An Outbreak of ESBL-producing Klebsiella pneumoniae in an Iranian Referral Hospital: Epidemiology and Molecular Typing.
Klebsiella pneumoniae is a common cause of nosocomial infections; however, there is limited information in Iran regarding nosocomial outbreaks due to extended-spectrum β-lactamase (ESBL) producing K pneumoniae strains, particularly using molecular methods. The present study focused on the molecular mechanism of ESBL resistance and genetic relatedness in K. pneumoniae isolates causing nosocomial infections in an Iranian referral hospital. This study evaluated the antimicrobial resistance and molecular epidemiology of K. pneumoniae causing nosocomial infections in children between October 2013 and March 2014. The ESBL detection was carried out for all the isolates by the CLSI method and PCR was carried out for the detection of the blaSHV, blaTEM, and blaCTX-M genes among ESBL-producing K. pneumonia. Molecular typing of the K. pneumoniae was performed using random amplification of polymorphic DNA-polymerase chain reaction (RAPD-PCR). A total of 30 isolates of K. pneumoniae were used for epidemiological analysis. High rates of resistance to cefotaxime (n=29, 97%), cefazolin (n=29, 97%), cefepime (n=25, 83%) and gentamicin (n=23, 77%) were observed. A total of 29 strains (97%) produced ESBLs. The frequency of blaSHV, blaCTX-M and blaTEM genes among these isolates was 83% (n=25), 70% (n=21) and 57% (n=17), respectively. Surprisingly 11 isolated (37%) carried blaSHV, blaCTX-M and blaTEM genes simultaneously. Moreover, the concurrent presence of "blaSHV and blaCTX-M" and "blaSHV and blaTEM" was seen in 8 (27%) and 4 (13%) isolates, respectively. RAPDPCR analyses revealed that K. pneumoniae isolates belonged to 2 RAPD-PCR types among which one cluster counted for 28 isolates. To our knowledge, this is the first published report of a nosocomial outbreak of ESBL-producing K. pneumoniae in children in Iran. Although the epidemiology of nosocomial infections with ESBL-producing organisms has not yet been explored in depth in Iran, our findings suggest that ESBL-producing organisms are already an established public health threat in our country.


Eryptotic phenotype in chronic myeloid leukemia: contribution of neutrophilic cathepsin g.
In pathological conditions with concurrent neutrophilia, modifications of erythrocyte membrane proteins are reported. In chronic myeloid leukemia (CML), a myeloproliferative disease wherein neutrophilia is accompanied by enhanced erythrophagocytosis, we report for the first time excessive cleavage of erythrocyte band 3. Distinct fragments of band 3 serve as senescent cell antigens leading to erythrophagocytosis. Using immunoproteomics, we report the identification of immunogenic 43 kDa fragment of band 3 in 68% of CML samples compared to their detection in only 38% of healthy individuals. Thus, excessive fragmentation of band 3 in CML, detected in our study, corroborated with the eryptotic phenotype. We demonstrate the role of neutrophilic cathepsin G, detected as an immunogen on erythrocyte membrane, in band 3 cleavage. Cathepsin G from serum adsorbs to the erythrocyte membrane to mediate cleavage of band 3 and therefore contribute to the eryptotic phenotype in CML.


Loss of deoxcytidine kinase expression and tetraploidization of HL60 cells following long-term culture in 1,25-dihydroxyvitamin D3.
Development of drug resistance is a major problem in attempts to control the growth of neoplastic cell populations. The resistance can he either inherent or acquired by an exposure to a chemotherapeutic drug. The available models for study of these phenomena have not led to major improvements in the therapy for human cancers. Therefore, in order to develop a new model for such studies, we have exposed human myeloid leukemia cells HL60 to increasing concentrations of 1,25-dihydroxyvitamin D3 (1,25D3) and characterized the emerging new phenotypes of these cells over a period of 4 years. During the stepwise development of resistance only cells which did not adhere to the flask walls were passaged. Beginning at 30 nM 1,25D3 the sublines became resistant to the differentiation-inducing and growth-retarding properties of 1,25D3 even at 400 nM. Also, their growth rates in 1,25D3-free media increased. In addition, beginning at 40 nM 1,25D3 the sublines acquired resistance to 5-beta-D-arabinocytosine (araC) due to the lack of expression of the deoxycytidine kinase gene. The araC-resistant sublines were also near-tetraploid, as judged by their DNA content. When grown in 1,25D3-free long-term culture the phenotype was essentially stable. The development of cross-resistance to araC during growth in the presence of an unrelated compound (i.e., 1,25D3) shows that in some instances an apparently inherent drug resistance may in fact he due to a metabolic defect resulting from an exposure to another agent.


Reversible myocardial dysfunction following intraocular bevacizumab administration.
Heart failure has been reported as a rare side effect of bevacizumab, a chemotherapeutic agent, used in the treatment of breast cancer. However, reversible left ventricular systolic dysfunction with a pattern similar to stress-induced cardiomyopathy has not been reported. The etiopathogenesis of stress-induced cardiomyopathy is poorly understood. Given this uncertainty, we should always look out for other potential offenders causing similar presentation, rather than label all of them as "stress-induced".


Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix.
The structure of human BCL-w, an anti-apoptotic member of the BCL-2 family, was determined by triple-resonance NMR spectroscopy and molecular modeling. Introduction of a single amino acid substitution (P117V) significantly improved the quality of the NMR spectra obtained. The cytosolic domain of BCL-w consists of 8 alpha-helices, which adopt a fold similar to that of BCL-xL, BCL-2, and BAX proteins. Pairwise root meant square deviation values were less than 3 A for backbone atoms of structurally equivalent regions. Interestingly, the C-terminal helix alpha8 of BCL-w folds into the BH3-binding hydrophobic cleft of the protein, in a fashion similar to the C-terminal transmembrane helix of BAX. A peptide corresponding to the BH3 region of the pro-apoptotic protein, BID, could displace helix alpha8 from the BCL-w cleft, resulting in helix unfolding. Deletion of helix alpha8 increased binding affinities of BCL-w for BAK and BID BH3-peptides, indicating that this helix competes for peptide binding to the hydrophobic cleft. These results suggest that although the cytosolic domain of BCL-w exhibits an overall structure similar to that of BCL-xL and BCL-2, the unique organization of its C-terminal helix may modulate BCL-w interactions with pro-apoptotic binding partners.


Fidelity of animal cell DNA polymerases alpha and delta and of a human DNA replication complex.
We are investigating the mechanisms by which mutations are produced or avoided during DNA synthesis. Using in vitro fidelity assays, we have defined the error frequency and mutational specificity of the replicative animal cell DNA polymerases (alpha and delta). With DNA polymerase alpha or the four-subunit DNA polymerase alpha-DNA primase complex, neither of which contains detectable associated exonuclease activity, the fidelity of the polymerization step is low relative to spontaneous mutation rates in vivo. DNA polymerase delta is much more accurate, partly due to proofreading by the 3'----5' exonuclease activity associated with this polymerase. These fidelity studies have been extended to the replication apparatus present in extracts of human HeLa cells. The replication complex is highly accurate, suggesting that additional fidelity components are operating in the extract during bidirectional, semiconservative replication of double-stranded DNA. Nevertheless, in highly sensitive reversion assays, base substitution errors can be readily detected at frequencies greater than the estimated rate of spontaneous mutation in vivo. This suggests that fidelity components may be missing and/or that human cells depend heavily on postreplicative repair processes to correct replication errors.


RGB Thermally Activated Delayed Fluorescence Emitters for Organic Light-Emitting Diodes toward Realizing the BT.2020 Standard.
With the surging demand for ultra-high-resolution displays, the International Telecommunication Union (ITU) announce the next-generation color gamut standard, named ITU-R Recommendation BT.2020, which not only sets a seductive but challenging milestone for display technologies but also urges researchers to recognize the importance of color coordinates. Organic light-emitting diodes (OLEDs) are an important display technology in current daily life, but they face challenges in approaching the BT.2020 standard. Thermally activated delayed fluorescence (TADF) emitters have bright prospects in OLEDs because they possess 100% theoretical exciton utilization. Thus, the development of TADF emitters emitting primary red (R), green (R), and blue (B) emission is of great significance. Here, a comprehensive overview of the latest advancements in TADF emitters that exhibit Commission Internationale de l'Éclairage (CIE) coordinates surpassing the National Television System Committee (NTSC) and approaching BT.2020 standards is presented. Rational strategies for molecular designs, as well as the resulting photophysical properties and OLED performances, are discussed to elucidate the underlying mechanisms for shifting the CIE coordinates of both donor-acceptor and multiple resonance (MR) typed TADF emitters toward the BT.2020 standard. Finally, the challenges in realization of the wide-color-gamut BT.2020 standard and the prospects for this research area are provided.


Sensitization to acute procedural pain in pediatric sickle cell disease: modulation by painful vaso-occlusive episodes, age, and endothelin-1.
The impact of pain early in life is a salient issue for sickle cell disease (SCD), a genetic condition characterized by painful vaso-occlusive episodes (VOEs) that can begin in the first year of life and persist into adulthood. This study examined the effects of age and pain history (age of onset and frequency of recent VOEs) on acute procedural pain in children with SCD. Endothelin-1, a vaso-active peptide released during VOEs and acute tissue injury, and its precursor, Big Endothelin, were explored as markers of pain sensitization and vaso-occlusion. Sixty-one children with SCD (ages 2 to 18) underwent venipuncture at routine health visits. Procedural pain was assessed via child and caregiver reports and observational distress. Pain history was assessed using retrospective chart review. Three primary results were found: 1) younger age was associated with greater procedural pain across pain outcomes; 2) higher frequency of VOEs was associated with greater procedural pain based on observational distress (regardless of age); and 3) age was found to moderate the relationship between VOEs and procedural pain for child-reported pain and observational distress for children 5 years of age and older. Associations between the endothelin variables and pain prior to venipuncture were also observed. For children with SCD, the child's age and recent pain history should be considered in procedural pain management. The endothelin system may be involved in preprocedure pain, but additional research is needed to understand the role of endothelins in pain sensitization.


