Diagnosis and management strategies in congenital atresia of the external auditory canal. Study Group on Otological Malformations and Hearing Impairment.
This consensus report represents a distillation of current opinion regarding diagnosis and management of congenital aural atresia. It also takes into account the philosophical differences which exist in Europe. Congenital aural atresia requires prompt diagnosis, genetic counselling and an early assessment of hearing. In bilateral atresia, early amplification with a bone conduction hearing aid is essential for proper speech development. Further rehabilitation in bilateral cases is managed with surgical reconstruction in selected patients or by implantation of a bone-anchored hearing aid. Atresia repair surgery is worthwhile if proper patient selection is made by use of stringent audiological and radiological criteria and state of the art surgery is performed. The divergent views concerning indications, ideal age for surgery and surgical approach to achieve better hearing are discussed. Review of the literature demonstrated that even in the hands of the best surgeons a mean hearing gain of only 20-25 dB is achieved in atresia Type II, with 30-35 dB in Type I. Therefore, surgical reconstruction should only be done in the more favourable cases where post-operative hearing of <25-30 dB is attainable. Less favoured patients should be helped with bone-anchored hearing aids, as this type of surgery does not interfere with the future use of new techniques.


Construction of a novel plasmid-phage hybrid: use of the hybrid to demonstrate ColE1 DNA replication in vivo in the absence of a ColE1-specified protein.
A hybrid bacteriophage, P420, was constructed in vitro; it contains part of bacteriophage P4 and a 3.6-kilobase derivative of plasmid ColE1. In Escherichia coli, the plasmid-phage hybrid can exist as a stable plasmid or can be packaged into infective bacteriophage particles. Replication of P420, directed by the ColE1 replicon, was found to occur after P420 phage infection of E. coli cells that had been incubated in the presence of chloramphenicol. Replication began without a lag period and resulted in the synthesis of covalently closed circles of P420 DNA. Like ColE1 DNA replication but unlike that of P4, replication was dependent on DNA polymerase I and was sensitive to rifampicin. The presence of a resident ColE1 plasmid in the infected cells resulted in an inhibition of the replication of the incoming P420 DNA. These results indicate that ColE1 does not require a plasmid-coded protein to replicate its DNA in vivo and demonstrate the utility of P4 bacteriophage for coupling bacteriophage properties to a plasmid replicon.


Enasidenib in patients with mutant IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicentre, AG221-C-001 trial.
Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial. The multicentre, open-label, phase 1-2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60-300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov, NCT01915498, status ongoing but closed to recruitment. 17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5-73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8-23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2-15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3-4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28-77]), with a median duration of response of 9·2 months (95% CI 1·0-not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5-32·3), and median event-free survival was 11·0 months (1·5-16·7). Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful. Celgene and Agios Pharmaceuticals.


Optoacoustic detection of NO(2) using a pulsed dye laser.
Using a pulsed dye laser and a nonresonant optoacoustic detector, the absorption spectrum of NO(2) has been measured in the spectral region of 480-625 nm at various cell pressures and at various concentrations in air. The results of the measurements as a function of NO(2) concentration in air demonstrate the detection capability of the system. An extrapolated sensitivity of 4 ppb NO(2)/W of laser power has been achieved.


Stigma and HIV disclosure in the Cape Metropolitan area, South Africa.
Disclosure rates of HIV-positive status remain low and are considered to be related to stigmatisation. Determining the factors that influence a person's decision to disclose a positive status is essential to understanding the process of and ways to improve disclosure rates. This study investigated the factors that influence the disclosure of a person's HIV-positive status and focused on socio-demographic factors, stigma and discrimination, religion, culture, fear of abandonment and rejection as well as knowledge of the disease that may all influence disclosure rates. A facility based descriptive cross-sectional research design with a quantitative approach was applied using convenience sampling. The sample comprised 150 individuals which was 12.5% of the study population. A self-administered questionnaire comprising mainly closed-ended questions, with a limited number of open ended questions was designed, tested and utilised. Statistical associations were determined between the demographic factors and responses to the questions. The open ended questions were analysed thematically by means of content analysis to extract meaning. The results revealed that fear of stigmatisation, especially among the male participants, was a major reason for delayed or non-disclosure. The results of the total study sample also showed that the level of education influenced the fear of stigmatisation; those with secondary school level education were most afraid of this (29%). There was a statistically significant association between fear of blame or discrimination and disclosure to the sexual partner. This fear was most often cited by the participants who had never married (19%). The participants who feared blame or discrimination the most reported having no income (23%). The findings of this study indicate that numerous factors influence HIV disclosure. Stigma of individuals who are HIV-positive remains a barrier to disclosure as well as fear of blame and discrimination. Recommendations were made to facilitate and increase disclosure rates. This should include community based support groups and advocating partners to attend voluntary counselling and testing together to minimise the fear of blame.


Trends in mortality rates for infectious and parasitic diseases in Australia: 1907-1997.
To characterize long-term mortality trends for infectious and parasitic diseases in Australia during the twentieth century, explore influencing factors and provide suggestions to health policy-makers. A descriptive study was conducted. Deaths due to communicable diseases from 1907 to 1997 were tallied, according to the International Classification of Diseases version 9 (ICD-9). Trends in infectious disease mortality in overall population and in the 0-4 years age group were examined and standardized by sex. Death rates were also studied for: (i) diarrhoea/enteritis, (ii) pneumonia and all respiratory diseases and (iii) tuberculosis. There has been a substantial decline in -mortality from communicable diseases over the study period. The death rate dropped from 258.9 per 100,000 population in 1907 to 7.2 per 100,000 population in 1997. Six phases of the decline were observed. A combination of improved living conditions and access to readily available treatments over the twentieth century played an important role in the reduction of infectious disease mortality in Australia.


[Prospects for using antigenic nanosystems in the diagnosis and treatment of inflammatory rheumatic diseases].
To study whether immobilized antigenic nanosystems (ANS) may be designed on the basis of antigens of varying chemical nature to identify and to remove specific antibodies (Ab) from the blood of patients with systemic lupus erythematosus (SLE). Sixty patients with the diagnosis of SLE verified by the 1997 American College of Rheumatology criteria and 30 apparently healthy individuals were followed up. The levels of Ab to catalase (Cat), xanthine oxidase (XO), and cardiolipin (CL) were measured by enzyme immunoassay, by applying the respective ANS as an antigenic matrix. There was a significant relationship of the levels of Ab to Cat and XO to the activity of SLE. It was shown that Ab to Cat and XO could affect the functional activity of serum enzymes. The level of Ab to CL in patients with SLE was found to depend on two parameters - the intensity of the disease and the presence of antiphospholipid syndrome; acute cerebral circulatory disorder and thrombocytopenia were observed to have a significant unidirectional impact on the level of Ab to CL. Immobilized CL-based ANSs were effective in eliminating Ab to CL from the whole blood of patients with SLE, without resulting in a significant hemolysis of blood corpuscles and in a reduction of total protein concentrations. The development and introduction of preventive methods for the early diagnosis of SLE may be extended, by using ANS based on Cat, XO, and CL antigen. The designing and putting into practice novel ANS-based hemosorbents may allow immunosorption to occupy a prominent place in the pathogenetic therapy of inflammatory autoimmune diseases.


Yogurt consumption and colorectal polyps.
Diet modifies the risk of colorectal cancer (CRC), and inconclusive evidence suggests that yogurt may protect against CRC. We analysed the data collected from two separate colonoscopy-based case-control studies. The Tennessee Colorectal Polyp Study (TCPS) and Johns Hopkins Biofilm Study included 5446 and 1061 participants, respectively, diagnosed with hyperplastic polyp (HP), sessile serrated polyp, adenomatous polyp (AP) or without any polyps. Multinomial logistic regression models were used to derive OR and 95 % CI to evaluate comparisons between cases and polyp-free controls and case-case comparisons between different polyp types. We evaluated the association between frequency of yogurt intake and probiotic use with the diagnosis of colorectal polyps. In the TCPS, daily yogurt intake v. no/rare intake was associated with decreased odds of HP (OR 0·54; 95 % CI 0·31, 0·95) and weekly yogurt intake was associated with decreased odds of AP among women (OR 0·73; 95 % CI 0·55, 0·98). In the Biofilm Study, both weekly yogurt intake and probiotic use were associated with a non-significant reduction in odds of overall AP (OR 0·75; 95 % CI 0·54, 1·04) and (OR 0·72; 95 % CI 0·49, 1·06) in comparison with no use, respectively. In summary, yogurt intake may be associated with decreased odds of HP and AP and probiotic use may be associated with decreased odds of AP. Further prospective studies are needed to verify these associations.


Glycogen synthase kinase 3 is an insulin-regulated C/EBPalpha kinase.
CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in creating and maintaining the adipocyte phenotype. We have shown previously that insulin stimulates dephosphorylation of C/EBPalpha in 3T3-L1 adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation reveal that a C/EBPalpha peptide (amino acids H215 to K250) is phosphorylated on T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. Accordingly, GSK3 phosphorylates the predicted region of C/EBPalpha on threonine in vitro, and GSK3 uses C/EBPalpha as a substrate in vivo. In addition, the effect of pharmacological agents on GSK3 activity correlates with regulation of C/EBPalpha phosphorylation. Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPalpha, whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPalpha. Collectively, these data indicate that insulin stimulates dephosphorylation of C/EBPalpha on T222 and T226 through inactivation of GSK3. Since dephosphorylation of C/EBPalpha in response to lithium is blocked by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease accessibility of widespread sites within the N terminus of C/EBPalpha, consistent with phosphorylation causing profound conformational changes. Finally, phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.


