Does Moderate Coronary Stenosis Affect the Fate of the Left Internal Thoracic Artery Graft?
In this study we try to observe the fate of the left internal thoracic artery grafts that were bypassed to left anterior descending artery with moderate stenosis identified with fractional flow reserve (FFR) technique. Doppler ultrasonography was chosen as a noninvasive screening method. A total of 30 patients who underwent coronary artery bypass grafting depending on results of the fractional flow reserve between January 2007 and January 2012, were subjected to transthoracic color Doppler ultrasonographic evaluation irrespective of the presence of symptoms, and the presence of a systolic-diastolic flow pattern was investigated using the supraclavicular approach. The left internal thoracic artery graft was found to be functional in 63.3% of patients within a mean period of 35.1±19.7 months between coronary bypass and color Doppler ultrasonography. This period was found to be 29.4±19.6 months in the functional graft group, and 44.7±16.6 months in the dysfunctional graft group (P=0.046). Preoperative complaints of angina were reported to fall from 88.9% to 16.7% in the functional graft group, when compared to the postoperative period (P<0.001), but fell from 90.9% to 36.4% in the dysfunctional graft group (P=0.034). Functional left internal thoracic artery graft rates of the study population were found to be lower than the studies reported in the literature.


[Microbiological etiology in children with community acquired pneumonia].
To study the distribution of pathogenic microorganisms of community acquired pneumonia (CAP) in children. Respiratory secretion and blood specimens were collected in 1167 children with CAP within 4 hrs of admission. Mycoplasma pneumonia and Chlamydia trachomatis were detected by RT-PCR in respiratory secretion specimens. Respiratory syncytial virus (RSV-IgM) and Adenovirus (ADV-IgM) were tested using ELISA in blood samples. A total of 308 strains of bacteria were isolated from the respiratory tract secretions, with gram positive strains of 53.6% and gram negative strains of 46.4%. The top five bacteria strains detected were Streptococcus pneumoniae (35.1%), Escherichia coli (11.7%), Staphylococcus aureus (8.8%), Klebsiella pneumonia (6.5%) and Moraxelle catarrhalis (5.8%) in turn. Beta-lactamase and ESBLs producing strains accounted for 30.1% in the top five bacteria strains. The non-bacteria pathogens were found in 281 specimens (24.1%). Respiratory syncytial virus accounted for the most prevalent pathogen (19.3%). The mixed infection of respiratory syncytial virus and Streptococcus pneumoniae was common (35.2%). The infection rate from most of pathogenic microorganisms among children under the age of one was higher than that in children over one year old. Respiratory syncytial virus and Streptococcus pneumoniae are the major pathogens of CAP in children. The risk of pathogenic microorganism infections in children under the age of one is higher than that of children over one year old.


The aspirin metabolite salicylate inhibits lysine acetyltransferases and MUC1 induced epithelial to mesenchymal transition.
MUC1 is a transmembrane mucin that can promote cancer progression, and its upregulation correlates with a worse prognosis in colon cancer. We examined the effects of overexpression of MUC1 in colon cancer cells, finding that it induced epithelial to mesenchymal transition (EMT), including enhanced migration and invasion, and increased Akt phosphorylation. When the clones were treated with the aspirin metabolite salicylate, Akt phosphorylation was decreased and EMT inhibited. As the salicylate motif is necessary for the activity of the lysine acetyltransferase (KAT) inhibitor anacardic acid, we hypothesized these effects were associated with the inhibition of KAT activity. This was supported by anacardic acid treatment producing the same effect on EMT. In vitro KAT assays confirmed that salicylate directly inhibited PCAF/Kat2b, Tip60/Kat5 and hMOF/Kat8, and this inhibition was likely involved in the reversal of EMT in the metastatic prostate cancer cell line PC-3. Salicylate treatment also inhibited EMT induced by cytokines, illustrating the general effect it had on this process. The inhibition of both EMT and KATs by salicylate presents a little explored activity that could explain some of the anti-cancer effects of aspirin.


[Acute renal insufficiency caused by Amanita proxima poisoning: experience of the Poison Center of Marseille].
In southern France, some Amanita species are usually eaten like Amanita ovoidea (Quélet, 1872) which is a common white mushroom. In same areas, a similar and less common fungus can be encountered: Amanita proxima (Dumee, 1916). The first published cases of Amanita proxima poisonings with acute renal failure have been reported in 1994 by a medical team from Montpellier. A second article was published in 1995 by physicians from Marseille. In order to evaluate the importance of the confusion between the 2 species, we looked after these mushroom poisonings collected by the Poison Centre of Marseille. We found 31 cases concerning 53 patients. We observed the first intoxication in 1968. Poisonings took place in the south of Provence. Ingestions are in 26 cases (83% of the 31 cases) due to the confusion with Amanita ovoidea. The average delay between the meal and the first signs was 13 hours and 12 minutes. All patients had gastro-intestinal symptoms, and for 14 of them, oliguria or anuria appeared in a few days after ingestion. 11 patients needed temporary dialysis, and for 10 of them, moderate hepatic cytolysis was observed. The severity of symptoms seems to be dose-dependent: we collected cases in the same family with no signs after just tasting the meal, digestive symptoms only when patients at more, and renal failure for the hungry people.


Radiological detection and diagnosis of pouch of Douglas lesions.
The pouch of Douglas (cul-de-sac) represents the caudal extension of the peritoneal cavity. It is the rectovaginal pouch in the female and the rectovesical pouch in the male. The cul-de-sac is in a dependent position when either upright or supine; it is, therefore, a frequent location for seeded lesions. Abnormalities in the cul-de-sac include metastases, abscesses, and endometriosis. These lesions may be detected by multiple modalities, including barium enema, computed tomography, and ultrasound. Examples of numerous cul-de-sac lesions are presented as they appear with different imaging modalities.


The first palladium(iv) aryldiazenido complex: relevance for C-C coupling.
Overall two-electron oxidative addition of the aryldiazonium cation para-methoxybenzenediazonium (pmbd+) to [(Tp*)PdIIMe2]- (Tp*- = hydridotris-(3,5-dimethylpyrazolyl)borate) produces the first characterized palladium(iv) aryldiazenido complex, [(Tp*)PdIVMe2(pmbd)] (pmbd- = para-methoxybenzenediazenido). Thermolysis in benzene forms a mixture of products that contains [(Tp*)PdIVMe3] and the C-C coupled product, 4,4'-dimethoxybiphenyl. The use of acetone as the thermolysis solvent changes the product distribution towards the formation of anisole. While some involvement of two-electron pathways in the decomposition cannot be ruled out, radicals, through one-electron steps, are involved in the major pathways for decomposition. The involvement of radicals is confirmed by the solvent dependent nature of the product distribution and by observing that the added N-tert-butyl-α-phenylnitrone efficiently traps aryl radicals.


Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis.
To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Fms-like tyrosine kinase 3 (Flt3) receptor in leukemogenesis, we introduced the Flt3-ITD, W51, into human cord blood CD34+ cells and evaluated their phenotype in diverse hematopoietic assays. W51 expression resulted in a strong proliferative advantage and enhanced erythropoiesis as determined by immunophenotyping, colony assays, and molecular analyses. In MS-5 stromal cocultures, numerous early cobblestone areas (CAs) were generated within 10 to 14 days. Such W51-associated early CAs disappeared by 4 weeks, yet retained self-renewal properties as demonstrated by generation of secondary and tertiary CAs upon replating. This phenotype appears related to the expression of W51 since it was abolished by exposure to the FLT3 inhibitor, AG1295, but not to the c-kit inhibitor PD16. Wild-type Flt3-overexpressing CD34+ cells exposed to high levels of its physiologic ligand did not produce early CAs, highlighting differences in intracellular signaling between wild-type Flt3 and W51. W51-associated signal transducer and activator of transcription 5 (Stat5) activation plays a major role in this phenotype, although additional downstream targets of W51 may be relevant. Flt3-ITD+ acute myeloid leukemia (AML) blasts from patients invariably generated early AG1295-sensitive CAs in MS-5 cocultures, further validating the phenotype observed in transduced CD34+ cells.


Somatic IDH1 mutation in a pituitary adenoma of a patient with Maffucci syndrome.
Maffucci syndrome is a rare disease characterized by multiple enchondromas and soft-tissue hemangiomas. Additionally, neuroendocrine tumors including pituitary adenomas have been described in these patients. The underlying genetic etiology lies in somatic mosaicism of mutations in isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2). This report describes a patient with Maffucci syndrome who presented with intracranial tumors of the skull base and suprasellar region. The patient underwent resection of both intracranial tumors, revealing histopathological diagnoses of chondrosarcoma and pituitary adenoma. DNA sequencing of the tumors was performed to identify common IDH1/2 mutations. Clinical, radiological, and biochemical assessments were performed. Genotypic studies used standard Sanger sequencing in conjunction with a target-specific peptide nucleic acid to detect IDH1 mutations in tumor tissues. DNA sequencing demonstrated identical IDH1 mutations (c.394C > T) in both tumors. To the authors' knowledge, this report provides the first genetic evidence for the inclusion of pituitary adenomas among tumors characterizing Maffucci syndrome. In patients who are newly diagnosed with Maffucci syndrome, it is appropriate to monitor for development of pituitary pathology and neuroendocrine dysfunction.