[Professional autonomy in the choice and management of therapy. Medicolegal aspects].
Any discussion of the delicate subject of a doctor's autonomy in the choice and management of therapy entails addressing the intimate question of professional and ethical conduct. The professional freedom to choose which therapy to use continues to be the most quintessential expression of the medical professional and, in respect of the primary purpose of safeguarding health, must be aligned with: the choices of the informed patient or his/her legal representatives, existing guidelines and the equitable allocation of resources. On these grounds, the author sets out brief considerations regarding a number of issues frequently raised in the everyday work of the pediatrician and neonatologist: from the doctor's autonomy to adopt a diagnostic-therapeutic approach, with special reference to the prescription of drugs and the subtle differences compared to pharmacological trials, to the promotion and protection of breastfeeding, with explicit reference to the Ministry of Health's recent Circular no. 16 of 24.10.2000 ("Promotion and protection of breastfeeding") which, following a cursory reading of the text, appears to highlight restrictions to the pediatrician's decision-making autonomy. Special emphasis is also given to the medicolegal problems of caring for high-risk neonates. The clinical practice of neonatology often places the doctor in "critical" decision-making situations, with far from negligible ethical and moral implications, not to mention juridical and forensic ones. The author sets out a number of decision-making parameters for use as guidelines: the statistical criterion, the legal criterion and the clinical criterion, the only one capable of adjusting to scientific progress and to the specific technical and professional resources of the medical centre where the doctor is required to intervene in order to preserve even the simple "possibility" of autonomous life for the fetus. From this point of view, the so-called chronological vitality and scientifically proven statistics form part of the numerous criteria available for clinical evaluation. If the clinical criterion is not met, namely if the product of conception is not vital and has never been fully alive in the biologically complete sense of the term, then the omission of therapeutic support is not particularly important in professional and juridical terms. On the contrary, it would show an obstinate persistence of therapy, which would be both ethically and professionally incorrect. Lastly, even during the final stages of life, the doctor must play a participatory role not only by providing palliative treatment but also, and above all, offering moral assistance to sanction the ineluctable end of the therapeutic alliance, that "feeling together" which is the most literal and profound meaning of the word "consent", indicating both "information" but to an even greater extent "discussion" and "empathy" with the patient and his/her family.


Morgagni hernia and thoracic deformities.
We report two cases of Morgagni hernia associated with pectus carinatum. This association is exceptional; only two other cases have been reported so far. In one of our patients, an abdominal surgical approach was used to repair the Morgagni hernia and to perform a Nissen-Rossetti procedure (for an associated endobrachyesophagus); the patient did not require correction of the pectus carinatum. In the other patient, both thoracic deformity and Morgagni hernia were repaired using the same thoracic approach.


Photoinduced oxidation of sterically hindered amines in acetonitrile solutions and titania suspensions (an EPR study).
The reactions of sterically hindered amines (SHA) were investigated in acetonitrile solutions and TiO(2) suspensions upon exposure to monochromatic radiation, λ=365 nm, by means of in situ EPR spectroscopy. The formation of singlet oxygen, as one of the possible oxidation agents for SHA, in these systems is affected significantly by solvent used and the experimental conditions. Experiments in homogeneous media evidenced alternative pathways for the SHA oxidation with a variety reactive oxygen species involved. In anhydrous acetonitrile solutions containing KO(2), the SHA oxidation was negligible not only in the dark but also on continuous exposure. However, the presence of water, even at low concentrations, led to the transformation of O(2)(•-) to singlet oxygen and hydrogen peroxide, which served as a source of hydroxyl radicals. These species participated in oxidation of SHA resulting in the generation of nitroxide radicals. To investigate the influence of different competitive reactions of SHA with other ROS formed upon TiO(2) photoexcitation, a series of experiments using different additives (e.g. KO(2), H(2)O(2), NaN(3), dimethylsulfoxide, methanol as organic cosolvents) under air or argon were performed. The detailed analysis of paramagnetic intermediates formed upon the irradiation of the studied systems was accomplished using EPR spin trapping technique.


A comparative and descriptive study of asthma in chronic rhinosinusitis with nasal polyps.
Chronic rhinosinusitis (CRS) is a common health problem that is subclassified as CRS with nasal polyps (CRSwNPs) or CRS without NPs (CRSsNP). In accordance with the united airways concept, CRSwNPs frequently coexists with asthma but to date, this association remains unexplained and its strength is uncertain. Here, we aimed to examine the association between CRSwNPs and asthma in collaboration between the neighboring specialities: otorhinolaryngology and respiratory medicine. A prospective clinical study was performed comprising 40 CRS patients scheduled for functional endoscopic sinus surgery and 21 control persons. We performed nasal endoscopy, peak expiratory flow, spirometry, and bronchodilation tests. In selected cases, additional pulmonary tests were performed. Atopy was assessed by skin-prick test or by measuring specific IgE in serum. Asthma was diagnosed in 26 patients with CRSwNPs (65%; odds ratio = 5.9 [1.79, 19.65]; p = 0.003), and 5 control persons (24%). Twenty-five percent of the CRSwNP patients had undiagnosed asthma. Atopy was not significantly associated with CRSwNPs (p = 0.39) or with coexisting asthma within the CRSwNP group (p = 0.50). Compared with previous studies, we found a very high prevalence of asthma and, frequently, asthma was undiagnosed. Furthermore, CRSwNPs was associated with chronic bronchitis and, in those with asthma, lower airway obstruction. These results call for a closer collaboration between otorhinolaryngology and respiratory medicine in relation to patients with CRSwNPs, in research as well as in clinical practice.


Chromium propionate supplementation alters animal growth performance, carcass characteristics, and skeletal muscle properties in feedlot steers.
The objective of this study was to evaluate the effects of increasing concentrations of Cr propionate (CrP) on feedlot performance, blood parameters, carcass characteristics, and skeletal muscle fiber properties in feedlot steers. Crossbred steers (n = 32; 367 ± 2.5 kg; 16 pens; 2 hd/pen) were blocked by body weight (BW), and treatment was randomly assigned to pen: (1) 0 mg added Cr/kg diet dry matter (DM) (control), (2) 0.15 mg added Cr/kg diet DM (CrP; KemTRACE Chromium 0.04%, Kemin Industries, Des Moines, IA), (3) 0.30 mg added Cr/kg diet DM, and (4) 0.45 mg added Cr/kg diet DM. Steers were fed ad libitum, and the treatment was top-dressed at the time of feeding. Body weights, blood samples, and longissimus biopsies were collected before feeding on days 0, 28, 56, 91, 119, and 147. Blood sera were harvested for analysis of glucose, insulin, sera urea nitrogen, and non-esterified fatty acid concentrations. Longissimus biopsies were collected for gene expression, protein expression, and immunohistochemical (IHC) analysis. Pen was the experimental unit for live and carcass data, and steer was the experimental unit with day as a repeated measure for sera and IHC analyses. For the entire duration of the trial, a linear increase in average daily gain (ADG) (P = 0.01) and improvement in G:F was observed (P = 0.01) with no change in DMI (P = 0.11) with increasing CrP. A linear increase in hot carcass weight (HCW) (P ≤ 0.01) with no other changes in carcass composition were noted (P ≥ 0.38) as the level of dietary CrP increased. There was no effect of treatment on any sera parameters measured (P ≥ 0.10). No difference was detected for gene or protein expression of glucose transporter type 4 (GLUT4) due to CrP supplementation (P ≥ 0.10). For skeletal muscle fiber distribution and cross-sectional area, there was no effect of treatment (P ≥ 0.10). Density of total GLUT4 did not change due to CrP (P ≥ 0.10). Internalization of GLUT4 was increased in the 0.30 and 0.45 mg/kg treatments (P < 0.01). For total nuclei density and myonuclei density, there were treatment × day interaction tendencies (P ≤ 0.08). Supplementation of CrP did not alter density of satellite cells (P ≥ 0.10). The number of transporters located in the sarcolemma of skeletal muscle fibers did decrease, implying fewer proteins were needed to transport extracellular glucose into the muscle fiber. Therefore, CrP may augment cellular function and growth via increased efficiency of GLUT4 function. These results indicated CrP increases BW, ADG, and HCW, without changes in circulating sera parameters or total GLUT4 expression.