The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity.
Drug hypersensitivity reactions that resemble acute immune reactions are linked to certain human leucocyte antigen (HLA) alleles. Severe and life-threatening Stevens Johnson Syndrome and Toxic Epidermal Necrolysis following treatment with the antiepileptic and psychotropic drug Carbamazepine are associated with HLA-B*15:02; whereas carriers of HLA-A*31:01 develop milder symptoms. It is not understood how these immunogenic differences emerge genotype-specific. For HLA-B*15:02 an altered peptide presentation has been described following exposure to the main metabolite of carbamazepine that is binding to certain amino acids in the F pocket of the HLA molecule. The difference in the molecular mechanism of these diseases has not been comprehensively analyzed, yet; and is addressed in this study. Soluble HLA-technology was utilized to examine peptide presentation of HLA-A*31:01 in presence and absence of carbamazepine and its main metabolite and to examine the mode of peptide loading. Proteome analysis of drug-treated and untreated cells was performed. Alterations in sA*31:01-presented peptides after treatment with carbamazepine revealed different half-life times of peptide-HLA- or peptide-drug-HLA complexes. Together with observed changes in the proteome elicited through carbamazepine or its metabolite these results illustrate the mechanistic differences in carbamazepine hypersensitivity for HLA-A*31:01 or B*15:02 patients and constitute the bridge between pharmacology and pharmacogenetics for personalized therapeutics.


The effect of temperature on bisphenol: an elution from dental resins.
Bisphenol A (BPA) elution from baby bottles into content has been of great public interest and debate in recent year. Uncontrolled BPA elution due to temperature increase may create a risk factor for human health. However, dental resins that are used in pediatric dentistry also have BPA derivatives. The aim of this study is to evaluate BPA elution from dental resins and to determine the effect of temperature increase on this elution. Four dental resins containing BPA derivatives (Filtek Z250, Filtek Supreme XT, Fissurit FX, and Admira) and a control group (BPA free G-aenial) were used in this study. Each specimen was stored in 2 ml of 75% ethanol-water solution at 37°C. Water at a temperature of 59°C ± 1°C (preferred temperature of hot drinks) was added to the study samples at certain time intervals (1, 6, 24 hours and 2, 3, 4, 5 and 6 days). The methanol samples were analyzed using high-performance liquid chromatography (HPLC). Data was analyzed using multivariate and repeated measures analysis of variance (p < 0.05). The study samples generally eluted more BPA than the control samples (p < 0.05). The greatest amount of BPA for an individual time period was measured after 6 hours for the groups A to D; the same was found after 24 hours for group E. While the BPA elution levels evaluated in the study samples were more than control samples, all measured values were under the reference levels and the amounts do not constitute a risk. Resin-based dental materials can act as a source of BPA (within safety margins), especially when they react with hot water.


Effects of intraarticular glucocorticoids on macrophage infiltration and mediators of joint damage in osteoarthritis synovial membranes: findings in a double-blind, placebo-controlled study.
To investigate the effects of intraarticular glucocorticoid treatment on macrophage infiltration, the expression of the chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1alpha (MIP-1alpha), and the expression of matrix metalloproteinases 1 and 3 (MMPs 1 and 3) and their inhibitors, the tissue inhibitors of metalloproteinases 1 and 2 (TIMPs 1 and 2), in osteoarthritis (OA) synovial membranes. Forty patients underwent arthroscopic biopsy before and 1 month after intraarticular injection of glucocorticoids. Twenty-one patients received 120 mg of methylprednisolone acetate (Depo-Medrol; Upjohn, Kalamazoo, MI), and 20 patients received placebo (1 patient received placebo in 1 knee and methylprednisolone acetate in the other). Immunoperoxidase staining for the expression of CD68, MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 was performed, and the immunostaining was quantified by color video image analysis. CD68, MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 immunostaining was observed in all synovial membranes. Intraarticular glucocorticoid treatment was associated with a small (30%) but statistically significant (P = 0.048) reduction in CD68+ macrophage staining in the synovial lining layer, but there was no change in the CD68 expression in the synovial sublining layer. No significant differences were observed for MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 immunostaining in the synovial lining or sublining layers. Intraarticular glucocorticoids may reduce CD68+ macrophage infiltration into the synovial lining layer, but not the expression of MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, and TIMP-2 in the synovial membrane, in patients with OA.


Tsukamurella spongiae sp. nov., a novel actinomycete isolated from a deep-water marine sponge.
A Gram-positive, rod-shaped, non-spore-forming bacterium (strain K362(T)) was isolated from a deep-water marine sponge collected off the coast of Curaçao in the Netherlands Antilles. On the basis of 16S rRNA gene sequence similarities, strain K362(T) was shown to belong to the genus Tsukamurella, being most closely related to Tsukamurella pulmonis (99.2 %), Tsukamurella tyrosinosolvens (98.9 %), Tsukamurella strandjordii (98.8 %), Tsukamurella pseudospumae (98.8 %) and Tsukamurella spumae (98.8 %). A combination of the substrate utilization patterns, the fatty acid and mycolic acid profiles and the DNA-DNA hybridization results supported the affiliation of strain K362(T) to the genus Tsukamurella and enabled the genotypic and phenotypic differentiation of strain K362(T) from the seven recognized Tsukamurella species. Strain K362(T) therefore represents a novel species of the genus Tsukamurella, for which the name Tsukamurella spongiae sp. nov. is proposed. The type strain is K362(T) (=DSM 44990(T)=NRRL B-24467(T)).


Hypertriglyceridemia in patients with chronic renal failure: possible mechanisms.
Cardiovascular disease (CVD) is a major cause of mortality in patients with chronic renal failure (CRF) caused by numerous factors defined as traditional and uremia-related risk factors. One of these risk factors, dyslipidemia, is often observed in patients with CRF, resulting in abnormal concentrations and composition of plasma lipoproteins. The prominent features of uremic dyslipidemia are an increase in plasma triglycerides and cholesterol in nearly all lipoproteins, and a reduction in high-density lipoprotein (HDL) cholesterol. Because of its direct contact with the circulating blood, the endothelium is preferentially subjected to the modulatory effects of these altered lipoproteins. Little is known about the mechanisms for hypertriglyceridemia in CRF. This review highlights several studies over the past years that have contributed to knowledge of hypertriglyceridemia, especially in combination with renal diseases and their dialysis treatment. The underlying mechanisms behind hypertriglyceridemia have not been fully clarified and may indeed be multifactorial. Hypertriglyceridemia may contribute to the progression of atherosclerosis. Therefore, it is essential to study the putative mechanisms for uremic dyslipidemia, since optimal treatment is essential for the prevention or delay of cardiovascular complications in patients with CRF.


[Comparative analysis of ergogenic efficacy of energy drinks components (caffeine and bitter orange extract) in combination with alcohol].
Estimation of ergogenic effects of caffeine and bitter orange exract combined with alcohol is presented in the article. Investigations were performed on 3 groups (8 animals in each group) of male Wistar rats aged 4 months. Animals in group 1 were treated orally for 7 days, the mixture comprising caffeine and alcohol (0.6 g of caffeine, 72 ml of ethanol, water to 1 liter) in an amount equivalent to 4.28 mg caffeine per kg of body weight. Animals in group 2 received a mixture containing bitter orange extract and alcohol (1 g bitter orange extract, 72 ml of ethanol, water to 1 liter) in an amount equivalent to 0.43 mg of synephrine per kg body weight. Animals in the control group received the same volume (7.1 ml/kg) 7.2% aqueous solution of ethanol. Group of animals consumed caffeine in mixture with alcohol and the control group exhibited a significant weight gain, while the body weight of animals treated with the extract of bitter orange didn't significantly change. Using the methodology of the open field the effects of caffeine and bitter orange extract in combination with alcohol on the ratio of the active components of the orienting-exploratory behavior and passive-defensive behavior have been determined. Administration of mixture with caffeine increased locomotory activity by 164%, administration of bitter orange extract didn't affect this performance. Introduction of caffeine containing mixture significantly reduced the level of situational anxiety, which was manifested in the reduction of time spent by the animal in the center of the arena. The effects of ergogenic components on the performance of static and dynamic muscle endurance have been investigated. Single administration of the mixture containing caffeine, after 30 min caused a significant increase in performance and, consequently, endurance of glycolytic muscle fibers measured using the "inverted grid" test. Animals from this group produced 186% more work compared with control animals. Acute administration of bitter orange extract did not cause significant changes in static endurance. At the same time after 7 days of its daily administration a slight increase in dynamic endurance (test "treadmill") has been determined, which was expressed in some increase in the amount of work done by animals fed bitter orange extract compared with the control group of animals. Death of 1 animal in the group consumed bitter orange exract mixture with alcohol indicates potential risks of synephrine consumation together with alcohol.


Immunosuppression in toxoplasmosis: further studies on mice infected with louping-ill virus.
Mice were infected with an avirulent cyst-producing strain of Toxoplasma gondii and given injections of louping-ill virus 7 days later; control mice were given virus but not Toxoplasma. Test and control mice were then killed, in groups, 2, 4, 6, 8 and 10 days later. In the dually infected mice viraemia was later, greater and more prolonged; titres of virus recovered from brain and spleen were greater; production and haemagglutinating antibody to louping-ill virus was later and less, and inflammation in the brain was more severe, than in mice given virus alone. We suggest that T. gondii suppressed the immunity of mice, making them more susceptible to the virus, and that a significant proportion of the increased number of inflammatory cells observed in the brain could have been toxoplasma specific and not virus-specific and hence contributed to the increased susceptibility of the dually infected mice to louping-ill virus.