Influence of surface roughness and surface moisture of plastics on sensor-based sorting in the near infrared range.
In the project 'NEW-MINE' the use of sensor-based sorting machinery in the field of 'landfill mining' is investigated. Defilements pose a particular challenge in the treatment and sorting of plastics contained in landfills. For this reason, the effects of various pollutants caused by the interactions in the landfill body or the mechanical treatment steps in landfill mining are examined. In the following elaboration, the focus is on the influences of surface moisture and surface roughness of plastics on sensor-based sorting by means of near-infrared technology. Near-infrared radiation (NIR) in a wavelength range of 990 nm to 1500 nm has been used for the detection and classification of plastic particles. The experiments demonstrate that increased surface roughness reduces signal noise and thereby improves the classification of both spectrally similar and transparent plastics, but reduces the yield of low-softening plastics because their sliding speed on a sensor-based chute sorter varies as a result of the heating of the chute. Surface moisture causes the absorption of radiation from 1115 nm (high density polyethylene [HDPE], linear low density polyethylene [LLDPE], polyethylen terephthalate [PET] and polyvinylchloride [PVC]) or from 1230 nm (low density polyethylene [LDPE], polypropylene [PP] and thermoplastic polyurethane [TPU]) up to at least 1680 nm, which causes amplification or attenuation of various extremes in the derivative. However, the influence of surface moisture on the yield of plastics is usually very low and depends on the spectral differences between the different plastics.


Neurologic, psychiatric, and cardiovascular complications in children struck by lightning.
The neurologic changes following lightning injury include coma with cerebral edema, inappropriate secretion of antidiuretic hormone (ADH), seizures, cerebellar ataxia, and painful sensory disturbances. Deteriorating neurologic status may warrant the use of intracranial pressure monitoring devices. Myocardial injury and transient hypertension are generally evident at the onset. Monitoring of the cardiac rhythm may be needed for as long as a week for late onset arrythmia. Abnormalities of memory, mood, and affect noted on recovery of consciousness may persist for months, necessitating close psychiatric and neurlologic follow-up.


Psychosocial and Environmental Correlates of Sedentary Behaviors in Spanish Children.
Purpose. To evaluate children's psychosocial and environmental factors associated with sedentary behavior (SB). Method. The study involved a total of 420 children (mean 9.2 years; 52.9% girls) from the community of Madrid, Spain. SB and physical activity (PA) were objectively measured using accelerometers. TV viewing and potential correlates were assessed by questionnaire. Mixed-model regression analysis, adjusted for clustering within school locations, evaluated the relation of each independent variable with SBs. Results. Girls showed higher levels of SB than boys, whereas boys reported more TV viewing (p < .001 in all cases). Regression analysis showed that MVPA levels were negatively related to objective SB measurement in both boys and girls (p < .001). Parent and friend support to PA were negatively associated with SB on weekdays in boys and girls, respectively (p < .05). In the boys' group, parental professional level was a positive predictor of SB on weekend days (p = .011). Boys with more positive neighborhood perceptions spent less time watching TV (p < .001), whereas mother's leisure-time PA level was a negative correlate of TV viewing in girls' group (p < .01). Conclusion. Different psychosocial and environmental correlates of SB were identified. Present findings are promising targets for interventions to improve children's health.


The effect of antihistamines on seizures induced by increasing-current electroshocks: ketotifen, but not olopatadine, promotes the seizures in infant rats.
Clinical reports have shown that some antihistamines, such as ketotifen, occasionally produced seizures, especially in pre-school age children or young patients with epilepsy. The purpose of this study was to investigate whether olopatadine, one of the most efficacious antihistamines, promotes seizures induced by electroshocks in young rats. We investigated the seizures induced by electroshock using increasing-current delivery in 3- or 4-week-old rats, and found that the threshold-current of tonic extensor seizures was elevated with age in weeks in the vehicle-treatment groups. While caffeine decreased the threshold-current in every age group of rats, pentylenetetrazole, a γ-aminobutyric acid (GABA)(A) receptor antagonist, significantly decreased them only in 4-week-old rats. On the other hand, ketotifen decreased them only in 3-weeks-old rats. In the 3-week-old rats, neither olopatadine nor fexofenadine had any effect on the threshold-currents of tonic extensor seizures. These results showed that histaminergic neuro-transmission in the brain plays a crucial role in inhibiting seizures in rats soon after weaning, but is no longer effective in rats as they approach sexual maturation. In addition, unlike ketotifen, olopatadine, as well as fexofenadine, do not promote the occurrence of seizures in infant rats.


Pilot and Revision of a Basal-Bolus Dosing Guideline for the Management of Hyperglycemia in Noncritically Ill Adult Patients.
The use of basal-bolus insulin (BBI) regimens for the treatment of inpatient hyperglycemia has become standard of care. The purpose of this study was to develop and evaluate a newly piloted dosing guideline and utilize the results to adjust it prior to its implementation hospital-wide. This was an institutional review board approved, prospective, and multiphase study. An interdisciplinary team was developed and created a dosing guideline, which was followed by a 3-month, single-unit pilot of the guideline in noncritically ill adult patients. The resulting data were used to revise the guideline. Forty-three patients were included. There was a significant decrease in median blood glucose (BG) with use of the guideline (219 mg/dL [162-281] vs 190 mg/dL [136-246], P < .05) in patients not utilizing it. There was also a significant increase in the number of values within the target range of 70 to 180 mg/dL (30.2% vs 41.4%, P < .05). Moreover, there was comparable hypoglycemia before and after the intervention (1.6% vs 2.4%, P = .51). Based on these results, the dosing factor used for the total daily dose of insulin was increased in certain populations. Use of a BBI dosing guideline is safe and effective in decreasing BG values in noncritically ill patients at our institution.


Bioavailability of mercury in power plant wastewater and ambient river samples: Evidence that the regulation of total mercury is not appropriate.
Mercury (Hg) is a neurotoxin that can cause debilitating effects to human and environmental receptors under high exposure conditions. For industrial and municipal point sources that discharge Hg, wastewater limitations on total Hg (THg) concentrations or loads are typical. While this regulatory practice provides simplicity for regulated industry and water resource agencies (i.e., for analytical detection and reporting purposes), it ignores the important considerations of speciation and bioavailability. In this study, water samples were collected from multiple power plant wastewater, simulated mixing zone, and ambient river locations (N = 10 to 20) and were analyzed for bioavailable Hg forms (methylmercury and acid-labile Hg, or BHg), THg, and dissolved Hg. The median concentration of THg in wastewater, mixing zone, and ambient river samples was 7.1, 5.3, and 2.3 ng/L, respectively. The percentages of THg as BHg (median values) were 18.7%, 29.3%, and 8.5% for wastewater, mixing zone, and ambient river samples. The percentages of methylmercury (MeHg) as THg were not statistically different between paired ambient and mixing zone samples (P > 0.05); this result indicates that wastewater did not increase the MeHg fraction when mixed with ambient water. Multiple regression analysis indicated that variation in THg for combined wastewater and mixing zone samples could be adequately explained by pooled water quality parameters (total suspended solids, total dissolved solids, sulfate, total organic carbon, pH, specific conductivity; r2 = 0.51; P < 0.05); however, no significant regression relationships were apparent for the percentage of BHg. These results, at least for the wastewater samples evaluated, indicate that regulating THg is likely overly conservative, and mechanisms to regulate the bioavailable forms of Hg are needed. If Hg fish tissue monitoring data indicate that concentrations are less than consumption thresholds, metal translator methodologies or bioavailability-based criterion techniques (as currently used for non-Hg trace elements) should be allowed for Hg. Integr Environ Assess Manag 2019;15:142-147. © 2018 SETAC.


Colossal Dielectric Responses from the Wide Band Gap 2D-Semiconducting Amine Templated Hybrid Framework Materials.
Two unprecedented organic amine templated silver organophosphonate hybrid solids have been synthesized hydrothermally by varying the molar ratio of the reactants. Both of the compounds consist of novel tetra- and penta-nuclear silver phosphonate basic building units. The dielectric constants are extremely large due to the charge separation of anionic metal phosphonate frameworks and cationic templated piperazine moieties in the compounds, as found for the first time in a hybrid organophosphate family. The conductivity and UV-visible absorption studies provide strong evidence about the semiconducting nature of the present compounds.


Dying well? A colloquy on euthanasia and assisted suicide.
With this special issue the Report once again joins the debate on what patients, physicians, and society can -- and cannot -- live with at the end of life. The articles gathered here address in various ways, from various perspectives, the questions that inform the debate on euthanasia and assisted suicide. Do the canons of self-determination and respect for persons compel us to honor the choices of those who request active assistance in dying? Can we coherently argue that physicians' professional obligations to alleviate suffering extend so far as to taking life on request? To what extent ought our policy decisions rest on consideration of possible consequences?


Oxidative stress in a novel model of chronic acidosis in LLC-PK1 cells.
Chronic metabolic acidosis occurs commonly in chronic renal failure (CRF). The proximal renal tubular cell is the site in the kidney of high oxidative metabolic activity and in CRF is associated with adaptive hypertrophy and hypermetabolism. We hypothesised that chronic acidosis may lead to increased generation of reactive oxygen species due to increased oxidative activity. We developed a novel model of chronic acidosis in LLC-PK1 cells and measured markers of oxidative stress and metabolism. Acidosis led to a reduction in cellular total glutathione and protein thiol content and an increase in glutathione peroxidase activity and NH3 generation. The expression of constitutively expressed heat stress protein (HSP) HSC70 and HSP60 increased at pH 7.0.