Primary Total Knee Arthroplasty in Patients With Neuropathic (Charcot) Arthropathy: Contemporary Results.
Total knee arthroplasty (TKA) for neuropathic (Charcot) arthropathy is technically challenging with higher complication rates than primary TKA for osteoarthritis. There is a paucity of data regarding outcomes of TKA in contemporary cohorts with modern implants, techniques, and indications. Our study aimed to determine the (1) survivorship of implants, (2) rates and types of complications, (3) clinical outcomes, and (4) radiographic outcomes in patients treated with primary TKA for Charcot arthropathy. Twenty-seven patients undergoing 37 TKAs for Charcot arthropathy from 2000 to 2015 were retrospectively reviewed. Mean patient age and follow-up were 60 years and 6 years, respectively. Eighty-one percent were treated with either a varus-valgus constrained or rotating-hinge device, and 81% had supplemental stem fixation. Metaphyseal cones were utilized in 19% of cases. The 10-year survivorship free of aseptic revision was 88% and free of any revision was 70%. There were 6 revisions (16%): 4 for infection, 1 for tibial component loosening, and 1 for global instability. There were 3 reoperations (8%). Additional complications occurred in 6 patients (16%) including 3 patients with an intraoperative fracture. Mean Knee Society scores improved from 37 preoperatively to 82 postoperatively (P < .001). There was no radiographic evidence of component loosening in any unrevised knee at latest follow-up. Primary TKA for Charcot arthropathy with selective use of increased constraint and enhanced metaphyseal component fixation led to significant improvement in pain and clinical outcomes when compared with older techniques; however, there was a high perioperative complication rate. While 10-year survivorship free of aseptic revision was 88%, periprosthetic joint infection led to the poorer survivorship free of any revision of 70% at 10 years. Level IV.


[Clinical outcomes and characteristics of concurrent eclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome].
the purpose was to describe the outcomes and characteristics of the obstetric patients with concurrent eclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP) syndrome. we retrospectively collected the materials between December 1999 and December 2008 in Obstetric Critical Care Center of Guangzhou. There were 76 patients in rolled then they were divided into two groups according to with or without HELLP syndrome. All the patients were injected Magnesium Sulfate to control seizure and to prevent the recurring of seizure. We analyzed the characteristics (such as age, gestational weeks, blood pressure after seizure), complications, biochemistry markers, the rate for intensive care unit (ICU) admittion, the need for mechanical ventilation, the Glasgow coma score (GCS) when admitted into ICU, computed tomography scan (CT) or magnetic resonance imaging (MRI), death rate of maternal and others, then compared between the two groups. (1) general data: There were 17 patients admitted with both eclampsia and HELLP syndrome, and 59 patients admitted eclampsia without HELLP syndrome. The incidence of eclampsia with HELLP syndrome was 22% (17/76). In eclampsia with HELLP syndrome group, the systolic blood pressure was higher and the rate of preterm also was higher [(182 ± 20) mm Hg (1 mm Hg = 0.133 kPa) vs. (159 ± 21) mm Hg, P < 0.05]. But in regard to the age, gestational weeks, the rate of regular prenatal care and diastolic blood pressure, there were no differences between the two groups. (2) Biochemistry markers: the aspartate transaminase (AST), lanine transaminase (ALT), blood urea nitrogen and creatinine were significantly increased in eclampsia with HELLP syndrome group than eclampsia without HELLP syndrome group [(879 ± 337) U/L vs. (90 ± 27) U/L, (344 ± 83) U/L vs. (43 ± 11)U/L, (2245 ± 294) U/L vs. (485 ± 61) U/L, (14 ± 9) mmol/L vs. (7 ± 3) mmol/L, (140 ± 92) µmol/L vs. (83 ± 28) µmol/L, P < 0.01, P < 0.05], and the platelet was lower in eclampsia with HELLP syndrome group [(38 ± 13) × 10(9)/L vs (172 ± 46) × 10(9)/L, P < 0.01]. (3) Clinical outcomes: The maternal death rate was 35% (6/17) in eclampsia with HELLP syndrome patients, and significantly higher than the rate in eclampsia without HELLP syndrome group (3%, 2/59) (P < 0.05). There were more patients admitted to ICU and more patients who need mechanical ventilation in eclampsia with HELLP syndrome (13/17 vs. 34%, 9/17 vs. 24/, P < 0.05), also more patients with GCS ≤ 8 in eclampsia with HELLP syndrome when admitted to ICU (8/17 vs. 7/59, P < 0.05), compared to the eclampsia without HELLP syndrome group. There were more patients complicated with cerebral venous thrombosis and cerebral hemorrhage in eclampsia with HELLP syndrome group than other group (8/17 vs. 7%, P < 0.05). Five of six patients died of cerebral hemorrhage in eclampsia with HELLP syndrome group, while other two missing cases in eclampsia without HELLP syndrome group all died of cerebral hemorrhage. The all missing cases were performed CT or MRI and seven (7/8) of them showed cerebral hemorrhage. the incidence of concurrent eclampsia and HELLP syndrome was not rare, it happened seriously and with more mortalities, such as cerebral hemorrhage, and also the maternal mortality rate was significantly higher. It should be warning that the obstetrician should take great attention for these women, and consider life support treatment for them.


The ins and outs of endocytic trafficking in platelet functions.
Although platelet endocytosis has been recognized in granule cargo loading and the trafficking of several platelet surface receptors, its acute physiological relevance is poorly understood as is its mechanism. The present review discusses the current understanding of platelet endocytosis and its implications for platelet function. Recent studies are beginning to identify and define the proteins that mediate platelet endocytosis. These studies have shown that platelets contain different endosomal compartments and may use multiple endocytic routes to take in circulating molecules and surface proteins. The studies have also shown that platelet endocytosis is involved in several aspects of platelet function such as signaling, spreading, and granule cargo loading. Mechanistic studies of platelet endocytosis have shown it to be not only involved in granule cargo loading but also in various other platelet functions important for hemostasis and beyond.


Addiction medicine for the primary care physician.
Addiction and the consequences including medical, social, and legal are seen almost daily in a primary care office. To effectively deal with these problems it is imperative that the physician view addiction as a disease. This article explores the disease concept and the basis for the view as well as providing a guide to diagnosis and assessment. Useful screening tools are also provided as well as a discussion of biochemical markers currently available. A guideline for delivering the diagnosis is also discussed. An overview of the stages of treatment is provided as well, with particular emphasis on what the primary care physician needs to know. Outcome data regarding types of treatment looking at abstinence, harm reduction, and economic impacts are provided. Finally a look at parity for addiction treatment with a discussion of the cost and the benefits to society are also outlined.


Biologic interventions for fatigue in rheumatoid arthritis.
Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence-based management guidelines. Evidence suggests that biologic interventions improve symptoms and signs in RA as well as reducing joint damage. To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis. We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation Abstracts International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors. We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure. Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta-analyses using a random-effects model. We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of -0.43 (95% confidence interval (CI) -0.38 to -0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at -0.42 (95% CI -0.35 to -0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was -0.46 (95% CI -0.39 to -0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue. Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.


Composite broad-band fiber Raman amplifiers using incoherent pumping.
This report presents an investigation of composite fiber Raman amplifiers (i.e., a distributed fiber Raman amplifier followed by a discrete fiber Raman amplifier) with in-coherent pumping, compared to conventional coherent pumping. It is shown that a flatter gain, noise figure and optical signal-to-noise ratio (OSNR) over 100-nm bandwidth can be achieved simultaneously by using two counter-incoherent pumps, compared to using six counter-coherent pumps. Moreover, it is found that a further improvement in gain, noise figure and OSNR flatness can be obtained in composite fiber Raman amplifiers with bi-directional incoherent pumping. The flatness of both gain and OSNR with a ripple of 1 dB is predicted by using one co-incoherent pump and one counter-incoherent pump.


Injury risk is different in team and individual youth sport.
This study compared sports injury incidence in young high-level athletes from various team and individual sports and investigated if sport participation patterns are linked to injuries. Prospective cohort follow-up. Pupils from a public sports school (12-19 years) were recruited over two separate school years (2008-2009: 42 weeks, n=199 athletes; 2009-2010: 40 weeks, n=89 athletes). Training and competition volume and intensity were recorded via a personal sports diary. Sports injuries (time-loss definition) were registered by medical staff members using a standardized questionnaire. Injury incidence was significantly higher in team compared with individual sports (6.16 versus 2.88 injuries/1000h, respectively), as a result of a higher incidence of both traumatic (RR=2.17; CI95%=1.75-2.70; p<0.001), and overuse injuries (RR=2.06; CI95%=1.46-2.91; p<0.001). A Cox proportional hazards regression revealed that team sports participation had a hazard ratio of 2.00 (CI95%=1.49-2.68; p<0.001) compared to individual sports, with additionally previous injury being a risk and age a protective factor. The number of competitions per 100 days was significantly higher in team sports, whereas the number of intense training sessions per 100 days was significantly lower. In team sports, the number of competitions per 100 days was positively associated with injuries (HR=1.072; CI95% [1.033; 1.113]; p<0.001), while in individual sports the number of competitions per 100 days had a protective effect (HR=0.940; CI95% [0.893; 0.989]; p=0.017). Team sports participation entailed a higher injury risk, whatever the injury category. Further research should elucidate the role of characteristics related to sport participation in injury causation.


Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells.
A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10(-7) M), T(4) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T(3)) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T(4) and T(3) to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T(4)>T(3)) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T(4)-induced, but not T(3)-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.


Resolving the CaP-bone interface: a review of discoveries with light and electron microscopy.
It has long been known that the interfacial relationship between synthetic materials and tissue is influential in the success of implant materials. Instability at the implant interface has been shown, in some cases, to lead to complete implant failure. Bioceramics, and in particular calcium phosphates, form a large fraction of the implantable devices on the market today due to the biocompatibility they exhibit in contact with bone and tooth-like tissues. The characterization of such bioceramic-tissue interfaces has played a crucial role in understanding the behavior of bioceramics in vivo. In this review, we shed light on the preparation methods, technological approaches and key advances in resolving the interface between calcium phosphate bioceramics and bone, and share a future outlook on this field.