The diabetes education study: a controlled trial of the effects of diabetes patient education.
The Diabetes Education Study (DIABEDS) was a randomized, controlled trial of the effects of patient and physician education. This article describes a systematic education program for diabetes patients and its effects on patient knowledge, skills, self-care behaviors, and relevant physiologic outcomes. The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center. Patients were predominantly elderly, black women with non-insulin-dependent diabetes mellitus of long duration. Patients randomly assigned to experimental groups (N = 263) were offered up to seven modules of patient education. Each content area module contained didactic instruction (lecture, discussion, audio-visual presentation), skill exercises (demonstration, practice, feedback), and behavioral modification techniques (goal setting, contracting, regular follow-up). Two hundred seventy-five patients remained in the study throughout baseline, intervention, and postintervention periods (August 1978 to July 1982). Despite the requirement that patients demonstrate mastery of educational objectives for each module, postintervention assessment 11-14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge. However, statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous. Experimental group patients experienced significantly greater reductions in fasting blood glucose (-27.5 mg/dl versus -2.8 mg/dl, P less than 0.05) and glycosylated hemoglobin (-0.43% versus + 0.35%, P less than 0.05) as compared with control subjects. Patient education also had similar effects on body weight, blood pressure, and serum creatinine. Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization.


MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients.
Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma. In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%). Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma. Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit.


The technique of percutaneous transluminal coronary angioplasty. Uses, abuses, training requirements, benefits, complications.
Like coronary artery bypass grafting, PTCA is used to manage multilesion and multivessel disease, new complete occlusions, and partial occlusions of saphenous vein or internal mammary artery grafts. PTCA is contraindicated for patients with a significant obstructive lesion in the left main coronary artery or with severe diffuse atherosclerosis. In determining whether this procedure provides the best treatment option, the risk of abrupt vessel closure, restenosis, MI, or incomplete revascularization must be considered. Guidelines for the performance of PTCA and physician and institutional responsibilities have been established; these guidelines must be regarded as necessary criteria for wide adoption.


[Contrast echocardiography].
The intravenous application of an ultrasound contrast agent induces enhanced display of blood in all its pathways. Within cardiology, this principle is mainly utilized for signal enhancement of color Doppler and spectral Doppler in order to improve quantification of congenital and acquired valvular lesions and also for improved endocardial delineation during stress tests and in the evaluation of LV function. The new domaine of myocardial perfusion imaging by contrast echocardiography, however, needed profound technical developments before realization of the clinical potential could even be conceived. These are based on the complex reactions of microbubbbles in the acoustic field in order to allow the sensitive and bubble specific display of intramyocardial contrast effects. The presently available acquisition techniques, second harmonic imaging and harmonic power Doppler, demonstrate significant improvements if compared to traditional fundamental 2-d echocardiography; however, they are still subjected to important limitations. There are many anatomical, physiological, and technical reasons for insufficient display of intramyocardial microbubbles, the most important one being attenuation. It is hoped that the most recently developed imaging modality, pulse inversion technique, allows the necessary diagnostic accuracy and reproducibility in myocardial perfusion imaging.


Circulating endothelial cells and endothelial activation in essential thrombocythemia: results from CD146+ immunomagnetic enrichment--flow cytometry and soluble E-selectin detection.
Circulating endothelial cells (CECs) have been studied in cardiovascular disorders and as a marker of angiogenetic activity; clinical applications are limited by a lack of consensus on their phenotypic identification and quantification. We determined CECs in essential thrombocythemia (ET) patients, to investigate their possible pathogenetic role. We considered CECs as CD146⁺/CD45⁻ nucleated cells, detected in peripheral blood from 21 healthy controls and 39 ET patients, performing a combination of pre-enrichment of CD146⁺ circulating cells and multiparametric flow cytometry measurement (FCM). Levels of CECs in ET patients were higher with respect to controls (median 2844 CECs/mL vs. 121.3 CECs/mL, P < 0.0001). Apparently hydroxyurea treatment did not influence the levels of CECs. As another established marker of endothelial activation, we also assessed soluble E-selectin (sE-selectin) levels in 31 of the ET patients and compared with 39 healthy volunteers: median sE-selectin level in ET patients was 35.3 ng/mL, higher with respect to controls (24.48 ng/mL), P = 0.0369. Our data suggest that endothelium in ET is activated, reflecting a significant role of angiogenesis in this disorder and suggesting an important endothelial contribution in the hypercoagulable state of ET patients.


New potentially antihypertensive peptides liberated in milk during fermentation with selected lactic acid bacteria and kombucha cultures.
Compounds with the ability to inhibit angiotensin-converting enzyme (ACE) are used medically to treat human hypertension. The presence of such compounds naturally in food is potentially useful for treating the disease state. The goal of this study was to screen lactic acid bacteria, including species commonly used as dairy starter cultures, for the ability to produce new potent ACE-inhibiting peptides during milk fermentation. Strains of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus helveticus, Lactobacillus paracasei, Lactococcus lactis, Leuconostoc mesenteroides, and Pediococcus acidilactici were tested in this study. Additionally, a symbiotic consortium of yeast and bacteria, used commercially to produce kombucha tea, was tested. Commercially sterile milk was inoculated with lactic acid bacteria strains and kombucha culture and incubated at 37°C for up to 72 h, and the liberation of ACE-inhibiting compounds during fermentation was monitored. Fermented milk was centrifuged and the supernatant (crude extract) was subjected to ultrafiltration using 3- and 10-kDa cut-off filters. Crude and ultrafiltered extracts were tested for ACE-inhibitory activity. The 10-kDa filtrate resulting from L. casei ATCC 7469 and kombucha culture fermentations (72 h) showed the highest ACE-inhibitory activity. Two-step purification of these filtrates was done using HPLC equipped with a reverse-phase column. Analysis of HPLC-purified fractions by liquid chromatography-mass spectrometry/mass spectrometry identified several new peptides with potent ACE-inhibitory activities. Some of these peptides were synthesized, and their ACE-inhibitory activities were confirmed. Use of organisms producing these unique peptides in food fermentations could contribute positively to human health.


Efficacy and safety of long-term thiopurine maintenance treatment for ulcerative colitis in Turkey: A single-center experience.
Thiopurines are widely used in the treatment of inflammatory bowel disease, but data are limited. Or aim was to determine the outcome of thiopurine application in children diagnosed with ulcerative colitis (UC). Forty-eight patients with UC, diagnosed at our center between 2005 and 2016 and applied azathiopurine (AZA), were included in the study. Data were collected retrospectively. The diagnosis of UC was based on the conventional clinical, radiological, histological, and endoscopic assessment. All patients with UC at this intercept were analyzed at the 4- and 6-week and 3-month intervals after remission to determine patient characteristics, thiopurine properties, and its efficacy and toxicity. Determination of remission, relapse, and steroid refractoriness/dependency were guided according to the European Crohn's and Colitis Organisation consensus. Azathiopurine was started at the median 1 month (0-12 months), and it was applied thereafter for maintenance (n=43). Response to remission induction was obtained in 40 (93.7%) patients. The median duration of the AZA treatment was 24 months (5-63). In 34 (85%) of the 40 children, it was well tolerated until the last visit. During the follow-up, adverse events occurred in 6 patients. These are leucopenia, neutropenia, vomiting, diarrhea, and skin rush. Thiopurine is an appropriate treatment option for remission in patients with UC. For a long-term follow-up, it is very important to identify patients with UC who have clinical remission with side effects and with thiopurine application.


Head roll stabilisation in the nocturnal bull ant Myrmecia pyriformis: implications for visual navigation.
Ant foragers are known to memorise visual scenes that allow them to repeatedly travel along idiosyncratic routes and to return to specific places. Guidance is provided by a comparison between visual memories and current views, which critically depends on how well the attitude of the visual system is controlled. Here we show that nocturnal bull ants stabilise their head to varying degrees against locomotion-induced body roll movements, and this ability decreases as light levels fall. There are always un-compensated head roll oscillations that match the frequency of the stride cycle. Head roll stabilisation involves both visual and non-visual cues as ants compensate for body roll in complete darkness and also respond with head roll movements when confronted with visual pattern oscillations. We show that imperfect head roll control degrades navigation-relevant visual information and discuss ways in which navigating ants may deal with this problem.


Allogeneic transplant physician and center capacity in the United States.
Shortage of manpower and center capacity is expected to be a major challenge to the anticipated future growth in the utilization of allogeneic hematopoietic cell transplantation (HCT) in the United States. Using data from the National Marrow Donor Program's Transplant Center Network Renewal Survey, we describe transplant center and transplant physician capacity in the United States from 2005 to 2009. Over this 5-year period, the number of allogeneic transplants increased by 30%, bed capacity increased by 17%, and physician full-time equivalents increased by 26%. The number of related donor HCT increased by 15% and unrelated donor HCT increased by 45%. In addition to large centers, small- and medium-sized centers also made a major contribution to overall national transplant volumes for both related and unrelated donor HCT. Increase in utilization of unrelated donor HCT occurred in centers irrespective of their size. The majority of transplant centers were performing more transplantations using existing physician and bed capacity. Our study provides important descriptions of allogeneic transplant activity and capacity of U.S. centers, and our data will assist policy makers plan for the projected growth in the use of transplantation.


