A naturalistic longitudinal study of the order of service provision with respect to cocaine use and outcomes in an urban homeless sample.
Little is known about outcomes of drug abuse related to attainment of stable housing. This study examined outcomes of cocaine use and service provision in an urban homeless sample. Two-year longitudinal study of systematically selected homeless individuals (N = 255) in St. Louis, Missouri from 1999 to 2001. The sample was interviewed three times annually using a structured diagnostic interview. Urine drug testing was conducted at every interview, and service utilisation data were obtained from the structured interviews and the agency-provided service use data. Cocaine use disorder and cocaine use proved to be distinct concepts because they predicted different outcomes across time. Cocaine use predicted subsequent poor housing outcomes, but stable housing had no apparent effect on subsequent use of cocaine. Service use predicted neither subsequent reduced cocaine use nor attainment of stable housing. Services used were appropriate to type of mental health need, but cocaine use may have reduced successful utilisation of appropriate psychiatric services. These findings reinforce the concept that homelessness represents a complex phenomenon and consequently, service systems need to address multiple problems. Service approaches are needed that simultaneously address the complex needs of homeless individuals.


GABA(B) receptors couple directly to the transcription factor ATF4.
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA), acts at ionotropic (GABA(A) and GABA(C)) and metabotropic (GABA(B)) receptors. Functional GABA(B) receptors are heterodimers of GABA(B(1)) and GABA(B(2)) subunits. Here we show a robust, direct, and specific interaction between the coiled-coil domain present in the C-terminus of the GABA(B(1)) subunit and the transcription factor ATF4 (also known as CREB2). ATF4 and GABA(B(2)) binding to the GABA(B(1)) subunit were mutually exclusive. In rat hippocampal neurons native GABA(B(1)) showed surprisingly little similarity to GABA(B(2)) in its subcellular distribution. GABA(B(1)) and ATF4, however, were highly colocalized throughout the cell and displayed a punctate distribution within the dendrites. Activation of GABA(B) receptors in hippocampal neurons caused a dramatic translocation of ATF4 out of the nucleus into the cytoplasm. These data suggest a novel neuronal signaling pathway that could regulate the functional expression of GABA(B) receptors and/or modulate gene transcription.


New World camelids are sentinels for the presence of Borna disease virus.
Borna disease (BD), a frequently fatal neurologic disorder caused by Borna disease virus 1 (BoDV-1), has been observed for decades in horses, sheep, and other mammals in certain regions of Europe. The bicoloured white-toothed shrew (Crocidura leucodon) was identified as a persistently infected species involved in virus transmission. Recently, BoDV-1 attracted attention as a cause of fatal encephalitis in humans. Here, we report investigations on BoDV-1-infected llamas from a farm in a BD endemic area of Switzerland, and alpacas from holdings in a region of Germany where BD was last seen in the 1960s but not thereafter. All New World camelids showed apathy and abnormal behaviour, necessitating euthanasia. Histologically, severe non-suppurative meningoencephalitis with neuronal Joest-Degen inclusion bodies was observed. BoDV-1 was confirmed by immunohistology, RT-qPCR, and sequencing in selected animals. Analysis of the llama herd over 20 years showed that losses due to clinically suspected BD increased within the last decade. BoDV-1 whole-genome sequences from one Swiss llama and one German alpaca and-for comparison-from one Swiss horse and one German shrew were established. They represent the first published whole-genome sequences of BoDV-1 clusters 1B and 3, respectively. Our analysis suggests that New World camelids may have a role as a sentinel species for BoDV-1 infection, even when symptomatic cases are lacking in other animal species.


Automatic target validation based on neuroscientific literature mining for tractography.
Target identification for tractography studies requires solid anatomical knowledge validated by an extensive literature review across species for each seed structure to be studied. Manual literature review to identify targets for a given seed region is tedious and potentially subjective. Therefore, complementary approaches would be useful. We propose to use text-mining models to automatically suggest potential targets from the neuroscientific literature, full-text articles and abstracts, so that they can be used for anatomical connection studies and more specifically for tractography. We applied text-mining models to three structures: two well-studied structures, since validated deep brain stimulation targets, the internal globus pallidus and the subthalamic nucleus and, the nucleus accumbens, an exploratory target for treating psychiatric disorders. We performed a systematic review of the literature to document the projections of the three selected structures and compared it with the targets proposed by text-mining models, both in rat and primate (including human). We ran probabilistic tractography on the nucleus accumbens and compared the output with the results of the text-mining models and literature review. Overall, text-mining the literature could find three times as many targets as two man-weeks of curation could. The overall efficiency of the text-mining against literature review in our study was 98% recall (at 36% precision), meaning that over all the targets for the three selected seeds, only one target has been missed by text-mining. We demonstrate that connectivity for a structure of interest can be extracted from a very large amount of publications and abstracts. We believe this tool will be useful in helping the neuroscience community to facilitate connectivity studies of particular brain regions. The text mining tools used for the study are part of the HBP Neuroinformatics Platform, publicly available at http://connectivity-brainer.rhcloud.com/.


Metallo-organic G-quadruplex ligands in anticancer drug design.
Guanine-rich DNA sequences can form planar four-stranded structures via Hoogsteen hydrogen bonds. These sequences in telomeric DNA and some oncogenes have been identified as targets for novel anticancer drugs. Consequently, there is great current interest in developing small molecules that can facilitate the formation of, and stabilize G-quadruplexes as potent antitumor chemotherapeutic agents. Metal complexes with planar geometries and phi-delocalised ligands are emerging as a new class of quadruplex DNA ligand with unique features for optimal binding. This review will summarize the different types of metal-based compounds that target G-quadruplexes and provide useful information on the design of small ligands.


Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after stroke.
Botulinum toxin is effective in reducing spasticity post stroke. As there are limited data on post stroke spasticity in Asia, we undertake this study to determine the effectiveness and safety of intramuscular injection of botulinum toxin type-A (BTX-A), in the treatment of chronic focal post-stroke hand spasticity, and the impact of BTX-A on the activities of daily living and quality of life, in comparison to placebo, in Malaysian stroke patients. This was a randomized, double-blind, placebo-controlled study to assess the efficacy and safety of BTX-A in 27 subjects with wrist and finger spasticity after a stroke. The outcome measures were assessed with the Modified Ashworth Scale (MAS) to assess spasticity of the flexor muscles, Barthel Index (BI) for activities of daily living and EQ-5D and EQ VAS for quality of life. Assessments were performed at baseline and 1 and 3 months after injection. Compared to placebo, the BTX-A group had greater improvement in the flexor tone of the wrist and fingers (p = 0.001 and p < 0.001, respectively), at first month follow-up visit and sustained the improvement through to three months. Although there was an improvement in the measures of global function and quality of life in the BTX-A group, there was no significant improvement in between the two groups. No serious BTX-A related adverse effects were reported. The results of this study demonstrate that intramuscular injection of botulinum toxin A is safe and effective in the treatment of chronic focal post-stroke spasticity of the hand.