Synthesis of ultrathin WSe2 nanosheets and their high-performance catalysis for conversion of amines to imines.
Tungsten diselenide (WSe2) is the material with the lowest thermal conductivity in the world. Most physical methods are used for the synthesis of tungsten diselenide. Here, a simple colloidal method is reported for the synthesis of WSe2 nanosheets. The composition, valence, size, morphology and properties of the samples were characterized and measured. Results showed that the obtained WSe2 nanosheets with a thickness of 0.7 nm had strong blue fluorescence. Significantly, the synthesized WSe2 nanosheets exhibited excellent catalytic activity for the aerobic coupling of amines to imines, with 100% yield under visible light irradiation and air atmosphere. As a photocatalyst, it exhibited excellent recyclability, and maintained a high yield after 5 cycles. It was found that this reaction could also happen in the presence of natural light by slightly extending the reaction time. Moreover, H2O was used as a solvent in the catalytic process, avoiding expensive and toxic organic solvents. This work provides an efficient, economical and sustainable process for the synthesis of imines and shows the great potential of WSe2 nanosheets as photocatalysts for organic synthesis.


SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles.
Autism is a neurodevelopmental disorder characterized by impaired social reciprocity, impaired communication and stereotypical behaviors. Despite strong evidence for a genetic basis, few susceptibility genes have been identified. Here, we describe the positional cloning of SCAMP5, CLIC4 and PPCDC as candidate genes for autism, starting from a person with idiopathic, sporadic autism carrying a de novo chromosomal translocation. One of these genes, SCAMP5 is silenced on the derivative chromosome, and encodes a brain-enriched protein involved in membrane trafficking, similar to the previously identified candidate genes NBEA and AMISYN. Gene silencing of Nbea, Amisyn and Scamp5 in mouse beta-TC3 cells resulted in a 2-fold increase in stimulated secretion of large dense-core vesicles (LDCVs), while overexpression suppressed secretion. Moreover, ultrastructural analysis of blood platelets from the patients with haploinsufficieny of one of the three candidate genes, showed morphological abnormalities of dense-core granules, which closely resemble LDCVs. Taken together, this study shows that in three independent patients with autism three different negative regulators of LDCV secretion are affected, respectively, suggesting that in at least a subgroup of patients the regulation of neuronal vesicle trafficking may be involved in the pathogenesis of autism.


Differential cofactor requirements for histone eviction from two nucleosomes at the yeast PHO84 promoter are determined by intrinsic nucleosome stability.
We showed previously that the strong PHO5 promoter is less dependent on chromatin cofactors than the weaker coregulated PHO8 promoter. In this study we asked if chromatin remodeling at the even stronger PHO84 promoter was correspondingly less cofactor dependent. The repressed PHO84 promoter showed a short hypersensitive region that was flanked upstream and downstream by a positioned nucleosome and contained two transactivator Pho4 sites. Promoter induction generated an extensive hypersensitive and histone-depleted region, yielding two more Pho4 sites accessible. This remodeling was strictly Pho4 dependent, strongly dependent on the remodelers Snf2 and Ino80 and on the histone acetyltransferase Gcn5, and more weakly on the acetyltransferase Rtt109. Importantly, remodeling of each of the two positioned nucleosomes required Snf2 and Ino80 to different degrees. Only remodeling of the upstream nucleosome was strictly dependent on Snf2. Further, remodeling of the upstream nucleosome was more dependent on Ino80 than remodeling of the downstream nucleosome. Both nucleosomes differed in their intrinsic stabilities as predicted in silico and measured in vitro. The causal relationship between the different nucleosome stabilities and the different cofactor requirements was shown by introducing destabilizing mutations in vivo. Therefore, chromatin cofactor requirements were determined by intrinsic nucleosome stabilities rather than correlated to promoter strength.


The involvement of adherens junction components in myofibrillogenesis in cultured cardiac myocytes.
The distribution of adherens junction (AJ) components was investigated in cultured heart myocytes. These cells, derived from either newborn rats or chick embryos, develop elaborate arrays of myofibrils which become extensive and laterally aligned following several days in culture. The Z-disks in these cells, visualized by immunolabeling with antibodies to muscle-specific alpha-actinin, exhibit a characteristic periodicity of about 2 microns and are in register with those of neighboring myofibrils throughout the sarcoplasm. Vinculin, in these cells, associates with intercellular AJ and cell-matrix adhesions. In addition, this protein is detected in periodic bands located along the lateral cell membranes corresponding to "costamers" previously described by Pardo, J.V., Siliciano, J.D. and Craig, S.W. (Proc. Natn. Acad. Sci. USA, 80, 1008). Similarly, N-cadherin, which is predominantly associated with intercellular junctions, is also detected in periodic striations located mainly on the dorsal and lateral cell surfaces. Using computer-aided three-dimensional microscopy confirmed that these vinculin- and N-cadherin-containing structures are located in extrajunctional sites, apparently associated with Z-disks of peripheral myofibrils. Based on these findings an alternative pathway is proposed for the assembly of vinculin and N-cadherin, which is not triggered by adhesive interactions with extracellular surfaces but rather by interactions at the membrane-cytoplasm interphase with the periphery of the pre-assembled myofibrils. Moreover, we present evidence that antibodies to N-cadherin, which are capable of blocking AJ formation in culture, have an inhibitory effect also on the development and alignment of myofibrils. We discuss the functional significance of the "costameric" organization of vinculin and N-cadherin and consider its involvement both in the lateral alignment of neighboring muscle cells and in the stabilization of developing myofibrils.


Oxidized LDL/CD36 interaction induces loss of cell polarity and inhibits macrophage locomotion.
Cell polarization is essential for migration and the exploratory function of leukocytes. However, the mechanism by which cells maintain polarity or how cells revert to the immobilized state by gaining cellular symmetry is not clear. Previously we showed that interaction between oxidized low-density lipoprotein (oxLDL) and CD36 inhibits macrophage migration; in the current study we tested the hypothesis that oxLDL/CD36-induced inhibition of migration is the result of intracellular signals that regulate cell polarity. Live cell imaging of macrophages showed that oxLDL actuated retraction of macrophage front end lamellipodia and induced loss of cell polarity. Cd36 null and macrophages null for Vav, a guanine nucleotide exchange factor (GEF), did not show this effect. These findings were caused by Rac-mediated inhibition of nonmuscle myosin II, a cell polarity determinant. OxLDL induced dephosphorylation of myosin regulatory light chain (MRLC) by increasing the activity of Rac. Six-thioguanine triphosphate (6-thio-GTP), which inhibits Vav-mediated activation of Rac, abrogated the effect of oxLDL. Activation of the Vav-Rac-myosin II pathway by oxidant stress may induce trapping of macrophages at sites of chronic inflammation such as atherosclerotic plaque.


Characteristics of malignant lymphoma in eastern Taiwan: comparison between aborigines and nonaborigines.
To study the characteristics of malignant lymphoma in aboriginal and nonaboriginal patients in eastern Taiwan, the records of 90 patients treated from July 1986 to September 1994 were reviewed. Immunohistologic staining with UCHL-1 and L-26 was used to determine immunophenotype. There were 20 aboriginal and 70 nonaboriginal patients (22% vs 78%). Among them, three had Hodgkin's diseases (HD) and 87 had non-Hodgkin's lymphomas (NHL). Comparing the histology of malignant lymphoma in aboriginal and nonaboriginal patients, there was no case of HD or follicular lymphoma in aborigines. Concerning primary extranodal lymphoma, no aboriginal patients were found to have gastric lymphoma, while eight nonaboriginal patients did. Among patients with intermediate and high-grade NHL, aboriginal patients had a higher rate of B symptoms (weight loss, fever, night sweats) than did nonaboriginal patients. In T cell lymphoma, three out of four (75%) aboriginal patients had angioimmunoblastic lymphadenopathy with dysproteinemia as compared with three out of 20 (15%) nonaboriginal patients. There were no significant differences in demographic data, stage or distribution of immunophenotype between the two groups. Several combination chemotherapy regimens were used and only 31 patients were considered evaluable, of which 12 were aboriginal and 19 were nonaboriginal patients. No distinct difference was found between aboriginal and nonaboriginal patients in overall response rate, complete response rate, disease-free survival or overall survival. Comparison of our results with other lymphoma studies in Taiwan revealed that the frequencies of HD and follicular lymphoma were higher in northern Taiwan studies than in southern and eastern Taiwan studies, and the frequency of primary extranodal lymphoma was much higher in eastern Taiwan than in other areas. While the rate of T cell lymphoma in NHL for nonaboriginal patients was similar to that of northern Taiwan studies, it was closer to that of southern Taiwan studies in aboriginal patients.


Metabotropic glutamate receptor 1 promotes cementoblast proliferation via MAP kinase signaling pathways.
Glutamate is one of the signaling molecules responsible for transmission in the central nervous system. Periodontal ligament (PDL) cells were recently reported to express metabotropic glutamate receptors (mGluRs). However, the functions of mGluR signaling in PDL cells or PDL-related cells remain largely unknown. The aim of this study was to investigate the expression and function of mGluRs in PDL-related cells. OCCM-30 cells, immortalized murine cementoblasts, were stimulated with l-glutamate or mGluRs antagonists. The cells' proliferative response was evaluated using a colorimetric assay and gene expression was assessed using real-time polymerase chain reaction. The nuclear translocation of cyclin D1 was evaluated by immunohistochemistry. l-Glutamate promoted the proliferation of OCCM-30 cells, which expressed mGluR1, but not mGluR5. Dihydroxyphenylglycine (DHPG), an agonist of group I mGluRs (mGluR1 and mGluR5), also promoted cell proliferation, and this was inhibited by LY456236, an mGluR1 antagonist. DHPG increased the expression of cyclin D1, a key regulator of cell proliferation, and its nuclear translocation. DHPG also increased the expression of Bcl2A1, an antiapoptotic oncogene and simultaneously reduced the expression of Bax, a pro-apoptotic marker. Furthermore, the DHPG-induced proliferation of OCCM-30 cells was reduced by pretreatment with SB203580, SP600125, and PD98059, inhibitors of p38, JNK, and ERK1/2, respectively. These findings indicate that activation of mGluR1 expressed by OCCM-30 cells induces cell proliferation in a manner that is dependent on mitogen-activated protein kinase pathways and that cyclin D1 and Bcl2A1/Bax may be involved. Our results provide useful information for elucidating the mechanisms underlying cementum homeostasis and regeneration.