Efficacy of a dynamic collimator for overranging dose reduction in a second- and third-generation dual source CT scanner.
The purpose of this study was to assess the efficacy of the renewed dynamic collimator in a third-generation dual source CT (DSCT) scanner and to determine the improvements over the second-generation scanner. Collimator efficacy is defined as the percentage overranging dose in terms of dose-length product (DLP) that is blocked by the dynamic collimator relative to the total overranging dose in case of a static collimator. Efficacy was assessed at various pitch values and different scan lengths. The number of additional rotations due to overranging and effective scan length were calculated on the basis of reported scanning parameters. On the basis of these values, the efficacy of the collimator was calculated. The second-generation scanner showed decreased performance of the dynamic collimator at increasing pitch. Efficacy dropped to 10% at the highest pitch. For the third-generation scanner the efficacy remained above 50% at higher pitch. Noise was for some pitch values slightly higher at the edge of the imaged volume, indicating a reduced scan range to reduce the overranging dose. The improved dynamic collimator in the third-generation scanner blocks the overranging dose for more than 50% and is more capable of shielding radiation dose, especially in high pitch scan modes. • Overranging dose is to a large extent blocked by the dynamic collimator • Efficacy is strongly improved within the third-generation DSCT scanner • Reducing the number of additional rotations can reduce overranging with increased noise.


A cautionary note on the use of nested PCR for parasite screening--an example from avian blood parasites.
The use of new powerful nested polymerase chain reaction (PCR) techniques to identify and screen for prevalence of parasites has a huge potential. It allows for the detection and identification of low-intensity infections, but its high sensitivity and technical setup may also induce problems. Here, we report a cautionary note regarding misleading amplification of avian malaria species (Haemoproteus and Plasmodium) during Leucocytozoon spp. detection. We used a previously described nested PCR method for the molecular detection of avian malaria and Leucocytozoon spp. In the first step of the PCR protocol, these parasites are detected simultaneously; in the second PCR, Haemoproteus and Plasmodium spp. are separated from Leucocytozoon spp. However, in certain cases when a bird was infected with avian malaria, we obtained a slightly longer PCR product during the detection of Leucocytozoon spp. Our data imply that these "false" Leucocytozoon fragments are the consequences of strong amplification of certain malaria lineages in the first PCR, which can also be detected after the second PCR amplification that is specific to Leucocytozoon spp. parasites. Because these "false" Leucocytozoon fragments are slightly longer than the normal Leucocytozoon fragments, we suggest the use of well-separating agarose gels, several positive controls, and molecular standards to facilitate their separation. If one obtains a fragment that differs in length from the one expected for Leucocytozoon spp., sequencing is essential. More generally, in order to limit this type of problem with nested PCR protocols, we suggest that the first and the second primer pair be chosen so that they have different annealing temperatures.


Hypoxia-sensitive reporter system for high-throughput screening.
The induction of anti-hypoxic stress enzymes and proteins has the potential to be a potent therapeutic strategy to prevent the progression of ischemic heart, kidney or brain diseases. To realize this idea, small chemical compounds, which mimic hypoxic conditions by activating the PHD-HIF-α system, have been developed. However, to date, none of these compounds were identified by monitoring the transcriptional activation of hypoxia-inducible factors (HIFs). Thus, to facilitate the discovery of potent inducers of HIF-α, we have developed an effective high-throughput screening (HTS) system to directly monitor the output of HIF-α transcription. We generated a HIF-α-dependent reporter system that responds to hypoxic stimuli in a concentration- and time-dependent manner. This system was developed through multiple optimization steps, resulting in the generation of a construct that consists of the secretion-type luciferase gene (Metridia luciferase, MLuc) under the transcriptional regulation of an enhancer containing 7 copies of 40-bp hypoxia responsive element (HRE) upstream of a mini-TATA promoter. This construct was stably integrated into the human neuroblastoma cell line, SK-N-BE(2)c, to generate a reporter system, named SKN:HRE-MLuc. To improve this system and to increase its suitability for the HTS platform, we incorporated the next generation luciferase, Nano luciferase (NLuc), whose longer half-life provides us with flexibility for the use of this reporter. We thus generated a stably transformed clone with NLuc, named SKN:HRE-NLuc, and found that it showed significantly improved reporter activity compared to SKN:HRE-MLuc. In this study, we have successfully developed the SKN:HRE-NLuc screening system as an efficient platform for future HTS.


The implications of household greywater treatment and reuse for municipal wastewater flows and micropollutant loads.
An increasing worldwide interest in water recycling technologies such as greywater treatment and reuse suggests that additional research to elucidate the fate of xenobiotics during such practices would be beneficial. In this paper, scenario analyses supported by empirical data are used for highlighting the potential fate of a selection of xenobiotic micropollutants in decentralised greywater treatment systems, and for investigation of the possible implications of greywater recycling for the wider urban water cycle. Potential potable water savings of up to 43% are predicted for greywater recycling based on Danish water use statistics and priority substance monitoring at a greywater treatment plant in Denmark. Adsorption represents an important mechanism for the removal of cadmium, nickel, lead and nonylphenol from influent greywater and therefore the disposal route adopted for the generated sludge can exert a major impact on the overall efficiency and environmental sustainability of greywater treatment.


Tunable long-range spin transport in a van der Waals Fe3GeTe2/WSe2/Fe3GeTe2 spin valve.
The seamless integration of two-dimensional (2D) ferromagnetic materials with similar or dissimilar materials can widen the scope of low-power spintronics. In this regard, a vertical van der Waals (vdW) heterostructure of 2D ferromagnets with semiconducting transition metal dichalcogenides (TMDCs) forms magnetic junctions with exceptional stability and electrical control. Interestingly, 2D metallic Fe3GeTe2 (FGT) reveals above room temperature Curie temperatures and has large magneto anisotropy due to spin-orbit coupling. In addition, it also possesses topological states and a large Berry curvature. Herein, we designed the FGT/WSe2/FGT vdW heterostructure with a uniform and sharp interface so that FGT could maintain its inherent electronic properties. Also, the uniform thickness of the barrier provides a smooth flow of spins through the junctions as tunneling exponentially decays with an increasing barrier thickness. However, strong energy-dependent spin polarization is crucial for achieving optimum spin valve properties, such as large tunneling magnetoresistance (TMR) along with the manipulation of the magnitude and sign reversal. We have observed a shifting of high-energy localized minority spin states toward low-energy regions, which causes spin polarization fluctuation between -42.5% and 41% over a wide range of bias voltage. This leads to a negative TMR% of ∼-100% at 0.1 V Å-1 and also a large positive TMR% at 0.2 V Å-1 and -0.4 V Å-1. Besides, the system exhibits a highly tunable large anomalous Hall conductivity (AHC) of 626 S cm-1. Interestingly, such unprecedented electronic behaviour with large and switchable spin polarization, anomalous Hall conductivity and TMR can be incorporated into MTJ devices, which provide electrical control and long-range spin transport. Additionally, the system emerges as a standout candidate in low-power spintronic devices (e.g., MRAM and magnetic sensors) owing to its distinctive energy-dependent electronic structure with a wide range of external bias.


Hyperferritinemia in dogs with splenic hemangiosarcoma.
Serum ferritin concentration increases in dogs in association with various diseases. In this study, we measured serum ferritin levels in dogs with splenic masses, using a sandwich ELISA assay. Eleven dogs with hemangiosarcoma (HSA), six with hematoma, 1 with hemangioma and 3 with lymphoma were enrolled. All dogs with HSA had serum ferritin concentrations above the normal limit (1,357 ng/ml, mean + 2× standard deviation of normal). Increased serum ferritin concentrations have also been observed in few cases of hematoma, hemangioma and lymphoma. Therefore, hyperferritinemia is not specific for splenic HSA, but may have clinical usefulness as a sensitive test for the disease. Further evaluation of serum ferritin concentrations in dogs with splenic HSA is needed.