Stage at diagnosis and cancer survival for Indigenous Australians in the Northern Territory.
To investigate whether Indigenous Australians with cancer have more advanced disease at diagnosis than other Australians, and whether late diagnosis explains lower Indigenous cancer survival rates. Retrospective cohort study. Indigenous and non-Indigenous people diagnosed with cancers of the colon and rectum, lung, breast or cervix and non-Hodgkin lymphoma in the Northern Territory of Australia in 1991-2000. SEER summary stage of cancer at diagnosis (local, regional or distant spread), cause-specific cancer survival rates and relative risk of cancer death. Diagnosis with advanced disease (regional or distant spread) was more common for Indigenous people (70%; 95% CI, 62%-78%) than for non-Indigenous people (51%; 95% CI, 53%-59%) with cancers of the colon and rectum, breast, cervix and non-Hodgkin lymphoma, but for lung cancer the opposite was found (Indigenous, 56% [95% CI, 46%-65%] v non-Indigenous, 69% [95% CI, 64%-75%]). Stage-adjusted survival rates were lower for Indigenous people for each cancer site. With few exceptions, the relative risk of cancer death was higher for Indigenous people for each category of stage at diagnosis for each cancer site. Health services apparently could, and should, be performing better for Indigenous people with cancer in the Northern Territory, and probably elsewhere in Australia. This study has demonstrated that data from cancer registers, enhanced with data on stage at diagnosis, can be used to monitor health service performance for Indigenous Australians in the Northern Territory; similar data is available in other States, and could be used to monitor health service performance for Indigenous people throughout Australia.


[Methodological approach to the study of gynecologic diseases among children and adolescents].
Guidelines for the assessment of gynecologic morbidity in children and adolescents have been developed by the authors. A methodology of elucidation of gynecologic morbidity in children and adolescents was obtained and a classification of gynecologic diseases suggested. Efficiency of current therapy in childhood and adolescence as a determinant of reproductive health in womanhood is shown.


Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy.
To evaluate the efficacy and safety of alpha-lipoic acid given intravenously, followed by oral treatment in type 2 diabetic patients with symptomatic polyneuropathy. In a multicenter randomized double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN] III Study), 509 outpatients were randomly assigned to sequential treatment with 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by 600 mg alpha-lipoic acid three times a day orally for 6 months (A-A; n = 167); 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (A-P; n = 174); and placebo once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (P-P; n = 168). Outcome measures included the Total Symptom Score (TSS) for neuropathic symptoms (pain, burning, paresthesias, and numbness) in the feet, and the Neuropathy Impairment Score (NIS). Data analysis was based on the intention to treat. No significant differences between the groups were noted for the demographic variables and the nerve function parameters at baseline. The TSS in the feet decreased from baseline to day 19 (median [range]) by -3.7 (-12.6 to 5.0) points in the group given alpha-lipoic acid intravenously and by -3.0 (-12.3 to 8.0) points in the placebo group (P = 0.447), but the area under curve on a daily basis was significantly smaller in the active as compared with the placebo group (85.6 [0-219] vs. 95.9 [5.5-220]); P = 0.033). After 7 months, the changes in the TSS from baseline were not significantly different between the three groups studied, which could be due to increasing intercenter variability in the TSS during the trial. The NIS decreased after 19 days by -4.34+/-0.35 points (mean +/- SEM) in A-A and A-P and -3.49+/-0.58 points in P-P (P = 0.02 for alpha-lipoic acid versus placebo) and after 7 months by -5.82+/-0.73 points in A-A, -5.76+/-0.69 points in A-P, and -4.37+/-0.83 points in P-P (P = 0.09 for A-A vs. P-P). The rates of adverse events were not different between the groups throughout the study. These findings indicate that a 3-week intravenous treatment with alpha-lipoic acid, followed by a 6-month oral treatment, had no effect on neuropathic symptoms distinguishable from placebo to a clinically meaningful degree, possibly due to increasing intercenter variability in symptom scoring during the study. However, this treatment was associated with a favorable effect on neuropathic deficits without causing significant adverse reactions. Long-term trials that focus on neuropathic deficits rather than symptoms as the primary criterion of efficacy are needed to see whether oral treatment with alpha-lipoic acid over several years may slow or reverse the progression of diabetic neuropathy.


Racial/Ethnic Disparities in Maternal Vaccine Knowledge, Attitudes, and Intentions.
Although disparities in maternal vaccine acceptance among racial/ethnic groups are well documented, the reasons for these disparities are unclear. The objective of this study was to describe differences in pregnant women's knowledge, attitudes, beliefs, intentions, and trust regarding maternal and infant vaccines by race/ethnicity. We collected survey data from 1862 pregnant women from diverse prenatal care practices in Georgia and Colorado from June 2017 through July 2018. We performed multiple logistic regressions to determine differences in intentions, knowledge, attitudes, beliefs, and trust by race/ethnicity and calculated odds ratios (ORs) and 95% CIs. Compared with White women, Black and Hispanic women were less confident in vaccine safety and efficacy and less likely to perceive risk of acquiring vaccine-preventable diseases, report provaccine social norms, indicate having enough vaccine knowledge, and trust vaccine information from health care providers and public health authorities. Black women were the least confident in the safety of the maternal influenza vaccine (OR = 0.37; 95% CI, 0.27-0.49); maternal tetanus, diphtheria, and acellular pertussis vaccine (OR = 0.37; 95% CI, 0.27-0.52); and infant vaccines overall (OR = 0.40; 95% CI, 0.28-0.58), and were least likely to intend to receive both maternal vaccines (OR = 0.35; 95% CI, 0.27-0.47) or all infant vaccines on time (OR = 0.45; 95% CI, 0.34-0.61) as compared with White women. Understanding differences in behavioral constructs integral to vaccine decision making among women of different races/ethnicities can lead to tailored interventions to improve vaccine acceptance.


Improving chemical synthesis using flow reactors.
Owing to the competitive nature of the pharmaceutical industry, researchers involved in lead compound generation are under continued pressure to identify and develop promising programmes of research in order to secure intellectual property. The potential of a compound for therapeutic development depends not only on structural complexity, but also on the identification of synthetic strategies that will enable the compound to be prepared on the desired scale. One approach that is of present interest to the pharmaceutical industry is the use of continuous flow reactors, with the flexible nature of the technology being particularly attractive as it bridges the changes in scale required between the initial identification of a target compound and its subsequent production. Based on these factors, a significant programme of research is presently underway into the development of flow reactors as tools for the synthetic chemist, with the transfer of many classes of reaction successfully reported to date. This article focuses on the application of continuous flow methodology to drug discovery and the subsequent production of pharmaceuticals.