Laminin alpha 3 forms a complex with beta3 and gamma3 chains that serves as the ligand for alpha 6beta1-integrin at the apical ectoplasmic specialization in adult rat testes.
Apical ectoplasmic specialization (ES) is a testis-specific hybrid cell/cell actin-based adherens junction and cell/matrix focal contact anchoring junction type restricted to the interface between Sertoli cells and developing spermatids. Recent studies have shown that laminin gamma3, restricted to elongating spermatids, is a putative binding partner of alpha 6beta 1-integrin localized in Sertoli cells at the apical ES. However, the identity of the alpha and beta chains, which constitute a functional laminin ligand with the gamma3 chain at the apical ES, is not known. Using reverse transcription-PCR and immunoblotting to survey all laminin chains in cells of the seminiferous epithelium, it was noted that alpha 2, alpha 3, beta1, beta2, beta3, and gamma3 chains were found in germ cells, whereas alpha 1, alpha 2, alpha 4, alpha 5, beta1, beta2, gamma1, gamma2, and gamma3 chains were found in Sertoli cells, implying that alpha 3 and beta3 are the plausible laminin chains restricted to germ cells that may be the bona fide partners of gamma3. To verify this postulate, recombinant proteins based on domain G of alpha 3 and domain I of beta3 and gamma3 chains were produced and used to obtain the corresponding specific polyclonal antibodies. Additional studies have demonstrated that the laminin alpha 3, beta3, and gamma3 chains indeed are restricted to germ cells at the apical ES, co-localizing with each other and with beta1-integrin. Furthermore, co-immunoprecipitation studies have confirmed the interactions among laminin alpha 3, beta3, and gamma3, as well as beta1-integrin. When the functional laminin ligand at the apical ES was disrupted via blocking antibodies, such as using anti-laminin alpha 3 or gamma3 IgG, this treatment perturbed adhesion between Sertoli and germ cells (mostly spermatids), leading to germ cell loss from the epithelium. More important, a transient disruption of the blood-testis barrier was also detected.


Quaternary Core-Shell Oxynitride Nanowire Photoanode Containing a Hole-Extraction Gradient for Photoelectrochemical Water Oxidation.
A nanowire photoanode SrTaO2N, a semiconductor suitable for overall water-splitting with a band gap of 2.3 eV, was coated with functional overlayers to yield a core-shell structure while maintaining its one-dimensional morphology. The nanowires were grown hydrothermally on tantalum, and the perovskite-related oxynitride structure was obtained by nitridation. Three functional overlayers have been deposited on the nanowires to enhance the efficiency of photoelectrochemical (PEC) water oxidation. The deposition of TiO x protects the oxynitride from photocorrosion and suppresses charge-carrier recombination at the surface. Ni(OH) x acts a hole-storage layer and decreases the dark-current contribution. This leads to a significantly improved extraction of photogenerated holes to the electrode-electrolyte surface. The photocurrents can be increased by the deposition of a cobalt phosphate (CoPi) layer as a cocatalyst. The heterojunction nanowire photoanode generates a current density of 0.27 mA cm-2 at 1.23 V vs the reversible hydrogen electrode (RHE) under simulated sunlight (AM 1.5G). Simultaneously, the dark-current contribution, a common problem for oxynitride photoanodes grown on metallic substrates, is almost completely minimized. This is the first report of a quaternary oxynitride nanowire photoanode in core-shell geometry containing functional overlayers for synergetic hole extraction and an electrocatalyst.


Covariate adjustment and estimation of mean response in randomised trials.
Analyses of randomised trials are often based on regression models which adjust for baseline covariates, in addition to randomised group. Based on such models, one can obtain estimates of the marginal mean outcome for the population under assignment to each treatment, by averaging the model-based predictions across the empirical distribution of the baseline covariates in the trial. We identify under what conditions such estimates are consistent, and in particular show that for canonical generalised linear models, the resulting estimates are always consistent. We show that a recently proposed variance estimator underestimates the variance of the estimator around the true marginal population mean when the baseline covariates are not fixed in repeated sampling and provide a simple adjustment to remedy this. We also describe an alternative semiparametric estimator, which is consistent even when the outcome regression model used is misspecified. The different estimators are compared through simulations and application to a recently conducted trial in asthma.


End-to-End Learnt Image Compression via Non-Local Attention Optimization and Improved Context Modeling.
This article proposes an end-to-end learnt lossy image compression approach, which is built on top of the deep nerual network (DNN)-based variational auto-encoder (VAE) structure with Non-Local Attention optimization and Improved Context modeling (NLAIC). Our NLAIC 1) embeds non-local network operations as non-linear transforms in both main and hyper coders for deriving respective latent features and hyperpriors by exploiting both local and global correlations, 2) applies attention mechanism to generate implicit masks that are used to weigh the features for adaptive bit allocation, and 3) implements the improved conditional entropy modeling of latent features using joint 3D convolutional neural network (CNN)-based autoregressive contexts and hyperpriors. Towards the practical application, additional enhancements are also introduced to speed up the computational processing (e.g., parallel 3D CNN-based context prediction), decrease the memory consumption (e.g., sparse non-local processing) and reduce the implementation complexity (e.g., a unified model for variable rates without re-training). The proposed model outperforms existing learnt and conventional (e.g., BPG, JPEG2000, JPEG) image compression methods, on both Kodak and Tecnick datasets with the state-of-the-art compression efficiency, for both PSNR and MS-SSIM quality measurements. We have made all materials publicly accessible at https://njuvision.github.io/NIC for reproducible research.


Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators.
Rationale: The endocannabinoidome mediators, N-Oleoylglycine (OlGly) and N-Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses. Objectives: To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats. Methods: Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5). Results: In Experiment 1, spontaneous morphine withdrawal produced somatic withdrawal reactions. The behavioral withdrawal reactions were accompanied by suppressed endogenous levels of OlGly in the nucleus accumbens, amygdala, and prefrontal cortex, N-Arachidonylglycerol and OlAla in the amygdala, 2-arachidonoylglycerol in the nucleus accumbens, amygdala and interoceptive insular cortex, and by changes in colonic microbiota composition. In Experiment 2, treatment with OlAla, but not OlGly, reduced spontaneous morphine withdrawal responses. In Experiment 3, OlAla attenuated spontaneous steady-state heroin withdrawal responses at both 5 and 20 mg/kg; OlGly only reduced withdrawal responses at the higher dose of 20 mg/kg. Experiment 4 demonstrated that naloxone-precipitated heroin withdrawal from steady-state exposure to heroin (7 mg/kg/day for 12 days) is accompanied by tissue-specific changes in brain or gut endocannabinoidome mediator, including OlGly and OlAla, levels and colonic microbiota composition, and that OlAla (5 mg/kg) attenuated behavioural withdrawal reactions, while also reversing some of the changes in brain and gut endocannabinoidome and gut microbiota induced by naloxone. Experiment 5 demonstrated that although OlAla (5 mg/kg) did not interfere with operant heroin self-administration on its own, it blocked naloxone-precipitated elevation of heroin self-administration behavior. Conclusion: These results suggest that OlAla and OlGly are two endogenous mediators whose brain concentrations respond to chronic opiate treatment and withdrawal concomitantly with changes in colon microbiota composition, and that OlAla may be more effective than OlGly in suppressing chronic opiate withdrawal responses.


Surgical management of tumors that produce gastrointestinal hormones.
Gastrointestinal hormones are produced by specialized endocrine cells found both in the pancreas and distributed throughout the gut. Tumors, both benign and malignant, produce excessive amounts of hormone and thereby cause characteristic syndromes. Surgical management must be primarily directed at tumor removal in order to effect cure of the syndrome, as well as to prevent complications of persistent tumor growth and, subsequently, metastasis.


RenaGel (Geltex Pharmaceuticals Inc).
RenaGel, developed by GelTex, is a polymer that binds and removes dietary phosphate from the intestinal tract without being absorbed into the bloodstream. A US NDA for control of hyperphosphatemia in patients with chronic renal failure was filed in October 1997 and accepted for review in January 1998. Marketing approval was granted in November 1998. The compound has also achieved part B status in Europe. Merrill Lynch predict RenaGel will achieve worldwide sales of $220 million by 2001.


Iroquois genes influence proximo-distal morphogenesis during rat lung development.
Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1-3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in beta-tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh- and Gli(2)-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways.