Under the volcano: phylogeography and evolution of the cave-dwelling Palmorchestia hypogaea (Amphipoda, Crustacea) at La Palma (Canary Islands).
The amphipod crustacean Palmorchestia hypogaea occurs only in La Palma (Canary Islands) and is one of the few terrestrial amphipods in the world that have adapted to a strictly troglobitic life in volcanic cave habitats. A surface-dwelling closely related species (Palmorchestia epigaea) lives in the humid laurel forest on the same island. Previous studies have suggested that an ancestral littoral Orchestia species colonized the humid forests of La Palma and that subsequent drought episodes in the Canaries reduced the distribution of P. epigaea favouring the colonization of lava tubes through an adaptive shift. This was followed by dispersal via the hypogean crevicular system. P. hypogaea and P. epigaea did not form reciprocally monophyletic mitochondrial DNA clades. They showed geographically highly structured and genetically divergent populations with current gene flow limited to geographically close surface locations. Coalescence times using Bayesian estimations assuming a non-correlated relaxed clock with a normal prior distribution of the age of La Palma, together with the lack of association of habitat type with ancestral and recent haplotypes, suggest that their adaptation to cave life is relatively ancient. The data gathered here provide evidence for multiple invasions of the volcanic cave systems that have acted as refuges. A re-evaluation of the taxonomic status of the extant species of Palmorchestia is needed, as the division of the two species by habitat and ecology is unnatural. The information obtained here, and that from previous studies on hypogean fauna, shows the importance of factors such as the uncoupling of morphological and genetic evolution, the role of climatic change and regressive evolution as key processes in leading to subterranean biodiversity.


charge storage behavior of nanowire transistors functionalized with bis(terpyridine)-Fe(II) molecules: dependence on molecular structure.
We studied the influence of three bis(terpyridine)-Fe(II) molecules-(X-tpy)2FeCl2 (X = H (1), SAc (2), and 4-phenyl-SAc (3)-on charge storage of a nanowire transistor. The molecules were assembled on the surface of an indium oxide nanowire that forms the conduction channel of the transistor. We found that the charge storage characteristics of such a device strongly depends on the structure of the terpyridine ligand: both retention time (tau) and threshold voltage shift (DeltaVth) increased in the order of 1 < 2 < 3, with tau of 200 s, 12 h, and 287 h and DeltaVth at 4.8, 12, and 28 V, respectively. Furthermore, when we placed the devices with molecules 1 and 3 in a vacuum and recorded the I-Vg curves in a two-day period, we observed higher hysteresis stability for device with molecule 3. For example, DeltaVth was reduced from 4.8 to 1.7 V for the device with molecule 1, while there was no reduction in DeltaVth for the device with molecule 2. These results suggest that thiolate headgroup and/or longer ligand length raises the charge tunneling barrier and results in longer charge retention and wider, more stable memory window. This work demonstrates the potential of chemical synthesis toward tailored device characteristics.


Identification of Small-Molecule Inhibitors Targeting Porphyromonas gingivalis Interspecies Adherence and Determination of Their In Vitro and In Vivo Efficacies.
Porphyromonas gingivalis is one of the primary causative agents of periodontal disease and initially colonizes the oral cavity by adhering to commensal streptococci. Adherence requires the interaction of a minor fimbrial protein (Mfa1) of P. gingivalis with streptococcal antigen I/II (AgI/II). Our previous work identified an AgI/II peptide that potently inhibited adherence and significantly reduced P. gingivalis virulence in vivo, suggesting that this interaction represents a potential target for drug discovery. To develop targeted small-molecule inhibitors of this protein-protein interaction, we performed a virtual screen of the ZINC databases to identify compounds that exhibit structural similarity with the two functional motifs (NITVK and VQDLL) of the AgI/II peptide. Thirty three compounds were tested for in vitro inhibition of P. gingivalis adherence and the three most potent compounds, namely, N7, N17, and V8, were selected for further analysis. The in vivo efficacy of these compounds was evaluated in a murine model of periodontitis. Treatment of mice with each of the compounds significantly reduced maxillary alveolar bone resorption in infected animals. Finally, a series of cytotoxicity tests were performed against human and murine cell lines. Compounds N17 and V8 exhibited no significant cytotoxic activity toward any of the cell lines, whereas compound N7 was cytotoxic at the highest concentrations that were tested (20 and 40 μM). These results identify compounds N17 and V8 as potential lead compounds that will facilitate the design of more potent therapeutic agents that may function to limit or prevent P. gingivalis colonization of the oral cavity.


Extracellular proteases and neuronal cell death.
Neuronal cell death occurs during development of the central nervous system as well as in pathological situations such as acute injury and progressive degenerative diseases. For instance, granule cells in the developing cerebellum and neuronal precursor cells in the cortex undergo programmed cell death, or apoptosis. There is currently strong debate conceming the mechanism of death in many degenerative events such as ischemia, blunt head trauma, excitotoxicity and neurodegenerative diseases, i.e. Alzheimer's disease. Neurons can die a necrotic death when the initial insult is too great; apoptosis requires "planning." For example, the cell death seen in the core of an ischemic infarct is necrotic, while in the surrounding penumbra region the death is probably apoptotic. Regardless of the degenerative pathway, damaged or dead neurons are a hallmark of many diseases including Alzheimer's, Parkinson's, glaucoma, ischemia and multiple sclerosis. Molecules such as cytokines, chemokines, reactive nitrogen/oxygen species, and proteases play an important role in promoting and/or mediating neurodegeneration. Proteases have been implicated in both physiological and pathological events, suggesting their intervention in key points when things go awry. In this review we will summarize recent findings linking extracellular proteases with neuronal cell death in both human diseases and their animal models.


Exercise habits in south Trinidad: motivating forces and barriers.
There are many benefits of regular exercise. The aim of this study was to determine the exercise habits and knowledge of the benefits of exercise in a south Trinidad population. This study also sought to determine the motivating factors for exercise and the barriers experienced by those who did not exercise. A self-administered questionnaire was distributed to 700 persons between the ages of 15-75-years in Princes Town, South Trinidad. The exercise habits of the population, the effect of age on exercise and the impact of knowledge of benefits of exercise on the desire to participate in exercise were determined. Of the 66.6% (95% CI: 62.6, 70.3) respondents who exercised, only 10.7% exercised adequately. Walking was the main form of exercise (60.6%). Health reasons were cited as the major motivating factor for exercising in the 60-75-year age group. Persons 15-59 years indicated that time constraints were the major reason for not exercising. Most participants (77.2%) felt that the healthcare provider should advise on exercise. Knowledge of at least one benefit of exercise increased the likelihood of exercising (p < 0.0001). Younger persons were more likely to exercise at least once weekly than older persons (p = 0.0002). A high proportion of persons do not exercise regularly or adequately and efforts are needed to encourage exercise in this population. This study suggests that encouragement should come from healthcare providers. Time management and accumulating daily exercise are two areas to consider when advising sedentary individuals about exercise.


Using tablet computers compared to interactive voice response to improve subject recruitment in osteoporosis pragmatic clinical trials: feasibility, satisfaction, and sample size.
Pragmatic clinical trials (PCTs) provide large sample sizes and enhanced generalizability to assess therapeutic effectiveness, but efficient patient enrollment procedures are a challenge, especially for community physicians. Advances in technology may improve methods of patient recruitment and screening in PCTs. Our study looked at a tablet computer versus an integrated voice response system (IVRS) for patient recruitment and screening for an osteoporosis PCT in community physician offices. We recruited women ≥ 65 years of age from community physician offices to answer screening questions for a hypothetical osteoporosis active comparator PCT using a tablet computer or IVRS. We assessed the feasibility of these technologies for patient recruitment as well as for patient, physician, and office staff satisfaction with the process. We also evaluated the implications of these novel recruitment processes in determining the number of primary care practices and screened patients needed to conduct the proposed trial. A total of 160 women (80% of those approached) agreed to complete the osteoporosis screening questions in ten family physicians' offices. Women using the tablet computer were able to complete all screening questions consistently and showed a nonsignificant trend towards greater ease of use and willingness to spend more time in their physician's office compared to those using IVRS. Using the proportion of women found to be eligible in this study (almost 20%) and other eligibility scenarios, we determined that between 240 and 670 community physician offices would be needed to recruit ample patients for our hypothetical study. We found good satisfaction and feasibility with a tablet computer interface for the recruitment and screening of patients for a hypothetical osteoporosis PCT in community office settings. In addition, we used this experience to estimate the number of research sites needed for such a study.


Influence of the process, season, and origin on volatile composition and antioxidant activity of Juniperus phoenicea L. leaves essential oils.
Essential oils of Juniperus phoenicea L. leaves cultivated in 3 regions, Korbos, Matmata, and Tabarka of Tunisia were obtained by hydrodistillation (HD), steam distillation (SD), and Soxhlet (SH) extraction methods. The essential oils were analyzed and quantified by capillary gas chromatography using flame ionization detection (GC-FID) and mass spectrometry (GC-MS). The highest yield was observed in HD process (1.12%). Tabarka essential oil provided the best yield 0.79% compared to other regions. December month SD essential oil was the highest in oxygenated monoterpenes (52.7%). Nevertheless, SH essential oil showed a higher content in sesquitepenes hydrocarbons (64.5%). α-Terpinol (25.5%) was the main oxygenated component in Matmata juniper essential oil, extracted by SD. Moreover, the antioxidant activity of essential oils was evaluated using ABTS assays. The strongest antioxidant activity (IC(50) = 22.6 ± 0.7 mg/L) was obtained by the Matmata (October 2007) SD essential oil.


Depletion sphere: Explaining the number of Ag islands on Au nanoparticles.
We report multi-site nucleation and growth of Ag islands on colloidal Au nanoparticles. By modifying a single factor, a range of products from Janus nanoparticles to satellite nanostructures are obtained. The identification of these key factors reveals the correlation between the concentration gradient and the choice of nucleation sites. In contrast to the inhibited homogeneous nucleation in the bulk solution, we argue that the non-steady-state concentration gradient plays a critical role in inhibiting nucleation within nanometer distance during the initial stage of growth-an essential but not yet recognized factor in colloidal synthesis. A depletion sphere model was developed, so that the multi-site nucleation is well integrated with the classic theory of nucleation and growth. Alternative explanations are carefully examined and ruled out. We believe that the synthetic know-how and the mechanistic insights can be broadly applied and are of importance to the advance of nanosynthesis.


