random effects single-rater intraclass correlation coefficient (ICC)consistency was used. Intra-rater reliability was measured by Cohen kappa (κ) by rating the same pictures in random order twice, with at least 1 week between the first and second scoring. Inter- and intra-rater reliability of the m-BSFS were above recommended minimal standards of 0.61 for the 32 general stool pictures as well as for the 7 pictures of stools in a diaper. ICCconsistency for the general stool pictures of the first and second ratings were 0.71 (n = 89) and 0.79 (n = 77), respectively, with a κ of 0.71 (n = 77). ICCconsistency for the stools in diaper pictures of the first and second ratings were 0.93 (n = 16) and 0.93 (n = 15), respectively, with a κ of 0.77 (n = 15). The m-BSFS is reliable, valid and user-friendly to use by Dutch-speaking parents, grandparents, and day childcare workers to evaluate stool consistency in both toilet- and nontoilet-trained toddlers in the Netherlands.


Biodegradation of synthetic base fluid surrogates in Gulf of Mexico sediments under simulated deep-sea conditions.
In this study, an anaerobic marine biodegradability test was adapted to study the fate of synthetic base fluid (SBF) surrogates, ethyl oleate and tetradecene, by deep-sea microorganisms. Sediment samples from hundreds of meters deep in the Gulf of Mexico were incubated at low temperatures (4 degrees C) and high hydrostatic pressure in steel vessels. Stimulation of indigenous microbial communities to SBF biodegradation was evident in the fact that the rate of removal of ethyl oleate was greater in sediments that had some previous exposure to SBF (first-order decay coefficient kof -0.22 +/- 0.02 week(-1)) compared to unexposed control sediments (first-order decay coefficient k of -0.11 +/- 0.02 week(-1)). When sulfate-linked tetradecene degradation occurred within the test period, the activity could also be modeled as a first-order decay following an initial lag phase, with an average decay coefficient of k = -0.05 +/- 0.01 week(-1). This study also revealed that the degradation of SBF surrogates by microorganisms collected from deep-sea sediments was not significantly effected by the hydrostatic incubation pressure.


Neisseria meningitidis: presentation, treatment, and prevention.
Neisseria meningitidis is a leading cause of meningitis and septicemia in children and young adults in the United States. Highly publicized outbreaks of disease caused by this organism in communities and on college campuses have resulted in a heightened public awareness of its potentially devastating effects. The rapid progression of signs and symptoms of meningococcemia necessitate early recognition and institution of appropriate therapeutic measures. Identifying contacts of index cases who are at high risk of acquiring the disease allows health care providers to institute appropriate chemoprophylaxis. During community outbreaks, health care providers play an equally important role in calming the fears of low-risk contacts and their families. Familiarity with the risks and benefits of the meningococcal vaccine allows health care providers to offer this immunization to appropriate patients.


Erythropoietic porphyria. Two cases and the results of metabolic alkalinization.
Two previously unreported cases of erythropoietic porphyria are presented. Therapeutic modalities are discussed along with the results of both short- and long-term metabolic alkalinization. Although there was a substantial increase in urinary coproporphyrin excretion during a six- to 8-day period of alkalinization, three months of alkalinization therapy resulted in no substantial depletion of porphyrin stores and both patients continued to have new skin lesions develop, indicating no clinical improvement.


Synthesis and some pharmacological properties of Z-Tyr(SO3H)-Met-Gly-Trp-Met-Asp(Phe-NH2)-OH, a 32-beta-aspartyl analogue of cholecystokinin (pancreozymin) 27-33.
The heptapeptide carbobenzoxy-L-tyrosyl(O-sulfate)-L-methionylglycyl-L-tryptophyl-L-methionyl-L- aspartyl-beta-L-phenylalanine amine (Z-32-beta-Asp-CCK-27-33) was synthesized and tested for its ability to stimulate secretion from dispersed pancreatic acini in vitro, to increase protein secretion from cat pancreas in vivo, and to cause contraction of guinea pig gallbladder in situ. In increasing amylase secretion in vitro, the Z-32-beta-Asp-CCK-27-33 was equal in efficacy with but approximatively one-third as potent as the Boc-CCK-27-33, and when tested in vivo its activity is approximately 10 Ivy dog units (Idu)/microgram. In stimulation of the contraction of the gallbladder, it showed an activity lower than 1 Idu/microgram. This analogue has more pancreozyminic activity than cholecystokin-like activity. This seems to indicate different affinities for the two receptors.


Co-doping of tellurium with bismuth enhances stability and photoluminescence quantum yield of Cs2AgInCl6 double perovskite nanocrystals.
The co-doping of double perovskites is a useful approach in terms of improving their stability and photoluminescence quantum yield. Herein, Bi3+ and Te4+ cations have been co-doped into Cs2AgInCl6 nanocrystals. Doping with Te4+ cations promotes radiative recombination of self-trapped excitons due to increased defect formation energies of silver and indium vacancies, according to experimental and theoretical results. When used in excess, the TeO2 precursor would generate residual TeO2, Te2O3Cl2, R2TeO, or all three of them, which confined undesired chlorine ions on oxygen vacancies to counteract the pull from the Cs2AgInCl6 host, resulting in improved coordination with surface oleic acid ligands. As a result, 1% Bi and 8% Te co-doped Cs2AgInCl6 nanocrystals reach a high photoluminescence quantum yield of 34% and show an improved stability, maintaining over 70% of their original emission intensity after storage for more than 1 month. These findings are important in the context of producing high-performance properly doped double perovskite nanocrystals for optoelectronic applications.


Computerized recording of the palatal rugae pattern and an evaluation of its application in forensic identification.
In circumstances where identification of an individual by fingerprint or dental record comparison is difficult, palatal rugae may be considered as an alternative source of comparative material. This article evaluates the use of palatal rugae patterns for forensic identification with an indigenously developed computer software program. Comprehensive computerized antemortem records were constructed for 250 subjects and a comparison matching process performed using both recorded and unrecorded samples. The efficiency of this computer-based identification method was then assessed. The program proved to have an average sensitivity of 0.93 and specificity of 1 and had a success rate of 92-97% in matches with digitized rugae pattern samples.


Matrix-metalloproteinase-2, -8 and -9 in serum and skin blister fluid in patients with severe sepsis.
Matrix metalloproteinases (MMPs) have various roles in inflammatory states. They seem to be able to modulate endothelial barriers and regulate the activity of chemokines and cytokines. The timely development of the levels during severe sepsis and thereafter have not been investigated. In addition it was of interest to study alterations of MMP-levels in intact skin, as the skin is the largest barrier against external pathogens and MMPs have not been studied at organ level in human sepsis. The aim of this study was to investigate the timely development of serum and skin MMP-2, -8 and -9 levels in human severe sepsis and their association with disease severity and mortality. Forty-four patients with severe sepsis and fifteen healthy controls were included in this prospective longitudinal study. The amounts of MMP-2, -8 and -9 were analyzed from serum at days 1, 4, 6, 8, and 10, and from skin suction blister fluid at days 1 and 5 from the beginning of severe sepsis. Additionally, samples from the survivors were obtained after three and six months. The levels of MMP-2 and -8 were up-regulated in severe sepsis in comparison to healthy controls in skin blister fluid and serum. Compared to the controls MMP-9 levels were lower in sepsis from the fourth day on in serum and both the first and fifth day in skin blister fluid. Active forms of MMP-2 and -9 were present only in severe sepsis. The non-survivors had higher pro- and active MMP-2 levels than the survivors in skin blister fluid samples. Furthermore, MMP-2 levels were more pronounced in blister fluid and serum samples in patients with more severe organ failures. In the survivors at 3 and 6 month follow-up the MMP levels had returned to normal. MMP-2 and -8 are elevated in serum and blister fluid in severe sepsis, implying that they may play a significant role in the pathogenesis of severe sepsis and organ dysfunctions. Active forms of MMP-2 and 9 were only present in patients with severe sepsis, and higher MMP-2 levels in skin blister and serum were associated with more severe organ dysfunctions.


