Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study.
The prevalence of anal squamous intraepithelial lesions is high among human immunodeficiency virus-positive homosexual males and, to a lesser extent, among human immunodeficiency virus-negative homosexual males. Furthermore, the incidence of high-grade squamous intraepithelial lesions, the putative precursor lesion to invasive cancer, is also high. We report the first prospective study of high-resolution anoscopy-directed surgical treatment of high-grade squamous intraepithelial lesions. A prospective study of patients undergoing surgical treatment of high-grade squamous intraepithelial lesions (excision/cauterization of lesions visualized with high-resolution anoscopy) was performed. Follow-up anoscopy with biopsy and Papanicolaou smear was performed every three to six months. Patients diagnosed with high-grade squamous intraepithelial lesions during the course of their participation in a prospective cohort study of anal squamous intraepithelial lesions were identified. From this group, 37 patients who were treated surgically between 1995 and 1999 were studied. Of these, 29 had tested positive for human immunodeficiency virus and 8 were negative for the virus. Mean patient age was 45 +/- 8 years. Mean duration of follow-up was 32.3 +/- 20.6 months in the human immunodeficiency virus-negative group and 28.6 +/- 12.9 months in the human immunodeficiency virus-positive group. No human immunodeficiency virus-negative patient developed recurrent high-grade squamous intraepithelial lesions. Twenty-three of 29 human immunodeficiency virus-positive patients had persistent or recurrent high-grade squamous intraepithelial lesions (P = 0.003; mean time to recurrence, 12 months). Six patients underwent reoperation for high-grade squamous intraepithelial lesions (4 recurred by 6 months). No patients developed incontinence, stenosis, postoperative infection, or significant bleeding after surgical treatment. Surgical intervention directed by high-resolution anoscopy is safe and eliminates high-grade squamous intraepithelial lesions in human immunodeficiency virus-negative patients. The high persistence or recurrence rate in human immunodeficiency virus-positive patients suggests that multiple staged procedures and continued surveillance may be necessary.


Laparoscopy associated mesenteric vascular complications.
Since the first reported case in 1994, a small but significant number of patients have developed major mesenteric arterial and venous thromboses after laparoscopy, usually with catastrophic outcomes. The basic science data in both animal and human models suggest that these events were due in part to specific predisposing patient factors, combined with the physiologic changes in splanchnic hemodynamics that occur during induction and maintenance of pneumoperitoneum. The following manuscript examines the science of this phenomenon in detail and the features of the reported cases to date, with the goal being to increase awareness of this serious and likely underreported phenomenon.


Characterization of Argentine honeys on the basis of their mineral content and some typical quality parameters.
The levels of 19 elements (As, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Se, Tl, U, V, Zn) from sixteen different Argentine production sites of unifloral [eucalyptus (Eucaliptus rostrata), chilca (Baccharis salicifolia), Algarrobo (Prosopis sp.), mistol (Ziziphus mistol) and citric] and multifloral honeys were measured with the aim to test the quality of the selected samples. Typical quality parameters of honeys were also determined (pH, sugar content, moisture). Mineral elements were determined by using inductively coupled plasma mass spectrometer (ICP-MS DRC). We also evaluated the suitability of honey as a possible biomonitor of environmental pollution. Thus, the sites were classified through cluster analysis (CA) and then pattern recognition methods such as Principal Component Analysis (PCA) and discriminant analysis (DA) were applied. MEAN VALUES FOR QUALITY PARAMETERS WERE: pH, 4.12 and 3.81; sugar 82.1 and 82.0 °brix; moisture, 16.90 and 17.00% for unifloral and multifloral honeys respectively. The water content showed good maturity. Likewise, the other parameters confirmed the good quality of the honeys analysed. Potassium was quantitatively the most abundant metal, accounting for 92,5% of the total metal contents with an average concentration of 832.0 and 816.2 μg g(-1) for unifloral and multifloral honeys respectively. Sodium was the second most abundant major metal in honeys with a mean value of 32.16 and 33.19 μg g(-1) for unifloral and multifloral honeys respectively. Mg, Ca, Fe, Mn, Zn and Cu were present at low-intermediate concentrations. For the other 11 trace elements determined in this study (As, Be, Cd, Co, Cr, Ni, Pb, Se, Tl, U and V), the mean concentrations were very low or below of the LODs. The sites were classified through CA by using elements' and physicochemical parameters data, then DA on the PCA factors was applied. Dendrograms identified three main groups. PCA explained 52.03% of the total variability with the first two factors. In general, there are no evidences of pollution for the analysed honeys. The analytical results obtained for the Argentine honeys indicate the products' high quality. In fact, most of the toxic elements were below LODs. The chemometric analysis combining CA, DA and PCA showed their aptness as useful tools for honey's classification. Eventually, this study confirms that the use of honey as biomonitor of environmental contamination is not reliable for sites with low levels of contamination.


Oral health 4 life: Design and methods of a semi-pragmatic randomized trial to promote oral health care and smoking abstinence among tobacco quitline callers.
Smokers are at high risk for oral disease. As a result, they represent an important target group for population-level, public oral health promotion efforts. While dental health professionals often address smoking with their patients, no systematic efforts have been made to offer smokers an intervention to improve their use of oral health care. This paper details the rationale, design, and methods of a large, semi-pragmatic, randomized clinical trial designed to address this gap. Participants are recruited via the Oregon, Nebraska and Louisiana state-sponsored tobacco quitlines and randomized to receive standard quitline care versus standard care plus a multi-modal oral health promotion program (Oral Health 4 Life) integrated within the quitline services. All participants are followed for 6months to assess the impact of the intervention on smoking abstinence and utilization of professional dental care. In addition, the study will assess the cost of the intervention and provide practical guidance to states on whether the intervention is financially feasible to implement, should the intervention be effective. This study protocol may be useful to others interested in promoting oral health among smokers, those interested in partnering with tobacco quitlines to extend standard services to address other high risk health behaviors among smokers, or those interested in semi-pragmatic trial design.


Etiology and pathogenesis of the cohesinopathies.
Cohesin is a chromosome-associated protein complex that plays many important roles in chromosome function. Genetic screens in yeast originally identified cohesin as a key regulator of chromosome segregation. Subsequently, work by various groups has identified cohesin as critical for additional processes such as DNA damage repair, insulator function, gene regulation, and chromosome condensation. Mutations in the genes encoding cohesin and its accessory factors result in a group of developmental and intellectual impairment diseases termed 'cohesinopathies.' How mutations in cohesin genes cause disease is not well understood as precocious chromosome segregation is not a common feature in cells derived from patients with these syndromes. In this review, the latest findings concerning cohesin's function in the organization of chromosome structure and gene regulation are discussed. We propose that the cohesinopathies are caused by changes in gene expression that can negatively impact translation. The similarities and differences between cohesinopathies and ribosomopathies, diseases caused by defects in ribosome biogenesis, are discussed. The contribution of cohesin and its accessory proteins to gene expression programs that support translation suggests that cohesin provides a means of coupling chromosome structure with the translational output of cells.


Overproduction of IL-2 by Cbl-b deficient CD4+ T cells provides resistance against regulatory T cells.
Regulatory T cells are integral to the regulation of autoimmune and anti-tumor immune responses. However, several studies have suggested that changes in T cell signaling networks can result in T cells that are resistant to the suppressive effects of regulatory T cells. Here, we investigated the role of Cbl-b, an E3 ubiquitin ligase, in establishing resistance to Treg-mediated suppression. We found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b KO CD4+FoxP3- T cells hyper-produced IL-2 and together with IL-2 Rα upregulation served as an essential mechanism to escape suppression by Treg cells. Furthermore, we report that IL-2 serves as the central molecule required for cytokine-induced Treg resistance. Collectively our data emphasize the role of IL-2 as a key mechanism that renders CD4+ T cells resistant to the inhibitory effects of Treg cells.


Herd immunity to filarial infection is a function of vector biting rate.
Despite the existence of an impressive body of work on human immune responses against filarial infections, the occurrence of a protective response to infection remains unclear. Here, we use a combined modelling and comparative data analysis framework to address this issue for human infections with the filarial parasite, Wuchereria bancrofti. By analogy with previous work, the analysis involves the comparison of observed field patterns of infection with epidemiological patterns predicted by a mathematical model of parasite immunity. Unlike most other human helminths, which are transmitted by ingestion or dermal penetration, exposure to infection with lymphatic filariasis can be measured explicitly in terms of vector mosquito biting rates, thereby also allowing, probably for the first time, examination of the suggested role of exposure in generating herd immunity to macroparasites. Observed field patterns in this study were derived from 19 different published studies, which gave parallel estimates of community exposure rates and the corresponding age--prevalence patterns of infection, while predictions of the epidemiological impact of herd immunity were obtained using a catalytic model framework. The results provide the first conclusive evidence to date that variations in the observed age--prevalence patterns of infection in filariasis can be effectively explained by the occurrence of an exposure-driven acquisition of herd immunity. We discuss this result in terms of implications for the new World Health Organization-led initiative for the global control of this parasitic disease.