Comparison of non-human primate and human whole blood tissue gene expression profiles.
Gene expression profiling is an important tool in the development of medical countermeasures against chemical warfare agents (CWAs). Non-human primates (NHPs), specifically the rhesus macaque (Macaca mulatta), the cynomologus macaque (Macaca fascicularis), and the African green monkey (Chlorocebus aethiops), are vital models in the development of CWA prophylactics, therapeutics, and diagnostics. However, gene expression profiling of these NHPs is complicated by the fact their genomes are not completely sequenced, and that no commercially available oligonucleotide microarrays (genechips) exist. We, therefore, sought to determine whether gene expression profiling of NHPs could be performed using human genechips. Whole blood RNA was isolated from each species and used to generate genechip probes. Hybridization of the NHP samples to human genechips (Affymetrix Human U133 Plus 2.0) resulted in comparable numbers of transcripts detected compared with human samples. Statistical analysis revealed intraspecies reproducibility of genechip quality control metrics; interspecies comparison between NHPs and humans showed little significant difference in the quality and reproducibility of data generated using human genechips. Expression profiles of each species were compared using principal component analysis (PCA) and hierarchical clustering to determine the similarity of the expression profiles within and across the species. The cynomologus group showed the least intraspecies variability, and the human group showed the greatest intraspecies variability. Intraspecies comparison of the expression profiles identified probe sets that were reproducibly detected within each species. Each NHP species was found to be dissimilar to humans; the cynomologus group was the most dissimilar. Interspecies comparison of the expression profiles revealed probe sets that were reproducibly detected in all species examined. These results show that human genechips can be used for expression profiling of NHP samples and provide a foundation for the development of tools for comparing human and NHP gene expression profiles.


Barriers and facilitators of implementation of a community cardiovascular disease prevention programme in Mukono and Buikwe districts in Uganda using the Consolidated Framework for Implementation Research.
In low- and middle-income countries, there is an increasing attention towards community approaches to deal with the growing burden of cardiovascular disease (CVD). However, few studies have explored the implementation processes of such interventions to inform their scale up and sustainability. Using the consolidated framework for implementation research (CFIR), we examined the barriers and facilitators influencing the implementation of a community CVD programme led by community health workers (CHWs) in Mukono and Buikwe districts in Uganda. This qualitative study is a process evaluation of an ongoing type II hybrid stepped wedge cluster trial guided by the CFIR. Data for this analysis were collected through regular meetings and focus group discussions (FGDs) conducted during the first cycle (6 months) of intervention implementation. A total of 20 CHWs participated in the implementation programme in 20 villages during the first cycle. Meeting reports and FGD transcripts were analysed following inductive thematic analysis with the aid of Nvivo 12.6 to generate emerging themes and sub-themes and thereafter deductive analysis was used to map themes and sub-themes onto the CFIR domains and constructs. The barriers to intervention implementation were the complexity of the intervention (complexity), compatibility with community culture (culture), the lack of an enabling environment for behaviour change (patient needs and resources) and mistrust of CHWs by community members (relative priority). In addition, the low community awareness of CVD (tension for change), competing demands (other personal attributes) and unfavourable policies (external policy and incentives) impeded intervention implementation. On the other hand, facilitators of intervention implementation were availability of inputs and protective equipment (design quality and packaging), training of CHWs (Available resources), working with community structures including leaders and groups (process-opinion leaders), frequent support supervision and engagements (process-formally appointed internal implementation leaders) and access to quality health services (process-champions). Using the CFIR, we identified drivers of implementation success or failure for a community CVD prevention programme in a low-income context. These findings are key to inform the design of impactful, scalable and sustainable CHW programmes for non-communicable diseases prevention and control.


Regulatory roles of HSPA6 in Actinidia chinensis Planch. root extract (acRoots)-inhibited lung cancer proliferation.
Actinidia chinensis Planch. root extract (acRoots) as one of Chinese traditional medications has been applied for antitumor therapy for decades, although the exact mechanisms have not been revealed. Our present study aimed to define the inhibitory specificity and pattern of acRoots in the lung cancer cell lines by comparing 40 types of cancer cell lines, select acRoots-associated inflammation target genes from transcriptional profiles of acRoots-sensitive and less-sensitive lung cancer cell lines, and validate the correlation of acRoots-associated inflammation target genes with prognosis of patients with lung cancer. We selected acRoots-sensitive (H1299) and less-sensitive lung cancer cells (H460) and found that the sensitivity was associated with the appearance of p53. The heat shock 70 kDa protein 6 (HSPA6) was defined as a critical factor in regulating cell sensitivity probably through the interaction with intra-HSPA family members, inter-HSP family members, and other families. The degree of cell sensitivity to acRoots increased in both sensitive and less-sensitive cells after deletion of HSPA6 genes. Thus, our data indicate that HSPA6 and HSPA6-dominated molecular network can be an alternative to modify cell sensitivity to drugs.


Association of cytomegalovirus infection and disease with death and graft loss after liver transplant in high-risk recipients.
In the era of effective antiviral chemoprophylaxis, cytomegalovirus (CMV) disease has been inconsistently associated with increased mortality in liver transplant (LT) recipients. A retrospective study evaluating the association of CMV infection and disease occurring within 1 year of transplant with the endpoints of death or the combined endpoint of graft loss or death was undertaken in a cohort of 227 CMV donor seropositive, recipient seronegative first LT recipients. Associations were evaluated using Cox proportional hazards regression models. CMV infection and disease occurred in 91 (40%) and 43 (19%) patients, respectively. Forty-eight (21%) died while 58 (26%) sustained graft loss or death. In multivariable analysis, CMV infection was associated with an increased risk of death (RR: 2.24, p = 0.008) and graft loss or death (RR: 2.85, p < 0.001). CMV disease was also associated with an increased risk of death (RR: 2.73, p = 0.003) and graft loss or death (RR: 3.04, p = 0.001). CMV infection and disease occurring within the first year after LT in high-risk recipients is associated with increased risk of death and of graft loss or death. Investigation of strategies to further reduce the risk of CMV infection and disease in high-risk LT recipients is warranted.


Opinions and observations of caregivers of children with cerebral palsy about changes seen after reflexology: A qualitative study.
The aim of this research was to examine the effect of reflexology on the problems of children with cerebral palsy from perspective of caregivers. Qualitative study was made after 24-session reflexology program. 12 caregivers who have 2-18 year-old children with spastic type cerebral palsy receiving special education and received reflexology. The thematic questions were determined and in-depth interviews were conducted. Themes of the study were determined as; the caregiver's views on reflexology, the effect of reflexology on health of children with CP and the caregivers' observations on child after reflexology therapy, positive and negative aspects and causes of reflexology treatment. As a results; the caregivers expressed that there were increases in self-confidence of children, improvement in walking, reduced spasticity, relaxation, decreases in constipation, and increases in communication, speech and perception after reflexology.


Coffee consumption and risk of chronic disease in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study.
Early studies suggested that coffee consumption may increase the risk of chronic disease. We investigated prospectively the association between coffee consumption and the risk of chronic diseases, including type 2 diabetes (T2D), myocardial infarction (MI), stroke, and cancer. We used data from 42,659 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany study. Coffee consumption was assessed by self-administered food-frequency questionnaire at baseline, and data on medically verified incident chronic diseases were collected by active and passive follow-up procedures. HRs and 95% CIs were calculated with multivariate Cox regression models and compared by competing risk analysis. During 8.9 y of follow-up, we observed 1432 cases of T2D, 394 of MI, 310 of stroke, and 1801 of cancer as first qualifying events. Caffeinated (HR: 0.94; 95% CI: 0.84, 1.05) or decaffeinated (HR: 1.05; 95% CI: 0.84, 1.31) coffee consumption (≥4 cups/d compared with <1 cup/d; 1 cup was defined as 150 mL) was not associated with the overall risk of chronic disease. A lower risk of T2D was associated with caffeinated (HR: 0.77; 95% CI: 0.63, 0.94; P-trend 0.009) and decaffeinated (HR: 0.70; 95% CI: 0.46, 1.06; P-trend: 0.043) coffee consumption (≥4 cups/d compared with <1 cup/d), but cardiovascular disease and cancer risk were not. The competing risk analysis showed no significant differences between the risk associations of individual diseases. Our findings suggest that coffee consumption does not increase the risk of chronic disease, but it may be linked to a lower risk of T2D.


Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage.
Chaperone-mediated autophagy (CMA) is activated in response to cellular stressors to prevent cellular proteotoxicity through selective degradation of altered proteins in lysosomes. Reduced CMA activity contributes to the decrease in proteome quality in disease and ageing. Here, we report that CMA is also upregulated in response to genotoxic insults and that declined CMA functionality leads to reduced cell survival and genomic instability. This role of CMA in genome quality control is exerted through regulated degradation of activated checkpoint kinase 1 (Chk1) by this pathway after the genotoxic insult. Nuclear accumulation of Chk1 in CMA-deficient cells compromises cell cycle progression and prolongs the time that DNA damage persists in these cells. Furthermore, blockage of CMA leads to hyperphosphorylation and destabilization of the MRN (Mre11-Rad50-Nbs1) complex, which participates in early steps of particular DNA repair pathways. We propose that CMA contributes to maintain genome stability by assuring nuclear proteostasis.


Child Sex Trafficking: Strategies for Identification, Counseling, and Advocacy.
The human rights violation of sex trafficking continues to occur in the United States at alarming rates. Although sex trafficking affects individuals across various demographic groups, this crime disproportionately affects children. Counselors who work with children and adolescents are uniquely positioned to identify, support, and advocate on behalf of sex trafficked youth who may experience barriers to emotional and physical wellness. Extant literature on counseling sex trafficking survivors remain scarce and illuminate the need for victim identification, trauma-informed interventions, and advocacy strategies that support the unique needs of child sex trafficking survivors. To address these disparities, this article describes victim identification techniques, outlines trauma-focused interventions for counseling sex trafficked youth, and presents advocacy strategies. The implications for counseling child sex trafficking survivors are illuminated through a case study.