Dissolution of cellulose [correction of cellose] with ionic liquids.
We report here initial results that demonstrate that cellulose can be dissolved without activation or pretreatment in, and regenerated from, 1-butyl-3-methylimidazolium chloride and other hydrophilic ionic liquids. This may enable the application of ionic liquids as alternatives to environmentally undesirable solvents currently used for dissolution of this important bioresource.


Impact of Cross-Tie Properties on the Modal Behavior of Cable Networks on Cable-Stayed Bridges.
Dynamic behaviour of cable networks is highly dependent on the installation location, stiffness, and damping of cross-ties. Thus, these are the important design parameters for a cable network. While the effects of the former two on the network response have been investigated to some extent in the past, the impact of cross-tie damping has rarely been addressed. To comprehend our knowledge of mechanics associated with cable networks, in the current study, an analytical model of a cable network will be proposed by taking into account both cross-tie stiffness and damping. In addition, the damping property of main cables in the network will also be considered in the formulation. This would allow exploring not only the effectiveness of a cross-tie design on enhancing the in-plane stiffness of a constituted cable network, but also its energy dissipation capacity. The proposed analytical model will be applied to networks with different configurations. The influence of cross-tie stiffness and damping on the modal response of various types of networks will be investigated by using the corresponding undamped rigid cross-tie network as a reference base. Results will provide valuable information on the selection of cross-tie properties to achieve more effective cable vibration control.


Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.
The benefit of intravenous thrombolytic therapy in elderly patients with myocardial infarction is uncertain. There are no randomized trials of thrombolytic efficacy or observational studies of clinical effectiveness that focus specifically on the elderly. To determine whether thrombolytic therapy for elderly patients is associated with a survival advantage in a large observational database, we conducted a retrospective cohort study of 7864 Medicare fee-for-service patients aged 65 to 86 years with the primary discharge diagnosis of acute myocardial infarction who were admitted with clinical and ECG indications for thrombolytic therapy and no absolute contraindications. The study included all US acute care nongovernment hospitals without on-site angioplasty capability. Using proportional-hazards methods, we found that in a comprehensive multivariate model, there was a significant interaction (P<0.001) between age and the effect of thrombolytic therapy on 30-day mortality rates. For patients 65 to 75 years old, thrombolytic therapy was associated with a survival benefit, consistent with randomized trials. Among patients aged 76 to 86 years, thrombolytic therapy was associated with a survival disadvantage, with a 30-day mortality hazard ratio of 1.38 (95% CI 1. 12 to 1.71, P=0.003). For these patients, there was no benefit from thrombolytic therapy in any clinical subgroup. In nationwide clinical practice, thrombolytic therapy for patients >75 years old is unlikely to confer survival benefit and may have a significant survival disadvantage. Reperfusion research that is focused on elderly patients is urgently needed.


Epidemiology 1, 2, 3: origins, objectives, organization, and implementation.
This supplement is a report on the Epidemiology 1, 2, 3 (EPI 1, 2, 3) investigation, its origins, evolution, and findings that were carried out over a period beginning in 1990 and ending in 1994 in Egypt. The large scope and size of the study, the largest to date on schistosomiasis in Egypt, was a rationale for publishing a supplement to document EPI 1, 2, 3 methods and results collectively in sufficient detail to serve as a reference for planning, designing, and analyzing future epidemiologic studies and evaluation of schistosomiasis control in Egypt. The 3 objectives of EPI 1, 2, 3 were to 1) determine the changing patterns of Schistosoma haematobium and S. mansoni, 2) investigate factors contributing to differences between villages in the Nile Delta, Middle Egypt, and Upper Egypt, and 3) investigate risk factors for morbidity. The objectives were addressed using standardized techniques, stool and urine examinations, clinical examinations (including abdominal ultrasound), and questionnaires on a selected sample of the populations of selected villages in 9 governorates in Egypt.


[Occupational medical counseling in rehabilitation].
The present contribution seeks to outline the counselling possibilities on the part of the industrial medical service. Starting out from the legal bases (the Act concerning safety at work), the scope for action available internally and externally is examined. Towards the background of the assertion (which is in agreement with numerous other authors) that rehabilitation invariably means teamwork, the author seeks to describe the internally competent authorities and departments in terms of internal team, and to contrast it with the external team involved. A number of opportunities for cooperation are outlined, and already implemented practical approaches are pointed out. The company services are viewed in a community based rehabilitation context, and the relationships with the financially responsible administrations and their facilities in respect of vocational and medical rehabilitation are set out. Systematic in-plant procedures are explained by a conceptual model, practical implementations (for ex. in the EAM system) are touched on.


Bacterial adherence to respiratory tract cells. Relationships between in vivo and in vitro pH and bacterial attachment.
Alterations in in vitro pH have been shown to have a significant effect on the bacterial binding capacity of epithelial cells for certain organisms. We investigated the effect of in vivo pH and in vitro changes in pH on the adherence of Pseudomonas aeruginosa to buccal and tracheal cells of 19 chronic tracheostomy patients. In addition, airway pH was measured in 5 normal volunteers. Oropharyngeal and endobronchial pH were measured with a flexible electrode that could be passed through a bronchoscope under direct visualization. In vitro adherence of Pseudomonas to respiratory epithelial cells was determined at pH 6.5 and 7.2. Colonization status of the patients was determined by culture of oropharyngeal and tracheal secretions. The pH value of each site in the respiratory tract and its secretions were different in the tracheostomy patients (buccal pH 6.3; tracheal, 6.9; sputum, 7.5). No difference was noted in pH of the 2 sites in control subjects (buccal, 6.7; tracheal, 6.7). Changes in in vitro pH had a significant effect (p less than 0.004) on bacterial binding to epithelial cells from both sites. The pH had its greatest effect on tracheal cells of patients colonized with Pseudomonas. Increased in vitro binding of these organisms was noted at the more alkaline pH. The magnitude of the effect of in vitro pH alteration on bacterial binding correlated directly with the degree of binding. These results demonstrated that pH has a significant effect on in vitro Pseudomonas adherence and the effect is most marked on cells obtained from the lower respiratory tract of patients colonized with this organism.(ABSTRACT TRUNCATED AT 250 WORDS)


Daily precipitation performances of regression-based statistical downscaling models in a basin with mountain and semi-arid climates.
The impacts of climate change on current and future water resources are important to study local scale. This study aims to investigate the prediction performances of daily precipitation using five regression-based statistical downscaling models (RBSDMs), for the first time, and the ERA-5 reanalysis dataset in the Susurluk Basin with mountain and semi-arid climates for 1979-2018. In addition, comparisons were also performed with an artificial neural network (ANN). Before achieving the aim, the effects of atmospheric variables, grid resolution, and long-distance grid on precipitation prediction were holistically investigated for the first time. Kling-Gupta efficiency was modified and used for holistic evaluation of statistical moments parameters at precipitation prediction comparison. The standard triangular diagram, quite new in the literature, was also modified and used for graphical evaluation. The results of the study revealed that near grids were more effective on precipitation than single or far grids, and 1.50° × 1.50° resolution showed similar performance to 0.25° × 0.25° resolution. When the polynomial multivariate adaptive regression splines model, which performed slightly higher than ANN, tended to capture skewness and standard deviation values of precipitations and to hit wet/dry occurrence than the other models, all models were quite well able to predict the mean value of precipitations. Therefore, RBSDMs can be used in different basins instead of black-box models. RBSDMs can also be established for mean precipitation values without dry/wet classification in the basin. A certain success was observed in the models; however, it was justified that bias correction was required to capture extreme values in the basin. The online version contains supplementary material available at 10.1007/s00477-022-02345-5.