Family members' experiences of the intensive care unit waiting room.
This paper is a report of a study to explore family members' perspectives and experiences of waiting rooms in adult intensive care units. Waiting to visit family members who are hospitalized in intensive care units can be very stressful. Although flexible and or open visiting is practised in many hospitals, family members may spend a great deal of time in the waiting room. A qualitative design using semi-structured interviews was used and the data were collected in 2004. A convenience sample of six visitors was recruited from waiting rooms of three different adult intensive care units. Data collection and analysis were concurrent. Six categories emerged from the data that included structural and subjective aspects of waiting: 'close proximity' referred to the importance of a close physical distance to their family member; 'caring staff' captured the comfort family members felt when staff showed caring behaviours towards relative; 'need for a comfortable environment' represented the impact of the design of the waiting room on family members well-being; 'emotional support' referred to the waiting room as a place where comfort was found by sharing with others; 'rollercoaster of emotions' captured the range of emotions experienced by family members; 'information' referred to the importance of receiving information about their relative. Future research should focus on the impact of the interior design of waiting rooms on the comfort and welfare of family members and on identifying needs of family members across different cultures.


Effects of methylene-blue staining on the extent of pilonidal sinus excision.
We aimed to examine the effects of methylene-blue staining (MBS) on the volume of specimens after excision of pilonidal sinuses. This was a retrospective analysis of 135 excised specimens after pilonidal sinus (PS) surgery. All patients underwent procedures at the Department of Surgery of University Hospital Jena between 2000 and 2010. All specimens were measured in three dimensions. To calculate the volumes of excised specimens, we used a model of a hemi-ellipsoid. Demographic information (age, height, weight, body mass index, smoking status) were also obtained for all patients. Excised specimens with MBS had significantly larger volumes (p<0.001) as reflected in length (p=0.001), width (p=0.001), and depth (p=0.017) of the excised specimen compared with specimens that were not stained with methylene blue (MB). In addition, the volume was larger in subjects with a recurrent PS (p=0.021), which was predominantly the case in female subjects (p=0.025). These data suggest that excised specimens with MBS had significantly larger volumes of the excised specimen compared with specimens that were not stained with MB. MBS of a fistula system could enable such a system to be marked sufficiently, thereby facilitating complete resection of a PS.


Estimation of electronegativity values of elements in different valence states.
The electronegativities of 82 elements in different valence states and with the most common coordination numbers have been quantitatively calculated on the basis of an effective ionic potential defined by the ionization energy and ionic radius. It is found that for a given cation, the electronegativity increases with increasing oxidation state and decreases with increasing coordination number. For the transition-metal cations, the electronegativity of the low-spin state is higher than that of the high-spin state. The ligand field stabilization, the first filling of p orbitals, the transition-metal contraction, and especially the lanthanide contraction are well-reflected by the relative values of our proposed electronegativity. This new scale is useful for us to estimate some quantities (e.g., the Lewis acid strength for the main group elements and the hydration free energy for the first transition series) and predict the structure and property of materials.


Integrative CO2 Capture and Hydrogenation to Methanol with Reusable Catalyst and Amine: Toward a Carbon Neutral Methanol Economy.
Herein we report an efficient and recyclable system for tandem CO2 capture and hydrogenation to methanol. After capture in an aqueous amine solution, CO2 is hydrogenated in high yield to CH3OH (>90%) in a biphasic 2-MTHF/water system, which also allows for easy separation and recycling of the amine and catalyst for multiple reaction cycles. Between cycles, the produced methanol can be conveniently removed in vacuo. Employing this strategy, catalyst Ru-MACHO-BH and polyamine PEHA were recycled three times with 87% of the methanol producibility of the first cycle retained, along with 95% of catalyst activity after four cycles. CO2 from dilute sources such as air can also be converted to CH3OH using this route. We postulate that the CO2 capture and hydrogenation to methanol system presented here could be an important step toward the implementation of the carbon neutral methanol economy concept.


Rhizopogon olivaceotinctus increases its inoculum potential in heated soil independent of competitive release from other ectomycorrhizal fungi.
Rhizopogon olivaceotinctus is a rarely collected ectomycorrhizal fungus that has been found primarily in California and southern Oregon. Prior work has shown that it (i) is common in soil spore banks associated with pine forests from these areas; (ii) is rare or absent on trees in undisturbed forests in these same areas; (iii) exhibits an increased abundance on pine seedlings following fire or experimental soil heating; and (iv) has spores that are more resistant to heat than those of several other ectomycorrhizal species tested to date. Here, we reject the hypothesis that the increased abundance of the species following soil heating is caused only by reduced competition with other ectomycorrnizal fungi and show instead that heating alone significantly increases the inoculum potential of its spores. We argue that this is likely caused by heat stimulation of the spores, a process that has precedent in saprotrophic fungi and plant seeds. This result, in combination with those of previous studies, shows that Rhizopogon olivaceotinctus is well adapted to fire.


Why did the Wolbachia transinfection cross the road? drift, deterministic dynamics, and disease control.
Maternally inherited Wolbachia transinfections are being introduced into natural mosquito populations to reduce the transmission of dengue, Zika, and other arboviruses. Wolbachia-induced cytoplasmic incompatibility provides a frequency-dependent reproductive advantage to infected females that can spread transinfections within and among populations. However, because transinfections generally reduce host fitness, they tend to spread within populations only after their frequency exceeds a critical threshold. This produces bistability with stable equilibrium frequencies at both 0 and 1, analogous to the bistability produced by underdominance between alleles or karyotypes and by population dynamics under Allee effects. Here, we analyze how stochastic frequency variation produced by finite population size can facilitate the local spread of variants with bistable dynamics into areas where invasion is unexpected from deterministic models. Our exemplar is the establishment of wMel Wolbachia in the Aedes aegypti population of Pyramid Estates (PE), a small community in far north Queensland, Australia. In 2011, wMel was stably introduced into Gordonvale, separated from PE by barriers to A. aegypti dispersal. After nearly 6 years during which wMel was observed only at low frequencies in PE, corresponding to an apparent equilibrium between immigration and selection, wMel rose to fixation by 2018. Using analytic approximations and statistical analyses, we demonstrate that the observed fixation of wMel at PE is consistent with both stochastic transition past an unstable threshold frequency and deterministic transformation produced by steady immigration at a rate just above the threshold required for deterministic invasion. The indeterminacy results from a delicate balance of parameters needed to produce the delayed transition observed. Our analyses suggest that once Wolbachia transinfections are established locally through systematic introductions, stochastic "threshold crossing" is likely to only minimally enhance spatial spread, providing a local ratchet that slightly-but systematically-aids area-wide transformation of disease-vector populations in heterogeneous landscapes.


An intrastrain cross-reactive idiotype associated with anti-p-azophenylarsonate antibodies of BALB/c mice.
This paper describes an intrastrain cross-reactive idiotype, associated with the anti-Ar antibodies of all BALB/c mice tested. The idiotype is present on 20 to 65% of the anti-Ar antibodies of individual BALB/c mice and is localized to the Fab fragment. Adsorption of anti-Ar antibody from an immune serum completely removes the idiotypic activity. Inheritance of the idiotype is linked to the Igh locus, as shown by results obtained with congenic mice. It is present in strains that are Igh-Ia but not in the allotypically related Igh-Ij strains. The idiotype is also present in certain strains belonging to other allotype linkage groups. Expression of the idiotype is suppressed by the administration of rabbit antiidiotypic antibodies before immunization. The BALB/c idiotype is cross-reactive with an idiotype present in a small proportion of anti-Ar antibodies of A/J mice.


Evaluating how electronic charting affects resident productivity.
Electronic medical records (EMRs) are becoming standard to improve the communication of information and longevity of patient records. Using an EMR in the emergency department (ED) could potentially slow residents evaluating patients. We evaluated how introducing an EMR affected resident productivity in an academic ED. We retrospectively studied first year emergency medicine residents from a large, academic, tertiary care center before-and-after the institution of an EMR on July 1st, 2010. No residents from the 2009-2010 class used the EMR, while all of the 2010-2011 residents used the EMR. We performed univariate and multivariate analyses using productivity, measured in patients per hour (pt/hr), as the primary outcome. A mixed-model multivariate regression, stratified by acuity zone, was created incorporating EMR and other possible confounders: admissions, signouts, daily ED volume, and days after July 1st for each shift. The study was granted IRB waiver of informed. We reviewed 2,405 shifts: 1,259 shifts before and 1,146 shifts after EMR implementation. When using the EMR, the univariate analysis estimated a 0.084 pt/hr increase in the high acuity zone (p = 0.1317) and 0.029 pt/hr decrease (p = 0.7085) in the low acuity zone. The multivariate regression estimated a 0.038 pt/hr increase (p = 0.3413) in the high acuity zone and a 0.009 pt/hr increase (p = 0.9049) in the low acuity zone with the EMR. Despite the expectation that electronic charting is detrimental to resident productivity, our analyses do not suggest a significant relationship between resident productivity and using the EMR.


Prostaglandin analogue misoprostol attenuates neurotoxin 1-methyl-4-phenylpyridinium-induced mitochondrial damage and cell death in differentiated PC12 cells.
Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The present study assessed the preventive effect of a prostaglandin E(1) analogue misoprostol against the toxicity of parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) with respect to the mitochondria-mediated cell death process and oxidative stress. MPP(+) induced the nuclear damage, the changes in the mitochondrial membrane permeability, the formation of reactive oxygen species and the depletion of GSH, which leads to cell death in differentiated PC12 cells. Misoprostol prevented the toxic effect of MPP(+). Treatment with misoprostol significantly attenuated the MPP(+)-induced mitochondrial membrane permeability change that leads to the increase in pro-apoptotic Bax and Cytochrome c levels, and subsequent caspase-3 activation. The protective effect of misoprostol may be supported by the inhibitory effect of prostaglandin E(1) on the MPP(+) toxicity. Misoprostol significantly attenuated another parkinsonian neurotoxin rotenone-induced cell death. The results show that misoprostol may prevent the MPP(+) toxicity by suppressing the mitochondrial membrane permeability change that leads to the Cytochrome c release and caspase-3 activation. The preventive effect seems to be ascribed to the inhibitory effect on the formation of reactive oxygen species and depletion of GSH.