Higher levels of endogenous estradiol are associated with frailty in postmenopausal women from the toledo study for healthy aging.
Adverse effects of higher endogenous estradiol (E2) levels on various clinical outcomes and on determinants of the frailty syndrome have recently been reported. However, there are no data about the potential relationship between E2 and frailty. We aimed to study the association between E2 levels and frailty among older postmenopausal women not taking hormonal therapy. We used data from the Toledo Study for Healthy Aging, a Spanish population-based cohort study. Frailty was defined according to Fried's approach. Multivariate odds ratios (OR) and 95% confidence intervals (CI) associated with E2 levels were estimated using polytomous logistic regression. E2 levels decreased significantly with age and educational level, whereas they increased with body mass index, high-sensitivity C-reactive protein (hs-CRP), and impairment in Katz activities of daily living. Higher E2 levels were associated with the prevalence of frailty among women younger than 79 yr, but not in the oldest group (p interaction = 0.047). After adjustment, OR of frailty associated with a 1 sd increase of E2 was 1.51 (95% CI, 1.04-2.20; P = 0.03). We identified an interaction between E2 and hs-CRP on the prevalence of frailty (P value = 0.042). Women with both higher E2 and hs-CRP (defined as values into the upper tertile) had an age-adjusted OR of 4.2 (95% CI, 1.7-10.5; P = 0.002), compared with women with low levels of both E2 and hs-CRP. Higher E2 levels were associated with frailty in postmenopausal women. The synergism between higher E2 and hs-CRP levels suggests the existence of physiopathological mechanisms connecting inflammation and estrogen to frailty.


Assessing the underlying structure of the United States Medical Licensing Examination Step 2 test of clinical skills using confirmatory factor analysis.
The purpose of the present study was to assess the fit of three factor analytic (FA) models with a representative set of United States Medical Licensing Examination (USMLE) Step 2 Clinical Skills (CS) cases and examinees based on substantive considerations. Checklist, patient note, communication and interpersonal skills, as well as spoken English proficiency data were collected from 387 examinees on a set of four USMLE Step 2 CS cases. The fit of skills-based, case-based, and hybrid models was assessed. Findings show that a skills-based model best accounted for performance on the set of four CS cases. Results of this study provide evidence to support the structural aspect of validity. The proficiency set used by examinees when performing on the Step 2 CS cases is consistent with the scoring rubric employed and the blueprint used in form assembly. These findings will be discussed in light of past research in this area.


IRC3 Regulates Mitochondrial Translation in Response to Metabolic Cues in Saccharomyces cerevisiae.
Mitochondrial oxidative phosphorylation (OXPHOS) enzymes have a dual genetic origin. Mechanisms regulating the expression of nucleus-encoded OXPHOS subunits in response to metabolic cues (glucose versus glycerol) are well understood, while the regulation of mitochondrially encoded OXPHOS subunits is poorly defined. Here, we show that IRC3, a DEAD/H box helicase gene, previously implicated in mitochondrial DNA maintenance, is central to integrating metabolic cues with mitochondrial translation. Irc3 associates with mitochondrial small ribosomal subunits in cells consistent with its role in regulating translation elongation based on the Arg8m reporter system. IRC3-deleted cells retained mitochondrial DNA despite a growth defect on glycerol plates. Glucose-grown Δirc3ρ+ and irc3 temperature-sensitive cells at 37°C have reduced translation rates from the majority of mRNAs. In contrast, when galactose was the carbon source, a reduction in mitochondrial translation was observed predominantly from Cox1 mRNA in Δirc3ρ+ cells but no defect was observed in irc3 temperature-sensitive cells, at 37°C. In support of a model whereby IRC3 responds to metabolic cues to regulate mitochondrial translation, Δirc3 suppressor strains isolated for restoration of growth on glycerol medium restore mitochondrial protein synthesis differentially in the presence of glucose versus glycerol.


Gradual extinction reduces reinstatement.
The current study investigated whether gradually reducing the frequency of aversive stimuli during extinction can prevent the return of fear. Thirty-one participants of a three-stage procedure (acquisition, extinction and a reinstatement test on day 2) were randomly assigned to a standard extinction (SE) and gradual extinction (GE) procedure. The two groups differed only in the extinction procedure. While the SE group ran through a regular extinction process without any negative events, the frequency of the aversive stimuli during the extinction phase was gradually reduced for the GE group. The unconditioned stimulus (US) was an air blast (5 bar, 10 ms). A spider and a scorpion were used as conditioned stimuli (CS). The outcome variables were contingency ratings and physiological measures (skin conductance response, SCR and startle response). There were no differences found between the two groups for the acquisition and extinction phases concerning contingency ratings, SCR, or startle response. GE compared to SE significantly reduced the return of fear in the reinstatement test for the startle response but not for SCR or contingency ratings. This study was successful in translating the findings in rodent to humans. The results suggest that the GE process is suitable for increasing the efficacy of fear extinction.


Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies.
In mammals, nonsense-mediated mRNA decay (NMD) is a quality-control mechanism that degrades mRNA harboring a premature termination codon to prevent the synthesis of truncated proteins. To gain insight into the NMD mechanism, we identified NMD inhibitor 1 (NMDI 1) as a small molecule inhibitor of the NMD pathway. We characterized the mode of action of this compound and demonstrated that it acts upstream of hUPF1. NMDI 1 induced the loss of interactions between hSMG5 and hUPF1 and the stabilization of hyperphosphorylated isoforms of hUPF1. Incubation of cells with NMDI 1 allowed us to demonstrate that NMD factors and mRNAs subject to NMD transit through processing bodies (P-bodies), as is the case in yeast. The results suggest a model in which mRNA and NMD factors are sequentially recruited to P-bodies.


Salvage Gamma Knife Radiosurgery after failed management of bilateral trigeminal neuralgia.
The incidence of bilateral trigeminal neuralgia (TN) is 1-6% of total number of TN cases. Gamma Knife Radiosurgery (GKRS) is effective in treating unilateral TN; however, outcomes of bilateral TN treated by GKRS have not been well evaluated. The purpose of this study is to evaluate the long-term GKRS outcomes of bilateral TN at our institution and compare with our published treatment outcomes of unilateral TN. Between 2000 and 2006, eight patients with bilateral TN were treated with GKRS. Data available on seven patients were collected. Facial pain outcomes were defined using the Barrow Neurological Institute pain intensity scale. Outcomes and toxicities were compared to published outcomes of unilateral TN patients treated with GKRS at our institution. The incidence of bilateral TN in our series is 2.3%. Treatment outcomes were excellent in 5/14, good in 1/14, and poor in 8/14. Median follow-up time was 58 months. Median time-to-failure was 38 months. Pain control rate was 80% at 12 months and 65% at 36 months. Bothersome side effects were seen in 4/14 nerves treated. Compared with our long-term unilateral TN cohort, there was no statistically significant difference in outcome, time-to-failure, or rate of toxicity. Bilateral TN is rare, and effective treatment is crucial to improve the quality of life of those afflicted. Salvage GKRS is a reasonable treatment modality for individuals with bilateral TN.


Threats to bioethical principles in medical practice in Brazil: new medical ethics code period.
We aimed to outline the profile of medical professionals in Brazil who have violated the deontological norms set forth in the ethics code of the profession, and whose cases were judged by the higher tribunal for medical ethics between 2010 and 2016. This survey was conducted using a database formed from professional ethics cases extracted from the plenary of the medical ethics tribunal of the Federal Council of Medicine. These were disciplinary ethics cases that were judged at appeal level between 2010 and 2016. Most of these professionals were male (88.5%) and their mean age was 59.9 years (SD=11.62) on the date of judgment of their appeals, ranging from 28 to 95 years. Most of them were based in the southeastern region of Brazil (50.89%). Articles 1 and 18 of the medical ethics code were the rules most frequently violated. The sentence given most often was the cancellation of their professional license (37.6%) and the acts most often sentenced involved malpractice, imprudence, and negligence (18.49%). It is acknowledged that concern for the principles of bioethics was present in the appeal decisions made by the plenary of the medical ethics tribunal of the Federal Council of Medicine.


[Diagnosis and therapy of iron overload with desferrioxamine].
In polytransfused patients the diagnostics of the iron overload belongs to the strategic programme of the treatment. It is particularly referred to the value of the desferal test. In the therapy of the transfusion haemosiderosis desferrioxamine is the remedy of choice. Its at present most favourable form of application is the subcutaneous infusion by means of the infusion group. A success of the treatment is only to be guaranteed, when the therapy is consequently performed over years under balancing the iron supply and excretion.