New laser technique for the treatment of malignant esophageal obstruction.
Endoscopic laser therapy for malignant esophageal obstruction is rapidly gaining widespread acceptance by the medical community. The standard approach utilizing the neodymium: yttrium, aluminum, garnet (Nd: YAG) laser was first described by Fleischer for squamous cell carcinoma of the esophagus and subsequently for adenocarcinoma of the gastroesophageal junction. According to his technique, treatment was begun at the proximal tumor margin and proceeded distally; as many as 13 treatments were necessary to complete therapy and relieve the obstruction. A new technique has been developed utilizing tumor dilatation so that treatment can be started at the distal tumor margin working retrogradely. This new technique has allowed treatment to be completed in a single session in most patients. This rapid completion of therapy has reduced the length of hospitalization and thereby hospital costs. It has also allowed patients to aliment earlier, thereby minimizing the metabolic consequences of prolonged intravenous feedings, has allowed patients to receive other forms of therapy on an outpatient basis, and has obviated the need for the chronic placement of tubes for drainage and feeding. The technique is described and discussed.


A new protocol of iron therapy combined with epoetin alpha as a treatment for preoperative autologous blood donation in gynaecological tumor surgery.
The use of epoetin alpha and sodium ferrous gluconate has been shown to be a safe and effective treatment which can be used to avoid allogeneic blood transfusions and to plan short term elective surgery. In this study the authors submitted 20 patients, scheduled to undergo surgery for gynaecological tumors, to a program of pre-operative autologous blood donation. All the patients received both epoetin alpha and sodium ferrous gluconate in the pre- and post-donation period. Epoetin alpha was administered subcutaneously at a dose of 200 IU/kg thrice a week during the week before and after autologous blood donation (400 ml). Sodium ferrous gluconate was administered intravenously shortly before the first and fourth administration of 125 mg epoetin alpha, and shortly before the third and sixth administration of 62.5 mg epoetin alpha. Surgery was scheduled to be performed 10-15 days after the last epoetin alpha administration, i.e. within 15-20 days from blood donation. All the patients were tested for the following blood chemistry parameters: hematocrit, haemoglobin, sideraemia and ferritin at treatment start, before donation, at treatment end, before autologous blood infusion and on the third and seventh day after surgery. No patient receiving epoetin alpha required allogeneic blood transfusion, as both the hematocrit and haemoglobin values remained normal. Epoetin alpha was observed to be a safe and effective treatment to be used in autologous blood donation programs in all patients scheduled to undergo surgery. It limits the decrease of hematocrit values following autologous blood donation thus enabling all the patients, who for a variety of reasons refuse allogeneic blood infusion, to predeposit autologous blood shortly before the date scheduled for surgery.


Carotid intima media-thickness is increased in obese children metabolically healthy, metabolically unhealthy, and with metabolic syndrome, compared to the non-obese controls.
The prevalence of obesity continues to increase. Obesity is associated with cardiovascular risk factors: elevated blood pressure, dyslipidemia and glycemic alterations, causing metabolic syndrome. A subgroup of obese, Metabolically Healthy Obese (MHO), appears to be less prone to the development of metabolic disturbances. Carotid intima-media thickness (cIMT) is a non-invasive marker of subclinical atherosclerosis and it is associated with increased risk of CVD events. To investigate the cardiovascular risk, demonstrated through the increase of cIMT in obese subjects without Metabolic Syndrome (MetS), we have studied cIMT in MHO, metabolically unhealthy obese (MUO) and obese with MetS diagnosed with the IDEFICS criteria and compared to a control group. 224 obese children aged 6 to 21 years (13,50 ± 4.01 years) and 103 normal weight subjects aged 7 to 19 years (13.2 ± 4.1 years) were studied. The body mass index (BMI) of the obese children was ≥ the 95th percentile. Based on the IDEFICS criteria, we divided the obese subjects in three groups: MHO if no criteria were out of range, MUO if, at least, one of the criteria was out of range and MetS group if all the IDEFICS criteria were present. In all the subjects cIMT was measured with color Doppler by a vascular surgeon. Differences in the means of the variables were tested by ANOVA. Based on the IDEFICS criteria, 32 subjects were affected by MetS (14..3%), 66 were considered MUO (29.4%) and 126 MHO (56.3%). Comparison of mean cIMT highlighted a significant difference (p < 0.05) between the groups of obese children (MHO, MUO and MetS) and controls for both carotid arteries. We did not find significative difference in the value of cIMT in MHO, MUO and MetS subjects, and all groups showed cIMT value higher compared to cIMT of the controls.


Functionalized MXenes as effective polyselenide immobilizers for lithium-selenium batteries: a density functional theory (DFT) study.
The practical applications of lithium selenium (Li-Se) batteries are impeded primarily due to the dissolution and migration of higher-order polyselenides (Li2Sen) into the electrolyte (known as the shuttle effect) and inactive deposition of lower-order polyselenides. The high electrical conductivity and mechanical strength of MXenes make them a suitable candidate to provide adequate anchoring to prevent polyselenide dissolution and improved electrochemical performance. Herein, we used density functional theory (DFT) calculations to understand the binding mechanism of Li2Sen on graphene and surface-functionalized Ti3C2 MXenes. We used graphene as a reference material to assess Li2Sen binding strengths on functionalized Ti3C2X2 (where X = S, O, F, and Cl). We observed that Ti3C2S2 and Ti3C2O2 exhibit superior anchoring behavior compared to graphene, Ti3C2F2, and Ti3C2Cl2. The calculated Li2Sen adsorption strengths, provided by S- and O-terminated Ti3C2, are greater than those of the commonly used ether-based electrolyte, which is a requisite for effective suppression of Li2Sen shuttling. Ti3C2X2 and graphene with adsorbed Li2Sen retain their structural integrity without chemical decomposition. Density of states (DOS) analysis demonstrates that the conductive behavior of Ti3C2X2 is preserved even after Li2Sen adsorption, which can provide electronic pathways to stimulate the redox electrochemistry of Li2Sen. Overall, our unprecedented simulation results reveal superior anchoring behavior of Ti3C2S2 and Ti3C2O2 for Li2Sen adsorption, and this developed understanding can be leveraged for designing carbon-free Ti3C2 MXene-based selenium cathode materials to boost the electrochemical performance of Li-Se batteries.


Competitive repair by naturally dispersed repetitive DNA during non-allelic homologous recombination.
Genome rearrangements often result from non-allelic homologous recombination (NAHR) between repetitive DNA elements dispersed throughout the genome. Here we systematically analyze NAHR between Ty retrotransposons using a genome-wide approach that exploits unique features of Saccharomyces cerevisiae purebred and Saccharomyces cerevisiae/Saccharomyces bayanus hybrid diploids. We find that DNA double-strand breaks (DSBs) induce NAHR-dependent rearrangements using Ty elements located 12 to 48 kilobases distal to the break site. This break-distal recombination (BDR) occurs frequently, even when allelic recombination can repair the break using the homolog. Robust BDR-dependent NAHR demonstrates that sequences very distal to DSBs can effectively compete with proximal sequences for repair of the break. In addition, our analysis of NAHR partner choice between Ty repeats shows that intrachromosomal Ty partners are preferred despite the abundance of potential interchromosomal Ty partners that share higher sequence identity. This competitive advantage of intrachromosomal Tys results from the relative efficiencies of different NAHR repair pathways. Finally, NAHR generates deleterious rearrangements more frequently when DSBs occur outside rather than within a Ty repeat. These findings yield insights into mechanisms of repeat-mediated genome rearrangements associated with evolution and cancer.


Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth.
Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in three-dimensional matrices and in vivo. A novel, potent catalytic inhibitor of TAO3 was developed that inhibited invadopodia formation and function as well as tumor cell extravasation and growth. Treatment with this inhibitor demonstrated that TAO3 activity is required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action. SIGNIFICANCE: An unbiased screening approach identifies TAO3 as a regulator of invadopodia formation and function, supporting clinical development of this class of target.


The angiogenic behaviors of human umbilical vein endothelial cells (HUVEC) in co-culture with osteoblast-like cells (MG-63) on different titanium surfaces.
Interaction between osteogenesis and angiogenesis plays an important role in implant osseointegration. In the present study we investigated the influence of titanium surface properties on the angiogenic behaviors of endothelial cells grown in direct contact co-culture with osteoblasts. Human umbilical vein endothelial cells (HUVECs) and osteoblast-like cells (MG-63 cells) were grown in direct co-culture on the following titanium surfaces: acid-etched (A), hydrophilic A (modA), coarse-gritblasted and acid-etched (SLA) and hydrophilic SLA (SLActive). Cell proliferation was evaluated by cell counting combined with flow cytometry. The expression of von Willebrand Factor (vWF), thrombomodulin (TM), endothelial cell protein C receptor (EPCR), E-Selectin, as well as vascular endothelial growth factor (VEGF) receptors Flt-1 and KDR in HUVECs and VEGF in MG-63 were measured by qPCR. The dynamic behavior of endothelial cells was recorded by time-lapse microscopy. Proliferation of HUVECs was highest on A, followed by SLA, modA and SLActive surfaces. The expression of vWF, TM, EPCR, E-Selectin and Flt-1 in HUVECs was significantly higher on A than on all other surfaces. The expression of KDR in HUVECs grown on A surface was below detection limit. VEGF expression in MG-63 cells was significantly higher on SLActive vs SLA and modA vs A surfaces. Time-lapse microscopy revealed that HUVECs moved quickest and formed cell clusters earlier on A surface, followed by SLA, modA and SLActive surface. In co-culture conditions, proliferation and expression of angiogenesis associated genes in HUVECs are promoted by smooth hydrophobic Ti surface, which is in contrast to previous mono-culture studies.