Occupational Heat Stress Profiles in Selected Workplaces in India.
Health and productivity impacts from occupational heat stress have significant ramifications for the large workforce of India. This study profiled occupational heat stress impacts on the health and productivity of workers in select organized and unorganized Indian work sectors. During hotter and cooler seasons, Wet Bulb Globe Temperatures (WBGT) were used to quantify the risk of heat stress, according to International workplace guidelines. Questionnaires assessed workers' perceived health and productivity impacts from heat stress. A total of 442 workers from 18 Indian workplaces participated (22% and 78% from the organized and unorganized sector, respectively). Overall 82% and 42% of workers were exposed to higher than recommended WBGT during hotter and cooler periods, respectively. Workers with heavy workloads reported more heat-related health issues (chi square = 23.67, p ≤ 0.001) and reduced productivity (chi square = 15.82, p ≤ 0.001), especially the outdoor workers. Heat-rashes, dehydration, heat-syncope and urinogenital symptoms were self-reported health issues. Cited reasons for productivity losses were: extended-work hours due to fatigue/exhaustion, sickness/hospitalization and wages lost. Reducing workplace heat stress will benefit industries and workers via improving worker health and productivity. Adaptation and mitigation measures to tackle heat stress are imperative to protect the present and future workforce as climate change progresses.


Alcohol acutely enhances decoding of positive emotions and emotional concern for positive stimuli and facilitates the viewing of sexual images.
Social cognition influences social interactions. Alcohol reportedly facilitates social interactions. However, the acute effects of alcohol on social cognition are relatively poorly studied. We investigated the effects of alcoholic or non-alcoholic beer on emotion recognition, empathy, and sexual arousal using the dynamic face emotion recognition task (FERT), Multifaceted Empathy Test (MET), and Sexual Arousal Task (SAT) in a double-blind, random-order, cross-over study in 60 healthy social drinkers. We also assessed subjective effects using visual analog scales (VASs), blood alcohol concentrations, and plasma oxytocin levels. Alcohol increased VAS ratings of stimulated, happy, talkative, open, and want to be with others. The subjective effects of alcohol were greater in participants with higher trait inhibitedness. Alcohol facilitated the recognition of happy faces on the FERT and enhanced emotional empathy for positive stimuli on the MET, particularly in participants with low trait empathy. Pictures of explicit sexual content were rated as less pleasant than neutral pictures after non-alcoholic beer but not after alcoholic beer. Explicit sexual pictures were rated as more pleasant after alcoholic beer compared with non-alcoholic beer, particularly in women. Alcohol did not alter the levels of circulating oxytocin. Alcohol biased emotion recognition toward better decoding of positive emotions and increased emotional concern for positive stimuli. No support was found for a modulatory role of oxytocin. Alcohol also facilitated the viewing of sexual images, consistent with disinhibition, but it did not actually enhance sexual arousal. These effects of alcohol on social cognition likely enhance sociability. www.clinicaltrials.gov/ct2/show/NCT02318823.


Racial discrimination and health: a systematic review of scales with a focus on their psychometric properties.
The literature addressing the use of the race variable to study causes of racial inequities in health is characterized by a dense discussion on the pitfalls in interpreting statistical associations as causal relationships. In contrast, fewer studies have addressed the use of racial discrimination scales to estimate discrimination effects on health, and none of them provided a thorough assessment of the scales' psychometric properties. Our aim was to systematically review self-reported racial discrimination scales to describe their development processes and to provide a synthesis of their psychometric properties. A computer-based search in PubMed, LILACS, PsycInfo, Scielo, Scopus and Web of Science was conducted without any type of restriction, using search queries containing free and controlled vocabulary. After initially identifying 3060 references, 24 scales were included in the review. Despite the fact that discrimination stands as topic of international relevance, 23 (96%) scales were developed within the United States. Most studies (67%, N = 16) were published in the last 12 years, documenting initial attempts at scale development, with a dearth of investigations on scale refinements or cross-cultural adaptations. Psychometric properties were acceptable; sixteen of all scales presented reliability scores above 0.7, 19 out of 20 instruments confirmed at least 75% of all previously stated hypotheses regarding the constructs under consideration, and conceptual dimensional structure was supported by means of any type of factor analysis in 17 of 21 scales. However, independent researchers, apart from the original scale developers, have rarely examined such scales. The use of racial terminology and how it may influence self-reported experiences of discrimination has not yet been thoroughly examined. The need to consider other types of unfair treatment as concurrently important health-damaging exposures, and the idea of a universal instrument which would permit cross-cultural adaptations, should be discussed among researchers in this emerging field of inquiry.


Production of 1,2-diacylglycerol and phosphatidate in human erythrocytes treated with calcium ions and ionophore A23187.
1. When the ionophore A23187 and Ca2+ were added to normal human erythrocytes, the incorporation of 32P into phosphatidate was enhanced within 1 min, but there was only slight labelling of other phospholipids. 2. Labelling of phosphatidate in these cells did not continue to increase after about 20min at 37 degrees C; by this time, radioactivity in phosphatidate was about ten times higher inionophore A23187-treated cells than in controls. A net synthesis of phosphatidate was measured in response to the increase in intracellular Ca2+ concentration; the content of this phospholipid in the cell was increased by approximately 50%. 3. In the presence of 2.5 mM-Ca2+ a maximum effect was seen with about 0.5 mug of ionophore/ml. 4. The concentration of Ca2+ giving half-maximal labelling of phosphatidate in the presence of 10 mug of ionophore A23187/ml was about 10 muM. 5. A rapid decrease of ATP content in the cell occurred in ionophore-treated cells. 6. Labelling of phosphatidate appeared to be secondary to the production of 1,2-diacylglycerol in the cells; accumulation of 1,2-diacylglycerol was only seen after about 15 min. After 60 min, the 1,2-diacylglycerol content of the cells was five to seven times that of untreated control cells. 7. The change in the shape of erythrocytes treated with Ca2+ and ionophore appeared to be related to accumulation of 1,2-diacylglycerol. 8. The source of 1,2-diacylglycerol has not been definitely identified, but its fatty acid compositon was similar to that of phosphatidylcholine. However, it has an unusually high content of hexadecenoic acid, a fatty acid not common in the major erythrocyte phospholipids. 9. Accumulation of 1,2-diacyglycerol also occurred in energy-starved cells, even in the absence of calcium; in this case it appeared to be produced by phosphatidate breakdown.


Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema.
The glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 µM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor.


The rapid, massive growth of COVID-19 authors in the scientific literature.
We examined the extent to which the scientific workforce in different fields was engaged in publishing COVID-19-related papers. According to Scopus (data cut, 1 August 2021), 210 183 COVID-19-related publications included 720 801 unique authors, of which 360 005 authors had published at least five full papers in their career and 23 520 authors were at the top 2% of their scientific subfield based on a career-long composite citation indicator. The growth of COVID-19 authors was far more rapid and massive compared with cohorts of authors historically publishing on H1N1, Zika, Ebola, HIV/AIDS and tuberculosis. All 174 scientific subfields had some specialists who had published on COVID-19. In 109 of the 174 subfields of science, at least one in 10 active, influential (top 2% composite citation indicator) authors in the subfield had authored something on COVID-19. Fifty-three hyper-prolific authors had already at least 60 (and up to 227) COVID-19 publications each. Among the 300 authors with the highest composite citation indicator for their COVID-19 publications, most common countries were USA (n = 67), China (n = 52), UK (n = 32) and Italy (n = 18). The rapid and massive involvement of the scientific workforce in COVID-19-related work is unprecedented and creates opportunities and challenges. There is evidence for hyper-prolific productivity.


Pulmonary immune-compartment-specific interferon gamma responses in HIV-infected individuals with active tuberculosis (TB) in an area of high TB prevalence.
There is a paucity of data on the pulmonary immune-compartment interferon gamma (IFNγ) response to M. tuberculosis, particularly in settings of high tuberculosis (TB) prevalence and in HIV-coinfected individuals. This data is necessary to understand the diagnostic potential of commercially available interferon gamma release assays (IGRAs) in both the pulmonary immune-compartment and peripheral blood. We used intracellular cytokine staining by flow cytometry to assess the IFNγ response to purified protein derivative (PPD) and early secretory antigen 6 (ESAT6) in induced sputa (ISp) and blood samples from HIV-infected, smear-negative, TB suspects. We found that individuals with active TB disease produced significantly less IFNγ in response to PPD in their induced sputa samples than individuals with non-active TB (control group). This difference was not reflected in the peripheral blood, even within the CD27- CD4+ memory T lymphocyte population. These findings suggest that progression to active TB disease may be associated with the loss of IFNγ secretion at the site of primary infection. Our findings highlight the importance of studying pulmonary immune-compartment M. tuberculosis specific responses to elucidate IFNγ secretion across the spectrum of TB disease.


Representation of activity knowledge for project management.
Representation of activity knowledge is important to any application which must reason about activities such as new product management, factory scheduling, robot control, vehicle control, software engineering, and air traffic control. This paper provides an integration of the underlying theories needed for modeling activities. Using the domain of large computer design projects as an example, the semantics of activity modeling is described. While the past research in knowledge representation has discovered most of the underlying concepts, our attempt is toward their integration. This includes the epistemological concepts for erecting the required knowledge structure; the concepts of activity, state, goal, and manifestation for the adequate description of the plan and the progress; and the concepts of time and causality to infer the progression among the activities. We also address the issues which arise due to the integration of aggregation, time, and causality among activities and states.


Avoiding common pitfalls of geriatric prescribing.
Ultimate drug levels and, therefore, maximum drug effect in general are inversely related to the function of the organ of excretion. If organ deficit is known, dose reduction should be automatic; if a drug level is very high at an ordinary dose, the organ of excretion should be investigated. The physician must not assume that a patient is not taking drugs just because the physician himself has not prescribed them. The elderly take more over-the-counter drugs than other segments of the population and frequently go to many health care providers.