Synergistic effects of eukaryotic co-expression plasmid-based STAT3-specific siRNA and LKB1 on ovarian cancer in vitro and in vivo.
The signal transducer and activator of transcription 3 (STAT3) are ideal targets for ovarian cancer. Previous studies showed that downregulation of STAT3 using specific short hairpin RNAs (shRNA) can significantly reduce ovarian tumor growth. However, RNA interference does not fully ablate target gene expression due to idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of STAT3-specific shRNA, we employed a combinatorial expression of STAT3-specific shRNA and liver kinase B1 (LKB1), a tumor suppressor. Thus, the LKB1 coding sequences and STAT3-specific shRNAs were constructed in a eukaryotic co-expression plasmid pCDNA3.1, and then transfected into ovarian cancer cells to evaluate the synergistic effects of this combination on anticancer activity and explore the relevant molecular mechanisms. Co-expression of STAT3‑specific siRNA and LKB1 (pSi-STAT3-LKB1) synergistically inhibited ovarian cancer cell growth, invasion and migration, induced cell apoptosis and arrested the cell cycle in vitro when compared with monotherapy. The results showed that the co-expression of plasmid pSi-STAT3-LKB1 inserted subcutaneously into ovarian tumor xenograft resulted in more significant inhibition of tumor growth. Further study showed that the synergistic anti-ovarian cancer effects of the co-expression of STAT3-specific siRNA and LKB1 may be associated with the upregulation of p-p53, p21 and downregulation of survivin, BCL-2 and cyclin D1. Results of the present study suggested that combined therapy with eukaryotic co-expression of the plasmid‑carrying STAT3-specific siRNA and LKB1 is a novel and efficient treatment strategy for human ovarian cancer.


A journey to continence: a case study of overactive bladder syndrome.
Overactive bladder is a problem that many women experience and suffer with in silence for years. This is a case study about one such woman. Anna had problems with incontinence for more than five years when she sought treatment. This article presents the story of her journey and perseverance to achieve control of her bladder.


[Prevalence of nutritional risks, malnutrition and application of nutritional support rates at one Chongqing teaching hospital].
To prospectively explore the prevalence of nutritional risks and undernutrition, obesity and the application of nutritional support in First Affiliated Hospital of Chongqing Medical University and compare the data with those of big hospitals in Beijing. A total of 2255 inpatients from the department of gastroenterology, gastrointestinal surgery, neurology and respiratory medicine at our hospital were consecutively recruited from June to October 2011. Nutritional Risk Screening 2002 (NRS2002) was performed at 24 h post-admission. And nutritional support was examined during the period of hospitalization. Among them, 2166 patients (96.1%) received NRS2002. The overall prevalence of nutritional risk was 29.5% (638/2166), undernutrition 12.2% (265/2166) and the incidence of obesity 2.4% (52/2166). For the patients at nutritional risks, only 9.2% (59/638) of them received nutrition support. The nutrition support of gastrointestinal surgery department was higher than Beijing, and that of neurology department was lower than Beijing. For those not at nutritional risks, 1.0% (16/1528) received nutritional support. And that of 4 department were all lower than Beijing (all P < 0.01). The nutritional risk patients on nutritional support rates is lower at First Affiliated Hospital of Chongqing Medical University and excessive use of parenteral nutrition support seems routine. The Chinese Society for Parenteral and Enteral Nutrition (CSPEN) guidelines of rational nutrition support should be vigorously promoted.


Pharmacokinetics of artesunate following oral and rectal administration in healthy Sudanese volunteers.
The aims of this study were to determine the pharmacokinetic parameters of a single dose of 200 mg oral and rectal artesunate in healthy volunteers, and to suggest a rational dosage regimen for rectal administration. The study design was a randomized open cross-over study of 12 healthy volunteers; the analytical method used was a reversed phase high performance liquid chromatography with post column derivatization and subsequent ultraviolet detection. Pharmacokinetic parameters were derived from the main metabolite alpha-dihydroartemisinin data due to the rapid disappearance of artesunate from the plasma. Dihydroartemisinin following oral administration of artesunate had a significantly higher AUC(0-infinity) (P<0.05 95% confidence interval (CI) -1168.73, -667.61 ng x h/mL(-1)) and Cmax (P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)), and had shorter tmax (P<0.05; 95% CI -0.97, -0.10 h) than that following rectal artesunate. There was no statistically significant difference in the elimination half-life between both routes of administration (P>0.05; 95% CI -0.14, 0.53 h). The relative bioavailability of rectal artesunate was [mean (coefficient of variation %) 54.9 (24.8%) %]. On the basis of these data an 8 hourly dosing regimen per day with rectal artesunate is proposed.


[Functional voiding disorders: rehabilitation of children with urge syndrome].
Urge syndrome is a condition associated with functional voiding disorders. Urological symptoms (urgency, frequency and incontinence) are manifestations of uninhibited detrusor contractions. The goal of rehabilitation programs is to develop voluntary bladder control, to improve urologic symptoms and to increase bladder capacity. Bladder training, strategies to suppress urgency, electrical stimulations such are anogenital, transcutaneous and percutaneous electrical nerve stimulations have been used in the treatment.


Is the incidence of malaria decreasing in endemic area of Turkey?
Much international business and tourism travels occur, as well as the deployment of soldiers to other places. The aim of this study was both to determine incidence of malaria in the military hospital, Diyarbakir, southeast region of Turkey, and to point out the incidence of this disease. During the study period (1997-2004), 609 cases were found in a military hospital, which is in an endemic area for vivax malaria. This article review trends in current malaria status as well as possible factors for the decreasing prevalence throughout the study period.


Preliminary assessment of intrahemispheric QEEG measures in bipolar mood disorders.
This study assessed the quantitative electroenchephalographic (QEEG) absolute power and coherence differences between a group of patients with bipolar I mood disorder (BMD I) and a group of patients with schizophrenia. We also examined the correlation between QEEG measures and family history of BMD. Using the National Institutes of Mental Health (NIMH) Global Rating Scale, we rated 18 adult inpatients with a DSM-III-R diagnosis of BMD I for the severity of the current episode. We also collected data on the family history of the illness. This group was then matched for age, sex, and handedness with an equal number of inpatients with a DSM-III-R diagnosis of schizophrenia. QEEG absolute power and coherence was calculated for the alpha bandwidth (8.0 to 12.0 Hz), assessed at 18 pairs of electrodes in both hemispheres during resting, eyes-closed condition in all the patients. The patients with schizophrenia showed significantly higher coherence (P = 0.047) at 6 pairs of electrodes on the right side. The group with BMD showed significantly higher power (P = 0.042) at 2 pairs of electrodes on the right side. Correlational analysis showed that QEEG measures were significantly correlated (P = 0.01) with positive family history of BMD. These findings suggest that the patients with BMD are more disorganized in the right anterior hemisphere and that there is a significant positive correlation between the QEEG measures and the presence of family history of BMD. Further studies in a larger sample are required to confirm these preliminary findings.


Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue.
Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 ± 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss.


Advanced nanocarriers based on heparin and its derivatives for cancer management.
To obtain a satisfying anticancer effect, rationally designed nanocarriers are intensively studied. In this field, heparin and its derivatives have been widely attempted recently as potential component of nanocarriers due to their unique biological and physiochemical features, especially the anticancer activity. This review focuses on state-of-the-art nanocarriers with heparin/heparin derivatives as backbone or coating material. At the beginning, the unique advantages of heparin used in cancer nanotechnology are discussed. After that, different strategies of heparin chemical modification are reviewed, laying the foundation of developing various nanocarriers. Then a systematic summary of diverse nanoparticles with heparin as component is exhibited, involving heparin-drug conjugate, polymeric nanoparticles, nanogels, polyelectrolyte complex nanoparticles, and heparin-coated organic and inorganic nanoparticles. The application of these nanoparticles in various novel cancer therapy (containing targeted therapy, magnetic therapy, photodynamic therapy, and gene therapy) will be highlighted. Finally, future challenges and opportunities of heparin-based biomaterials in cancer nanotechnology are discussed.


Transverse relaxation in rat optic nerve.
In vitro investigations were performed to study the proton T(2) relaxation spectrum of rat optic nerve. Studies in which the nerve was incubated in a D(2)O-based solution revealed that >98% of the spectrum originated from the water protons. The spectrum was found to consist of three components having relaxation times and sizes similar to those reported in the literature for peripheral nerve. Procedures were taken to confirm the existence of a third optic nerve component and that it was not an artifact of the long-lived water protons of the in vitro incubation solution. Evidence using paramagnetic agents in the incubation solution, which removed the two longest-lived nerve components from the spectrum, revealed the existence of a small fourth component (<10% of total) having a T(2) relaxation time similar to that of the intermediate-lived nerve component. Bathing the nerves in a 10 mM glutamate solution, glutamate known to result in cellular swelling in mammalian central nervous system (CNS), was found to increase the component size of the longest-lived nerve component, suggestive that this component may result from cellular water.