Penetrating abdominal injuries in children and adolescents.
One hundred thirty-two children and adolescents with penetrating abdominal trauma have been reported. Eighty-two of these patients had intraperitoneal injuries. Five of the injured patients died, and 35 suffered complications. Patterns of organ injuries were found to be similar to a previously studied adult series. Satisfactory results were obtained by simple management of specific injuries. Ninety-five per cent of the injured patients and 80% of uninjured patients could be accurately identified at initial physical examination. Selective observation of penetrating abdominal injuries can be safely employed in children and adolescents.


[The peculiarities of formation and approaches to the treatment of chronic fatigue syndrome in young patients with focal brain damage].
Chronic fatigue (CF) is a syndrome manifesting in cases with focal brain damage. It is frequent in multiple sclerosis (MS) and encephalopathies (post-traumatic, cerebrovascular, etc). Treatment of this syndrome remains problematic. The study aimed to analyze the genesis of CF in patients with different non-active neurological diseases with brain damage and possibility of its treatment with the complex drug fezam (piracetam plus cinnarizin) in dosage 2 capsules 3 times per day. Before the treatment, all the patients had CF, which was directly associated with severity of depression in patients with encephalopathies. In MS patients, changes in the valuable-and-sense sphere that plays a significant role in human behavior and activity underlying self-regulation in critical situations were found. Neuropsychological data revealed that in patients with encephalopathies psychological and behavioral aspects were more significant in regard with CF genesis than in patients with MS. Fesam caused significant decrease of the CF severity, which was more prominent in the MS group, while in another group it was associated with a decrease of depression severity. Mild side-effects were observed in 6 patients (12%) and appeared mainly as sleep disorders. This trial allows recommending Fezam for complex treatment of CF syndrome in MS and in combination with psychocorrective medicines in cases of encephalopathies.


[Research progress of optical coherence tomography in the airway].
Optical coherence tomography (OCT) is a specialized optical imaging technique with a history of more than 30 years, known as'optical biopsy' because of its high resolution and high sensitivity. OCT has been used in the airway for more than 20 years, and researchers have explored and improved the imaging methods of OCT in the airway, focusing mainly on expanding the imaging site and enriching the imaging content. In terms of broadening the imaging site, it covers the airway from generation 0 to 9. In terms of enriching imaging content, additional assessment of airway wall blood vessels, airway smooth muscle, fibrous tissue, and airway compliance can be performed. It plays an important role in the study of various respiratory diseases. Therefore, this paper mainly summarized the exploration of the imaging site and content of airway OCT as follows.


Increasing the siRNA knockdown efficiency of lipid nanoparticles by morphological transformation with the use of dihydrosphingomyelin as a helper lipid.
Lipid nanoparticles (LNPs), comprising ionizable lipids, helper lipids, cholesterol, and PEG lipids, can act as delivery carriers for nucleic acids and have achieved clinical success in the delivery of siRNA and mRNA. It has been shown that the morphology of LNPs varies depending on their lipid composition, but the influence of their morphology on nucleic acid efficacy has not been fully elucidated. In this study, we used our previously developed novel lipid, dioleoylglycerophosphate-diethylenediamine conjugate (DOP-DEDA), to create pH-responsive LNPs (DOP-DEDA LNPs). We evaluated the morphology of DOP-DEDA LNPs composed of different helper lipids and the knockdown efficiency of small interfering RNA (siRNA). A distinctive difference in morphology was observed between DOP-DEDA LNPs of different helper lipids. Significant differences were also observed in the apparent pKa of DOP-DEDA LNPs and the knockdown efficiency of siRNA, which may be due to the difference in the localization of DOP-DEDA molecules in DOP-DEDA LNPs. These findings suggest that changing helper lipids alters the morphology of the DOP-DEDA LNP system, which affects the apparent pKa and knockdown efficiency of siRNA.


Effects of chronic sugar consumption on lipid accumulation and autophagy in the skeletal muscle.
In recent years, the increasing consumption of soft drinks containing high-fructose corn syrup or sucrose has caused a rise in fructose intake, which has been related to the epidemic of metabolic diseases. As fructose and glucose intake varies in parallel, it is still unclear what the effects of the increased consumption of the two single sugars are. In the present study, the impact of chronic consumption of glucose or fructose on skeletal muscle of healthy mice was investigated. C57BL/6J male mice received water (C), 15 % fructose (ChF) or 15 % glucose (ChG) to drink for up to 7 months. Lipid metabolism and markers of inflammation and autophagy were assessed in gastrocnemius muscle. Increased body weight and gastrocnemius muscle mass, as well as circulating glucose, insulin, and lipid plasma levels were observed in sugar-drinking mice. Although triglycerides increased in the gastrocnemius muscle of both ChF and ChG mice (+32 and +26 %, vs C, respectively), intramyocellular lipids accumulated to a significantly greater extent in ChF than in ChG animals (ChF +10 % vs ChG). Such perturbations were associated with increased muscle interleukin-6 levels (threefold of C) and with the activation of autophagy, as demonstrated by the overexpression of LC3B-II (ChF, threefold and ChG, twofold of C) and beclin-1 (ChF, sevenfold and ChG, tenfold of C). The present results suggest that intramyocellular lipids and the pro-inflammatory signaling could contribute to the onset of insulin resistance and lead to the induction of autophagy, which could be an adaptive response to lipotoxicity.


Effects of the somatostatin analogue SMS 201-995 (sandostatin) on mouth-to-caecum transit time and absorption of fat and carbohydrates in normal man.
1. Somatostatin analogues, such as SMS 201-995 (sandostatin), have been suggested as treatment for a variety of disease states including acromegaly, secretory gastrointestinal tumours and diabetes mellitus. 2. Somatostatin-14 has actions to prolong gastro-intestinal transit time and inhibit intestinal absorption, and we have therefore studied the effects of SMS 201-995 on these processes. Five male subjects received a test meal having been given either saline or 50 micrograms of SMS 201-995 subcutaneously 30 min before ingestion. 3. SMS 201-995 caused a delay in mouth-to-caecum transit time for lactulose assessed by breath hydrogen analysis (316 +/- 17 vs 192 +/- 14 min, mean +/- SEM, P less than 0.01), a delay (234 vs 120 min, P less than 0.05) in the plasma peak of the non-metabolizable glucose analogue 3-O-methylglucose and conversion of the expected postprandial rise in serum triglycerides (with saline 1.02 +/- 0.20 to 1.51 +/- 0.28 mmol/l, P less than 0.05) to a decrease below basal values (with SMS 201-995 0.97 +/- 0.80 to 0.79 +/- 0.11 mmol/l, P less than 0.05). 4. After SMS 201-995, an enhancement of the increase in blood glucose (8.2 +/- 0.7 vs 4.7 +/- 0.2 mmol/l, P less than 0.01) and inhibition and postponement of the postprandial rise in insulin (27.6 +/- 6.7 vs 9.9 +/- 2.1 m-units/l, P less than 0.05) occurred. Furthermore, a rise in non-esterified fatty acids, glycerol and 3-hydroxybutyrate, compared with the decline in concentrations of these metabolites after saline, was observed.(ABSTRACT TRUNCATED AT 250 WORDS)


CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy.
De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the β subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the α subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the β subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders.


Synthesis of a Double-Helical Naphthotetraindole Core via an Intramolecular Dehydrogenative Homocoupling Reaction.
A novel naphthotetraindole (NTI) core was synthesized in two steps via the McMurry reaction and a [Cu]/[Ag]-promoted intramolecular dehydrogenative homocoupling reaction. NTI shows a unique X-shaped double-helical structure as determined by single-crystal X-ray diffraction analysis. The hole-transport mobility of the bare NTI core was measured to be 2.3 × 10-5 cm2 V-1 s-1, which is comparable with the commonly used Spiro-OMeTAD.


Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial.
Hematopoietic stem cell transplantation from HLA-matched sibling donors results in disease-free survival of >90% in patients with sickle cell disease (SCD); however, only approximately 18% of these patients have suitable donors available. Unrelated cord blood transplantation (UCBT) is one way to expand donor options for patients with severe SCD, but historically has been associated with high graft rejection rates (50% to 62%). We hypothesized that the addition of thiotepa to a previously tested reduced-intensity conditioning (RIC) regimen would support engraftment after UCBT in patients with SCD. Nine children (age 3 to 10 years) with cerebrovascular complications of SCD underwent 5-6/6 HLA-matched (A, B, and DRB1 loci) UCBT after conditioning with hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. A calcineurin inhibitor and mycophenolate mofetil were used for graft-versus-host-disease (GVHD) prophylaxis. With median follow up of 2.1 years (range, 1 to 4.2 years), 7 patients had sustained donor cell engraftment and are free of SCD, and 2 patients had autologous recovery. Acute GVHD (grade II-IV) and mild and moderate chronic GVHD developed in 3 patients, 2 patients, and 1 patient, respectively. At >2 years post-UCBT, 4 of 5 patients discontinued systemic immunosuppression. Seven patients had viral infections (cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, or adenovirus) and recovered. The 1-year overall survival and disease-free survival rates were 100% and 78%, respectively. Thus, this RIC regimen was able to achieve donor engraftment in the majority of patients. Future efforts will focus on further reducing rates of acute GVHD and viral infection.