Gender-differences in predictors for time to metabolic syndrome resolution: A secondary analysis of a randomized controlled trial study.
Understanding gender differences in health-related behaviors and their impacts is a crucial aspect of effective primary care. We studied gender-based differences in predictors of metabolic syndrome (MetS) resolution among newly diagnosed MetS patients. This study was a secondary analysis of a prospective clinical trial study comprising of 637 middle-aged and older adults (226 men and 411 women) who underwent a regular health checkup and were newly diagnosed with MetS at 16 different health clinics of 14 metropolitan cities and provinces. We conducted Cox proportional hazard analysis to estimate cumulative probability of MetS resolution within a 12-month observation period. Among the 637 patients, 47.6% of participants achieved MetS resolution. The resolution rate was similar among men and women (44.7% and 49.1%, respectively, P = 0.320). Low household income (Hazard ratio = 2.62, 95% confidence interval: 1.13-6.08) and current employment (2.29, 1.26-4.13) were associated with a higher cumulative probability of MetS resolution in men than in women. For women, however, longer sleeping hours (1.18, 1.04-1.34) and living with a partner (1.58, 1.06-2.35) were positive predictors of MetS resolution. Being overweight (0.63, 0.44-0.89) was associated with lower cumulative probability of MetS resolution in women than in men. The factors associated with cumulative probability of MetS resolution within the 12-month follow-up were different between men and women. These findings facilitate further exploration on gender-based differences in risk factors for less optimal improvements in MetS.


[Endometriosis of the efferent urinary pathways].
Two cases of ureteral endometriosis and 1 case of vesical endometriosis are reported and a short review of the literature is presented. The diagnostic problems, despite modern image procedures, and therapeutic modalities are discussed.


Results of prosthetic grafts in femoro-crural bypass operations as compared to autogenous saphenous vein grafts.
Since 1971 175 femoro-crural bypasses were performed. Rest pain and gangrene were present in 90% of the cases; 28% had undergone previous surgery for ischemia of the same limb. The autogenous saphenous vein was the first choice and could be used in 81% of cases. Prosthetic material consisted consecutively of the regular PTFE (N = 12), the Dardik biograft (N = 13) and the thin-walled reinforced PTFE (N = 7). One dacron prosthesis was used. The two-year patency (Life-table) for the prostheses was 18%. Results of the composite grafts were as poor as those of complete prosthetic grafts. Saphenous vein grafts had a two-year patency of 70% and a five-year patency of 59%. Veno-venous anastomoses had no adverse influence on patency. Exploration of both legs for acceptable parts of the saphenous vein is indicated before the use of prosthetic material is justified.


Traditional Indian spices and their health significance.
India has been recognized all over the world for spices and medicinal plants. Both exhibit a wide range of physiological and pharmacological properties. Current biomedical efforts are focused on their scientific merits, to provide science-based evidence for the traditional uses and to develop either functional foods or nutraceuticals. The Indian traditional medical systems use turmeric for wound healing, rheumatic disorders, gastrointestinal symptoms, deworming, rhinitis and as a cosmetic. Studies in India have explored its anti-inflammatory, cholekinetic and anti-oxidant potentials with the recent investigations focusing on its preventive effect on precarcinogenic, anti-inflammatory and anti atherosclerotic effects in biological systems both under in vitro and in vivo conditions in animals and humans. Both turmeric and curcumin were found to increase detoxifying enzymes, prevent DNA damage, improve DNA repair, decrease mutations and tumour formation and exhibit antioxidative potential in animals. Limited clinical studies suggest that turmeric can significantly impact excretion of mutagens in urine in smokers and regress precancerous palatal lesions. It reduces DNA adducts and micronuclei in oral epithelial cells. It prevents formation of nitroso compounds both in vivo and in vitro. It delays induced cataract in diabetes and reduces hyperlipidemia in obese rats. Recently several molecular targets have been identified for therapeutic / preventive effects of turmeric. Fenugreek seeds, a rich source of soluble fiber used in Indian cuisine reduces blood glucose and lipids and can be used as a food adjuvant in diabetes. Similarly garlic, onions, and ginger have been found to modulate favourably the process of carcinogenesis.


Alternatives to the journal impact factor: I3 and the top-10% (or top-25%?) of the most-highly cited papers.
Journal impact factors (IFs) can be considered historically as the first attempt to normalize citation distributions by using averages over 2 years. However, it has been recognized that citation distributions vary among fields of science and that one needs to normalize for this. Furthermore, the mean-or any central-tendency statistics-is not a good representation of the citation distribution because these distributions are skewed. Important steps have been taken to solve these two problems during the last few years. First, one can normalize at the article level using the citing audience as the reference set. Second, one can use non-parametric statistics for testing the significance of differences among ratings. A proportion of most-highly cited papers (the top-10% or top-quartile) on the basis of fractional counting of the citations may provide an alternative to the current IF. This indicator is intuitively simple, allows for statistical testing, and accords with the state of the art.


Physiological fictions and the fin-de-siècle female brain.
An important area of French medical research in the first half of the nineteenth-century was the supposedly anomalous, sensation-based functioning of the female brain (Drs. Voisin, Virey, Brachet, Briquet). This paper explores the late-century resurgence of such theory around the question of whether women could support an intense advanced education. It examines the conflicted attitudes of four females, the novelists Rachilde, Georges de Peyrebrune and Daniel Lesuer, and a medical doctor, Georgette Déga, as they tried to resist or rationalize the dogma that saw the female as a mentally diminished male. The juxtaposition of medical and fictional texts demonstrates that the so-called "automatic" functioning of the female brain led to her being embodied, in the male mind, as a symbol of the dreaded unconscious.