Anterior Skull Base and Pericranial Flap Ossification after Frontofacial Monobloc Advancement.
Frontofacial monobloc advancement creates a communication between the anterior cranial fossa and nasal cavities. To tackle this issue, transorbital pericranial pedicled flaps are routinely performed in the authors' center. This study aimed to assess the postoperative ossification of the anterior skull base and pedicled flaps following frontofacial monobloc advancement, and to identify factors influencing this ossification. Measurements of the skull base only and of the ossified pedicled flaps together with the skull base were performed on computed tomographic scans at the nasofrontal and the nasoethmoid frontal junctions. The total thickness of the skull vault was measured and a qualitative defect score for the anterior skull base was computed. Twenty-two patients who underwent frontofacial monobloc advancement at a median age of 3.1 years (range, 1.9 to 3.6 years) were included: 14 with Crouzon, five with Pfeiffer, and three with Apert syndrome. One year and 5 years after surgery, the distraction gap was completely ossified in the anterior skull base midline in all patients. Ossified pedicled flaps together with the skull base were thicker in patients than in controls at these two time points (p < 0.005 and p < 0.02). Patients with Pfeiffer syndrome had a significantly thicker skull base only and ossified pedicled flaps together with the skull base thicknesses (p = 0.01 and p = 0.03) and lower defect scores than patients with Crouzon or Apert syndrome (p = 0.03) 1 year postoperatively. As ossification of the pedicled flaps and total reossification of the anterior skull base midline were observed in all patients, the authors indicate that performing pedicled flaps in frontofacial monobloc advancement surgery could promote the reossification of the anterior skull base. Therapeutic, IV.


Recurrent orbital inflammation from metastatic orbital carcinoid tumor.
To report an unusual clinical presentation for carcinoid tumor metastatic to the orbit. Two adult patients with metastatic carcinoid tumor and unilateral orbital masses are described. Both patients sought treatment for acute unilateral orbital inflammation. Neuroimaging revealed orbital metastases adjacent to the inflamed adnexal tissue. Based on each patient's description of similar, prior, untreated episodes, minimal medical management was initiated. Resolution of the inflammatory signs was spontaneous in one case and assisted by pulsed, systemic corticosteroids in the second case. Compressive neuropathic vision loss occurred 11 months later in the second case. Carcinoid tumor metastatic to the orbit may manifest as recurrent orbital and ocular adnexal inflammation. These signs differ from systemic carcinoid syndrome in that they are unilateral, limited to only the orbital and ocular adnexal soft tissues, and resolve over days. Clinicians must carefully differentiate this manifestation from that of tumor necrosis, adnexal infection, or orbital outlet obstruction. This presentation may result from the spontaneous release of local inflammatory mediators intrinsic to the orbital tumor.


Tough on Crime? Pfizer and the CIHR.
The appointment of Dr. Bernard Prigent, vice-president and medical director of Pfizer Canada, to the Governing Council of the Canadian Institutes of Health Research, outraged many Canadian health researchers. Pfizer has been a "habitual offender," persistently engaging in illegal and corrupt marketing practices, bribing physicians and suppressing adverse trial results. Since 2002 the company and its subsidiaries have been assessed $3 billion in criminal convictions, civil penalties and jury awards. The $2.3-billion settlement in September 2009 - a month before Dr. Prigent's appointment - set a new record for both criminal fines and total penalties. A link with Pfizer might well advance the commercialization of Canadian research - unhindered by law or morality. Is that now the only mandate, Dr. Beaudet?


Optimization of Poly(methyl vinyl ether-co-maleic acid) Electrospun Nanofibers as a Fast-Dissolving Drug Delivery System.
Poly(methyl vinyl ether-maleic acid) (PMVEMA) is a water-soluble, biodegradable polymer used for drug delivery. The aim of the present study was to prepare nanofibers of this polymer as a fast-dissolving carrier for montelukast. Polymeric nanofibers were spun by electrospinning method using different ratios of biodegradable polymer of PMVEMA. The processing variables including voltage, distance of the needle to rotating screen, and flow rate of the solution were optimized based on the diameter of the nanofibers, drug content, and release efficiency by a Taguchi design. The morphology, diameter, and diameter distribution of the nanofibers were studied by scanning electron microscopy (SEM). Drug loading and its release rate from the nanofibers were analyzed spectrophotometrically. The possible molecular between the polymer and the drug was characterized with Fourier-transform-infrared spectroscopy. The results showed the best situation for electrospinning of the polymer obtained at the polymer concentration of 37%, the distance of the needle to rotating screen of 19 cm, the voltage of 120 kV, and the rate of injection of 0.2 ml/h. In these situations, the fiber diameter and drug loading efficiency percentage were 273 nm and 83%, respectively. These nanofibers released the total loaded drug within 1-3 s with no residue in the dissolution medium. SEM results showed that the optimized nanofibers were quite smooth and without beads. The results indicated that the nanofibers of PMVEMA could dissolve the drug very rapidly and can be adopted for fast-dissolving dosage forms.


A Review of Methods for Estimating Algorithmic Complexity: Options, Challenges, and New Directions.
Some established and also novel techniques in the field of applications of algorithmic (Kolmogorov) complexity currently co-exist for the first time and are here reviewed, ranging from dominant ones such as statistical lossless compression to newer approaches that advance, complement and also pose new challenges and may exhibit their own limitations. Evidence suggesting that these different methods complement each other for different regimes is presented and despite their many challenges, some of these methods can be better motivated by and better grounded in the principles of algorithmic information theory. It will be explained how different approaches to algorithmic complexity can explore the relaxation of different necessary and sufficient conditions in their pursuit of numerical applicability, with some of these approaches entailing greater risks than others in exchange for greater relevance. We conclude with a discussion of possible directions that may or should be taken into consideration to advance the field and encourage methodological innovation, but more importantly, to contribute to scientific discovery. This paper also serves as a rebuttal of claims made in a previously published minireview by another author, and offers an alternative account.


Metformin and the sulphonylureas: the comparative risk.
A review of the world literature until December 1982 revealed 843 cases of sulphonylurea-induced hypoglycaemia (SIH) with a mortality of 9%. There were 42 cases of metformin-associated lactic acidosis (MALA) with 18 deaths (43%); 40 of the MALA cases had documented contra-indications, especially renal impairment, and the remaining two cases were due to drug overdosage, one being a suicide. A comparative mortality risk was obtained from the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) where there is accurate information regarding MALA and glibenclamide-associated hypoglycaemia. The calculated mortality risk for MALA and glibenclamide-associated hypoglycaemia showed no significant differences with values of 0.0240 and 0.0332 per 1,000 patient years, respectively. The incidence of hypoglycaemia with glibenclamide was greater than that of lactic acidosis associated with metformin (2p = 0.036). Sulphonylureas are not less dangerous than metformin and both groups of drugs should be used with care in non-insulin-dependent diabetics, especially in alderly subjects and those with impaired renal or hepatic function.


The clinical outcome of childhood masturbation.
This study was performed to investigate the clinical outcome of childhood masturbation. For this purpose 50 children (mean age = 48.7 +/- 24.5 months, 34 girls females and 16 boys males) with masturbation symptoms were examined at first visit to the Department of Child Psychiatry and two years thereafter with psychiatric interviews. The mean masturbation frequency at the initial interview was significantly decreased after two years. It was noted that 39 children (78%) were completely recovered and 11 children (22%) continued to masturbate after two years. Children who did not recover were significantly younger, began to masturbate earlier and masturbated more frequently than others at the time of initial evaluation. It was concluded that the findings about the beneficial effect of sedative drugs in combination with parental guidance, education and means for behavior modification were promising.


Could imatinib replace surgery in esophageal gastrointestinal stromal tumor.
Gastrointestinal stromal tumors GISTs are cellular spindle, or epithelioid tumors that occur in the stomach, intestine, and rarely in the esophagus. A 61-year-old man was complaining of resistant dry cough with dysphagia for one month duration. Upper gastrointestinal tract endoscopic examination showed a polypoid mass 30 cm from the incisors obstructing 50% of the lumen, where multiple biopsies were taken. Magnetic resonance imaging MRI showed a mass in the wall of the esophagus extending into the thoracic cavity. Histologically, the stained sections with the routine hematoxylin and eosin as well as the immunohistochemical stains for CD117, CD34, S100, vimentin, and smooth muscle actin confirmed the diagnosis of esophageal GIST. The patient was treated with imatinib, 400 mg/day. There was a dramatic reduction in the size of the tumor with successful improvement of his symptoms after 2 months of treatment, which was confirmed by repeated upper GIT endoscopy, and MRI.


6-day amoxicillin versus 10-day penicillin V for group A beta-haemolytic streptococcal acute tonsillitis in adults: a French multicentre, open-label, randomized study. The French Study Group Clamorange.
We compared the efficacy and safety of amoxicillin 1 g b.i.d. for 6 days and penicillin V 1 MU t.i.d. for 10 days in the treatment of group A beta-haemolytic streptococcal (GABHS) tonsillitis in adults. 342 patients with acute tonsillitis and a positive test for streptococcal antigen were included in a multicentre, randomized, open-label study; 338 patients were evaluable in an intention-to-treat analysis, and 234 with a positive throat swab culture in a per-protocol analysis. In the per-protocol analysis, the GABHS eradication rate at the end of treatment was comparable in the two groups: 92% (115/125) on amoxicillin and 92.7% (101/109) on penicillin (p = 0.95), as were the clinical success rates of 96% and 95.4%, respectively (p = 0.92). At the follow-up visit (day 28-32), 90.8% of patients treated with amoxicillin and 92.6% of those treated with penicillin V were free of GABHS (p = 0.85). Sore throat disappeared significantly faster on day 2 (p = 0.039) in the amoxicillin group. The intention-to-treat analysis gave similar clinical results. Tolerability was good in both groups. The efficacy and safety of amoxicillin 1 g b.i.d. for 6 days were not statistically different from those of penicillin V 1 MU t.i.d. for 10 days in the treatment of streptococcal tonsillitis in adults.