[Old people in the Emergency Department; Icelandic results from the InterRAI multinational ED study].
Old people attend emergency departments (ED´s) in increasing numbers. Old people have age related changes in all organ systems and tend to have multiple chronic diseases, be on multiple medications and often have physical and cognitive functional impairments. Hence, they have complex health and social service needs. The purpose of this study was to describe function and geriatric syndromes of old people who present at Landspitali Emergency Department, Iceland, with comparison to ED´s in six other countries. A prospective descriptive study of people (>75 year´s) attending ED´s in seven countries, including Iceland. The InterRAI assessment tool for ED´s was used by nurses to assess participants. At Landspitali ED, 202 individuals were assessed, of whom 55% were women. Of the 202 individuals, 34% attended the ED within 90 days and of those 48% lived alone. On admission to the ED, 59% had physical or cognitive functional impairment; 13% had only cognitive impairment and 36% were unable to walk without assistance. Caregiver distress was identified in 28% and 11% felt overwhelming burden. From the ED, 46% were admitted to the hospital. Compared with foreign results greater number of Icelandic participants lived alone and caregiver's distress was slightly higher (28% vs. 18%). Fewer individuals in Iceland were admitted to a hospital and Iceland had higher admission rate to rehabilitation compared with the overall group. Geriatric syndromes and functional impairment afflicted majority of old people who attended the Landspitali ED. These observations should be taken into account in ED design and care planning for old people to maximize efficiency, safety and quality.


Sorption of ferrous and ferric iron by extracellular polymeric substances (EPS) from acidophilic bacteria.
The sorption of Fe(II) and Fe(III) by extracellular polymeric substances (EPS) of acidophilic bacteria Acidiphilium 3.2Sup(5) and Acidithiobacillus ferrooxidans, harvested from the ecosystem of the Tinto River (Huelva, Spain), was investigated. EPS from mixed cultures of both bacteria (EPS(mixed)) and pure cultures of A. 3.2Sup(5) (EPS(pure)) were extracted with ethylenediamine tetraacetic acid (EDTA) and were characterized by Fourier-transform infrared (FTIR), electron photoemission (XPS), x-ray diffraction (DRX), and energy dispersive x-ray (EDX) spectroscopy and scanning electron microscopy (SEM). EPS pure were loaded, in sorption tests, with Fe(II) and Fe(III). The results obtained indicate that the biochemical composition and structure of EPS(mixed) was very similar to that of EPS(pure). Besides, results indicate that EPS(mixed) adsorbed Fe(II) and Fe(III) by preferential interaction with the carboxyl group, which favored the formation of Fe(II)/Fe(III) oxalates. These species were also formed in EPS(pure) loaded with Fe(II)/Fe(III). All this behavior suggested that the sorption of iron by EPS(mixed) was similar to sorption of EPS(pure), which fitted the Freundlich model. Thus, the iron uptake of EPS(mixed) reached 516.7 ± 23.4 mg Fe/g-EPS at an initial concentration of 2.0 g/L of Fe(total) and Fe(II)/Fe(III) ratio of 1.0.


Effects of Statin Treatment on the Development of Tendinopathy: A Nationwide Population-Based Cohort Study.
Previous longitudinal cohort studies have reported the conflicting results of the relationship between statin use and the development of tendinopathy disorder. It is unclear if there is a relationship between statin use, particularly the type or cumulative doses, and the development of tendinopathy disorder. To investigate an association between statin treatment and the development of tendinopathy. Cohort study; Level of evidence, 3. A total of 594,130 participants were enrolled in this study in 2002 and evaluated until 2015. There were 84,102 statin users and 168,204 nonusers (controls) selected at a ratio of 1:2 using propensity score matching analysis. The types of included tendinopathy were as follows: (1) trigger finger, (2) radial styloid tenosynovitis, (3) elbow epicondylitis, (4) rotator cuff tendinopathy, and (5) Achilles tendinitis. Cox proportional hazards models with time-varying covariates were constructed to identify the association between statin use and tendinopathy development. Statin treatments regardless of statin types were associated with a significantly greater risk of all types of tendinopathy development (hazard ratio, 1.435; 95% CI, 1.411-1.460) compared with no statin treatment. A trend toward risk reduction was observed according to cumulative statin doses, which was indicated by hazard ratios of 2.337 (95% CI, 2.269-2.406), 2.210 (95% CI, 2.132-2.290), and 1.1 (95% CI, 1.098-1.146) in patients with cumulative defined daily doses of 90, 91-180, and >180, respectively. This nationwide population-based cohort study suggests that statin use regardless of the statin type was associated with a greater risk of tendinopathy compared with that of nonusers. The risk of tendinopathy development was diluted with the increasing cumulative defined daily dose.


Genotoxicity of flubendazole and its metabolites in vitro and the impact of a new formulation on in vivo aneugenicity.
The anti-parasitic benzimidazole flubendazole has been used for many years to treat intestinal infections in humans and animals. Previous genotoxicity studies have shown that the compound is not a bacterial mutagen and a bone marrow micronucleus test, using a formulation that limited systemic absorption, was negative. The purpose of this study is to explore the genotoxicity of flubendazole and its main metabolites in in vitro micronucleus studies and to test a new oral formulation that improves systemic absorption in an in vivo micronucleus test. The isolated metabolites were also screened using the Ames test for bacterial mutagenicity. It was found that flubendazole, like other chemically related benzimidazoles used in anti-parasitic therapies, is a potent aneugen in vitro The hydrolysed metabolite of flubendazole is negative in these tests, but the reduced metabolite (R- and S-forms) shows both aneugenic and clastogenic activity. However, in vitro micronucleus tests of flubendazole in the presence of rat liver S9 gave almost identical signals for aneugenicity as they did in the absence of S9, suggesting that any clastogenicity from the reduced metabolite is not sufficient to change the overall profile. Like flubendazole itself, both metabolites are negative in the Ames test. Analysis of dose-response curves from the in vitro tests, using recently developed point of departure approaches, demonstrate that the aneugenic potency of flubendazole is very similar to related anti-parasitic benzimidazoles, including albendazole, which is used in mass drug administration programmes to combat endemic filarial diseases. The in vivo micronucleus test of the new formulation of flubendazole also showed evidence of induced aneugenicity. Analysis of the in vivo data allowed a reference dose for aneugenicity to be established which can be compared with therapeutic exposures of flubendazole when this has been established. Analysis of the plasma from the animals used in the in vivo micronucleus test showed that there is increased exposure to flubendazole compared with previously tested formulations, as well as significant formation of the non-genotoxic hydrolysed metabolite of flubendazole and small levels of the reduced metabolite. In conclusion, this study shows that flubendazole is a potent aneugen in vitro with similar potency to chemically related benzimidazoles currently used as anti-parasitic therapies. The reduced metabolite also has aneugenic properties as well as clastogenic properties. Treatment with a new formulation of flubendazole that allows increased systemic exposure, compared with previously used formulations, also results in detectable aneugenicity in vivo. Based on the lack of carcinogenicity of this class of benzimidazoles and the intended short-term dosing, it is unlikely that flubendazole treatment will pose a carcinogenic risk to patients.


Relations of body esteem factors with exercise session attendance in women initiating a physical activity program.
Based on tenets of cognitive behavioral and social cognitive theory, the association of change in body-esteem factors and attendance in a newly initiated, 12-wk. cardiovascular exercise program was estimated in women (age range=21 to 60 years, M=41.4, SD= 12.2). For the group given the exercise program (n=48), there were significant positive changes on the Weight Control and Physical Condition scores of the Body Esteem Scale at 12 weeks, but not on Sexual Attractiveness scores. For the no-exercise control group (n=30), no significant changes were found on any of the Body Esteem Scale subscales. For the exercise group, regression analyses indicated between 8% and 9% of the variance in exercise session attendance was accounted for by the changes in scores on each of the three subscales. Entering age into multiple regression equations did not increase the explained variances in attendance. The fit of the findings within behavioral theory, implications for change in exercise behavior, and the need for replication and extension were discussed.


Ictal Asystole in Focal Epilepsy: To Pace or Not to Pace?
Ictal bradyarrhythmias are rare episodes occurring in patients with or without a past cardiac history. These episodes go unnoticed unless the patient is monitored on simultaneous video-electroencephalogram and 1-lead electrocardiogram. Recognizing ictal bradyarrhythmias is important, since episodes may predispose patients to sudden, unexplained death in epilepsy. We present 2 cases of ictal asystole in patients with right temporal lobe epilepsy. The first patient had seizures refractory to medical therapy and received a pacemaker. The seizures in the second patient responded well to antiepileptic medication, and a pacemaker was deferred. These cases highlight the differing cardiovascular treatment options for ictal asystole.


Monte Carlo simulation on symmetric ABA/AB copolymer blends in confined thin films.
The effects of blend composition on morphology, order-disorder transition (ODT), and chain conformation of symmetric ABA/AB copolymer blends confined between two neutral hard walls have been investigated by lattice Monte Carlo simulation. Only lamellar structure is observed in all the simulation morphologies under thermodynamic equilibrium state, which is supported by theoretical prediction. When the composition of AB diblock copolymer (phi) increases, both lamellar spacing and the corresponding ODT temperature increase, which can be attributed to the variation of conformation distribution of the diblock and the triblock copolymer chains. In addition, both diblock and triblock copolymer, chains with bridge conformation extend dramatically in the direction parallel to the surface when the system is in ordered state. Finally, the copolymer chain conformation depends strongly on both the blend composition and the incompatibility parameter chiN.


Evaluation of a boosted-p24 antigen assay for the early diagnosis of pediatric HIV-1 infection in Cambodia.
Methods for early diagnosis of pediatric HIV-1 infection (DNA-polymerase chain reaction [PCR], RNA quantification, viral cultures) are expensive. Most Cambodian infants wait 18 months for HIV serologic tests. We observed that boosted-p24-antigen profile assay, with performances similar to viral cultures and costs similar to DNA-PCR, is easier to perform and could readily be set up in resource-poor settings.