Influence of the hydrophilic head size and hydrophobic tail length of surfactants on the ability of micelles to stabilize citral.
Surfactant-made micelles can control the rate of chemical degradation of poorly water-soluble food flavors. To evaluate how the molecular structure of surfactant has an influence on the chemical decomposition rate of citral, micelles were prepared with polyoxyethylene alkyl ether-type surfactants that had similar molecular structures but various hydrophilic head sizes and hydrophobic tail lengths. At a critical 20× micelle concentration of surfactant, there was no significant difference in the chemical degradation rate of citral in micelles in neutral pH, regardless of the hydrophilic head size or hydrophobic tail length. In an acidic environment, the degradation rate constant of citral generally increased proportionally with increasing hydrophilic head size of surfactant (0.1563 and 0.2217 for surfactants with 23 and 100 oxyethylene units, respectively) but the length of hydrophobic tail did not affect the citral stability. Also, little difference (0.2217 and 0.2265 for surfactant having 100 oxyethylene units with and without Fe(3+) ) in degradation rate constant of citral between simple micellar solution and micellar solution containing iron suggested that iron ions could not accelerate citral degradation in micelles, regardless of the form of iron (Fe(2+) and Fe(3+) ). This work concludes that although the concentration of surfactant could be relevant, if its concentration could be controlled in the same manner as the critical micelle concentration, then a polyethylene alkyl ether-type surfactant with a small hydrophilic head could more efficiently stabilize citral at an acidic pH. © 2015 Society of Chemical Industry.


Physical state of human papillomavirus type 16 in cervical cell DNA.
Multiplex PCR with specific primers for E2/E6 genes was used to assess the viral integration status of HPV-16 in women with low and high grade squamous intraepithelial lesions (LSIL and HSIL, respectively) in comparison to cervical cancer patients. Women with confirmed HPV-16 infection were examined: 30 with LSIL, 12 with HSIL and 23 with cervical cancer. The PCR products were separated electrophoretically in agarose gels and densitometric analysis was performed using Bio-Rad Quantity One software. E2 and E6 sequences of HPV-16 were detected in 91% of the women. The free episomal viral genome was not detected in the cervical carcinoma group. Twenty six percent of the samples obtained from this group harboured the integrated form, whereas the remaining samples possessed a mixture, i.e. episomal and integrated forms of viral DNA. The free episomal form dominated in women with LSIL and HSIL. In 6 cases the episomal and integrated forms were detected simultaneously. HPV-16 integration occurred in a subset of LSILs and HSILs, not only in the cervical cancer patients and correlated with progression of cytological changes. The assessment of the status of HPV-16 may be the molecular factor preceding the morphological features leading to malignancy.


Changes in hypertension prevalence, awareness, treatment and control rates over 20 years in National Capital Region of India: results from a repeat cross-sectional study.
Despite being one of the leading risk factors of cardiovascular mortality, there are limited data on changes in hypertension burden and management from India. This study evaluates trend in the prevalence, awareness, treatment and control of hypertension in the urban and rural areas of India's National Capital Region (NCR). Two representative cross-sectional surveys were conducted in urban and rural areas (survey 1 (1991-1994); survey 2 (2010-2012)) of NCR using similar methodologies. A total of 3048 (mean age: 46.8±9.0 years; 52.3% women) and 2052 (mean age: 46.5±8.4 years; 54.2% women) subjects of urban areas and 2487 (mean age: 46.6±8.8 years; 57.0% women) and 1917 (mean age: 46.5±8.5 years; 51.3% women) subjects of rural areas were included in survey 1 and survey 2, respectively. Hypertension was defined as per Joint National Committee VII guidelines. Structured questionnaire was used to measure the awareness and treatment status of hypertension. A mean systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg was defined as control of hypertension among the participants with hypertension. The age and sex standardised prevalence of hypertension increased from 23.0% to 42.2% (p<0.001) and 11.2% to 28.9% (p<0.001) in urban and rural NCR, respectively. In both surveys, those with high education, alcohol use, obesity and high fasting blood glucose were at a higher risk for hypertension. However, the change in hypertension prevalence between the surveys was independent of these risk factors (adjusted OR (95% CI): urban (2.3 (2.0 to 2.7)) rural (3.1 (2.4 to 4.0))). Overall, there was no improvement in awareness, treatment and control rates of hypertension in the population. There was marked increase in prevalence of hypertension over two decades with no improvement in management.


Stapled hemorrhoidectomy for the treatment of hemorrhoids.
The use of circular staplers in the treatment of hemorrhoidal disease is known as a simple procedure, with low morbidity, less post-treatment pain and with the same efficacy when compared to the classical hemorrhoidectomy. Analyze the operative technique, intra-operative and immediate postoperative complications and late results in 100 patients treated for hemorrhoid disease by stapling technique. The group included 53 males and 47 females with mean age of 49.8 years, operated during the period June 2000 to June 2002 in the "Hospital Universitário" (São Paulo University Hospital) and "Hospital Sírio Libanês", in São Paulo, SP, Brazil. The majority of patients (78%) were discharged on the first post-operative day. Eight patients required supplementary analgesia and were given intramuscular diclofenac sodium and four of them received intramuscular tramadol. One intraoperative complication was bleeding which was difficult to control and required a blood transfusion. One patient was reoperated on the first postoperative day due to intermittent and persistent bleeding, however without hemodynamic changes or a drop in hematocrit. Two patients presented hemorrhoidal thrombosis in the early postoperative stage. The postoperative follow-up displayed: recurrence of prolapse, five cases (5%); anal sub-stenosis, two cases (2%); anal fissure, one case (1%); persistent pain, two cases (2%). Seven reoperations were performed: one due to bleeding, one due to sub-stenosis and five due to recurrence of hemorrhoidal prolapse and persistence of symptoms. Stapling is simple to accomplish, has low postoperative pain and rate of complications, however, the incidence of late reoperations is rather high and therefore major follow-up for better analysis is required.


Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells.
Clinical outcome in patients with primary nodal diffuse large B-cell lymphomas (DLBCLs) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including X-linked inhibitor of apoptosis protein (XIAP). XIAP suppresses apoptosis through inhibiting active caspase-3, caspase-7, and caspase-9. In this study, we investigated to see if the small-molecule XIAP antagonist 1396-12 induces cell death in cultured lymphoma cells of patients with DLBCL. Treatment with this XIAP antagonist resulted in relief of caspase-3 inhibition and in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy-refractory and -responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal-center B cells from healthy donors. XIAP antagonist-sensitive samples were characterized by high expression levels of XIAP, relatively low expression levels of Bcl-2, and by constitutive caspase-9 activation. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in cultured DLBCL cells and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers, suggesting the possibility of predefining patients most likely to benefit from XIAP antagonist therapy.


[Effectiveness of pedicle screw fixation combined with non-fusion technology for treatment of thoracolumbar fracture through Wiltse paraspinal approach].
To explore the effectiveness of pedicle screw fixation combined with non-fusion technology for the treatment of thoracolumbar fracture (AO type A) through Wiltse paraspinal approach. Between March 2011 and December 2012, 35 cases of thoracolumbar fractures were treated with pedicle screw fixation combined with non- fusion technology by Wiltse paraspinal approach. There were 27 males and 8 females, aged from 19 to 51 years (mean, 39.7 years). The time from injury to operation varied from 3 to 15 days (mean, 5.9 days). The causes of injury were traffic accident in 17 cases, falling from height in 11 cases, and crush trauma in 7 cases. All fractures were single-segment fracture, including Ts in 1 case, T9 in 2 cases, T10 in 2 cases, T11 in 3 cases, T12 in 12 cases, L1 in 10 cases, L2 in 4 cases, and L3 in 1 case. According to AO classification, there were 17 type A1 fractures (compression fracture), 3 type A2 fractures (splitting fracture), and 15 type A3 fractures (burst fracture). Based on American Spinal Injury Association (ASIA) spinal cord injury grade, all cases were in grade E before operation. Perioperative parameters were recorded; the anterior vertebral height and kyphotic Cobb angle of vertebral bodies were measured before and after operation to evaluate the effect of correction. The mean operating time was 74 minutes; the mean blood loss was 125 mL; and the mean drainage volume was 51 mL. Skin necrosis of incision occurred in 2 cases and was cured after dressing change; primary healing of incision was obtained in the others. All patients were followed up 15-24 months (mean, 17.3 months). No loosening or breakage of internal fixation was found. The internal fixator was removed at 12-19 months after operation (mean, 15 months). There were significant differences in Cobb's angle and anterior vertebral body height between before operation and immediately after operation, before internal fixator removal as well as at last follow- up (P < 0.05). There was no significant difference in anterior vertebral body height among the postoperative time points (P > 0.05). There was significant difference in Cobb's angle between immediately after operation and before internal fixator removal as well as at last follow-up (P < 0.05), but the difference was not significant between before internal fixator removal and at last follow-up (P > 0.05). The motion of fixed segment was restored after internal fixator removal. It is an effective method of pedicle screw fixation combined with non-fusion technology through Wiltse paraspinal approach for the treatment of thoracolumbar fracture (AO type A). The method has the advantages of simple operation and less trauma. It can effectively rebuild the height of vertebral body and correct kyphotic deformity.