A pragmatic randomised controlled trial to evaluate the cost-effectiveness of a physical activity intervention as a treatment for depression: the treating depression with physical activity (TREAD) trial.
The TREAting Depression with physical activity (TREAD) study investigated the cost-effectiveness of a physical activity intervention, in addition to usual general practitioner care, as a treatment for people with depression. An individually randomised, pragmatic, multicentre randomised controlled trial with follow-up at 4, 8 and 12 months. A subset of participants took part in a qualitative study that investigated the acceptability and perceived benefits of the intervention. General practices in the Bristol and Exeter areas. Aged 18-69 years with an International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10) diagnosis of depression and scoring ≥ 14 on the Beck Depression Inventory (BDI). Those who were unable to complete self-administered questionnaires in English, with medical contraindications to physical activity or with psychosis, bipolar disorder or serious drug abuse were excluded. We devised an intervention designed to encourage choice and autonomy in the adoption of physical activity. It consisted of up to three face-to-face and ten telephone contacts delivered by a trained physical activity facilitator over an 8-month period. The primary outcome was the BDI score measured at 4 months. Secondary outcomes included depressive symptoms over the 12 months and quality of life, antidepressant use and level of physical activity. The study recruited 361 patients, with 182 randomised to the intervention arm and 179 to the usual care arm; there was 80% retention at the 4-month follow-up. The intervention group had a slightly lower BDI score at 4 months [-0.54, 95% confidence interval (CI) -3.06 to 1.99] but there was no evidence that the intervention improved outcome for depression. Neither was there any evidence to suggest a difference in the prescription of or self-reported use of antidepressants. However, the amount of physical activity undertaken by those who had received the intervention was increased (odds ratio 2.3, 95% CI 1.3 to 3.9) and was sustained beyond the end of the intervention. From a health-care perspective, the intervention group was more costly than the usual care group, with the cost of the intervention £220 per person on average. It is therefore extremely unlikely that the intervention is cost-effective as a treatment for depression using current willingness-to-pay thresholds. This physical activity intervention is very unlikely to lead to any clinical benefit in terms of depressive symptoms or to be a cost-effective treatment for depression. Previous research has reported some benefit and there are three possible reasons for this discrepancy: first, even though the intervention increased self-reported physical activity, the increase in activity was not sufficiently large to lead to a measurable influence; second, only more vigorous activity might be of benefit; and third, previous studies had recruited individuals with a pre-existing commitment to physical activity. Future research is needed to identify and explain the mechanisms by which depression might be effectively treated, including, in particular, specific guidance on the optimum type, intensity and duration of physical activity required to produce a therapeutic effect. Current Controlled Trials ISRCTN16900744. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 10. See the HTA programme website for further project information.


Proteome Analysis of the Hypothalamic Arcuate Nucleus in Chronic High-Fat Diet-Induced Obesity.
The hypothalamus plays a central role in the integrated regulation of feeding and energy homeostasis. The hypothalamic arcuate nucleus (ARC) contains a population of neurons that express orexigenic and anorexigenic factors and is thought to control feeding behavior via several neuronal circuits. In this study, a comparative proteomic analysis of low-fat control diet- (LFD-) and high-fat diet- (HFD-) induced hypothalamic ARC was performed to identify differentially expressed proteins (DEPs) related to changes in body weight. In the ARC in the hypothalamus, 6621 proteins (FDR < 0.01) were detected, and 178 proteins were categorized as DEPs (89 upregulated and 89 downregulated in the HFD group). Among the Gene Ontology molecular function terms associated with the DEPs, protein binding was the most significant. Fibroblast growth factor receptor substrate 2 (Frs2) and SHC adaptor protein 3 (Shc3) were related to protein binding and involved in the neurotrophin signaling pathway according to Kyoto Encyclopedia of Genes and Genomes analysis. Furthermore, high-precision quantitative proteomic analysis revealed that the protein profile of the ARC in mice with HFD-induced obesity differed from that in LFD mice, thereby offering insight into the molecular basis of feeding regulation and suggesting Frs2 and Shc3 as novel treatment targets for central anorexigenic signal induction.


Enhancing potency of liposomal monensin on ricin cytotoxicity in mouse macrophage tumor cells.
Monensin, a carboxylic ionophore, which is known to disrupt intracellular trafficking of proteins was intercalated in liposomes and its effect on the stability of liposomes and cytotoxicities of ricin and Pseudomonas exotoxin A in mouse macrophage tumor cells J774A.1 was studied. Stability of liposomes containing monensin was comparable to liposomes without monensin. The cytotoxicity of ricin and Pseudomonas exotoxin A was significantly enhanced by 1nM liposomal monensin (15.7 and 3.6 fold respectively). The enhancing potency of monensin in neutral and negative vesicles was found to be similar, while it was drastically reduced in positive vesicles. The specific uptake of 125I-gelonin from neutral and negative vesicles was not significantly different, whereas from positive vesicles no uptake was observed. Serum strongly influenced the binding at 4 degrees C of positive vesicles as well as the enhancing potency of monensin in these vesicles. Monensin in neutral and negative vesicles significantly reduced the lag period of ricin action, while in positive vesicles, it had no effect. These studies clearly indicate that liposomes could be used as a delivery vehicle for monensin.


Effect of perillic acid, a putative isoprenylation inhibitor, on the cultured rat lens.
Previous studies have demonstrated that agents affecting the cholesterol synthetic pathway can have cataractogenic effects. We have suggested that opacification of cultured lenses resulting from exposure to the cholesterol-lowering agent lovastatin is caused by inhibition of isoprenylation of small GTPases. To test that hypothesis we have investigated the effects of perillic acid, an agent reported to inhibit isoprenylation, on rat lenses in organ culture. Perillic acid caused dose and time dependent opacification of cultured lenses. While the opacities appeared grossly similar to those produced by lovastatin, they differed dramatically when analysed histologically. It also produced marked morphological changes to lens epithelial cells in culture. Analysis of small GTPases in the perillic acid treated cells failed to detect any accumulation in the water soluble fraction as would be expected if isoprenylation was inhibited. Further, studies on the isoprenylation of radiolabelled isoprenoids into proteins in cultured lenses showed no significant decrease following perillic acid exposure. It was concluded that perillic acid causes cataract in this system by a mechanism different from lovastatin and that inhibition of isoprenylation is unlikely to be a primary factor in the perillic acid cataract.


Testing and quantifying phylogenetic signals and homoplasy in morphometric data.
The relationship between morphometrics and phylogenetic analysis has long been controversial. Here we propose an approach that is based on mapping morphometric traits onto phylogenies derived from other data and thus avoids the pitfalls encountered by previous studies. This method treats shape as a single, multidimensional character. We propose a test for the presence of a phylogenetic signal in morphometric data, which simulates the null hypothesis of the complete absence of phylogenetic structure by permutation of the shape data among the terminal taxa. We also propose 2 measures of the fit of morphometric data to the phylogeny that are direct extensions of the consistency index and retention index used in traditional cladistics. We apply these methods to a small study of the evolution of wing shape in the Drosophila melanogaster subgroup, for which a very strongly supported phylogeny is available. This case study reveals a significant phylogenetic signal and a relatively low degree of homoplasy. Despite the low homoplasy, the shortest tree computed from landmark data on wing shape is inconsistent with the well-supported phylogenetic tree from molecular data, underscoring that morphometric data may not provide reliable information for inferring phylogeny.


Simultaneous Presence of Macular Corneal Dystrophy and Retinitis Pigmentosa in Three Members of a Family.
Macular corneal dystrophy (MCD) is an autosomal recessive hereditary disease. In most cases, various mutations in carbohydrate sulfotransferase 6 (CHST6) gene are the main cause of MCD. These mutations lead to a defect in keratan sulfate synthesis. Retinitis pigmentosa (RP) is another eye disorder with nyctalopia as its common symptom. It has been shown that more than 65 genes have been implicated in different forms of RP. Herein, we report on a 9-member family with 2 girls and 5 boys. Both parents, one of the girls and one of the boys had normal eye vision and another boy had keratoconus. Other children (1 girl and 2 boys) suffered from both MCD and RP. Corneal transplantation and medical supplements were used for MCD and RP during the follow-up period, respectively. Based on the family tree, it seems that the inheritance of both diseases is autosomal recessive. Based on our search of databases, there is no report on the simultaneous presence of MCD and RP. To the best of our knowledge, the present article is the first case report on this topic. Molecular genetic investigation is needed to clarify the mechanism of concurrent MCD and RP.


[Optical and non-optical aids for the vision-impaired older patient].
Increase of contrast and enlargement of retinal image may lead to an improvement of reading ability of the elderly visually handicapped patient. Pros and cons of available low visual aids are discussed based on the examination or 266 patients of over 60 years of age. High-power addition was sufficient in 27% of the patients. A hand-magnifier of standmagnifier, as well as a telescopic reading unit, or so-called 'prism-loupe' sufficed in 36% of cases. The closed circuit television ('television loupe') was advocated in 17% of cases. The immobility and relative high costs of this apparatus, however, was in a sense prohibitive for further extension of use of this unique instrument, devised for the highly visually handicapped patient. In 20 per cent of cases it was impossible to improve reading ability altogether.