Structural Brain Network Alteration and its Correlation With Structural Impairments in Patients With Depression in de novo and Drug-Naïve Parkinson's Disease.
Purpose: Depression is common in Parkinson's disease (PD) and is correlated with the severity of motor deficits and quality of life. The present study aimed to investigate alterations in the structural brain network related to depression in Parkinson's disease (d-PD) and their correlations with structural impairments of white matter (WM). Materials and Methods: Data were acquired from the Parkinson Progression Markers Initiative (PPMI) database. A total of 84 de novo and drug-naïve PD patients were screened and classified into two groups according to the 15-item Geriatric Depression Scale (GDS-15): d-PD (n = 28) and nondepression in PD (nd-PD, n = 56). Additionally, 37 healthy controls (HC) were screened. All subjects underwent DTI and 3D-T1WI on a 3.0 T MR scanner. Individual structural brain networks were constructed and analyses were performed using graph theory and network-based statistics (NBS) at both global and local levels. Differences in global topological properties were explored among the three groups. The association models between node and edge changes and the GDS-15 were constructed to detect regions that were specifically correlated with d-PD. Tract-based spatial statistics (TBSS) was used to detect structural impairments of WM between the d-PD and nd-PD groups. The correlations between altered global topological properties and structural impairments were analyzed in the d-PD group. Results: The global efficiency and characteristic path length of the structural brain network were impaired in the d-PD group compared with those in the nd-PD and HC groups. Thirteen nodes and 1 subnetwork with 10 nodes and 12 edges specifically correlated with d-PD were detected. The left hippocampus, left parahippocampal, left lingual, left middle occipital, left inferior occipital, left fusiform, left middle temporal, and left inferior temporal regions were all involved in the results of node and edge analysis. No WM microstructural impairments were identified in the d-PD group. Conclusion: Our study suggests that the integration of the structural brain network is impaired with disrupted connectivity of limbic system and visual system in the de novo and drug-naïve d-PD patients.The topological properties assessing integration of the structural brain network can serve as a potential objective neuroimaging marker for early diagnosis of d-PD.


[Forensic neuropsychology at the challenge of the relationship between cognition and emotion in psychopathy].
The relationship between frontal lobe damage and criminality is especially complex. The neural substrates of psychopathic behavior seem to involve structural and functional abnormalities in the frontal lobes and the limbic system. AIM. To analyze the repercussions that brain structural and functional abnormalities in psychopathic individuals may have for forensic neuropsychology. Consistent evidence indicate that response inhibition problems in psychopathic subjects are linked to structural or functional damage in the frontal cortex. Furthermore, the prefrontal cortex, along with the amygdala and the hippocampus forms the limbic system, which is an important neural substrate of emotion processing; therefore the psychopath's capacity of affective processing could also be impaired. The theoretical frameworks of the somatic marker and mirror neuron hypotheses, along with the empirical study of executive functions may contribute to explain the inability of the psychopathic subjects to feel empathy, which is one of the main inhibitors of violence and antisocial behavior. The relationship between frontal lobe dysfunction and antisocial behavior arises an important legal issue. In order to consider some type of minor liability in the case of psychopaths it is suggested to gather further research data about the relationship between frontal lobe dysfunction and the ability to inhibit antisocial behavior by making an adequate use of empathy and emotional ties.


The Anti-Stress Effect of Mentha arvensis in Immobilized Rats.
Stress can lead to inflammation, accelerated aging, and some chronic diseases condition. Mentha arvensis (MA) is a traditional medicine having antioxidant and anti-inflammatory activities. The present study investigated the anti-stress role of MA and fermented MA (FMA) extract in immobilized rats. We studied the lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 cells and rats were immobilized for 2 h per day for 14 days using a restraining cage. MA (100 mg/kg) and FMA (100 mg/kg) were orally administered to rats 1 h prior to immobilization. Using high-performance liquid chromatography (HPLC) analysis, we determined the rosmarinic acid content of MA and FMA. The generation of malondialdehyde (MDA) and nitric oxide (NO) in RAW 246.7 cells were suppressed by both MA and FMA. In rats, MA and FMA notably improved the body weight, daily food intake, and duodenum histology. MDA and NO level were gradually decreased by MA and FMA treatment. MA and FMA significantly controlled the stress-related hormones by decreasing corticosterone and β-endorphin and increasing serotonin level. Moreover, protein expression levels of mitogen activated protein kinases (MAPK) and cyclooxygenase-2 (COX-2) were markedly downregulated by MA and FMA. Taken together, MA and FMA could ameliorate immobilized-stress by reducing oxidative stress, regulating stress-related hormones, and MAPK/COX-2 signaling pathways in rats. Particularly, FMA has shown greater anti-stress activities than MA.


Cytomegalovirus adrenalitis mimicking adrenal metastasis in an immunocompetent patient.
The adrenal gland is a common site of metastasis due to its rich blood supply. Adrenalectomy is typical treatment in the management of oligometastatic disease. We present an unexpected finding of cytomegalovirus (CMV)-related adrenalitis mimicking adrenal metastasis. A 54-year-old female was reviewed with a history of BRCA2-mutated, hormone receptor-positive invasive ductal cancer of the right breast diagnosed 12 years prior. Surveillance fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated a new focus of FDG avidity in the left adrenal gland, for which she underwent adrenalectomy. Histopathology revealed CMV-related adrenalitis in an otherwise immunocompetent patient without history of human immunodeficiency virus (HIV) or other immunocompromise. We describe the first case of CMV adrenalitis in a patient without acquired immunodeficiency syndrome. This case was initially presumed to be adrenal metastasis in the context of disseminated metastatic breast cancer and a PET-avid left adrenal lesion.


[3 osteosarcoma therapy dropouts. Clinical cases].
We report on 3 cases of male late-adolescent/young-adult osteogenic sarcoma patients who refused complete chemical therapy according to the treatment plan "COSS 80". They all originated from disturbed family situations. Characteristic was their early independence and autonomy, dominance tendency, low level of self control, and high level of sociability. Primary motivation for refusal was the experienced intolerability of the chemotherapeutical side-effects and extreme fear of medical procedures (e.g. injections).


The Heterogeneous Diffusion of Polystyrene Nanoparticles and the Effect on the Expression of Quorum-Sensing Genes and EPS Production as a Function of Particle Charge and Biofilm Age.
Biofilms are abundantly present in both natural and engineered environmental systems and will likely influence broader particle fate and transport phenomena. While some developed models describe the interactions between nanoparticles and biofilms, studies are only beginning to uncover the complexity of nanoparticle diffusion patterns. With the knowledge of the nanoparticle potential to influence bacterial processes, more systematic studies are needed to uncover the dynamics of bacteria-nanoparticle interactions. This study explored specific microbial responses to nanoparticles and the heterogeneity of nanoparticle diffusion. Pseudomonas aeruginosa biofilms (cultivated for 48 and 96 hours, representing early and late stages of development) were exposed to charged (aminated and carboxylated) polystyrene nanoparticles. With a combination of advanced fluorescence microscopy and real time quantitative PCR, we characterized the diffusion of polystyrene nanoparticles in P. aeruginosa biofilms and evaluated how biofilms respond to the presence of nanoparticles in terms of the expression of key EPS production-associated genes (pelA and rpsL) and quorum-sensing associated (lasR) genes. Our findings show that nanoparticle diffusion coefficients are independent of the particle surface charge only in mature biofilms and that the presence of nanoparticles influences bacterial gene expression. Independent of the particle's charge polystyrene nanoparticles down-regulated pelA in mature biofilms. By contrast, charge-specific responses were identified in lasR and rpsL gene expression. The targeted genes expression analysis and heterogeneous diffusion models demonstrate that particle charge influences nanoparticle mobility and provides significant insight into the intrinsic structural heterogeneity of P. aeruginosa biofilms. These findings suggest that biofilm maturity and particle charge are essential factors to consider when evaluating the transport of nanoparticles within a biofilm matrix.


ANTIGENS AND ENZYMES MADE INSOLUBLE BY ENTRAPPING THEM INTO LATTICES OF SYNTHETIC POLYMERS.
Biologically active, insoluble products have been prepared from soluble antigens or enzymes by entrapping them into the lattice of an insoluble, highly cross-linked synthetic polymer as it forms. Antigens, made insoluble, removed quantitatively certain or all antibiotics from complex mixtures. Seven enzymes so treated are described.