High-performance, color-tunable fiber shaped organic light-emitting diodes.
In recent years, extensive research has been undertaken to develop fiber-shaped optoelectronic devices, because they are aesthetically pleasing, light in weight, and exhibit superior light emitting properties when compared with conventional planar analogues. In this work, we have successfully developed hollow-fiber shaped organic light emitting diodes (HF-OLED) with an exceptionally high luminance and facile color tunability. The HF-OLED device was fabricated by hierarchically depositing amorphous indium-doped tin oxide electrode on a hollow-fiber, followed by the sequential deposition of light-emitting organic layers and Al cathode. The external quantum efficiency of the HF-OLED is more than ∼2.0 times higher than that of a planar-OLED. The experimental results are in good agreement with the output of optical simulations, revealing that the use of a hollow-fiber has contributed to a ∼2.3 times improvement in light extraction efficiency. Furthermore, the color emission of a single HF-OLED device could be easily tuned from a green to yellowish-green wavelength after the injection of a super-yellow solution. The novel color tunable nature of the HF-OLED further broadens its application in the field of modern lighting and display technology.


Deletion of cytochrome P450 oxidoreductase enhances metabolism and DNA adduct formation of benzo[a]pyrene in Hepa1c1c7 cells.
The environmental carcinogen benzo[a]pyrene (BaP) is presumed to exert its genotoxic effects after metabolic activation by cytochrome P450 (CYP) enzymes. However, studies using the Hepatic Reductase Null (HRN) mouse model, in which cytochrome P450 oxidoreductase (POR), the electron donor to CYP enzymes, is deleted specifically in hepatocytes, have shown that loss of hepatic POR-mediated CYP function leads to greater BaP-DNA adduct formation in livers of these mice than in wild-type (WT) mice. Here, we used CRISPR/Cas9 technology to knockout (KO) POR expression in mouse hepatoma Hepa1c1c7 cells to create an in vitro model that can mimic the HRN mouse model. Western blotting confirmed the deletion of POR in POR KO Hepa1c1c7 cells whereas expression of other components of the mixed-function oxidase system including cytochrome b5 (Cyb5) and NADH:cytochrome b5 reductase (which can also serve as electron donors to CYP enzymes), and CYP1A1 was similar in BaP-exposed WT and POR KO Hepa1c1c7 cells. BaP exposure caused cytotoxicity in WT Hepa1c1c7 cells but not in POR KO Hepa1c1c7 cells. In contrast, CYP-catalysed BaP-DNA adduct levels were ~10-fold higher in POR KO Hepa1c1c7 cells than in WT Hepa1c1c7 cells, in concordance with the presence of higher levels of BaP metabolite (e.g. BaP-7,8-dihydrodiol) in the medium of cultured BaP-exposed POR KO Hepa1c1c7 cells. As was seen in the HRN mouse model, these results suggest that Cyb5 contributes to the bioactivation of BaP in POR KO Hepa1c1c7 cells. These results indicate that CYP enzymes may play a more important role in the detoxication of BaP, as opposed to its bioactivation.


Tn5041: a chimeric mercury resistance transposon closely related to the toluene degradative transposon Tn4651.
This paper reports the discovery and characterization of Tn5041, a novel-type transposon vehicle for dissemination of mercury resistance in natural bacterial populations. Tn5041 (14876 bp), identified in a Pseudomonas strain from a mercury mine, is a Tn3 family mercury resistance transposon far outside the Tn21 subgroup. As in other Tn3 family transposons, Tn5041 duplicates 5 bp of the target sequence following insertion. Tn5041 apparently acquired its mer operon as a single-ended relic of a transposon belonging to the classical mercury resistance transposons of the Tn21 subgroup. The putative transposase and the 47 bp terminal inverted repeats of Tn5041 are closely related to those of the toluene degradative transposon Tn4651 and fall into a distinct subgroup on the fringe of the Tn3 family. The amino acid sequence of the putative resolvase of Tn5041 resembles site-specific recombinases of the integrase family. Besides the mer operon and putative transposition genes, Tn5041 contains a 4 kb region that accommodates a number of apparently defective genes and mobile elements.


Citation analysis of otorhinolaryngology journals.
Bibliometric analysis is used to assess the 'impact' of scientific journals. The commonest method of evaluation is impact factor. The aim of this study was to analyse the citation data for otorhinolaryngology journals of the years 1994 to 1998. Data on the total number of citations and impact factor of journals was obtained from the CD-ROM editions 1994-98 of the Journal Citation Reports and 'Web of Science' database. The adjusted impact factor and five-year impact factor has been calculated. Fifteen otorhinolaryngology journals have been identified and ranked according to the impact factor. Head and Neck has the highest adjusted impact factor. Archives of Otolaryngology - Head and Neck Surgery has the highest five-year impact factor. There is considerable variation in the ranking of journals calculated by the five-year impact factor. Impact factors of otolaryngology journals can help to direct readers to those journals that have a track record of publishing data that are frequently cited. Although there are several limitations to the use of citation data to rank journals, the authors recommend the use of the five-year period for calculation of the impact factor for ranking of otolaryngology journals.


Sedimentation of macroscopic rigid knots and its relation to gel electrophoretic mobility of DNA knots.
We address the general question of the extent to which the hydrodynamic behaviour of microscopic freely fluctuating objects can be reproduced by macrosopic rigid objects. In particular, we compare the sedimentation speeds of knotted DNA molecules undergoing gel electrophoresis to the sedimentation speeds of rigid stereolithographic models of ideal knots in both water and silicon oil. We find that the sedimentation speeds grow roughly linearly with the average crossing number of the ideal knot configurations, and that the correlation is stronger within classes of knots. This is consistent with previous observations with DNA knots in gel electrophoresis.


Identification of the main urinary metabolites of omeprazole after an oral dose to rats and dogs.
The structures of seven urinary metabolites of omeprazole following high oral doses to rats and dogs were determined unambiguously by combining different analytical and spectroscopic techniques including derivatization and stable isotopes. Omeprazole was metabolized by aromatic hydroxylation at position 6 in the benzimidazole ring followed by glucuronidation. There was also oxidative O-dealkylation of both methoxy groups, and aliphatic hydroxylation of a pyridine methyl group followed by oxidation to the corresponding carboxylic acid. Due to the experimental design, implying no pH control of collected samples, all metabolites were isolated as sulfides. They were formed in both species with quantitative variations in the metabolic pattern. As far as identified metabolites are concerned, aromatic hydroxylation and subsequent glucuronide formation were the major biotransformation routes in the dog. In the rat, aliphatic hydroxylation and the formation of the carboxylic acid represented the major metabolic pathways. The identified metabolites corresponded approximately to 50% (rat) and 70% (dog) of the amount excreted in the 0-24-hr urine (about 12% of the given dose in both species).


The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy.
Thirty-eight patients with malignant mesothelioma of the pleura were seen at Peter MacCallum Cancer Institute between 1981 and 1985. In 35 patients presenting with disease confined to one hemithorax, the following treatments were given: radical surgery, 13 patients: radical radiotherapy, 12 patients; palliative radiotherapy, 20 patients; chemotherapy, 9 patients; observation only, 2 patients. Median survival from time of diagnosis for all 38 patients was 9 months, with an estimated 2-year survival rate of 16%. Treatment did not significantly affect survival, although there was an indication that patients having radical surgery did better (median survival 17 months) than those who did not (median survival 9 months) (p = 0.13). Fifteen patients were given radiotherapy with radical intent but only 12 completed treatment (50 Gy). The median survival of the 12 patients completing radiotherapy was 17 months, with an estimated 2-year survival rate of 17%. Two patient deaths were attributable to radical radiotherapy (one radiation hepatitis, one radiation myelopathy). Twenty-one patients received 31 courses of palliative radiotherapy for various symptoms, predominantly pain. The results were assessable for 26 courses, with 17 (65%) being at least partly successful. In conclusion, radiotherapy appears to be ineffective in prolonging survival in malignant mesothelioma of the pleura, but has a useful role in palliation.


[Biological role of histidine-containing dipeptides].
The biological role of histidine-containing dipeptides is reviewed. The role of carnosine and anserine in muscle function is discussed from the evolutionary viewpoint. Evidence on the antioxidative effect of carnosine and its protection of biological membranes against lipid peroxidation-induced damages is presented. The effects of presently known natural antioxidative agents and carnosine on lipid peroxidation are compared. Carnosine has been shown to be a more universal protector of membranes as compared to free radical scavengers.


A rare histiocytosis with severe cardiac involvement: Erdheim-Chester disease.
The term histiocytosis covers various disorders that lead to primary proliferation, infiltration and accumulation of cells of the mononuclear-phagocytic system within the affected tissues. Its pathophysiology is still unclear and the clinical course variable, which explains the lack of specific treatment and the need for a high level of suspicion to arrive at the diagnosis. The authors present the case of a patient with a complex cardiological clinical history, recently referred for surgical treatment of severe mitral insufficiency. Severe thickening of both atrial walls made it impossible to proceed with the intervention. After a complex etiological evaluation, a diagnosis of Erdheim-Chester disease was made. This is a rare, non-Langerhans cell histiocytosis and, to our knowledge, this represents the first case reported in Portugal. The authors also review the literature, particularly of the few cases with cardiac involvement.