An isocaloric glucose-fructose beverage's effect on simulated 100-km cycling performance compared with a glucose-only beverage.
A number of recent research studies have demonstrated that providing glucose and fructose together in a beverage consumed during exercise results in significantly higher oxidation rates of exogenous carbohydrate (CHO) than consuming glucose alone. However, there is insufficient evidence to determine whether the increased exogenous CHO oxidation improves endurance performance. The purpose of this study was to determine whether consuming a beverage containing glucose and fructose (GF) would result in improved cycling performance compared with an isocaloric glucose-only beverage (G). Nine male competitive cyclists (32.6 +/- 5.8 years, peak oxygen uptake 61.5 +/- 7.9 ml x kg(-1) x min(-1)) completed a familiarization trial and then 2 simulated 100-km cycling time trials on an electronically braked Lode cycle ergometer separated by 5-7 d. During the randomly ordered experimental trials, participants received 36 g of CHO of either G or GF in 250 ml of water every 15 min. All 9 participants completed the 100-km time trial significantly faster when they received the GF beverage than with G (204.0 +/- 23.7 vs. 220.6 +/- 36.6 min; p = .023). There was no difference at any time point between trials for blood glucose or for blood lactate. Total CHO oxidation increased significantly from rest during exercise but was not statistically significant between the GF and G trials, although there was a trend for CHO oxidation to be higher with GF in the latter stages of the time trial. Consumption of a CHO beverage containing glucose and fructose results in improved 100-km cycling performance compared with an isocaloric glucose-only beverage.


The Microbiome and Protein Carbamylation: Potential Targets for Protein-Restricted Diets Supplemented with Ketoanalogues in Predialysis Chronic Kidney Disease.
In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation.


Saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro.
We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro. Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained from several pharmaceutical companies. They were tested for their ability to inhibit [3H]tamsulosin binding to human prostatic alpha1-adrenoceptors and [3H]prazosin binding to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition of phenylephrine-stimulated [3H]inositol phosphate formation by cloned receptors was also investigated. Up to the highest concentration which could be tested, preparations of beta-sitosterol, stinging nettle, and medicinal pumpkin were without consistent inhibitory effect in all assays. In contrast, all tested saw palmetto extracts inhibited radioligand binding to human alpha1-adrenoceptors and agonist-induced [3H]inositol phosphate formation. Saturation binding experiments in the presence of a single saw palmetto extract concentration indicated a noncompetitive antagonism. The relationship between active concentrations in vitro and recommended therapeutic doses for the saw palmetto extracts was slightly lower than that for several chemically defined alpha1-adrenoceptor antagonists. Saw palmetto extracts have alpha1-adrenoceptor-inhibitory properties. If bioavailability and other pharmacokinetic properties of these ingredients are similar to those of the chemically defined alpha1-adrenoceptor antagonists, alpha1-adrenoceptor antagonism might be involved in the therapeutic effects of these extracts in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.


Association between moderate-to-severe diarrhea in young children in the global enteric multicenter study (GEMS) and types of handwashing materials used by caretakers in Mirzapur, Bangladesh.
Handwashing practices among caretakers of case and control children < 5 years of age enrolled in the Global Enteric Multicenter Study in Mirzapur, Bangladesh were characterized and analyzed for association with moderate-to-severe diarrhea. Soap or detergent ownership was common, yet 48% of case and 47.7% of control caretakers also kept ashes for handwashing, including 36.8% of the wealthiest households. Soap, detergent, and ash were used for multiple hygiene purposes and were kept together at handwashing areas. Caretakers preferred soap for handwashing, but frequently relied on ash, or a detergent/ash mixture, as a low-cost alternative. Moderate-to-severe diarrhea was equally likely for children of caretakers who kept soap versus those who kept ash (matched OR = 0.91; 0.62-1.32). Contact with ash and water reduced concentrations of bacterial enteropathogens, without mechanical scrubbing. Thus, washing hands with ash is a prevalent behavior in Mirzapur and may help diminish transmission of diarrheal pathogens to children.


General practitioners prefer prescribing indicators based on detailed information on individual patients: a Delphi study.
To assess the face validity of both simple and advanced quality indicators for prescribing in general practice. In a three-round Delphi study, 100 randomly selected general practitioners (GPs) in Denmark rated 18 indicators for prescribing of non-steroidal anti-inflammatory drugs. All indicators were based on prescription register data and focused on different prescribing aspects. Advanced indicators contained information at the patient level, viz. age, sex and history of drug use, while simple indicators only used drug statistics at practice level. Indicators were rated on a nine-point Likert scale. Consensus among GPs was defined as interquartile ranges of three or less. A median rating of 7-9 was interpreted as face validity and a median rating of 1-3 as no face validity. Participation in the study was accepted by 44 GPs and 37 completed all three rounds. Three indicators based on patient level data and focusing on adverse effects were assessed to have face value. One indicator focusing on costs and based on practice level data was considered unsuitable for evaluating the quality of prescribing. Consensus was not reached for the remaining indicators. GPs do not regard simple indicators based on aggregated data at practice level as suitable for evaluating the prescribing quality in general practice, but prefer indicators that rest on clinical data at the patient level.


Ticks (Acari: Ixodidae) infesting camels (Camelus dromedarius) in Northern Sudan.
Monthly total body tick collections from 13-20 camels were conducted for 2 consecutive years (2000-2001) in Northern Sudan. Tick populations were correlated with locality, season, predeliction site, sex and coat colour. Hyalomma dromedarii was found to be the predominant (89%) tick species infesting the camels. Other tick species found in very low numbers were Hyalomma impeltatum (7.7%), Hyalomma anatolicum anatolicum (3.3%), Hyalomma truncatum (0.29%), Hyalomma marginatum rufipes (0.25%), Rhipicephalus praetextatus (0.30%) and Rhipicephalus sanguineus group (0.09%). Nymphs of the genus Hyalomma were collected in significant numbers. Adult ticks significantly preferred to attach to the lower parts of the camel's body for feeding while the nymphs preferred the back of the animal. Female camels harboured more ticks than males while higher infestations were recorded on camels with a grey coat colour compared to those with a brown coat colour. Ticks were found on camels throughout the year and increased in numbers during March to October with a peak in September.


[Meeting of calory and protein requirements in developing countries].
While we have definite ideas regarding the requirements for energy and proteins, we have to rely on statistical data whether these requirements are actually met. In spite of the common unreliability of these data, they serve as an useful indicator of the general situation. The supply of nutritional energy represents the average energy requirement for the populations of most developing countries. However, the insufficient supply of high grade protein remains the main nutritional problem of most of these countries. To solve these problems, the following possibilities exist: --Ensuring a sufficient calorie supply so that valuable protein is not wasted for the production of energy --Improving the supply of protein-rich staple food --Supplementing of food with local protien-rich products --Introducing lifestock only when the foodstuff available cannot be used directly for human consumption -- Improving the staple food, introducing higher grade strains of cereals --Producing protein-rich vegetable mixture from local foodstuff --Utilization of synthetic amino acids and of new protein sources. To meet the requirements for calories, and especially for hgih grade protein, is possible only by international and interdisciplinary efforts of all experts concerned with nutrition in any way.