A multicriteria decision analysis framework to measure equitable healthcare access during COVID-19.
The ongoing novel coronavirus (COVID-19) pandemic has highlighted the need for individuals to have easy access to healthcare facilities for treatment as well as vaccinations. The surge in COVID-19 hospitalizations during 2020 also underscored the fact that accessibility to nearby hospitals for testing, treatment and vaccination sites is crucial for patients with fever or respiratory symptoms. Although necessary, quantifying healthcare access is challenging as it depends on a complex interaction between underlying socioeconomic and physical factors. In this case study, we deployed a Multi Criteria Decision Analysis (MCDA) approach to uncover the barriers and their effect on healthcare access. Using a least cost path (LCP) analysis we quantified the costs associated with healthcare access from each census block group in the Los Angeles metropolitan area (LA Metro) to the nearest hospital. Social vulnerability reported by the Centers for Disease Control and Prevention (CDC), the daily number of COVID-19 cases from the Los Angeles open data portal and built environment characteristics (slope of the street, car ownership, population density distribution, walkability, traffic collision density, and speed limit) were used to quantify overall accessibility index for the entire study area. Our results showed that the census block groups with a social vulnerability index above 0.75 (high vulnerability) had low accessibility owing to the higher cost of access to nearby hospitals. These areas were also coincident with the hotspots for COVID-19 cases and deaths which highlighted the inequitable exposure of socially disadvantaged populations to COVID-19 infections and how the pandemic impacts were exacerbated by the synergistic effect of socioeconomic status and built environment characteristics of the locations where the disadvantaged populations resided. The framework proposed herein could be adapted to geo-target testing/vaccination sites and improve accessibility to healthcare facilities in general and more specifically among the socially vulnerable populations residing in urban areas to reduce their overall health risks during future pandemic outbreaks.


Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.
Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.


Regulation of GH3-cell function via adenosine A1 receptors. Inhibition of prolactin release, cyclic AMP production and inositol phosphate generation.
We examined the mechanism by which adenosine inhibits prolactin secretion from GH3 cells, a rat pituitary tumour line. Prolactin release is enhanced by vasoactive intestinal peptide (VIP), which increases cyclic AMP, and by thyrotropin-releasing hormone (TRH), which increases inositol phosphates (IPx). Analogues of adenosine decreased prolactin release, VIP-stimulated cyclic AMP accumulation and TRH-stimulated inositol phospholipid hydrolysis and IPx generation. Inhibition of InsP3 production by R-N6-phenylisopropyladenosine (R-PIA) was rapid (15 s) and was not affected by the addition of forskolin or the removal of external Ca2+. Addition of adenosine deaminase or the potent adenosine-receptor antagonist, BW-A1433U, enhanced the accumulation of cyclic AMP by VIP, indicating that endogenously produced adenosine tonically inhibits adenylate cyclase. The potency order of adenosine analogues for inhibition of cyclic AMP and IPx responses (measured in the presence of adenosine deaminase) was N6-cyclopentyladenosine greater than R-PIA greater than 5'-N-ethylcarboxamidoadenosine. This rank order indicates that inhibitions of both cyclic AMP and InsP3 production are mediated by adenosine A1 receptors. Responses to R-PIA were blocked by BW-A1433U (1 microM) or by pretreatment of cells with pertussis toxin. A greater amount of toxin was required to eliminate the effect of R-PIA on inositol phosphate than on cyclic AMP accumulation. These data indicate that adenosine, in addition to inhibiting cyclic AMP accumulation, decreases IPx production in GH3 cells, possibly by directly inhibiting phosphoinositide hydrolysis.


Overutilization of proton-pump inhibitors: what the clinician needs to know.
Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.


Effects of epicatechin on rat islets of Langerhans.
Plants containing epicatechin (a flavonoid) have been used to treat diabetes mellitus in Indian medicine. The present study reports effects of this compound on isolated islets of Langerhans. The flavonoid (1 mM) was found to increase insulin secretion from isolated rat islets of Langerhans in the presence of either 2 or 20 mM glucose, in static incubations, or in perifusion. The increase in insulin secretion mediated by epicatechin was both ATP- and temperature-dependent. Ultrastructural studies showed no deleterious changes in the structure of the B-cells after 5 days of exposure to the compound. Intraperitoneal injection of 30 mg/kg body wt of epicatechin twice daily for 4 days increased the islet insulin content by 30%. Secretion of insulin from islets isolated from epicatechin-injected rats was significantly increased when exposed to 20 mM glucose in comparison with water-injected controls. Furthermore, islets of adult rats cultured with 5.5 mM glucose for 4 days showed a significant increase in DNA synthesis in the presence of 0.05 mM epicatechin. These results suggest direct effects of epicatechin on various aspects of islet function.


How do deployed health care providers experience moral injury?
Combat deployments put health care providers in ethically compromising and morally challenging situations. A sample of recently deployed nurses and physicians provided narratives that were analyzed to better appreciate individual perceptions of moral dilemmas that arise in combat. Specific questions to be answered by this inquiry are: 1) How do combat deployed nurses and physicians make sense of morally injurious traumatic exposures? and 2) What are the possible psychosocial consequences of these and other deployment stressors? This narrative inquiry involves analysis of ten deployed military nurses' and physicians' aversive or traumatic experiences. Burke's dramatist pentad is used for structural narrative analysis of stories that confirm and illuminate the impact of war zone events such as betrayal, disproportionate violence, incidents involving civilians, and within-rank violence on military health care provider narrators. Results indicate cognitive dissonance and psychosocial sequelae related to moral and psychological stressors faced by military medical personnel. Discussion addresses where healing efforts should be focused.


Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study.
To investigate brain amyloid pathology in a dementia-risk population defined as cardiovascular risk factors, aging, and dementia risk (CAIDE) score of at least 6 but with normal cognition and to examine associations between brain amyloid load and cognitive performance and vascular risk factors. A subgroup of 48 individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in brain 11C-Pittsburgh compound B (PiB)-PET imaging, brain MRI, and neuropsychological assessment at the beginning of the study. Lifestyle/vascular risk factors were determined as body mass index, blood pressure, total and low-density lipoprotein cholesterol, and glucose homeostasis model assessment. White matter lesions were visually rated from MRIs by a semiquantitative Fazekas score. Twenty participants (42%) had a positive PiB-PET on visual analysis. The PiB-positive group performed worse in executive functioning tests, included more participants with APOE ε4 allele (50%), and showed slightly better glucose homeostasis compared to PiB-negative participants. PiB-positive and -negative participants did not differ significantly in other cognitive domain scores or other vascular risk factors. There was no significant difference in Fazekas score between the PiB groups. The high percentage of PiB-positive participants provides evidence of a successful recruitment process of the at-risk population in the main FINGER intervention trial. The results suggest a possible association between early brain amyloid accumulation and decline in executive functions. APOE ε4 was clearly associated with amyloid positivity, but no other risk factor was found to be associated with positive PiB-PET.


Inhibition of Ras extracellular-signal-regulated kinase (ERK) mediated signaling promotes ciliary neurotrophic factor (CNTF) expression in Schwann cells.
Ciliary neurotrophic factor (CNTF) can prevent injury-induced motor neuron death. However, it is also evident that expression of CNTF in Schwann cells is suppressed during nerve regeneration. In this report, we have addressed the mechanism underlying the down-regulation of CNTF expression in injured nerves using a mouse Schwann cell line IMS32 and mouse sciatic nerve. In IMS32 cells, activation of the Ras extracellular-signal-regulated kinase (ERK) pathway by adenoviral vector-mediated expression of dominant active MEK1 did not alter a basal level of CNTF expression, whereas inhibition of the Ras-ERK pathway by using adenoviral vectors resulted in a marked increase in CNTF expression. This inverse relation between before and after axotomy was also observed in mouse sciatic nerve. In the axotomized sciatic nerve, the phosphorylated ERK was markedly increased; in contrast, the expression of CNTF was markedly decreased. These findings suggest that an inactive state of ERK is crucial for the CNTF expression in Schwann cells, and that activation of ERK following nerve injury critically influences the expression of CNTF. This might well explain why CNTF is highly expressed in quiescent Schwann cells in the peripheral nervous system, and also why CNTF is not abundant in axotomized nerves or cultured Schwann cells in which the proliferation signal is obviously active.


Targeting Twist expression with small molecules.
Twist, as one of the important embryonic transcription factors, regulates epithelial-mesenchymal transition (EMT) and migration in embryo formation and cancer development. Both Twist-1 and Twist-2 are rarely detectable in healthy adult tissues, but are frequently overexpressed in multiple kinds of human cancer tissues, such as breast, prostate, uterus, liver, melanoma, etc. Twist is considered as a crucial EMT inductor and correlated with carcinoma aggression, invasion and metastasis. In the past decades, in-depth investigation has been reported in terms of the role of Twist in cancers; in addition, several kinds of small molecules have played important roles in studying the effect of Twist on cancer development, suggesting that Twist can be regarded as one of the important potential targets for cancer treatment. Hence we provide a brief overview of Twist and several small molecules targeting its expression, highlighting the biological features that make it a charming target for cancer therapy.