Etiologies of parathyroid gland dysfunction in primary hyperparathyroidism.
Primary hyperparathyroidism is caused by defects in the parathyroid gland. Investigations have implicated three interesting genes whose mutation can cause primary hyperparathyroidism. Familial hypocalciuric hypercalcemia is believed to be an atypical form of primary hyperparathyroidism with an inherited defect in calcium recognition expressed not only in all parathyroid chief cells (thus a polyclonal defect) but in some renal tubular cells as well. In typical primary hyperparathyroidism a monoclonal parathyroid tumor is usually the central cause. Either of two apparently different genes on the long arm of chromosome 11 has been implicated in development of a parathyroid tumor clone. One gene (D11S287) was shown to have undergone a rearrangement with the parathyroid hormone gene on the short arm of the same chromosome (pericentromeric inversion) in a small fraction of tumors; the D11S287 locus may encode a growth stimulator. Another gene, the locus for familial multiple endocrine neoplasia type 1 (FEMEN1), is likely to encode a growth inhibitor. Inactivation of this gene or another nearby gene by somatic mutation has been indirectly implicated in one-quarter of sporadic parathyroid adenomas and in more than half of parathyroid tumors in FMEN1. In conclusion, studies have suggested three different mechanisms for parathyroid gland dysfunction in primary hyperparathyroidism: (1) a defect in calcium recognition, (2) a monoclonal tumor from overexpression of a growth stimulator, or (3) a monoclonal tumor from inactivation of a growth inhibitor.


Evolution of a Paradigm Switch in Diagnosis and Treatment of HPV-Driven Head and Neck Cancer-Striking the Balance Between Toxicity and Cure.
More than a decade after the discovery of p16 immunohistochemistry (IHC) as a surrogate for human papilloma virus (HPV)-driven head and neck squamous cell carcinoma (HNSCC), p16-IHC has become a routinely evaluated biomarker to stratify oropharyngeal squamous cell carcinoma (OPSCC) into a molecularly distinct subtype with favorable clinical prognosis. Clinical trials of treatment de-escalation frequently use combinations of biomarkers (p16-IHC, HPV-RNA in situ hybridization, and amplification of HPV-DNA by PCR) to further improve molecular stratification. Implementation of these methods into clinical routine may be limited in the case of RNA by the low RNA quality of formalin-fixed paraffin-embedded tissue blocks (FFPE) or in the case of DNA by cross contamination with HPV-DNA and false PCR amplification errors. Advanced technological developments such as investigation of tumor mutational landscape (NGS), liquid-biopsies (LBx and cell-free cfDNA), and other blood-based HPV immunity surrogates (antibodies in serum) may provide novel venues to further improve diagnostic uncertainties. Moreover, the value of HPV/p16-IHC outside the oropharynx in HNSCC patients needs to be clarified. With regards to therapy, postoperative (adjuvant) or definitive (primary) radiochemotherapy constitutes cornerstones for curative treatment of HNSCC. Side effects of chemotherapy such as bone-marrow suppression could lead to radiotherapy interruption and may compromise the therapy outcome. Therefore, reduction of chemotherapy or its replacement with targeted anticancer agents holds the promise to further optimize the toxicity profile of systemic treatment. Modern radiotherapy gradually adapts the dose. Higher doses are administered to the visible tumor bulk and positive lymph nodes, while a lower dose is prescribed to locoregional volumes empirically suspected to be invaded by tumor cells. Further attempts for radiotherapy de-escalation may improve acute toxicities, for example, the rates for dysphagia and feeding tube requirement, or ameliorate late toxicities like tissue scars (fibrosis) or dry mouth. The main objective of current de-intensification trials is therefore to reduce acute and/or late treatment-associated toxicity while preserving the favorable clinical outcomes. Deep molecular characterization of HPV-driven HNSCC and radiotherapy interactions with the tumor immune microenvironment may be instructive for the development of next-generation de-escalation strategies.


Pressure measurement based on a multimode phase retarder plastic optical fiber.
This paper demonstrates a polarimetric pressure measurement using a multimode phase retarder plastic optical fiber fabricated from a birefringence-controllable copolymer. An optimal composition that gives the most pronounced response to pressure was studied by comparing the extinction ratio of fibers fabricated with different copolymer compositions. A simple sensor design with a single-fiber structure was proposed that has detection capabilities similar to those of the conventional dual-path structure of a Mach-Zehnder interferometer. A linear relationship between the fiber birefringence and the applied pressure was observed in a range from 0 to 0.06 MPa. A polarimetric sensitivity of 1.56 x 10(-5) MPa(-1) was obtained experimentally from the relationship between the birefringence and pressure.


Inactivation of calcium ion-regulating inositol polyphosphate second messengers is impaired in subpopulations of human leukemia cells.
Inositol 1,4,5-triphosphate (IP3) and inositol 1,3,4,5-tetrakisphosphate (IP4) are calcium-regulating second messenger molecules generated following the binding of a wide range of hormones and growth factors to their receptors. The actions of these messengers, which play important roles in the regulation of cell proliferation as well as in other signaling pathways, are terminated by the action of a 5-phosphomonoesterase (5-PME) enzyme. We have assayed this enzyme in normal and malignant hemopoietic cells. Extracts from normal bone marrow cells and peripheral blood mononuclear cells (PBMNC) degraded [3H]IP3 at rates of 74.5 (+/- 3.4) and 84.5 (+/- 7.9) pmol/min/micrograms protein, respectively. PME activity in 10/13 (77%) acute lymphoblastic leukemia samples were significantly below the normal range and the enzyme was completely undetectable in three (23%) of these. Enzyme activity in 8/9 (89%) chronic lymphocytic leukemia samples were below the normal range, being undetectable in three of these (33%). Nine of 24 (38%) acute myeloid leukemia samples contained low 5-PME levels, which was undetectable in one sample. Reduced 5-PME activity was detected in 2/7 (28%) of chronic granulocytic leukemia samples. The data here are consistent with the hypothesis that a reduced rate of degradation of IP3 and IP4 in some leukemia cells may result in the aberrant operation of signaling pathways, possibly including those involved in the control of cell proliferation.


MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA.
We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125b is able to induce leukemia. In this study, we investigated the mechanism of myeloid transformation by miR-125b. To investigate the consequences of miR-125b over-expression on myeloid differentiation, apoptosis and proliferation, we used the NB4 and HL60 human promyelocytic cell lines and the 32Dclone3 murine promyelocytic cell line. To test whether miR-125b is able to transform myeloid cells, we used the non-tumorigenic and interleukin-3-dependent 32Dclone3 cell line over-expressing miR-125b, in xenograft experiments in nude mice and in conditions of interleukin-3 deprivation. To identify new miR-125b targets, we compared, by RNA-sequencing, the transcriptome of cell lines that do or do not over-express miR-125b. We showed that miR-125b over-expression blocks apoptosis and myeloid differentiation and enhances proliferation in both species. More importantly, we demonstrated that miR-125b is able to transform the 32Dclone3 cell line by conferring growth independence from interleukin-3; xenograft experiments showed that these cells form tumors in nude mice. Using RNA-sequencing and quantitative real-time polymerase chain reaction experiments, we identified multiple miR-125b targets. We demonstrated that ABTB1, an anti-proliferative factor, is a new direct target of miR-125b and we confirmed that CBFB, a transcription factor involved in hematopoiesis, is also targeted by miR-125b. MiR-125b controls apoptosis by down-regulating genes involved in the p53 pathway including BAK1 and TP53INP1. This study demonstrates that in a myeloid context, miR-125b is an oncomiR able to transform cell lines. miR-125b blocks myeloid differentiation in part by targeting CBFB, blocks apoptosis through down-regulation of multiple genes involved in the p53 pathway, and confers a proliferative advantage to human and mouse myeloid cell lines in part by targeting ABTB1.


Network neighborhood operates as a drug repositioning method for cancer treatment.
Computational drug repositioning approaches are important, as they cost less compared to the traditional drug development processes. This study proposes a novel network-based drug repositioning approach, which computes similarities between disease-causing genes and drug-affected genes in a network topology to suggest candidate drugs with highest similarity scores. This new method aims to identify better treatment options by integrating systems biology approaches. It uses a protein-protein interaction network that is the main topology to compute a similarity score between candidate drugs and disease-causing genes. The disease-causing genes were mapped on this network structure. Transcriptome profiles of drug candidates were taken from the LINCS project and mapped individually on the network structure. The similarity of these two networks was calculated by different network neighborhood metrics, including Adamic-Adar, PageRank and neighborhood scoring. The proposed approach identifies the best candidates by choosing the drugs with significant similarity scores. The method was experimented on melanoma, colorectal, and prostate cancers. Several candidate drugs were predicted by applying AUC values of 0.6 or higher. Some of the predictions were approved by clinical phase trials or other in-vivo studies found in literature. The proposed drug repositioning approach would suggest better treatment options with integration of functional information between genes and transcriptome level effects of drug perturbations and diseases.


Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases.
Oxidative stress, including the generation of reactive oxygen species (ROS), appears to be responsible for the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), and for the progression of CKD to end-stage renal disease. The processes for oxidative stress include increased generation and decreased elimination of ROS that could be caused by an impaired antioxidant defense system. Nuclear factor-erythroid-2-related factor 2 (Nrf2) helps protect the kidney against oxidative stress by playing a pivotal role in the cooperative induction of genes that encode antioxidant and detoxifying enzymes. Nrf2 is confined to the cytoplasm as an inactive complex bound to a repressor Kelch-like ECH-associated protein 1 (Keap1), which facilitates ubiquitination of Nrf2. Studies using CKD model animals showed that despite stimulated oxidative stress the nuclear Nrf2 level was suppressed, which led to downregulation of the antioxidant enzymes. Hence, deterioration in Nrf2-Keap1 signaling could contribute to the severity of oxidative stress and the progression of CKD. By contrast, acute kidney injury (AKI) induces activation of renal Nrf2. Nrf2 activators or its proteasomal degradation inhibitors enhance nuclear Nrf2 translocation, inducing potential renoprotective actions against CKD and AKI. In both chronic and acute kidney diseases, sulfate-conjugated uremic toxins appear to enhance ROS production when accumulated in renal cells. An intestinal indole adsorbent ameliorates the progression of CKD by decreasing accumulation of indoxyl sulfate. Therapeutic approaches to prevent oxidative stress via activation of the Nrf2-Keap1 signaling and/or suppression of uremic toxin-induced ROS production could be effective strategies for maintaining kidney function.


Targeted versus standard feedback: results from a randomized quality improvement trial.
Quality improvement is central to improving the care of patients with cardiovascular disease; however, the optimum type of data feedback to support such efforts is unknown. Over 26 months, 149 eligible Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines hospitals were randomized to receive either standard (n = 76 control) or targeted (n = 73 intervention) performance feedback reports for acute myocardial infarction patient care. Each report summarized performance on identified metrics (providing hospitals with detailed data on their 3 lowest-performing quality metrics, relative to their peers). Intervention sites received 5 targeted feedback reports. Overall composite performance was compared between cohorts at end of study and as a change from baseline. Intervention (n = 60) and control (n = 64) hospitals that completed the study had similar baseline performance (median score 83.7% vs 84.2%). Over 26 months of follow-up, the change in overall composite score across hospitals was neutral (median 0.1% [interquartile range {IQR} -2.4% to 3.3%]). There was no difference in observed improvement in either the intervention (median -0.2% [IQR-2.6% to 3.3%]) or control (median 0.1% [IQR -2.2% to 3.4%]) hospitals. We were unable to demonstrate that targeted performance feedback reports lead to more rapid care improvements than standard reports. Future directions should explore the relationship between hospital self-selection of targeted metrics and the identification and promulgation of less common metrics--particularly those that reflect processes of care.


Multilayer deformation planarization by substrate pit suturing.
In the pursuit of 1064 nm high-power laser resistance dielectric coatings in the nanosecond region, a group of HfO2/SiO2 high reflectors with and without suture layers were prepared on prearranged fused silica substrates with femtosecond laser pits. Surface morphology, global coating stress, and high-resolution cross sections were characterized to determine the effects of substrate pit suturing. Laser-induced damage resistance was investigated for samples with and without suture layers. Our results indicate considerable stability in terms of the nanosecond 1064 nm laser-induced damage threshold for samples having a suture layer, due to decreased electronic field (e-field) deformation with simultaneous elimination of internal cracks. In addition, a suture layer formed by plasma ion-assisted deposition could effectively improve global mechanical stress of the coatings. By effectively reducing the multilayer deformation using a suture layer, electron-beam high-reflective coatings, whose laser-induced damage resistance was not influenced by the substrate pit, can be prepared.


Electrical conductivity of oxidized-graphenic nanoplatelets obtained from bamboo: effect of the oxygen content.
The large-scale production of graphene and reduced-graphene oxide (rGO) requires low-cost and eco-friendly synthesis methods. We employed a new, simple, cost-effective pyrolytic method to synthetize oxidized-graphenic nanoplatelets (OGNP) using bamboo pyroligneous acid (BPA) as a source. Thorough analyses via high-resolution transmission electron microscopy and electron energy-loss spectroscopy provides a complete structural and chemical description at the local scale of these samples. In particular, we found that at the highest carbonization temperature the OGNP-BPA are mainly in a sp(2) bonding configuration (sp(2) fraction of 87%). To determine the electrical properties of single nanoplatelets, these were contacted by Pt nanowires deposited through focused-ion-beam-induced deposition techniques. Increased conductivity by two orders of magnitude is observed as oxygen content decreases from 17% to 5%, reaching a value of 2.3 × 10(3) S m(-1) at the lowest oxygen content. Temperature-dependent conductivity reveals a semiconductor transport behavior, described by the Mott three-dimensional variable range hopping mechanism. From the localization length, we estimate a band-gap value of 0.22(2) eV for an oxygen content of 5%. This investigation demonstrates the great potential of the OGNP-BPA for technological applications, given that their structural and electrical behavior is similar to the highly reduced rGO sheets obtained by more sophisticated conventional synthesis methods.


Prognostic role of albumin level in heart failure: A systematic review and meta-analysis.
Hypoalbuminemia (HA) is common in HF, however, its pathophysiology and clinical implications are poorly understood. While multiple studies have been published in the past decade investigating the role of serum albumin in HF, there is still no consensus on the prognostic value of this widely available measure. The objective of this study is to assess the prognostic role of albumin in heart failure (HF) patient. Unrestricted searches of MEDLINE, EMBASE, Cochrane databases were performed. The results were screened for relevance and eligibility criteria. Relevant data were extracted and analyzed using Comprehensive Meta-Analysis software. The Begg and Mazumdar rank correlation test was utilized to evaluate for publication bias. A total of 48 studies examining 44,048 patients with HF were analyzed. HA was found in 32% (95% confidence interval [CI] 28.4%-37.4%) HF patients with marked heterogeneity (I2 = 98%). In 10 studies evaluating acute HF, in-hospital mortality was almost 4 times more likely in HA with an odds ratios (OR) of 3.77 (95% CI 1.96-7.23). HA was also associated with a significant increase in long-term mortality (OR: 1.5; 95% CI: 1.36-1.64) especially at 1-year post-discharge (OR: 2.44; 95% CI: 2.05-2.91; I2 = 11%). Pooled area under the curve (AUC 0.73; 95% CI 0.67-0.78) was comparable to serum brain natriuretic peptide (BNP) in predicting mortality in HF patients. Our results suggest that HA is associated with significantly higher in-hospital mortality as well as long-term mortality with a predictive accuracy comparable to that reported for serum BNP. These findings suggest that serum albumin may be useful in determining high-risk patients.


Ki-67 is an independent prognostic marker for the recurrence and relapse of oral squamous cell carcinoma.
As a nuclear and nucleolar protein, proliferation marker protein Ki-67 (Ki-67) serves a vital role in tumorigenesis due to its positive correlation with tumor proliferation. High expression of Ki-67 in the cell cycle from the G1 to M phase makes it a potential biomarker for certain tumors and useful for selecting medical treatment. However, the diagnostic value of Ki-67 in oral squamous cell carcinoma (OSCC) has not been fully evaluated. In the present study, the objective was the elucidation of the prognostic value of Ki-67 in a large number of OSCC patients. Ki-67 expression was detected by immunohistochemical staining methods in 298 OSCC specimens and 98 tumor-free oral mucosa specimens (62 dysplasia mucosa and 36 normal mucosa), acquired from Nanjing Stomatological Hospital, Medical School of Nanjing University (Nanjing, China). Expression of Ki-67 in normal tissues, dysplasia tissues and OSCC tissues was compared. Associations between Ki-67 expression and clinicopathological parameters were analyzed by χ2 test. Kaplan-Meier survival curves and Cox progression analysis were used to assess the diagnostic value of Ki-67 for OSCC. The results showed that Ki-67 expression was higher in OSCC tissues than in tumor-free tissues and that it increased with the progression of dysplasia in oral mucosa tissues. In addition, patients with high Ki-67 expression had a worse clinical outcome, including poor tumor differentiation (P=0.001), increased positive lymph node metastasis (P=0.006) and increased worst pattern of invasion type (P<0.0001). Kaplan-Meier survival analysis demonstrated that higher Ki-67 expression was associated with poorer overall survival (OS) (P=0.035), recurrence-free survival (RFS) (P=0.017), metastasis-free survival (MFS) (P=0.032) and disease-free survival (DFS) (P=0.018) times. Additional multivariate analysis demonstrated that Ki-67 expression was negatively associated with OS, DFS, RFS and MFS. In conclusion, Ki-67 overexpression is associated with the progression of OSCC and serves as an independent prognostic factor for OSCC patients.