Ethinylestradiol interacts with liver microsomes and induces binding sites for steroid hormones in the male rat liver.
The present work focuses on the interaction of 17 alpha-ethinyl estrogen derivatives with the [3H]dexamethasone ([3H]DEX) binding site from male rat liver microsomes and the induction of this site by the in vivo administration of natural and synthetic estrogens. [3H]DEX binds to a single-saturating binding site (Kd = 100 nM; maximal binding = 13 pmol/mg of protein) in the liver microsomes. In competition experiments, ethinylestradiol (EE2) and mestranol were able to inhibit [3H]DEX binding to microsomes, whereas natural estrogens, tamoxifen or estrogen sulfates were ineffective. Saturation analysis performed by incubating [3H]EE2 with liver microsomes revealed the existence of a low-affinity (Kd = 280 +/- 30 nM) and high capacity (maximal binding = 16 +/- 2 pmol/mg of protein) binding site. Saturation, competition and dissociation experiments suggest that [3H]DEX and [3H]EE2 interact with the same microsomal entity. Synthetic and natural estrogens increased the hepatic expression of the [3H]DEX binding site in immature, hypothyroid and hypophysectomized male rats. This induction required at least 2 days of treatment, and could only be achieved by pharmacological doses of estrogens.(ABSTRACT TRUNCATED AT 250 WORDS)


Expectations and experience of labial reduction: a qualitative study.
To understand women's reasons for undergoing labial reduction surgery, their expectations and experiences. A retrospective qualitative study. British National Health Service Hospital. Six women who had experienced surgery for labial reduction. Method Qualitative study using semi-structured interviews. Results relating to 'Normality and defect', 'Sex lives' and 'The process of accessing surgery' are presented in this study. The women had seen their presurgery genital appearance as 'defective' and sought a 'normal' genital appearance. They thought that their presurgery genital appearance impacted on their sex lives, but their expectations of the effects of surgery on their sex lives were not all fulfilled. Information about labial surgery came from both the popular media and the health services. An emphasis on, for example, physical discomfort rather than appearance may have been used to legitimise a request for surgery. The process of accessing surgery had exposed them to potentially conflicting messages about their genital appearance. Women presenting for labial reduction may have unrealistic expectations of surgery, but their perceptions and expectations are long-standing and seem to be based on strong cultural norms. The gynaecologist is also meeting those women who have already negotiated the referral process. As demand for this surgery appears to be increasing, further research is needed. These findings may add to the case for the potential value of specialist staff to provide psychosocial interventions within gynaecology services.


Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.
Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.


Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain.
Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain.SIGNIFICANCE STATEMENT In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.


Normal instability of the hip in the neonate: US standards.
In recent years, the use of real-time ultrasonography (US) has enabled dynamic evaluation of the infant hip through a range of motion and stress. Preliminary experience has suggested that a certain amount of instability in the hips of newborns is normal, but no standards have been established. In this study, a group of term neonates whose physical examinations were normal were examined with US on the 1st and 2d days of life. Each hip was imaged in the transverse plane in nonstressed and stressed positions, and movement of the femoral head under stress was quantitated. This displacement under stress was used to establish a normal range of hip instability in neonates. Patterns of hip laxity in boys and girls are identical, and in most infants hip instability diminishes between the 1st and 2d days of life. Our method of quantitating hip instability produces consistent results, with intraobserver 95% confidence intervals of +/- 1.2 mm for each measurement.


Acute kidney injury in neurocritical care.
Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory changes associated with AKI likely contribute to prolonged brain injury and edema. As a result, recognizing its presence is important for effectively managing ABI and its sequelae. This review discusses the occurrence and effects of AKI in critically ill adults with neurological conditions, outlines potential mechanisms connecting AKI and ABI progression, and highlights AKI management principles. Tailored approaches include optimizing blood pressure, managing intracranial pressure, adjusting medication dosages, and assessing the type of administered fluids. Preventive measures include avoiding nephrotoxic drugs, improving hemodynamic and fluid balance, and addressing coexisting AKI syndromes. ABI patients undergoing renal replacement therapy (RRT) are more susceptible to neurological complications. RRT can negatively impact cerebral blood flow, intracranial pressure, and brain tissue oxygenation, with effects tied to specific RRT methods. Continuous RRT is favored for better hemodynamic stability and lower risk of dialysis disequilibrium syndrome. Potential RRT modifications for ABI patients include adjusted dialysate and blood flow rates, osmotherapy, and alternate anticoagulation methods. Future research should explore whether these strategies enhance outcomes and if using novel AKI biomarkers can mitigate AKI-related complications in ABI patients.


Postprandial changes in superoxide dismutase activity in subjects with Gilles de la Tourette syndrome and controls.
Erythrocyte measures of copper-zinc superoxide dismutase (CuZnSOD) were performed on 11 subjects with a clinical diagnosis of Gilles de la Tourette syndrome (GTS) and 6 healthy controls at specified intervals throughout the day. There were no significant differences between GTS subjects and controls but in both subjects and controls there was a significant increase in SOD, 75 min postprandially, which decreased to baseline 135 min postprandially. This has implications for the timing of biological samples in future studies of SOD. Possible reasons for the increase are discussed.


An overview of the pharmaceutical industry.
The research-based pharmaceutical industry is a large and diverse worldwide employer. Rapid changes in the health care marketplace have resulted in many changes for the industry, including a need to streamline the drug discovery and development process. To address this challenge, new technologies have been rapidly adapted. Another result of the changing marketplace has been a rapid consolidation with many recent mergers and acquisitions as well as internal reorganizations to better support new and varied customers.


STARCH GEL ELECTROPHORESIS OF A FRACTION OF CERTAIN OF THE PLEUROPNEUMONIA-LIKE GROUP OF MICROORGANISMS.
Fowler, Richard C. (George Washington University School of Medicine, Washington, D.C.), Don W. Coble, Norman C. Kramer, and Thomas McP. Brown. Starch gel electrophoresis of a fraction of certain of the pleuropneumonia-like group of microorganisms. J. Bacteriol. 86:1145-1151. 1963.-Starch gel electrophoresis is suggested as a means of further characterizing strains of the pleuropneumonia-like group of microorganisms (PPLO), defined herein as including both the various "L" forms of bacteria and the Mycoplasmataceae. The techniques used may be varied to "select" other groups of proteins or classes of compounds (e.g., glycoproteins, lipoproteins, and enzymes). Only the results by starch gel electrophoresis on the soluble portion of sonically treated, washed cultures, grown in a pancreatic digest of beef heart enriched with bovine serum, are reported. As yet, differences appear more significant than similarities among the electrophoretically separable proteins. The demonstration of characteristic protein patterns for each strain studied suggests possibilities of further dividing serological groups into sero-logically distinct subtypes. Tentative migration values (E(f)) have been assigned to the protein bands for convenience in designation. Numerous interrelationships are thereby suggested.


Algorithm to Predict Which Children With Chronic Abdominal Pain Are Low Suspicion for Significant Endoscopic Findings.
Chronic abdominal pain (CAP) is a common and challenging problem in pediatric primary and specialty care. We developed a diagnostic algorithm to organize workup for gastrointestinal causes of CAP and improve identification of patients who are low suspicion (LS) or high suspicion (HS) to have significant intestinal pathology identified with endoscopy. We retrospectively used this algorithm to categorize 150 outpatients with CAP as LS (n = 99) or HS (n = 51) and examined subsequent endoscopic findings for all patients. There were 6% significant diagnoses in the LS group compared with 34% in the HS group ( P < .0001). The LS group had no patients with celiac or inflammatory bowel disease. These results can be used to help a clinician approach CAP, and discuss with families the likelihood of endoscopy finding a cause for CAP based on LS or HS designation.


Giant lipoma of the back affecting quality of life.
Lipomas are benign tumours composed of adipose tissue. They may be localized in almost all body parts and may be in a giant form. Some of these giant lipomas may transform malignity and cause problems in daily living and detoriate quality of life. Mass localization also restrict body functions. In the present study, a 72-year-old man who presented with a mass enlarged in a time period of two years and because of this could not lie in the supine position, sit in an erect position and dress easily, go outside because of his physical appearance. With surgical treatment a 38 × 22 × 21 cm mass weighing 3575 g was successfully resected. Postoperative early phase complications did not occur. During 48 months of postoperative period, any recurrence was not detected and the patient was free of all his complaints. Cosmetic and functional results of the surgery and patient satisfaction were excellent. After surgery patient's quality of life was improved and restriction of body function was disappeared.


Tunable Synthesis of Indolo[3,2- c]quinolines or 3-(2-Aminophenyl)quinolines via Aerobic/Anaerobic Dimerization of 2-Alkynylanilines.
In this paper, an unprecedented selective synthesis of indolo[3,2- c]quinoline or 3-(2-aminophenyl)quinoline derivatives through Rh(III)-catalyzed stepwise dimerization of 2-alkynylanilines under aerobic or anaerobic conditions is presented. Notably, hexafluoroisopropanol is found to be a crucial solvent and promoter for the success of these reactions. In addition, the utility of the products thus obtained was showcased by their facile transformations into the pharmaceutically and photophysically significant naphthyridine derivatives.


Detrusor hyperreflexia induced by intravesical instillation of xylene in conscious rats.
Intravesical instillation of xylene (30-50%) produced detrusor hyperreflexia characterized by a decrease in both the bladder capacity (time to micturition in the cystometrogram) and the urine volume in conscious rats placed in a restraining cage. At this time, the bladder tissue showed evidence of experimental cystitis with degradation of the epithelium and edema and hemorrhage in the submucosa, and a slight increase in the content of prostaglandin E2, which stimulated directly and/or indirectly capsaicin-sensitive sensory fibers. In addition, the bladder exhibited high amplitude spontaneous activity, but the bladder contractions induced by acetylcholine, substance P, prostaglandin E2 and capsaicin were not changed following intravesical instillation of xylene. In these hyperreflexic rats, atropine suppressed the amplitude of the micturition contraction and morphine increased the bladder capacity at similar doses as in sham-treated rats, while thiopental and indomethacin increased the bladder capacity at lower doses than in sham-treated rats. These findings indicated that intravesical instillation of xylene had produced detrusor hyperreflexia in conscious rats, and that the detrusor hyperreflexia is thought to be a useful model for evaluating the effect of a newly-developed agent on bladder function.


Species identification of mustelids by comparing partial sequences on mitochondrial DNA from fecal samples.
Nucleotide sequences of cytochrome b/tRNA/D-loop region on mitochondrial DNA of mustelids feces were compared to identify species. PCR amplification of target sequence for 47 (24.9%) feces and species identification of five feces (2.6%) out of 189 feces, collected at several study sites in Hokkaido, were successful. Species of three feces were Martes zibellina and those of other two feces were Martes melampus and Mustela itatsi. The low success rate of identification appeared to be due to failure of PCR amplification by inhibitors in feces. It was suggested that the method used in this study was useful for not only identify mustelids species, but also analyzing their genetic relationships.