Characterization of retinal and hippocampal L-AP4 receptors using conformationally constrained AP4 analogues.
In the past, the absence of useful 2-amino-4-phosphonobutanoic acid (AP4) analogues has hampered the pharmacological study and comparison of different systems which are sensitive to L-AP4. Several conformationally constrained AP4 analogues have now been synthesized: (E)- and (Z)-1-amino-3-phosphonocyclopentanecarboxylic acid [(E)- and (Z)-cyclopentyl AP4], and (E)- and (Z)-1-amino-3-phosphonocyclohexanecarboxylic acid [(E)- and (Z)-cyclohexyl AP4], and the recently synthesized cyclopropyl analogues (E)- and (Z)-2-amino-2,3-methano-4-phosphonobutanoic acid [(E)- and (Z)-cyclopropyl AP4]. Therefore, we have examined and report here the pharmacology of two retinal and two hippocampal L-AP4 sensitive systems using these analogues. In addition, the pharmacology of two kainic acid/alpha-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (KAIN/AMPA) pathways and one N-methyl-D-aspartate (NMDA) hippocampal pathway was examined. We found that the rank order potency of the L-AP4 sensitive systems were similar though not identical. The KAIN/AMPA and NMDA systems had a quite different rank order of potencies than the L-AP4 systems. These data suggest that the L-AP4 receptors in these different systems are structurally similar to each other and differ from both KAIN/AMPA and NMDA receptors.


Vaccine repurposing approach for preventing COVID 19: can MMR vaccines reduce morbidity and mortality?
The coronavirus disease (COVID-19) is resulting in millions of infected individuals with several hundred thousands dead throughout the world. Amidst all the havoc, one interesting observation in the present COVID-19 pandemic is the negligible symptoms in the young; particularly children below 10 years of age. We assume the extensive pediatric vaccination with MMR vaccines followed globally could have resulted in innate immune responses, e.g., induction of interferons (IFNs) and activated natural killer (NK) cells, thereby offering natural immunity against SARS-CoV-2 in the young population. Possible cross-protective innate immunity offered by MMR vaccination prompted us to suggest repurposing MMR vaccination for immuno-prophylaxis against COVID-19.


The genome of Polaromonas sp. strain JS666: insights into the evolution of a hydrocarbon- and xenobiotic-degrading bacterium, and features of relevance to biotechnology.
Polaromonas sp. strain JS666 can grow on cis-1,2-dichloroethene (cDCE) as a sole carbon and energy source and may be useful for bioremediation of chlorinated solvent-contaminated sites. Analysis of the genome sequence of JS666 (5.9 Mb) shows a bacterium well adapted to pollution that carries many genes likely to be involved in hydrocarbon and xenobiotic catabolism and metal resistance. Clusters of genes coding for haloalkane, haloalkanoate, n-alkane, alicyclic acid, cyclic alcohol, and aromatic catabolism were analyzed in detail, and growth on acetate, catechol, chloroacetate, cyclohexane carboxylate, cyclohexanol, ferulate, heptane, 3-hydroxybenzoate, hydroxyquinol, gentisate, octane, protocatechuate, and salicylate was confirmed experimentally. Strain JS666 also harbors diverse putative mobile genetic elements, including retrons, inteins, a miniature inverted-repeat transposable element, insertion sequence transposases from 14 families, eight genomic islands, a Mu family bacteriophage, and two large (338- and 360-kb) plasmids. Both plasmids are likely to be self-transferable and carry genes for alkane, alcohol, aromatic, and haloacid metabolism. Overall, the JS666 genome sequence provides insights into the evolution of pollutant-degrading bacteria and provides a toolbox of catabolic genes with utility for biotechnology.


Polymeric nanoparticles in development for treatment of pulmonary infectious diseases.
Serious lung infections, such as pneumonia, tuberculosis, and chronic obstructive cystic fibrosis-related bacterial diseases, are increasingly difficult to treat and can be life-threatening. Over the last decades, an array of therapeutics and/or diagnostics have been exploited for management of pulmonary infections, but the advent of drug-resistant bacteria and the adverse conditions experienced upon reaching the lung environment urge the development of more effective delivery vehicles. Nanotechnology is revolutionizing the approach to circumventing these barriers, enabling better management of pulmonary infectious diseases. In particular, polymeric nanoparticle-based therapeutics have emerged as promising candidates, allowing for programmed design of multi-functional nanodevices and, subsequently, improved pharmacokinetics and therapeutic efficiency, as compared to conventional routes of delivery. Direct delivery to the lungs of such nanoparticles, loaded with appropriate antimicrobials and equipped with 'smart' features to overcome various mucosal and cellular barriers, is a promising approach to localize and concentrate therapeutics at the site of infection while minimizing systemic exposure to the therapeutic agents. The present review focuses on recent progress (2005-2015) important for the rational design of nanostructures, particularly polymeric nanoparticles, for the treatment of pulmonary infections with highlights on the influences of size, shape, composition, and surface characteristics of antimicrobial-bearing polymeric nanoparticles on their biodistribution, therapeutic efficacy, and toxicity. WIREs Nanomed Nanobiotechnol 2016, 8:842-871. doi: 10.1002/wnan.1401 For further resources related to this article, please visit the WIREs website.


[Suicide by schizophrenic patients in psychiatric hospitals].
A detailed investigation was carried out on the schizophrenics who committed suicide at the Tokyo Metropolitan Hospital Matsuzawa during the last 30 years. Of these 58 schizophrenics, 52 cases (male 25, female 27) were studied in this report. The mean age of suicide patients was 38.6 years (male: 34.3 years, female: 42.6 years); in males the suicide occurred between 20 and 39 years (80%), while females showed a wider distribution with two peaks in the 25 to 34 years group (26%) and the 40 to 54 years group (41%). 88% (22/25) of males were unmarried, whereas only 33% (9/27) of the women were unmarried. Suicide methods were comprised of hanging (51.9%-27 cases), being run over by a streetcar (28.8%-15 cases), drowning (6 cases), jumping off a high building (3 cases) and intoxication by creosol liquid soap (1 case). In case of male patients hanging was most frequent (72%), followed by jumping into a streetcar to get run over (24%). Likewise, hanging and jumping into a streetcar were most frequent in females (33.3%, respectively), followed by drowning (22.2%), a method selected by females only. From 1951 to 1960 (right before and after the introduction of psychopharmacotherapy) hanging ranked first, but the suicide methods were shifted to the jumping into a streetcar and drowning after installation of the Open-Door-System (around the years 1961-1970). During the last 10 years (from 1971 to 1980) suicide by jumping from a high building increased. Suicide committed in the open ward occurred 9 times only (17.3%); it was, therefore, a much rarer occurrence than had been expected. This fact may show that such an open ward system would be associated with a relatively low risk of suicide. After introduction of psychiatric pharmacotherapy and as social rehabilitation continued, the incidence was relatively stable and no increase was found in our data. Only 4 patients (7.7%) left suicide notes, which made it difficult to draw a clear conclusion on the motivations. Twenty-six cases (50%) died by the first attempted suicide, but in 13 cases (25%) suicide was finally accomplished after the second trial or more. Women performed several repeated suicide attempts (37%), whereas the male patients died at the first or second attempt (88%). Hospitalization lasted on an average for 5 years and 8 months (male: 3 years and 8 months, female: 7 years and 6 months); the shortest stay was 2 days and the longest was 25 years and 11 months.(ABSTRACT TRUNCATED AT 400 WORDS)


Factors Associated With Pre-hospital Delay in Patients With Acute Myocardial Infarction.
Treatment of patients with acute myocardial infarction (AMI) is time related, so delay in treatment could affect prognosis. Recognizing pre-hospital or in-hospital delays in initiating treatment and reducing these factors is very efficacious in treatment of these patients. The aim of this study is evaluate the causes of pre-hospital delay just as other studies on effect of different variables such as socioeconomic and personal factors on pre-hospital delay in with patients with AMI. A cross sectional study was carried out on 227 patients with acute myocardial infarction and demographic data, educational level, marital status, type of transfer to hospital and delay in arrival to hospital were recorded. 35.7% patients arrived during one hour of symptom onset, and 7.9% arrived after 24 hours. Patients having high level education (P = 0.0492) and with a family history of coronary artery disease (P = 0.01) had significantly less delay in arriving to hospital. Age, marital status, gender, and route of transfer to hospital were not related with pre-hospital delay (P > 0.05). Patients thought most common cause of delay in arrival was unawareness of coronary artery disease (38.8%) and self-medication (34.3%). Increasing awareness of patients about cardiovascular symptoms and their risk factors could be helpful in patient's decision in seeking medical help. So general education via media and primary and middle schools could be helpful.