[A hemostatic disorder caused by high shear stress: acquired von Willebrand syndrome].
The von Willebrand factors (VWFs) play critical role in hemostasis and thrombosis formation. VWFs are produced in and secreted as large multimers from endothelial cells, and shear stress-dependently cleaved into 2-80 multimers by their specific protease, ADATS13. Because high molecular weight VWFs play important roles in platelet aggregation, the loss of high molecular weight VWFs caused by pathological high-shear stress induces a hemostatic disorder known as acquired von Willebrand syndrome (AVWS) type IIA. The most well-known cause of this loss is aortic stenosis, which is accompanied by gastrointestinal bleeding most often as a result of angiodysplasia; this comprises a condition known as Heyde's syndrome. Additionally, various cardiovascular diseases that generate excessive high-shear stress in the blood stream, such as hypertrophic obstructive cardiomyopathy (HOCM), mitral regurgitation, pulmonary hypertension, and some congenital heart diseases, and mechanical circulatory support systems, such as left ventricular assist device (LVAD), cause AVWS.


Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis.
Cardiac allograft arteriosclerosis is a complex process of alloimmune response, chronic inflammation, and smooth muscle cell proliferation that includes cross talk between cytokines and growth factors. Our results in rat cardiac allografts established alloimmune response as an alternative stimulus capable of inducing vascular endothelial growth factor (VEGF) mRNA and protein expression in cardiomyocytes and graft-infiltrating mononuclear inflammatory cells, which suggests that these cells may function as a source of VEGF to the cells of coronary arteries. Linear regression analysis of these allografts with different stages of arteriosclerotic lesions revealed a strong correlation between intragraft VEGF protein expression and the development of intimal thickening, whereas blockade of signaling downstream of VEGF receptor significantly reduced arteriosclerotic lesions. In addition, in cholesterol-fed rabbits, intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector that encoded mouse VEGF(164) enhanced the formation of arteriosclerotic lesions, possibly secondary to increased intragraft influx of macrophages and neovascularization in the intimal lesions. Our findings suggest a positive regulatory role between VEGF and coronary arteriosclerotic lesion formation in the allograft cytokine microenvironment.


Unstable-stable resonators with toroidal mirrors.
A resonator with toroidal mirrors is described. This resonator behaves like an off-axis unstable confocal resonator in one transverse dimension and like an on-axis concave-convex stable resonator in the other orthogonal dimension. Some experimental results are reported for a fast flow high power cw-CO(2) laser whose transverse cross section is restricted in the stable-resonator direction. These cavities allow an output laser beam with a fully illuminated cross section which is well suited for focusing. Moreover, the fraction of the available laser power which may be concentrated in the central lobe of the focal plane intensity distribution is 2.5-4.5 times higher than other unstable resonators with similarly restricted modal volumes. Finally the alignment requirements are examined.


The development of interpersonal aggression during adolescence: the importance of parents, siblings, and family economics.
Latent growth curve modeling employed data from a longitudinal study of 451 sibling families to examine parents, siblings, and family economics as factors in individual differences in the developmental course of interpersonal aggression during adolescence. Findings suggest that individual change in interpersonal aggression during adolescence can be predicted by the gender and aggression of one's sibling; predictions varied by the gender composition of the sibling dyad. Rates of parental hostility predicted levels of interpersonal aggression for both older (mean age = 12 years) and younger siblings (mean age = 15), and growth in aggression for younger siblings. Family economic pressure predicted interpersonal aggression of both siblings indirectly through parental hostility. Implications for future research and preventive interventions are discussed.


[Attempt to Evaluate the Influence of Morphology, Blood Flow, and Hardness in Mammary Gland Malignant Disease].
It is important to make an appropriate diagnosis category by evaluating the morphology, blood flow, and hardness of mammary gland disease in breast ultrasound, such as screening and detailed examination. Therefore, understanding the characteristics and effects of B-mode (BM), color Doppler (CD), and elastography (EG) in ultrasonography is considered to lead to improvement in examination accuracy. In this study, we clarified the impact of each function on qualitative diagnosis, with the aim of assisting technologists with high-accuracy breast ultrasound. The subjects were 531 malignant tumor cases. The final evaluation of ultrasonography was classified into 5 levels, BM was classified into 5 levels, CD was classified into 4 levels based on blood flow evaluation, and EG was classified into 9 levels based on the Tsukuba elasticity score. The contribution rates of BM, CD, and EG were 70.4%, 15.0%, and 14.6% in all cases (correlation ratio 0.87). BM was most important at the time of breast ultrasound. No difference was observed between CD and EG. In the evaluation by malignant tumor, each characteristic was seen in the degree of influence. It became clear that comprehensive evaluation is important for benign/malignant evaluation and histological-type estimation.


Triple burden of malnutrition and role of anaemia in the development of complications associated with type 1 diabetes in Indian children and youth.
The double burden of malnutrition accompanied by micronutrient deficiency is referred to as the triple burden of malnutrition (TBM). Very few studies have highlighted the TBM in children with type-1 diabetes. We conducted this study with the objective of estimating the TBM in Indian children and youth with type-1 diabetes (T1D) and to study role of anaemia in the development of complications associated with T1D. This cross-sectional observational study included 394 subjects with T1D. Demographic data, anthropometry, blood pressure, biochemical measurements, dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography were performed using standard protocols. Estimated glucose disposal rate (eGDR) and estimated glomerular filtration rate (eGFR) were calculated for all subjects. We report a 16, 5.8, and 16.2% prevalence of anaemia, underweight and overweight/obese suggesting TBM with microcytic hypochromic anaemia as the most common morphological form. Haemoglobin concentrations showed positive correlation with systolic and diastolic blood pressure. The presence of anaemia was a significant predictor of eGDR and macrovascular complications in T1D which could not be attributed to glycemic control. Bone health of anaemic T1D subjects was poor than subjects without anaemia on DXA scan after adjusting for confounders. No systematic pattern between Hb concentrations and eGFR or ACR was found. TBM in Indian children and youth with T1D is a significant health problem and anaemia is an important predictor in the development of macrovascular complications and poor bone health associated with T1D. However, its role in development of microvascular complications remains to be explored.


Transcript expression profiling of fibromelanosis-related genes in black-bone chickens.
1. The aim of the present study was to identify differentially expressed genes (DEGs) and metabolic pathways involved in this phenotype. Fibromelanosis is the most striking feature of black-bone chickens, such as the Silkie and Dongxiang indigenous breeds. Due to the accumulation of eumelanin in connective tissues, fibromelanosis manifests as black colouration of the skin, muscles, gut, and periosteum. Studies on fibromelanosis can provide useful information pertaining to human diseases and offer commercial value to the poultry industry. However, the genetic basis of fibromelanosis remains unclear.2. Digital gene expression analysis was performed on black and white skin samples collected from the HW1 black-bone chicken line to detect differences in genome-wide expression patterns. A total of >30 billion bp were sequenced, and 2,707,926,466 bp and 2,948,782,964 bp of clean data obtained for creation of libraries for black and white skin, respectively. In total, 252 DEGs from 15,508 mapped genes were identified with 83 up-regulated in white skin and 169 up-regulated in black skin.3. Gene ontology analysis highlighted that genes from the extracellular region and associated components were abundant among the DEGs. Pathway analysis revealed that many DEGs were linked to amino acid metabolism and the immune system. qRT-PCR validation using 14 genes showed good conformity with the sequence analysis of fibromelanosis-related genes.4. The results showed that L-dopachrometautomerase precursor (DCT), tyrosine aminotransferase (TAT), 4-hydroxyphenylpyruvate dioxygenase (HPD) from the tyrosine metabolism pathway, coagulation factor II (F2), fibrinogen beta chain (FGB), plasminogen (PLG) and complement component 7 (C7) from the complement and coagulation cascades were important genes in the fibromelanosis process in black-bone chickens. These candidate genes require further correlation analysis and functional verification.