Epidemiological and molecular profile of blood donors infected with HTLV-1/2 in the state of Pará, northern Brazil.
The Human T-lymphotropic virus (HTLV) is a retrovirus of the genus Deltaretrovirus, which belongs to the family Retroviridae. The most important types are HTLV-1 and HTLV-2. It is estimated that between five and 10 million individuals are infected with HTLV-1, worldwide. Studies in the state of Pará indicate that it has the third highest prevalence of HTLV infections of any Brazilian state. The present study describes the epidemiological, serological, and molecular profile of blood donors from the state of Pará that were classified as unfit due to infection by HTLV-1 and 2. The present study is based on a descriptive, retrospective, and cross-sectional review of the epidemiological, serological, and molecular data on blood donations, between January 2015 and December 2019. The data were obtained from the blood bank system and were digitalized to form a database in the Statistical Package for Social Sciences program, version 20. Descriptive statistics were used to determine the absolute and relative frequencies of the qualitative variables. For the quantitative variables, the mean, standard deviation, and minimum and maximum values were calculated. A p < 0.05 significance level was adopted for all analyses. A total of 632 samples were analyzed, of which 496 (78%) had no detectable proviral DNA and 136 (22%) had detectable HTLV. The HTLV-1 was detected in most (78%; 106/136) of these samples, while only 30 (22%) were detected for HTLV-2. The HTLV proviral DNA was detected primarily in females (69.1%), with a mean age of 40 years, with the highest frequencies of detection being recorded in single individuals (66.2%), first-time donors (74.3%), and individuals that had graduated high school (44.1%). The molecular confirmation of HTLV showed that three-quarters (78%) of the serologically reactive individuals were negative for either types 1 or 2, so the epidemiological profile of these individuals was significantly different from their detectable profile. The HTLV is neglected in Brazil; there is thus a clear need for further research in the area of regional hemotherapy and hematology services, in order to contribute to the definition of regional infection profiles, that will be fundamental to the development of effective prophylactic practices for the prevention of the infection and the dissemination of knowledge on the dangers of HTLV in the community.


Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer.
Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron- exon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.


Hemorrhagic acneiform lesions in a teenager as the initial presentation of granulomatosis with polyangiitis.
A 19-year-old girl presented with hemorrhagic acneiform lesions on the face for several months that was unresponsive to conventional acne treatment. A biopsy revealed a noninfectious suppurative granulomatous dermatitis with hemorrhage, possibly representing a ruptured folliculitis. A second biopsy revealed chronic granulomatous dermal inflammation and hemorrhage with foreign body giant cells non-infectious by stains. No vasculitis was noted in either biopsy. Later in her course she developed a severe sinusitis and eventually presented with severe fevers, rapid weight loss, sinusitis, and cough. Further workup produced the diagnosis of granulomatosis with polyangiitis (Wegener's granulomatosis). She rapidly improved with intravenous steroids and rituximab. To date, acneiform lesions have only been reported in young adult patients and may represent a clinical manifestation of granulomatosis with polyangiitis unique to this age group, as illustrated in our patient.


Structural analysis of the hot spots in the binding between H1N1 HA and the 2D1 antibody: do mutations of H1N1 from 1918 to 2009 affect much on this binding?
Worldwide and substantial mortality caused by the 2009 H1N1 influenza A has stimulated a new surge of research on H1N1 viruses. An epitope conservation has been learned in the HA1 protein that allows antibodies to cross-neutralize both 1918 and 2009 H1N1. However, few works have thoroughly studied the binding hot spots in those two antigen-antibody interfaces which are responsible for the antibody cross-neutralization. We apply predictive methods to identify binding hot spots at the epitope sites of the HA1 proteins and at the paratope sites of the 2D1 antibody. We find that the six mutations at the HA1's epitope from 1918 to 2009 should not harm its binding to 2D1. Instead, the change of binding free energy on the whole exhibits an increased tendency after these mutations, making the binding stronger. This is consistent with the observation that the 1918 H1N1 neutralizing antibody can cross-react with 2009 H1N1. We identified three distinguished hot spot residues, including Lys(166), common between the two epitopes. These common hot spots again can explain why 2D1 cross-reacted. We believe that these hot spot residues are mutation candidates which may help H1N1 viruses to evade the immune system. We also identified eight residues at the paratope site of 2D1, five from its heavy chain and three from its light chain, that are predicted to be energetically important in the HA1 recognition. The identification of these hot spot residues and their structural analysis are potentially useful to fight against H1N1 viruses. email@example.com Z-score is available at http://18.104.22.168/liuqian/indexz.py Supplementary data are available at Bioinformatics online.


Louisiana's criteria of eligibility for occupational therapy services in the public school system.
Since the enactment of the Education for All Handicapped Children Act of 1975 (Public Law 94-142), occupational therapists in the public schools have been responsible for determining the occupational therapy needs of special education students. In Louisiana, therapists and special educators, in cooperation with the Louisiana Department of Education, have developed the criteria of eligibility for occupational therapy. These criteria do not alter the descriptive standards established in Public Law 94-142; instead, they provide an objective method for the selection of students in need of occupational therapy. The criteria, which have been revised and refined since 1981, were adopted recently by the Louisiana Board of Elementary and Secondary Education. This paper presents these criteria and examples of their implementation.


Protective Effect of Proanthocyanidins from Sea Buckthorn (Hippophae Rhamnoides L.) Seed against Visible Light-Induced Retinal Degeneration in Vivo.
Dietary proanthocyanidins (PACs) as health-protective agents have become an important area of human nutrition research because of their potent bioactivities. We investigated the retinoprotective effects of PACs from sea buckthorn (Hippophae rhamnoides L.) seed against visible light-induced retinal degeneration in vivo. Pigmented rabbits were orally administered sea buckthorn seed PACs (50 and 100 mg/kg/day) for 14 consecutive days of pre-illumination and seven consecutive days of post-illumination. Retinal function was quantified via electroretinography 7 days after light exposure. Retinal damage was evaluated by measuring the thickness of the full-thickness retina and outer nuclear layer 7 days after light exposure. Sea buckthorn seed PACs significantly attenuated the destruction of electroretinograms and maintained the retinal structure. Increased retinal photooxidative damage was expressed by the depletion of glutathione peroxidase and catalase activities, the decrease of total antioxidant capacity level and the increase of malondialdehyde level. Light exposure induced a significant increase of inflammatory cytokines (IL-1β, TNF-α and IL-6) and angiogenesis (VEGF) levels in retina. Light exposure upregulated the expression of pro-apoptotic proteins Bax and caspase-3 and downregulated the expression of anti-apoptotic protein Bcl-2. However, sea buckthorn seed PACs ameliorated these changes induced by light exposure. Sea buckthorn seed PACs mediated the protective effect against light-induced retinal degeneration via antioxidant, anti-inflammatory and antiapoptotic mechanisms.


Targeting Aflatoxin Biosynthetic Genes.
Chemical detoxification and physical destruction of aflatoxins in foods and feed commodities are mostly unattainable in a way that preserves the edibility of the food. Therefore, preventing mycotoxins in general and aflatoxins in particular from entering the food chain is a better approach. This requires early detection of the aflatoxin-causing organisms. Detection and quantification of aflatoxin-producing fungi has always been a challenge, especially within species of Aspergillus and Penicillium. Culture-based methods require a high level of expertise and a list of sophisticated equipment. Furthermore, even for a trained taxonomist, species that are identical in morphology, physiology, and nutritional aspects can be challenging to classify. Fungal taxonomy has changed over the past few decades; more species are being reclassified, and new species are being described due to advances in sequencing and genome assembly. These developments make the use of PCR-based approaches practical, rapid, and more reliable for the identification of fungi to the species level. This chapter presents a variety of protocols to detect and quantify aflatoxin-producing fungi using mycotoxin biosynthesis pathway genes.


High-efficiency induction of soybean hairy roots and propagation of the soybean cyst nematode.
Cotyledon explants of 10 soybean [Glycine max (L.) Merr.] cultivars were inoculated with Agrobacterium rhizogenes strain K599 with and without binary vectors pBI121 or pBINm-gfp5-ER possessing both neomycin phosphotransferase II (nptII) and beta-glucuronidase (gus) or nptII and green fluorescent protein (gfp) genes, respectively. Hairy roots were produced from the wounded surface of 54-95% of the cotyledon explants on MXB selective medium containing 200 microg ml(-1) kanamycin and 500 microg ml(-1) carbenicillin. Putative individual transformed hairy roots were identified by cucumopine analysis and were screened for transgene incorporation using polymerase chain reaction. All of the roots tested were found to be co-transformed with T-DNA from the Ri-plasmid and the transgene from the binary vectors. Southern blot analysis confirmed the presence of the 35S-gfp5 gene in the plant genomes. Transgene expression was also confirmed by histochemical GUS assay and Western blot analysis for the GFP. Attempts to induce shoot formation from the hairy roots failed. Infection of hairy roots of the soybean cyst nematode (Heterodera glycines Ichinohe)-susceptible cultivar, Williams 82, with eggs of H. glycines race 1, resulted in the development of mature cysts about 4-5 weeks after inoculation. Thus the soybean cyst nematode could complete its entire life cycle in transformed soybean hairy-root cultures expressing GFP. This system should be ideal for testing genes that might impart resistance to soybean cyst nematode.


[Spastic torticollis (clinical picture, etiology, pathogenesis)].
On the basis of observation of 51 patients with spastic torticollis (ST) the authors describe in detail the clinical picture of the disease, with the dystonic-hyperkinetic syndrome being its principal feature. ST is always caused by involvement of the extrapyramidal system, more frequently of its formations located in the upper portions of the brain stem. In the overwhelming majority of cases the underlying cause of ST is neuro-infection, predominantly epidemic encephalitis. In some cases ST etiology is insufficiently clear: a number of suggestions concerning its origin has been advanced. On the basis of their own and literature data the authors describe the pathogenesis of ST and of its main symptoms.