31P NMR and genetic analysis establish hinT as the only Escherchia coli purine nucleoside phosphoramidase and as essential for growth under high salt conditions.
Eukaryotic cells encode AMP-lysine (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester) 5'-phosphoramidate) hydrolases related to the rabbit histidine triad nucleotide-binding protein 1 (Hint1) sequence. Bacterial and archaeal cells have Hint homologs annotated in a variety of ways, but the enzymes have not been characterized, nor have phenotypes been described due to loss of enzymatic activity. We developed a quantitative (31)P NMR assay to determine whether Escherichia coli possesses an adenosine phosphoramidase activity. Indeed, soluble lysates prepared from wild-type laboratory E. coli exhibited activity on the model substrate adenosine 5'-monophosphoramidate (AMP-NH(2)). The E. coli Hint homolog, which had been comprehensively designated ycfF and is here named hinT, was cloned, overexpressed, purified, and characterized with respect to purine nucleoside phosphoramidate substrates. Bacterial hinT was several times more active than human or rabbit Hint1 on five model substrates. In addition, bacterial and mammalian enzymes preferred guanosine versus adenosine phosphoramidates as substrates. Analysis of the lysates from a constructed hinT knock-out strain of E. coli demonstrated that all of the cellular purine nucleoside phosphoramidase activity is due to hinT. Physiological analysis of this mutant revealed that the loss of hinT results in failure to grow in media containing 0.75 m KCl, 0.9 m NaCl, 0.5 m NaOAc, or 10 mm MnCl(2). Thus, cation-resistant bacterial cell growth may be dependent on the hydrolysis of adenylylated and/or guanylylated phosphoramidate substrates by hinT.


Creating Hostility and Conflict: Effects of Entitlement and Self-Image Goals.
People who feel entitled to admiration and respect from others do not make good companions. This research shows one reason why. Entitled people adopt self-image goals (goals that aim to construct and defend a positive self-image), which then lead to interpersonal conflict and hostility. Studies 1A and 1B documented a unique relation between entitlement and self-image goals. Study 2 extended these results by showing, via a longitudinal design, that entitlement prospectively predicts chronic self-image goals. These chronic self-image goals then predict chronic relationship conflict and hostility, all averaged over 10 weeks. Further, Study 2 revealed that self-image goals mediate the effect of pretest entitlement on both weekly hostility and conflict. These results suggest that by pursuing self-image goals, entitled people create conflict and hostility in their relationships.


Normalization of the delano diagram.
A normalization of the Delano y, ŷ diagram is proposed in which the y heights are normalized by the entrance pupil height, the ŷ heights by the image height. The normalization constants are expressed in terms of the system parameters, and it is seen that the reduced distances become normalized by the focal length of the system, the marginal ray reduced angles by the numerical aperture of the system, the chief ray angles by the field aperture, and the powers by the total power of the system. It is also shown that any number of refractions and transfers will not affect this normalization, but a stop or conjugate shift will destroy it, and renormalization then becomes necessary.


A higher order motion region in human inferior parietal lobule: evidence from fMRI.
The proposal that motion is processed by multiple mechanisms in the human brain has received little anatomical support so far. Here, we compared higher- and lower-level motion processing in the human brain using functional magnetic resonance imaging. We observed activation of an inferior parietal lobule (IPL) motion region by isoluminant red-green gratings when saliency of one color was increased and by long-range apparent motion at 7 Hz but not 2 Hz. This higher order motion region represents the entire visual field, while traditional motion regions predominantly process contralateral motion. Our results suggest that there are two motion-processing systems in the human brain: a contralateral lower-level luminance-based system, extending from hMT/V5+ into dorsal IPS and STS, and a bilateral higher-level saliency-based system in IPL.


H3K4me3 remodeling induced acquired resistance through O-GlcNAc transferase.
Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs. Deploying a model of adaptive cancer drug tolerance, H3K4me3 ChIP-Seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo. H3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in in vivo models. Upstream of OGT, we identified AMPK as an actionable target. AMPK activation by acetyl salicylic acid downregulated OGT with similar effects on delaying acquired resistance. Our findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes.


Psychological, sociocultural and economic coping strategies of mothers or female caregivers of children with a disability in Belu district, Indonesia.
Caring for children with a disability can cause a range of psychological and socioeconomic challenges for parents and caregivers, such as anxiety, depression, inability to find affordable and appropriate childcare, loss of income and expenses related to disability specific treatment. As part of a study exploring the impacts of childhood disability on mothers or female caregivers and families, and the copy strategies they used, this paper describes strategies employed by mothers or female caregivers to cope with challenges associated with childhood disability within their family in Belu district, Indonesia. A qualitative approach using one-on-one in-depth interviews was used to collect data from participants (n = 22) who were recruited using a combination of purposive and snowball sampling techniques. Interviews were recorded, transcribed verbatim and imported to NVivo 12 for analysis. A qualitative framework analysis was used to guide data analysis. The conceptual framework of coping strategies guided the conceptualisation and discussion of the findings. The findings showed that active psychological coping strategies, including cognitive or acceptance strategies, knowledge of both health condition and socio-academic related development of children with a disability, and family relationship and support, were used by the participants to cope with psychological challenges facing them. Self-reliance and religious/spiritual coping strategies were also utilised. Sociocultural strategies, such as social withdrawal or disengagement, professional support and culture-based support, were used by the participants to cope with social impacts, stigma, and discrimination associated with childhood disability. Participants also reported using financial strategies such as selling of family assets to cope with the economic challenges. The findings indicate the need for programs and interventions that address the needs of mothers and female caregivers and their families, to assist with effectively managing the significant challenges they face when caring for a child with a disability. Further studies are needed, with a larger number of participants and the inclusion of fathers or male caregivers, in order to better understand the broader coping experience of childhood disability impacts within families.


Antifungal carbazoles.
Carbazole derivatives are well known for their various pharmacological activities, including anti-HIV, anticancer, antibacterial and antifungal activities. This review will focus on carbazoles that possess antifungal activity against Candida albicans, the major human fungal pathogen. In our search for new fungicidal compounds, we identified a series of substituted carbazoles, termed N-alkylated 3,6-dihalogenocarbazoles, that exhibit fungicidal activity against C. albicans and the emerging pathogen Candida glabrata. The most potent fungicidal compounds of this series were characterized by minimal fungicidal concentration (MFC) between 8.5 and 25 microM. To analyse the structural determinants for fungicidal activity of these carbazole derivatives, we selected 10 such derivatives and performed further analyses. Interestingly, some of these N-alkaylated 3,6-dihalogenocarbazoles were active against Candida biofilms grown in microtiterplates. In this review, we will further discuss the putative therapeutic potential of the antifungal carbazole compounds as antimycotics.


Adaptation Component Based on Wearable Technology to Support Personalized Tracking of Physical Activity in Children.
Obesity is a chronic disease characterized by the accumulation of body fat. School-age children obesity is one of the most serious public health challenges since it progressively becomes a risk factor in adulthood. Recent studies and technological innovations have demonstrated the feasibility of game-based interventions for promoting physical activity among children. Nevertheless, there is a gap in fitting the system specifications to specific user profiles. This paper aims to present the development of an adaptation component for a particular exergame based on wearable technology that measures heart rate to support a personalized tracking system of the physical activity. The employed methodology was the General Adaptivity Model (GAM) that provides guidelines for the designing process of adaptivity models, incorporating user modeling and personalization in existing or new interactive systems. For validation purposes, an experiment was conducted at a primary school with thirty subjects aged between five to seven years to test the effectiveness of a user adaptive system against a conventional interactive system for the promotion of physical activity. Results indicate that the developed system was able to change its behavior according to the variations of the heart rate and therefore encouraging users to perform higher/lower physical activity levels.


Combinatorial liquid-phase synthesis of
A new method for the synthesis of [1,4]oxazepin-7-ones from readily available aldehydes and alpha-amino alcohols was developed using the Baylis-Hillman reaction as the key step. To determine the scope and limitations of the method, a mixture library was synthesized from six aldehydes and six alpha-amino alcohols on the soluble polymer support poly(ethylene glycol) 5000 monomethyl ether (MeOPEG) via split synthesis and analyzed by GC-EIMS. Those oxazepines that were formed predominantly were resynthesized in a parallel synthesis and fully characterized. Thus, we have shown that split synthesis on MeOPEG can be an efficient method to rapidly screen the substrate spectrum of a newly developed reaction sequence.


Additional glial cell line-derived neurotrophic factor in vitro promotes the proliferation of undifferentiated spermatogonia from sterile cattleyak.
Cattleyak is a typically male sterile species. The meiosis process is blocked and the scarcity of spermatogenic stems cells are both contributing factors to the inability of male cattleyak to produce sperm. While Glial cell line-derived neurotrophic factor (GDNF) is the first discovered growth factor known to promote the proliferation and self-renewal of spermatogenic stem cells, its relationship to the spermatogenesis arrest of cattleyak remains unclear. In this report, we studied the differential expression of GDNF in the testis of yak and cattleyak, and discussed the optimal concentration of GDNF in the culture medium of undifferentiated spermatogonia (UDSPG) of cattleyak in vitro and the effect of GDNF on the proliferation of cattleyak UDSPG. The results indicated that GDNF expression in the testicular tissue of cattleyak was inferior to that of yak. Moreover, the optimum value for the UDSPG in vitro culture was determined to be 20-30 ng/mL for cattleyak. In vitro, the proliferation activity of UDSPG was observed to increase with additional GDNF due to the up-regulation of proliferation-related genes and the down-regulation of differentiation-related genes. We hereby report that the scarcity of cattleyak UDSPG is due to insufficient expression of GDNF, and that the addition of GDNF in vitro can promote the proliferation of cattleyak UDSPG by regulating the expression of genes related to proliferation and differentiation. This work provides a new insight to solve the issue of spermatogenic arrest in cattleyak.