Phantoms of Gondwana?-phylogeny of the spider subfamily Mynogleninae (Araneae: Linyphiidae).
This is the first genus-level phylogeny of the subfamily Mynogleninae. It is based on 190 morphological characters scored for 44 taxa: 37 mynoglenine taxa (ingroup) representing 15 of the 17 known genera and seven outgroup taxa representing the subfamilies Stemonyphantinae, Linyphiinae (Linyphiini and Micronetini), and Erigoninae, and a representative of the family Pimoidae, the sister-group to Linyphiidae. No fewer than 147 of the morphological characters used in this study are new and defined for this study, and come mainly from male and female genitalia. Parsimony analysis with equal weights resulted in three most parsimonious trees of length 871. The monophyly of the subfamily Mynogleninae and the genera Novafroneta, Parafroneta, Laminafroneta, Afroneta, Promynoglenes, Metamynoglenes, and Haplinis are supported, whereas Pseudafroneta is paraphyletic. The remaining seven mynoglenine genera are either monotypic or represented by only one taxon. Diagnoses are given for all genera included in the analysis. The evolution of morphological traits is discussed and we summarize the diversity and distribution patterns of the 124 known species of mynoglenines. The preferred topology suggests a single origin of mynoglenines in New Zealand with two dispersal events to Africa, and does not support Gondwana origin.


Interobserver variation in the diagnosis of bronchiectasis on high-resolution computed tomography.
The purpose of our study was to determine interobserver variation in the analysis of high-resolution computed tomography (HRCT) in the lungs of patients with clinically suspected bronchiectasis. HRCT scans of 88 patients were analysed independently by three radiologists with variable experience in thoracic radiology using a subjective scoring system to record bronchi as normal, mildly abnormal or severely abnormal. The presence, severity and distribution of bronchial dilatation and bronchial wall thickening were recorded. Kappa values were calculated for assessment of interobserver agreement. Agreement between the three readers was good for the detection of bronchiectasis (kappa 0.78) and assessment of its severity (0.68), detection of bronchial wall thickening (0.64) and moderately good for the assessment of its severity (0.58) on a per-patient basis. When individual lobes were analysed, agreement was moderately good for the detection of abnormal bronchi (0.59). Agreement on the extent of abnormal bronchi using five categories was only fair (0.39), but was good when differences of one category were ignored (0.63). Interobserver variation with HRCT in suspected bronchiectasis appears satisfactory for comparative studies.


Effect of de-industrialisation on working conditions and self reported health in a sample of manufacturing workers.
To explore the impact of de-industrialisation over a 20 year period on working conditions and health among sawmill workers, in the province of British Columbia (BC), Canada. This investigation is based on a sample of 3000 sawmill workers employed in 1979 (a year before the beginning de-industrialisation) and interviewed in 1998. The sample was obtained by random selection from an already gathered cohort of approximately 28 000 BC sawmill workers. Change in working conditions from 1979 to 1998 are described. Self reported health status, in 1998, was used as a dependent variable in logistic regression after controlling for confounders. Downsizing in BC sawmills eliminated 60% of workers between 1979 and 1998. Working conditions in 1998 were better for those who left the sawmill industry and obtained re-employment elsewhere. Workers who remained employed in restructuring sawmills were approximately 50% more likely to report poor health than those re-employed elsewhere. Working conditions and health status were better for workers who, under pressure of de-industrialisation, left the sawmill industry and obtained re-employment outside this sector.


Lifestyle therapy changes and hypercholesterolemia: identifying risk groups in a community sample of Blacks and Whites.
To examine diet and exercise lifestyle therapy change (LTC), behaviors and their relation to hypercholesterolemia in a community sample of Blacks and Whites. Latent class analysis (LCA) was employed to identify homogeneous subgroups of community dwelling Blacks and Whites related to LTC for hypercholesterolemia. LCA is a statistical technique used to identify subgroups of individuals who share a similar pattern of responses to a set of observations. The relation between hypercholesterolemia and latent class membership was assessed. Adults age 18 and over who participated in a county-level adaptation of the Behavioral Risk Factor Surveillance System. Hypercholesterolemia (absence or presence). Eleven unique latent classes of LTC behavior emerged from LCA models. Exercisers and Fat Reducers represented between 19% and 29% of each race-sex group. Latent class membership probabilities varied substantially across race and sex. Only Black women had a class of Contemplators (21.5%). Overall, men and Blacks with self reported hypercholesterolemia were more likely to engage only in fat reduction but not increase in vegetable consumption, reduction of fat or regular exercise (odds ratios range from 1.8-3.5). The distribution of diet and exercise related LTC behaviors in relation to self-reported hypercholesterolemia can help to identify, understand and tailor culturally and sex specific interventions based on the proportions of men and women in different latent classes.


MLPAnalyzer: data analysis tool for reliable automated normalization of MLPA fragment data.
Multiplex Ligation dependent Probe Amplification (MLPA) is a rapid, simple, reliable and customized method for detection of copy number changes of individual genes at a high resolution and allows for high throughput analysis. This technique is typically applied for studying specific genes in large sample series. The large amount of data, dissimilarities in PCR efficiency among the different probe amplification products, and sample-to-sample variation pose a challenge to data analysis and interpretation. We therefore set out to develop an MLPA data analysis strategy and tool that is simple to use, while still taking into account the above-mentioned sources of variation. MLPAnalyzer was developed in Visual Basic for Applications, and can accept a large number of file formats directly from capillary sequence systems. Sizes of all MLPA probe signals are determined and filtered, quality control steps are performed, and variation in peak intensity related to size is corrected for. DNA copy number ratios of test samples are computed, displayed in a table view and a set of comprehensive figures is generated. To validate this approach, MLPA reactions were performed using a dedicated MLPA mix on 6 different colorectal cancer cell lines. The generated data were normalized using our program and results were compared to previously performed array-CGH results using both statistical methods and visual examination. Visual examination of bar graphs and direct ratios for both techniques showed very similar results, while the average Pearson moment correlation over all MLPA probes was found to be 0.42. Our results thus show that automated MLPA data processing following our suggested strategy may be of significant use, especially when handling large MLPA data sets, when samples are of different quality, or interpretation of MLPA electropherograms is too complex. It remains, however, important to recognize that automated MLPA data processing may only be successful when a dedicated experimental setup is also considered.