Night Shift Work, DNA Methylation and Telomere Length: An Investigation on Hospital Female Nurses.
Increased breast cancer risk has been reported in some night shift (NS) workers but underlying biological mechanisms are still unclear. We assessed the association between NS work and DNA methylation of tumor suppressor (TP53, CDKN2A, BRCA1, BRCA2) and estrogen receptor (ESR1, ESR2) genes, methylation of repetitive elements (LINE-1, Alu), and telomere length (TL). Forty six female nurses employed in NS for at least two years were matched by age (30-45 years) and length of service (≥1 year) with 51 female colleagues not working in NS. Each subject underwent a semi-structured interview and gave a blood sample. We applied linear regression and spline models adjusted for age, BMI, smoking habit, oral contraceptive use, parity and marital status/age at marriage. Currently working in NS was associated with ESR1 hypomethylation (β: -1.85 (95%CI: -3.03; -0.67), p = 0.003). In current and former NS workers we observed TP53 (-0.93 (-1.73; -0.12), p = 0.03) and BRCA1 (-1.14 (-1.71; -0.58), p <0.001) hypomethylation. We found an increase between TL and number of years in NS in subjects employed in NS <12 years (0.06 (0.03; 0.09), p <0.001), while a decrease if employed in NS ≥12 years (-0.07 -0.10; -0.04), p <0.001). Our findings show NS-associated markers potentially involved in cellular aging, genomic instability, and cancer development.


Electron bow-wave injection of electrons in laser-driven bubble acceleration.
An electron injection regime in laser wake-field acceleration, namely electron bow-wave injection, is investigated by two- and three-dimensional particle-in-cell simulation as well as analytical model. In this regime electrons in the intense electron bow wave behind the first bubble catch up with the bubble tail and are trapped by the bubble finally, resulting in considerable enhancement of the total trapped electron number. For example, with the increase of the laser intensity from 2 × 10(19) to 1 × 10(20) W/cm(2), the electron trapping changes from normal self-injection to bow-wave injection and the trapped electron number is enhanced by two orders of magnitude. An analytical model is proposed to explain the numerical observation.


The frequency and pattern of cardiac autonomic neuropathy (CAN) in type 2 DM patients in a diabetic clinic in Enugu South-East Nigeria.
To determine the frequency, pattern and grades of cardiac autonomic neuropathy (CAN) in type 2 diabetic patients in a diabetes mellitus (DM) clinic in Enugu South-East Nigeria. A cross sectional study of seventy (70) type 2 diabetic patients attending a DM clinic in Enugu South-East Nigeria was carried out. Cardiac autonomic function was determined using a battery of 5 noninvasive tests which include; Heart rate response (HRR) to Valsalva manoeuvre, HRR to deep breathing, HRR to standing, Resting heart rate, and Blood pressure (BP) response to standing. The frequency of cardiac autonomic neuropathy (CAN) in type 2 diabetic patients was 44.3%. Resting tachycardia was the most specific, HRR to Valsalva manoeuvre was most sensitive while BP response to standing had the best positive predictive value in detecting cardiac autonomic neuropathy. Cardiac autonomic neuropathy is a common complication in type 2 Diabetes Mellitus patients seen at Enugu. It is therefore recommended that tonomic function tests be part of the standard care of type 2 diabetic patients and appropriate management instituted for both primary and secondary prevention.


PD-1 inhibitor induced alopecia areata.
Immune checkpoint modulators are becoming more prevalent in clinical use for the treatment of metastatic melanoma and other malignancies. These drugs, including programmed death 1 (PD-1) inhibitors, have a high incidence of immune adverse events, including cutaneous manifestations. Alopecia is a known side effect with these drugs, but previous reports describe chemotherapy-induced alopecia. We report a case of alopecia areata in a patient on monotherapy with pembrolizumab (PD-1 inhibitor). It is important for the dermatologist to recognize and appropriately treat to decrease morbidity for these patients.


Effects of Smoking on Ischemic Stroke, Intracranial Hemorrhage, and Coronary Artery Events in Japanese Patients With Non-Valvular Atrial Fibrillation.
The effects of smoking on the prognosis of non-valvular atrial fibrillation (NVAF) patients are unclear.The Shinken Database 2004-11 (n = 17,517) includes all new patients visiting the Cardiovascular Institute between June 2004 and March 2012. Among these cases, 2,102 NVAF patients were identified. The effects of smoking on ischemic stroke (IS), intracranial hemorrhage (ICH), and coronary artery events including percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) were analyzed. Smokers were younger and had lower risk profiles compared with non-smokers. A similar tendency was observed between current and former smokers. In contrast, patients with high tobacco consumption were older and had higher risk profiles, including uncontrolled hypertension, compared with those with low tobacco consumption. In 8,159 patient-years, IS, ICH, PCI, and ACS occurred at rates of 7.7, 2.7, 12.4, and 3.0 per 1000 patient-years. In multivariate Cox regression analysis, smoking was not significantly associated with any adverse event. However, different effects of smoking were observed when stratified by age. In patients ≥ 65 years old, current smokers were independently associated with PCI. Moreover, current smokers and smokers with a total tobacco amount ≥ 800 were marginally and independently associated with IS. In patients < 65 years, current smokers were independently associated with ICH.Age appears to be one of the contributors to differentiation of the effects of smoking on cardiovascular events in our NVAF patients. In elderly patients who still smoke, smoking was associated with the promotion of atherosclerosis or thromboembolism, whereas in young patients it was associated with bleeding.


A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma.
Leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA approved for leiomyosarcoma and liposarcoma. This study aimed to evaluate the safety and efficacy of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma. A single-arm, open-label, Phase 1/2 study tested avelumab with trabectedin for advanced leiomyosarcoma and liposarcoma. The phase I portion evaluated safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was objective response rate (ORR) by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression. 33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In Phase 1, dose-limiting toxicities (DLT) were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended Phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13%) had partial response (PR) and 10 (43%) had stable disease (SD) as best response. Six-month PFS was 52%; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 vs. 0.067, P = 0.02) or progressive disease (0.182 vs. 0.064, P = 0.01). Although the trial did not meet the primary objective response rate endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.


Computed tomographic scanning of the brain in initial staging of bronchogenic carcinoma.
Hematogenous dissemination to the brain occurs frequently with bronchogenic carcinoma ( BGCA ). Advocates of computed tomographic (CT) scanning have proposed the use of CT scanning of the brain as a screening procedure to exclude metastasis. To establish CT's appropriate role, we have retrospectively reviewed patients who had CT scanning of the brain during the initial staging and evaluation of BGCA . Clinical factors indicative of metastatic disease, both organ-specific and nonorgan -specific, were extracted from the history, physical, and laboratory data. Eighty-nine patients were studied. Sixteen patients had abnormal CT scans of the brain (18 percent). Only nine of the 16 had evidence of central nervous system (CNS) disease on history or physical examination. All 16 patients had strong clinical indications of disseminated disease. With completely normal clinical examinations, no abnormal CT scans were identified. Among patients with three or more clinical abnormalities present, an abnormal CT scan occurred in 37.5 percent (12 of 32). The clinical examination is a sensitive indicator of metastatic CNS disease as identified by the CT scan. Both organ-specific and nonorgan -specific findings are important indicators of CNS metastatis .


Prevalence of drug-resistant HIV type 1 at the time of initiation of antiretroviral therapy in Portland, Oregon.
The presence of transmitted drug-resistant HIV-1 (TDR) at the time of antiretroviral therapy (ART) initiation is associated with failure to achieve viral load suppression. Rates of TDR in ART-naive patients have been reported from various parts of the world through ongoing national, regional, and global evaluations; however, surveillance of TDR in Portland, Oregon has not been previously described. We describe the prevalence of TDR in patients in the Portland area who have recently entered care. Genotypic data were obtained from plasma specimens collected between 2003 and 2009 from 165 recently identified HIV-1-positive, ART-naive adults in care at the Multnomah County Health Department. Median time from diagnosis to first genotype was 2.7 months. Mutations associated with TDR were observed in 33 (20.0%) patients. Mutations associated with resistance to nucleoside reverse transcriptase (RT) inhibitors (NRTI), nonnucleoside RT inhibitors (NNRTI), and protease inhibitors (PI) were found in 15 (9.1%), 17 (10.3%), and 5 (3.0%) patients, respectively (p=0.013 for NNRTI vs. PI, and 0.035 for NRTI vs. PI, Fisher exact test). Dual class resistance was observed in four (2.4%) patients. Predominant RT mutations included M41L, T215C or S, and K103N. The prevalence of HIV-1 with NRTI resistance-associated mutations increased from 2006 to 2008-2009 (p=0.004) based on date of diagnosis. These data indicate relatively high rates of drug resistance present prior to ART initiation among patients in the Portland area, and support continued surveillance of local trends of TDR to inform optimal individual treatment strategies and public health decisions.


Valproic Acid: second generation.
The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become second-generation VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.


Hepatitis C virus infection: establishment of chronicity and liver disease progression.
Hepatitis C virus (HCV) often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are no preventive or therapeutic vaccines available against HCV. Treatment strategies of HCV infection are likely to improve with recently discovered direct antiviral agents (DAAs). However, a proportion of patients still progress to liver failure and/or HCC despite having been cured of the infection. Thus, there is a need for early diagnosis and therapeutic modalities for HCV related end stage liver disease prevention. HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated evasion of immune responses and liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used a number of experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection modulates immune systems. Further, HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these ob-servations at the molecular level should aid in developing strategies for additional effective therapies against HCV mediated liver disease progression.