Dissecting the genetics of spectrum of Epilepsies with Eyelid Myoclonia by exome sequencing.
Epilepsy with Eyelid Myoclonia (EEM) spectrum, is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with EEG paroxysms, and photosensitivity. Based on the specific clinical features, age of onset and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF and RORB and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic aetiology of EEM. we studied a cohort of 105 individuals by using whole-exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability, ID, or any other neurodevelopmental/psychiatric disorder) RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these eight (five in CHD2, one in NEXMIF, one in SYNGAP1 and one in TRIM8) were found in the EEM+ sub-cohort (28.57%). Only one variant (IFIH1) was found in the EEM- sub-cohort (1.29%); however, since the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with co-morbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2 and the association of CHD2-EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. While we provided robust evidence for gene variants associated with EEM+, the core genetic aetiology of EEM- remains to be elucidated.


A new method to study glutathione adduct formation in periportal and pericentral regions of the liver lobule by micro-reflectance spectrophotometry.
A method was developed to measure the formation of glutathione adducts of 1-chloro-2,4-dinitrobenzene (CDNB) and 2,4-dichloro-1-nitrobenzene (DCNB) in periportal and pericentral regions of the liver lobule in the isolated perfused rat liver by surface reflectance spectrophotometry. Conjugates of DCNB and CDNB are released from livers of normal and phenobarbital-treated rats during perfusion in either the anterograde or the retrograde direction at maximal rates around 13-15 mumol/g/hr. The formation of S-(1-chloro-4-nitrophenyl)-glutathione and S-(2,4-dinitrophenyl)-glutathione by the liver decreased the amount of 366-nm light reflected from the liver surface detected with a large-tipped (2 mm) fiberoptic light guide. Initial rates of decrease in reflected light correlated highly with maximal rates of conjugate formation by the liver. Subsequently, micro-light guides were placed on periportal and pericentral regions of the liver lobule. Rates of glutathione adduct formation were calculated from the proportion of the total change in rate of reflected 366-nm light which occurred in each region and the overall rate of product formation by the liver. Changes in the reflectance signal require reduced glutathione (GSH) and were shown to originate from intracellular conjugate formation and not from adducts in the bile canaliculus. Livers from normal rats produced conjugated products from DCNB (100 microM) at maximal rates of 14 and 15 mumol/g/hr in periportal and pericentral regions of the liver lobule, respectively. With CDNB as substrate, changes in reflected light at 366 nm were detected nearly exclusively in periportal regions of the lobule in livers from normal rats. In sharp contrast, CDNB and DCNB were conjugated exclusively in periportal regions of the lobule at rates of 21-22 mumol/g/hr in livers from phenobarbital-treated rats (i.e., the reflectance signal was not altered by these substrates in pericentral areas). When CDNB and DCNB were infused into livers from phenobarbital-treated rats perfused in the retrograde direction, decreases in reflected light at 366 nm were detected initially in pericentral areas followed in about 12 min by changes in periportal regions. Maximal rates of adduct formation in both regions reached 25 mumol/g/hr during perfusion in the retrograde direction. Thus, pericentral regions indeed possess the capacity to conjugate both CDNB and DCNB. When glutathione synthesis was inhibited with L-buthionine sulfoximine treatment (6 mmol/kg), which partially depletes GSH, CDNB was conjugated in both periportal and pericentral regions of the liver lobule in livers from phenobarbital-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)


The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease.
Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP(swe)/PS1(ΔE9) (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40-50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.


The role of pseudorabies virus thymidine kinase expression in trigeminal ganglion infection.
The role of pseudorabies virus (PRV) thymidine kinase (TK) expression in the pathogenesis of PRV infection of mice was studied with TK-negative (TK-) mutants. Thymidine phosphorylation and arabinosylthymine inhibition of PRV replication and efficiency of plating were used to characterize TK+ and TK- PRV. In addition, a plaque autoradiography procedure was utilized to determine the TK phenotype of individual plaques. TK+ and TK- PRV replicated well in ocular tissues, while TK+ but not TK- did so in ganglion tissue. Mortality was absent after TK- PRV inoculation and widespread after inoculation of similar amounts of TK+ PRV. Latent infection in mice was not detected with either TK+ or TK- PRV. This study indicated the probable importance of PRV TK expression in acute trigeminal ganglion infection.


Black aspergilli: A remaining challenge in fungal taxonomy?
Aspergillus section Nigri is a taxonomically difficult but medically and economically important group. In this study, an update of the taxonomy of A. section Nigri strains within the BCCM/IHEM collection has been conducted. The identification accuracy of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was tested and the antifungal susceptibilities of clinical isolates were evaluated. A total of 175 strains were molecularly analyzed. Three regions were amplified (ITS, benA, and caM) and a multi-locus phylogeny of the combined loci was created by using maximum likelihood analysis. The in-house MALDI-TOF MS reference database was extended and an identification data set of 135 strains was run against a reference data set. Antifungal susceptibility was tested for voriconazole, itraconazole, and amphotericin B, using the EUCAST method. Phylogenetic analysis revealed 18 species in our data set. MALDI-TOF MS was able to distinguish between A. brasiliensis, A. brunneoviolaceus, A. neoniger, A. niger, A. tubingensis, and A. welwitschiae of A. sect. Nigri. In the routine clinical lab, isolates of A. sect. Nigri are often identified as A. niger. However, in the clinical isolates of our data set, A. tubingensis (n = 35) and A. welwitschiae (n = 34) are more common than A. niger (n = 9). Decreased antifungal susceptibility to azoles was observed in clinical isolates of the /tubingensis clade. This emphasizes the importance of identification up to species level or at least up to clade level in the clinical lab. Our results indicate that MALDI-TOF MS can be a powerful tool to replace classical morphology.


Bovine endometrial MSC: mesenchymal to epithelial transition during luteolysis and tropism to implantation niche for immunomodulation.
The uterus is a histologically dynamic organ, and the mechanisms coordinating its regeneration during the oestrous cycle and implantation are poorly understood. The aim of this study was to isolate, immortalize and characterize bovine endometrial mesenchymal stem cell (eMSC) lines from different oestrous cycle stages (embryo in the oviduct, embryo in the uterus or absence of embryo) and examine their migratory and immunomodulatory properties in an inflammatory or implantation-like environment, as well as possible changes in cell transdifferentiation. eMSCs were isolated and analysed in terms of morphological features, expression of cell surface and intracellular markers of pluripotency, inmunocytochemical analyses, alkaline phosphatase activity, proliferation and osteogenic or chondrogenic differentiation capacities, as well as their ability to migrate in response to inflammatory (TNF-α or IL-1β) or implantation (IFN-τ) cytokines and their immunomodulatory effect in the proliferation of T cells. All eMSCs showed MSC properties such as adherence to plastic, high proliferative capacity, expression of CD44 and vimentin, undetectable expression of CD34 or MHCII, positivity for Pou5F1 and alkaline phosphatase activity. In the absence of an embryo, eMSC showed an apparent mesenchymal to epithelial transition state. eMSC during the entire oestrous cycle differentiated to osteogenic or chondrogenic lineages, showed the ability to suppress T cell proliferation and showed migratory capacity towards pro-inflammatory signal, while responded with a block in their migration to the embryo-derived pregnancy signal. This study describes for the first time the isolation, immortalization and characterization of bovine mesenchymal stem cell lines from different oestrous cycle stages, with a clear mesenchymal pattern and immunomodulatory properties. Our study also reports that the migratory capacity of the eMSC was increased towards an inflammatory niche but was reduced in response to the expression of implantation cytokine by the embryo. The combination of both signals (pro-inflammatory and implantation) would ensure the retention of eMSC in case of pregnancy, to ensure the immunomodulation necessary in the mother for embryo survival. In addition, in the absence of an embryo, eMSC showed an apparent mesenchymal to epithelial transition state.


Impact of Comorbidities Among Medicaid Enrollees With Chronic Obstructive Pulmonary Disease, United States, 2009.
Multimorbidity, the presence of 2 or more chronic conditions, frequently affects people with chronic obstructive pulmonary disease (COPD). Many have high-cost, highly complex conditions that have a substantial impact on state Medicaid programs. We quantified the cost of Medicaid-insured patients with COPD co-diagnosed with other chronic disorders. We used nationally representative Medicaid claims data to analyze the impact of comorbidities (other chronic conditions) on the disease burden, emergency department (ED) use, hospitalizations, and total health care costs among 291,978 adult COPD patients. We measured the prevalence of common conditions and their influence on COPD-related and non-COPD-related resource use by using the Elixhauser Comorbidity Index. Elixhauser comorbidity counts were clustered from 0 to 7 or more. We performed multivariable logistic regression to determine the odds of ED visits by Elixhauser scores adjusting for age, sex, race/ethnicity, and residence. Acute care, hospital bed days, and total Medicaid-reimbursed costs increased as the number of comorbidities increased. ED visits unrelated to COPD were more common than visits for COPD, especially in patients self-identified as black or African American (designated black). Hypertension, diabetes, affective disorders, hyperlipidemia, and asthma were the most prevalent comorbid disorders. Substance abuse, congestive heart failure, and asthma were commonly associated with ED visits for COPD. Female sex was associated with COPD-related and non-COPD-related ED visits. Comorbidities markedly increased health services use among people with COPD insured with Medicaid, although ED visits in this study were predominantly unrelated to COPD. Achieving excellence in clinical practice with optimal clinical and economic outcomes requires a whole-person approach to the patient and a multidisciplinary health care team.