Advances in Activity/Property Prediction from Chemical Structures.
Recent technological advancement in AI modeling of molecular property databases has significantly expanded the opportunities for drug design and development. Quantitative structure-activity relationships (QSARs) are shown to provide more accurate predictions with regards to biological activity as well as toxicological assessment. By using a combination of in-silico models or by combining disparate structure-activity databases, researchers have been able to improve accuracy for a variety of drug discovery and analysis methods, generating viable compounds, which in certain cases, can be synthesized and further studied in vitro to find candidates for potential development. Additionally, the development of compounds of determined toxicology can be discontinued earlier, allowing alternative routes to be evaluated, preventing wasted time and resources. Although the progress that has been made is tremendous, expert review is still necessary for most in-silico generated predictions. Regardless, the scientific community continues to move ever closer to completely automated drug discovery and evaluation.


BRAINSTORMING: A study protocol for a randomised double-blind clinical trial to assess the impact of concurrent brain stimulation (tDCS) and working memory training on cognitive performance in Acquired Brain Injury (ABI).
Acquired Brain Injury (ABI) admissions have an incidence of 385 per 100,000 of the population in the UK, and as brain injury often involves the frontal networks, cognitive domains affected are likely to be executive control, working memory, and problem-solving deficits, resulting in difficulty with everyday activities. The above observations make working memory, and related constructs such as attention and executive functioning attractive targets for neurorehabilitation. We propose a combined home-based rehabilitation protocol involving the concurrent administration of a working memory training program (adaptive N-back task) with non-invasive transcranial direct current stimulation (tDCS) of the right dorsolateral prefrontal cortex to promote long-lasting modification of brain areas underlying working memory function. Patients with a working memory deficit will be recruited and assigned to two age-matched groups receiving working memory training for 2 weeks: an active group, receiving tDCS (2 mA for 20 min), and a control group, receiving sham stimulation. After the end of the first 2 weeks, both groups will continue the working memory training for three more weeks. Outcome measures will be recorded at timepoints throughout the intervention, including baseline, after the 2 weeks of stimulation, at the end of the working memory training regimen and 1 month after the completion of the training. The aim of the study is to assess if non-invasive tDCS stimulation has an impact on performance and benefits of a working memory training regimen. Specifically, we will examine the impact of brain stimulation on training gains, if changes in gains would last, and whether changes in training performance transfer to other cognitive domains. Furthermore, we will explore whether training improvements impact on everyday life activities and how the home-based training regimen is received by participants, with the view to develop an effective home healthcare tool that could enhance working memory and daily functioning. This study was registered with clinicaltrials.gov: NCT04010149 on July 8, 2019.


Effects of perfluorooctanoic acid (PFOA) exposure to pregnant mice on reproduction.
Perfluorooctanoic acid (PFOA) has similar characteristics to perfluorooctane sulfonate (PFOS) in reproduction toxicity featured by neonatal death. We found that PFOS exposure to mice during pregnancy led to intracranial blood vessel dilatation of fetuses accompanied by severe lung collapse which caused neonatal mortality. Thus, we adopted the corresponding experimental design to PFOS in order to characterize the neonatal death by PFOA. Pregnant ICR mice were given 1, 5 and 10 mg/kg PFOA daily by gavage from gestational day (GD) 0 to 17 and 18 for prenatal and postnatal evaluations, respectively. Five to nine dams per group were sacrificed on GD 18 for prenatal evaluation; other 10 dams were left to give birth. No maternal death was observed. The liver weight increased dose-dependently, with hepatocellular hypertrophy, necrosis, increased mitosis and mild calcification at 10 mg/kg. PFOA at 10 mg/kg increased serum enzyme activities (GGT, ALT, AST and ALP) with hypoproteinemia and hypolipidemia. PFOA treatment reduced the fetal body weight at 5 and 10 mg/kg. Teratological evaluation showed delayed ossification of the sternum and phalanges and delayed eruption of incisors at 10 mg/kg, but did not show intracranial blood vessel dilatation. Postnatal evaluation revealed that PFOA reduced the neonatal survival rate at 5 and 10 mg/kg. At 5 mg/kg pups were born alive and active and 16% died within 4 days observation, while all died within 6 hr after birth at 10 mg/kg without showing intracranial blood vessel dilatation. The cause of neonatal death by PFOA may be different from PFOS.


The role of exercise in migraine treatment.
This review aims to provide a comprehensive overview of the literature on the use of exercise for migraine treatment with regard to its efficacy, mechanism of action and role in practice. Many randomized studies have reported the efficacy of prophylactic treatment of migrane with medications such as beta blockers or antiepileptic drugs. Studies on alternative approaches, like aerobic exercise and biofeedback, are however limited but also considered to be effective. Scientific databases were searched with keywords "exercise" and "migraine". The resulting publications were gathered, examined and discussed throughly. Past studies had limitations and were few in number, but more recent randomized controlled studies have concretely provided level of evidence about the effectiveness of exercise in prophylactic treatment of migraine. Core properties of exercise like intensity, duration, frequency, type and warming up period are required to be monitored while treating migraine to increase the beneficial effects and, also to prevent injuries and side effects which may include exertional headache. Isometric neck exercise is helpful when the migraine is accompanied by neck pain. Patient population with low beta endorphin level in blood, high physical fitness and high motivation receives significant benefits from the exercise treatment. The action of exercise on migraine is in general related to neurochemical factors, psychological states and increase in cardivascular and cerebrovascular fitness. Considering its effectiveness and minimal side effects, migraine patients should often be encouraged to practice physical exercise with intensity, frequency and duration that should be carefully instituted to achieve the most beneficial outcome while preventing potential injuries and side effects.


Growing pains: contemporary knowledge and recommended practice.
Leg pain in children, described as growing pains, is a frequent clinical presentation seen by an array of health care professionals. Described since 1823, growing pains continues to puzzle practitioners, yet diagnostic criteria and evidence based treatment is available. The medical literature has been searched exhaustively to access all articles (English language) pertaining to leg pains in children which are ascribed to being 'growing pains'. The literature, whilst plentiful in quantity and spanning two centuries, is generally replete with reiterated opinion and anecdote and lacking in scientific rigour. The author searched 45 articles for relevance, determined according to title, abstract and full text, resulting in a yield of 22 original studies and 23 review articles. From the original studies, one small (non-blinded) randomised controlled trial that focused on GP treatment with leg muscle stretching was found. Nine prevalence studies were found revealing disparate estimates. Ten cohort (some case-controlled) studies, which investigated pain attribute differences in affected versus unaffected groups, were found. One series of single case experiment designs and one animal model study were found. Growing pains is prevalent in young children, presents frequently in the health care setting where it is poorly managed and is continuing to be researched. A common childhood complaint, growing pains needs to be acknowledged and better managed in the contemporary medical setting.


An Evidence-Based Review of the Efficacy of Perioperative Analgesic Techniques for Breast Cancer-Related Surgery.
To review the published evidence regarding perioperative analgesic techniques for breast cancer-related surgery. Topical review. Randomized, controlled trials (RCTs) were selected for inclusion in the review. Also included were large prospective series providing estimates of potential risks and technical reports and small case series demonstrating a new technique or approaches of interest to clinicians. A total of 514 abstracts were reviewed, with 284 studies meeting criteria for full review. The evidence regarding preemptive ketamine, scheduled opioids, perioperative non-steroidal anti-inflammatory drugs (NSAIDs), and intravenous lidocaine is mixed and deserves further investigation. There is strong evidence that both pregabalin and gabapentin provide analgesic benefits following breast surgery. There is minimal and conflicting data from high-quality randomized, controlled studies suggesting that directly infiltrating and/or infusing local anesthetic (liposome encapsulated or unencapsulated) into the surgical wound is a reliably effective analgesic. In contrast, there is a plethora of data demonstrating the potent analgesia, opioid sparing, and decreased opioid-related side effects from thoracic epidural infusion and both single-injection and continuous paravertebral nerve blocks (the latter two demonstrating decreased persistent post-surgical pain between 2.5 and 12 months). Techniques with limited-yet promising-data deserving additional investigation include brachial plexus blocks, cervical epidural infusion, interfascial plane blocks, and interpleural blocks. While there are currently multiple promising analgesic techniques for surgical procedures of the breast that deserve further study, the only modalities demonstrated to provide potent, consistent perioperative pain control are thoracic epidural infusion and paravertebral nerve blocks.


Archival tags reveal that Arctic charr Salvelinus alpinus and brown trout Salmo trutta can use estuarine and marine waters during winter.
By tagging north-Norwegian anadromous riverine Arctic charr Salvelinus alpinus and brown trout Salmo trutta with simple archival tags that measured ambient water temperature and relating the recordings to the temperature in the surrounding environments, it was demonstrated that 91% of the S. trutta and 80% of the S. alpinus utilized the estuarine and marine environment during the winter. There was large individual variation in migratory behaviour. Salvelinus alpinus on average entered the estuary on 12 January and the marine environment on 26 February, had continuous marine migrations lasting up to 55 days, and spent on average 40 days in the estuary and 25 days in the sea during the winter. The corresponding numbers for S. trutta were 15 December and 4 January for first entry in the estuary and sea, maximum 39 days in the marine environment and average number of days in the estuary and sea were 34 and 50. Most individuals of both species frequently shifted between the three habitats. These findings thus contradict previous studies conducted on lake-dwelling populations, which suggested that northern populations of both species solely overwinter in fresh water. The use of inexpensive temperature recording archival tags gave detailed continuous information on seasonal migrations between habitats with different thermal characteristics.