Exercise Therapy in Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis.
To conduct a systematic review to evaluate the efficacy of exercise interventions in improving outcomes across domains of functioning and disability in children and adolescents with juvenile idiopathic arthritis (JIA). Seven electronic databases were systematically searched up to November 16, 2016. Original data, analytic prospective design, physical therapy-led exercise intervention evaluation, children and adolescents with JIA, and assessment of functional, structural, activity, participation, or quality of life outcomes. Two authors screened search results, and discrepancies were resolved by consensus. Of 5037 potentially relevant studies, 9 randomized controlled trials and 1 cohort study were included and scored. Study quality (Downs and Black quality assessment tool) and level of evidence (Oxford Centre of Evidence-Based Medicine model) were assessed and meta-analysis conducted where appropriate. Alternatively, a descriptive summary approach was chosen. All randomized controlled trials were moderate-quality intervention studies (level 2b evidence; median Downs and Black score, 20 out of 32; range, 15-27). Interventions included aquatic, strengthening, proprioceptive, aerobic, and Pilates exercises. Pediatric activity capacity (Child Health Assessment Questionnaire) improved with exercise (mean difference, .45; 95% confidence interval, .05-.76). Furthermore, descriptive summaries indicated improved activity capacity, body function and structure (pain and muscle strength), and quality of life outcomes. Exercise therapy appears to be well tolerated and beneficial across clinically relevant outcomes in patients with JIA. The paucity of high-quality evidence and study heterogeneity limited the ability to provide conclusive, generalizing evidence for the efficacy of exercise therapy and to provide specific recommendations for clinical practice at this time. Future research evaluating exercise program implementation using validated outcomes and detailed adherence and safety assessment is needed to optimize clinical decision pathways in patients with JIA.


Managing Boundaries: The Role of Non-Profit Organisations in Russia's Managed Democracy.
This article examines Russian human service non-profit organisations (NPOs) to investigate the nature of civil society in a managed democracy. Specifically the focus is on emerging vertical ties between NPOs and ruling and governing elites. Drawing on qualitative data collected from health and education NPOs in three industrial regions, we find that in establishing such vertical ties the role of organisations and individuals within is changing - they have moved away from ignored outsiders towards accessing the circles of power and being tasked with managing the boundary between the state and civil society. In exploring these arrangements this article highlights that in the post-Soviet space, NPOs and the state are closely intertwined resembling co-optation. As a result the democratisation potential of human service NPOs is constrained. In discussing these insights we also draw parallels to contexts in which the state has outsourced welfare service to human service NPOs.


Two types of potassium channels in murine T lymphocytes.
The properties of two types of K+ channels in murine T lymphocytes are described on the basis of whole-cell and isolated-patch recordings using the gigohm-seal technique. Type l (standing for "lpr gene locus" or "large") channels were characterized mainly in T cells from mutant MRL/MpJ-lpr/lpr mice, in which they are present in large numbers. Type n ("normal") K+ channels are abundant and therefore most readily studied in concanavalin A-activated T cells from four strains of mice, MRL-+/+, CBA/J, C57BL/6J, and BALB/c. Type l channels, compared with type n, are activated at potentials approximately 30 mV more positive, and close much more rapidly upon repolarization. Type l channels inactivate more slowly and less completely than type n during maintained depolarization, but recover from inactivation more rapidly, so that little inactivation accumulates during repetitive pulses. Type l channels have a higher unitary conductance (21 pS) than type n (12 pS) and are less sensitive to block by external Co++, but are 100-fold more sensitive to block by external tetraethylammonium (TEA), with half-block of type l channels at 50-100 microM TEA compared with 8-16 mM for type n. TEA blocks both types of channels by reducing the apparent single channel current amplitude, with a dose-response relation similar to that for blocking macroscopic currents. Murine type n K+ channels resemble K+ channels in human T cells.


Genetic variation in the HLA region is associated with susceptibility to herpes zoster.
Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.


Prophylactic unfractionated heparin and hemorrhage in neurocritically ill underweight patients: A case series and review of the literature.
Three cases of major bleeding associated with thromboprophylactic unfractionated heparin (UFH) therapy in underweight neurocritically ill patients are reported. Three underweight patients (body mass index of <18.5 kg/m2) were treated in the intensive care unit with major bleeds associated with UFH thromboprophylaxis. Two of the patients, a 76-year-old female and a 56-year-old female, had hemorrhages on presentation; the third patient, a 29-year-old male, developed bleeding during his admission. All 3 patients had past medical histories consisting of acute neurologic conditions within 6 weeks of presentation, including subdural hematoma, subarachnoid hemorrhage, and obstructive hydrocephalus secondary to a brain mass. All hemorrhages developed following the receipt of prophylactic UFH at doses of 5,000 units every 8 to 12 hours, which translated to high weight-based dosages (>300 units/kg/d). Additionally, hemorrhages were associated with prolonged activated partial thromboplastin time, which declined following heparin discontinuation. The major bleeds following UFH administration included an acute on chronic subdural hematoma, acute rectus sheath hematoma, and cerebellar hematoma. Stabilization of the subdural hematoma was achieved without the use of protamine and the patient was discharged in stable condition. The other 2 patients expired secondary to their hemorrhagic events. Naranjo nomogram scores for the patients indicated that heparin was the probable cause of bleed in 2 cases and a possible cause in 1 case. Three major hemorrhages developed following the administration of UFH. Underweight patients with neurologic injury may require increased clinical vigilance, reduced doses, and pharmacodynamic monitoring to improve safety outcomes associated with thromboprophylaxis.


Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.
Data on the application of donor lymphocyte infusions (DLIs) following reduced-intensity transplantation (RIT) remain limited. Persistence of host antigen-presenting cells might increase the efficacy or toxicity of cellular immunotherapies. We report the results of dose-escalating DLIs in 46 patients undergoing RIT, who received a total of 109 infusions to treat mixed chimerism or residual or progressive disease. Diagnoses were myeloma (n = 19), Hodgkin lymphoma (n = 13), non-Hodgkin lymphoma (n = 10), and other (n = 4). Thirty-two had an HLA-matched family donor and 14 an unrelated donor. Grades II to IV graft-versus-host disease (GVHD) occurred in 5 sibling and 7 unrelated donor recipients. GVHD was more common (P =.002), occurred at lower T-cell doses, and was more severe in the unrelated donor cohort. Conversion from mixed to multilineage full donor chimerism occurred in 30 of 35 evaluable patients. Presence of mixed chimerism in the granulocyte lineage at the time of DLI did not predict for chimerism response or GVHD. Disease responses occurred in 63% of patients with myeloma and 70% of those with Hodgkin lymphoma and were not predicted by changes in chimerism. These data support the presence of clinically relevant graft-versus-Hodgkin activity and indicate that DLI may be associated with a significantly increased toxicity in unrelated compared to sibling donor transplant recipients receiving identical treatment protocols.


Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene.
One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.