Adrenoleukodystrophy: oleic acid lowers fibroblast saturated C22-26 fatty acids.
Monounsaturated fatty acids, especially oleic acid (C18:1), decreased the content of saturated very-long-chain fatty acids (VLFA) in cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and controls. When confluent ALD fibroblasts were incubated with oleic acid for 5 days in lipid-free medium, which eliminates uptake of exogenous VLFA, the mean cell content of C26:0 was decreased by 33.7 +/- 10.1%. Oleic acid inhibited C26:0 synthesis in ALD fibroblasts by 58% and total fatty acid synthesis by 68 to 78%. Therefore, the elevated C26:0 levels in ALD cells may be lowered by inhibiting fatty acid biosynthesis, and inhibition of saturated VLFA synthesis by oleate may be useful in treating ALD.


Prevention and control of infections in patients with severe congenital neutropenia; a follow up study.
Severe congenital neutropenia is one of primary immunodeficiency disorders that characterized by severe neutropenia and is associated with severe systemic bacterial infections from early infancy. Granulocyte colony stimulating factor (GCSF) is clinically used as a treatment for congenital and acquired neutropenia. The aim of this study was evaluation of GCSF (PD- Grastim) in treatment of these patients. Patients with severe congenital neutropenia referred to Immunology, Asthma and Allergy Research Institute between Jan 2007 and Dec 2010 enrolled the study. Other causes of neutropenia were excluded by serial CBC and bone marrow studies, medical and drug histories and immunological tests. Patients were visited and examined monthly to evaluate their CBC and ANC (absolute neutrophil count), GCSF side effects and dosage adjustment. Cytogenetic studies were being done for all the patients for early detection of progression to AML/MDS. From twenty two patients who enrolled this study, 16 patients regularly evaluated. They were ten males and six females, range in age from 2 to 18 years old. Two patients failed to continue our follow up unfortunately and four patients died due to disease complications. Patients were followed for 24 to 48 months. In a period of 12-24 months before treatment, the mean of hospitalization frequency was 3.1 times and duration was 10 days; while during receiving treatment, they decreased to 0.2 times and 3 days, respectively (p<0.01). Also significant increase in mean ANC was observed during follow up (315/µl before treatment versus 1749/µl after 12 month regular treatment). Bone pain was the most common side effect. There have been no evidences of developing AML/MDS up to present time. Treatment with GCSF significantly reduced the duration and the frequency of hospitalization. Because of plausible progression to AML/MDS, regular follow-up of patients should be continued.


Comparison of somatic reversions between the ivory allele and transposon-caused mutant alleles at the white locus of Drosophila melanogaster after larval treatment with X rays and ethyl methanesulfonate.
Somatic reversion of strains with the ivory (wi) allele, a mutation associated with a tandem duplication of a DNA sequence at the white locus, increased with the age of larvae at the time of X-irradiation as expected from the increase in the number of target cells. In contrast, two independently isolated strains with unstable w+ loci associated with insertion of transposable elements showed higher reversion frequencies after treatment with X rays or ethyl methanesulfonate (EMS) at early larval stages than at late stages. Nevertheless, both the wi strain and the two unstable w+ strains reverted at nearly equal rates after treatment with X rays or EMS at early larval stages. Possible similarity in "hot spot" structure for the high reversibility of the two types of mutations is discussed in relation to production of presumed "mutator-type" cofactors specific to the transposon-caused mutations at early larval stages.


New concepts for dynamic plant uptake models.
Models for the prediction of chemical uptake into plants are widely applied tools for human and wildlife exposure assessment, pesticide design and for environmental biotechnology such as phytoremediation. Steady-state considerations are often applied, because they are simple and have a small data need. However, often the emission pattern is non-steady. Examples are pesticide spraying, or the application of manure and sewage sludge on agricultural fields. In these scenarios, steady-state solutions are not valid, and dynamic simulation is required. We compared different approaches for dynamic modelling of plant uptake in order to identify relevant processes and timescales of processes in the soil-plant-air system. Based on the outcome, a new model concept for plant uptake models was developed, approximating logistic growth and coupling transpiration to growing plant mass. The underlying system of differential equations was solved analytically for the inhomogenous case, i.e. for constant input. By superposition of the results of n periods, changes in emission and input data between periods are considered. This combination allows to mimic most input functions that are relevant in practice. The model was set up, parameterized and tested for uptake into growing crops. The outcome was compared with a numerical solution, to verify the mathematical structure.


Cross-disciplinary research in cancer: an opportunity to narrow the knowledge-practice gap.
Health services researchers have consistently identified a gap between what is identified as "best practice" and what actually happens in clinical care. Despite nearly two decades of a growing evidence-based practice movement, narrowing the knowledge-practice gap continues to be a slow, complex, and poorly understood process. Here, we contend that cross-disciplinary research is increasingly relevant and important to reducing that gap, particularly research that encompasses the notion of transdisciplinarity, wherein multiple academic disciplines and non-academic individuals and groups are integrated into the research process. The assimilation of diverse perspectives, research approaches, and types of knowledge is potentially effective in helping research teams tackle real-world patient care issues, create more practice-based evidence, and translate the results to clinical and community care settings. The goals of this paper are to present and discuss cross-disciplinary approaches to health research and to provide two examples of how engaging in such research may optimize the use of research in cancer care.


The Relative Bioavailability of Ibuprofen After Administration With a Novel Soft Chewable Drug Formulation.
The first aim of the present study was to evaluate the bioavailability of ibuprofen dispersed in a novel soft chewable formulation compared with a traditional ibuprofen tablet; its second was to map the quality of taste masking and patient product satisfaction. In a phase 1, single-center, open-label, randomized, crossover study, healthy subjects received a soft-chew formulation or a hard tablet (reference), both containing 100 mg ibuprofen. Serial blood samples were collected over 24 hours to assess ibuprofen bioavailability. Taste and satisfaction after chewing the novel formulation 3 or 8 times were evaluated with a questionnaire. The soft-chew formulation showed comparable bioavailability to the reference tablet. The highest peak plasma concentration was observed after 3 chews, and the relative bioavailability was approximately 8% higher compared to 8 chews. The overall flavor was well appreciated, and chewing 3 times was significantly preferred (P = .043) over chewing 8 times. Soft chewable drug formulations may improve compliance and potentially benefit several subpopulations who experience dysphagia.


Microbial isolates in open fractures seen in the accident and emergency unit of a teaching hospital in a developing country.
In this prospective study, superficial and deep swabs of all open fractures seen at the accident and emergency unit of our hospital between January and June 2000 were taken (before wound debridement was done or anitibiotics commenced). Routine microscopy, culture and sensitivities for aerobic and anaerobic organisms were carried out on these specimens. The organisms were cultured and identified using standard techniques and the antibiotic sensitivity testing was carried out using the disc diffusion method of Stokes. Within six hours of injury, single-organism isolates were commonly found whilst after 48 hours a mixed or poly-microbial organism load were isolated. In 90% of the positive isolates, the organisms isolated form the superficial and the deep swabs were the same. The antibiotic sensitivity pattern of all the isolates shows that pefloxacin, ciprofloxacin and ceftriaxone were more effective compared to cefuroxime and amoxycillin which had substantial resistance to most of the isolates. 41 fractures were followed to union and 4 (9.7%) developed osteomyelitis.


Videoendoscopic single-port nipple-sparing mastectomy and immediate reconstruction.
Single-incision videoendoscopic surgery has recently become popular as a result of the ongoing search for less invasive procedures. The aim of this study was to evaluate the safety and efficacy of endoscopic single-port nipple-sparing mastectomy, axillary lymphadenectomy, and immediate reconstruction in patients with breast cancer. From May 14, 2012 through January 23, 2013, 10 patients underwent videoendoscopic single-port nipple-sparing mastectomy and axillary dissection via a single, limited incision and immediate prosthetic reconstruction. Patient charts were reviewed, and demographic data, operative time, complications and pathology results were analyzed. In all patients, videoendoscopic surgery was performed successfully. Of 10 patients, 7 were diagnosed as having invasive ductal carcinoma, 2 had a ductal carcinoma in situ, and 1 underwent bilateral prophylactic mastectomy. The weight of the resected gland was 300-650 g, with a mean of 420 g. There were no operative complications, and the mean operative time was 250 minutes (range, 160-330 minutes). One-stage reconstruction with implants was performed on 4 patients, whereas expanders were placed in the remaining 6. Surgical margins of all cases were pathologically negative, and there were no recurrences observed during the early follow-up period. Videoendoscopic single-port nipple-sparing mastectomy is technically feasible even in larger breasts, enabling immediate reconstruction with good cosmetic outcomes. However, further studies with larger clinical series and long-term follow-up are required to compare the safety and efficacy of the technique with those of the standard nipple-sparing mastectomy.


Awareness, perceptions, and provider recommendation related to genetic testing for hereditary breast cancer risk among at-risk Hispanic women: similarities and variations by sub-ethnicity.
This study explored awareness of risk factors for hereditary breast and ovarian cancer (HBOC), awareness, knowledge and concerns about genetic testing, and preference for how to have genetic testing recommended by a care provider among at-risk Hispanic women. Differences in these factors among Mexican, Cuban, and Puerto Rican women were also examined. Women with a personal or family history of breast or ovarian cancer from the Tampa Bay Area participated in a qualitative interview (N = 53). Data were analyzed using a combination of open and axial coding with a grounded theory approach. Study participants in all groups reported: being aware that family history was a breast cancer risk factor, limited knowledge of genetic testing, fear of test results, concerns about children's risks, and no physician referral for genetic testing. Noteworthy sub-ethnic differences included preferences for physician recommendation and information about genetic testing. This study provides important preliminary information about areas related to HBOC that require additional education in the Hispanic community as a whole and by sub-ethnicity.