Simultaneously metastatic cholangiocarcinoma and small intestine cancer from breast cancer misdiagnosed as primary cholangiocarcinoma: A case report.
Cholangiocarcinoma and small intestine cancer are common clinical malignancies, but metastatic cholangiocarcinoma and small intestine cancer are rare, especially simultaneous metastatic cholangiocarcinoma and small intestine cancer from breast cancer. Since the clinical presentation of metastatic cholangiocarcinoma and small intestine cancer does not differ from primary tumor, it may lead to misdiagnosis preoperatively. A 66-year-old woman was admitted to our hospital for further treatment due to abdominal pain and jaundice. Abdominal magnetic resonance imaging and magnetic resonance cholangiopancreatography showed an occupying lesion of the bile duct, considering a high possibility of primary bile duct tumor. Therefore, we performed a radical bile duct cancer surgery and cholecystectomy, and multiple tumors in the small intestine were found and removed during the surgery process. Postoperative pathology showed metastatic bile duct cancer and small intestine cancer from tumors in other parts. The patient underwent a right total mastectomy and axillary lymph node dissection because of right breast cancer 2 years ago. Combining with the immunohistochemical results, the patient was finally diagnosed as metastatic cholangiocarcinoma and metastatic small intestine cancer from breast cancer. Postoperatively, the patient received four cycles of chemotherapy and targeted therapy with docetaxel, capecitabine and trastuzumab. Unfortunately, the patient eventually died from tumor progression, thoracoabdominal infection, and sepsis 5 mo after surgery. Simultaneous metastatic cholangiocarcinoma and small intestine cancer from breast cancer are rare and the prognosis is extremely poor. Improving preoperative diagnostic accuracy is beneficial to avoid excessive surgical treatment. Treatment should be aimed at relieving biliary obstruction and abdominal pain, and then supplemented with chemotherapy and targeted therapy to control tumor progression and prolong the patient's life.


[Positivity of antineutrophil cytoplasmic antibodies in children: prevalence and etiologies].
In adults, anti-neutrophil cytoplasmic antibodies (ANCA) are considered as serological markers of several diseases, especially vasculitis and glomerulonephritis. Since ANCA are rarely positive in children, few data about the clinical relevance of these auto-antibodies in pediatric population have been reported. Therefore, our study aims to describe the spectrum of disorders associated with positive ANCA in Tunisian children. This study had been carried out over a period of 12 years and a half. All patients under the age of 15 for whom ANCA screening was performed in our laboratory were included. Clinical data were collected retrospectively. Indirect immunofluorescence (IFI) technique for ANCA detection was performed using PNN smears fixed with ethanol, formalin and, if necessary, methanol. Positive results were tested using immunodot to characterize the antigenic targets (myeloperoxydase (MPO) and proteinase 3 (PR3)). Our results showed that 410/5,990 (6.8%) laboratory requests for ANCA screening were for children. Forty (9.7%) requests were positive (24 children). Clinical data were available for 19 patients only. Sex-ratio (F/M) was 1.25. The mean age was 9 years and a half (3-15 years). The most frequent IIF patterns were x-ANCA (n=12) and p-ANCA (n=7). In our patients, the most frequent conditions associated to ANCA were treatment with benzylthiouracil for hypothyroidism (n=6), inflammatory bowel disease (n=4) and hemolytic anemia (n=4). In conclusion, the positivity of ANCA in children seems to be a rare event. Associated conditions include clinical disorders specific to the pediatric population. Treatment with benzylthiouracil is an etiology to be taken into consideration.


Towards a comprehensive regulatory map of Mammalian Genomes.
Genome mapping studies have generated a nearly complete collection of genes for the human genome, but we still lack an equivalently vetted inventory of human regulatory sequences. Cis-regulatory modules (CRMs) play important roles in controlling when, where, and how much a gene is expressed. We developed a training data-free CRM-prediction algorithm, the Mammalian Regulatory MOdule Detector (MrMOD) for accurate CRM prediction in mammalian genomes. MrMOD provides genome position-fixed CRM models similar to the fixed gene models for the mouse and human genomes using only genomic sequences as the inputs with one adjustable parameter - the significance p-value. Importantly, MrMOD predicts a comprehensive set of high-resolution CRMs in the mouse and human genomes including all types of regulatory modules not limited to any tissue, cell type, developmental stage, or condition. We computationally validated MrMOD predictions used a compendium of 21 orthogonal experimental data sets including thousands of experimentally defined CRMs and millions of putative regulatory elements derived from hundreds of different tissues, cell types, and stimulus conditions obtained from multiple databases. In ovo transgenic reporter assay demonstrates the power of our prediction in guiding experimental design. We analyzed CRMs located in the chromosome 17 using unsupervised machine learning and identified groups of CRMs with multiple lines of evidence supporting their functionality, linking CRMs with upstream binding transcription factors and downstream target genes. Our work provides a comprehensive base pair resolution annotation of the functional regulatory elements and non-functional regions in the mammalian genomes.


TIME FOR COFFEE is an essential component in the maintenance of metabolic homeostasis in Arabidopsis thaliana.
Plants often respond to environmental changes by reprogramming metabolic and stress-associated pathways. Homeostatic integration of signaling is a central requirement for ensuring metabolic stability in living organisms. Under diurnal conditions, properly timed rhythmic metabolism provides fitness benefits to plants. TIME FOR COFFEE (TIC) is a circadian regulator known to be involved in clock resetting at dawn. Here we explored the mechanism of influence of TIC in plant growth and development, as initiated by a microarray analysis. This global profiling showed that a loss of TIC function causes a major reprogramming of gene expression that predicts numerous developmental, metabolic, and stress-related phenotypes. This led us to demonstrate that this mutant exhibits late flowering, a plastochron defect, and diverse anatomical phenotypes. We further observed a starch-excess phenotype and altered soluble carbohydrate levels. tic exhibited hypersensitivity to oxidative stress and abscisic acid, and this was associated with a striking resistance to drought. These phenotypes were connected to an increase in total glutathione levels that correlated with a readjustment of amino acids and polyamine pools. By comparatively analyzing our transcriptomic and metabolomic data, we concluded that TIC is a central element in plant homeostasis that integrates and coordinates developmental, metabolic, and environmental signals.


A study of astrocyte activation in the periinfarct region after cerebral ischemia with electroacupuncture.
To investigate the effects of electroacupuncture (EA) on the activation of astrocytes (AST) in the periinfarct region after cerebral ischemia, as well as to evaluate potential behavioural improvement after EA treatment. Male Wistar rats were randomly divided into normal, model and EA groups. Rats in each group were further divided into 7, 14 and 28 days sub-groups. A model of middle cerebral artery occlusion was established, followed by 7, 14 or 28 days of EA on 'Bai hui' and 'Da zhui' acupoints. The number of GFAP-immunoreactive cells was determined and behavioural tests were performed. Many more GFAP-immunoreactive cells were detected in the EA group on day 14 than on day 7 after ischemia and a slightly decreased number of immunoreactive cells were observed on day 28. The results of behavioural tests of animals in the EA group on the beam balance performance and prehensile traction performance were superior to that of animals in the model group. These findings indicate that EA has the potential to activate AST in the periinfarct region and to avoid excess reactive gliosis and also can facilitate the recovery of post-ischemic behavioural dysfunction.


Glioblastoma survival is improving despite increasing incidence rates: a nationwide study between 2000 and 2013 in Finland.
We assessed population-level changes in glioblastoma survival between 2000 and 2013 in Finland, with focus on elderly patients (>70 y) in order to assess if changes in treatment of glioblastoma are reflected also in population-based survival rates. We identified all patients (age ≥18 y) from the Finnish Cancer Registry (FCR) with a histopathological diagnosis of primary glioblastoma in 2000-2013. Patients were followed up until December 2015. The accuracy of register-based search of glioblastoma patients was internally validated. We report age-standardized relative survival ratios and relative excess risks (RERs) of death in 2000-2006 (pre-period) and 2007-2013 (post-period). We identified 2045 glioblastoma patients from the FCR. The accuracy of the FCR-based search was 97%. Median age was 63.3 years, and 42% were women. Incidence increased on average by 1.6% (P = 0.004) and median age by 0.4 years per calendar year. Between the pre- and post-periods, the proportion of patients >70 years increased from 24% to 27%. In >70-year-old patients, the median survival time increased from 3.6 months in 2000-2006 to 4.5 months in 2007-2013 (RER 0.82, 95% CI: 0.68-0.98). In ≤70-year-old patients, the median survival time increased from 9.3 months in 2000-2006 to 11.7 months in 2007-2013 (RER 0.74, 95% CI: 0.67-0.82). Despite the increased proportion of elderly glioblastoma patients, population-level survival of glioblastoma patients has improved since the year 2000. However, increasing incidence, increasing age of patients, and poor survival in elderly are alarming, and future studies should perhaps focus more on elderly.