Depolarization initiates phasic acetylcholine release by relief of a tonic block imposed by presynaptic M2 muscarinic receptors.
The role of presynaptic muscarinic autoreceptors in the initiation of phasic acetylcholine (ACh) release at frog and mouse neuromuscular junctions was studied by measuring the dependency of the amount (m) of ACh release on the level of presynaptic depolarization. Addition of methoctramine (a blocker of M2 muscarinic receptors), or of acetylcholinesterase (AChE), increased release in a voltage-dependent manner; enhancement of release declined as the depolarizing pulse amplitude increased. In frogs and wild-type mice the slope of log m/log pulse amplitude (PA) was reduced from about 7 in the control to about 4 in the presence of methoctramine or AChE. In M2 muscarinic receptor knockout mice, the slope of log m/log PA was much smaller (about 4) and was not further reduced by addition of either methoctramine or AChE. The effect of a brief (0.1 ms), but strong (-1.2 microA) depolarizing prepulse on the dependency of m on PA was also studied. The depolarizing prepulse had effects similar to those of methoctramine and AChE. In particular, it enhanced release of test pulses in a voltage-dependent manner and reduced the slope of log m/log PA from about 7 to about 4. Methoctramine + AChE occluded the prepulse effects. In knockout mice, the depolarizing prepulse had no effects. The cumulative results suggest that initiation of phasic ACh release is achieved by depolarization-mediated relief of a tonic block imposed by presynaptic M2 muscarinic receptors.


Serum human telomerase reverse transcriptase messenger RNA as a novel tumor marker for hepatocellular carcinoma.
We previously reported the usefulness of a qualified highly sensitive detection method for human telomerase reverse transcriptase (hTERT) mRNA in serum with 89.7% sensitivity for hepatocellular carcinoma (HCC). In this study, we developed a quantitative detection method for serum hTERT mRNA and examined the clinical significance in HCC diagnosis. EXPERIMENTAL BACKGROUND: In 64 patients with HCC, 20 with liver cirrhosis, 20 with chronic hepatitis, and 50 healthy individuals, we measured serum hTERT mRNA by using the newly developed real-time quantitative reverse transcription-PCR with SYBR Green I. We examined its sensitivity and specificity in HCC diagnosis, clinical significance in comparison with other tumor markers, and its correlations with the clinical variables by using multivariate analyses. Serum hTERT mRNA showed higher values in patients with HCC than those with chronic liver diseases. hTERT mRNA expression was shown to be independently correlated with clinical variables such as tumor size, number, and degree of differentiation (P < 0.001, each). The sensitivity/specificity of hTERT mRNA and alpha-fetoprotein (AFP) mRNA in HCC diagnosis were 88.2%/70.0% for hTERT and 71.6%/67.5% for AFP, respectively. hTERT mRNA proved to be superior to AFP mRNA, AFP, and des-gamma-carboxy prothrombin in HCC diagnosis. Furthermore, hTERT mRNA in serum was associated with that in HCC tissue. The usefulness of hTERT mRNA expression in HCC diagnosis and its superiority to conventional tumor markers were shown. Therefore, serum hTERT mRNA is a novel and available marker for HCC diagnosis.


Measuring outcomes of nutrition intervention.
Along with other health care professions, The Canadian Dietetic Association is promoting outcomes assessment among its members. Defining outcomes and determining their measurement is a continuous process. Outcomes can refer to any consequence of health care, including changes in health status, knowledge, or behaviour. Establishing the link between the outcome and the interventions that led to it is important, but can be difficult. This is especially the case for the dietetic profession, in that nutrition status is often affected by factors other than our nutrition intervention. We reviewed the work of other professional associations: the American Dietetic Association, Canadian Association of Occupational Therapists, Canadian Physiotherapy Association, Canadian Psychological Association, and Canadian Nurses Association. All have formed expert committees or task forces to come to grips with the questions of outcome measurement relevant to their profession. All have found the process difficult and time-consuming. Many health professions are moving toward the position voiced by the CNA: using outcome information they will try to do what they do better, further, they will question whether they should be doing it.


[DNA synthesis and content and the accumulation of total protein and hemoglobin during the differentiation of primary erythroid cells in chickens].
Using cytophotometric and autoradiographic methods, it was shown that on days 2-3 of embryogenesis primary erythroid cells (PEC) divided actively. The distribution of erythroblasts (EB) according to their DNA content is not, however, typical of a proliferating population: it contains an unusually large number of 4c cells resulting from the cell cycle arrest at the G2 phase. It is established that reticulocytes (RC) do not divide and are arrested at G1 or G2 phases, since they do not incorporate 3H-thymidine after their formation is complete and their DNA contents are strictly confined to either 2c or 4c. All types of PEC include a large number of cells containing H2c DNA which is due either to the cell cycle arrest at the S phase, or to the formation of accessory nuclei. All PECs have much higher contents of hemoglobin and total protein than do adult hen erythrocytes (EC). Hemoglobin and total protein contents of H2c and accessory nuclei containing cells are much higher than those in 2c-cells. We have calculated that adult birds and embryos contain the same amount of hemoglobin per gram of weight, but the quantity of red blood cells in the former is ten times higher. A conclusion is drawn that proliferation and cytodifferentiation regulation mechanisms are directed, in primary erythropoiesis, to intense hemoglobinization of the cells, and, in adult erythropoiesis, to increasing their number. In both the cases homeostatic regulation of erythropoiesis works.(ABSTRACT TRUNCATED AT 250 WORDS)


Heart rate variability analysis in patients with allergic rhinitis.
Very few studies investigate the role of the autonomic nervous system in allergic rhinitis. In this study, we evaluated the autonomic nervous system in allergic rhinitis patients using heart rate variability (HRV) analysis. Eleven patients with allergic rhinitis and 13 healthy controls, aged between 19 and 40 years old, were enrolled in the study. Diagnosis of allergic rhinitis was based on clinical history, symptoms, and positive Phadiatop test. Electrocardiographic recordings on the sitting and supine positions were obtained for HRV analysis. In the supine position, there were no significant statistical differences in very-low-frequency power (VLF, ≤0.04 Hz), low-frequency power (LF, 0.04-0.15 Hz), high-frequency power (HF, 0.15-0.40 Hz), and the ratio of LF to HF (LF/HF) between the patient and control groups. The mean RR intervals significantly increased, while LF% and LF/HF significantly decreased in the patient group in the sitting position. Moreover, mean RR intervals, LF, and LF/HF, which were significantly different between the two positions in the control group, did not show a significant change with the posture change in the patient group. These suggest that patients with allergic rhinitis may have poor sympathetic modulation in the sitting position. Autonomic dysfunction may therefore play a role in the pathophysiology of allergic rhinitis.


[Role of LH in ovarian stimulation: present and future].
Contribution of LH to ovarian stimulation, distinguishing treatment of anovulation and ovarian stimulation with the objective of IVF. LH and ovarian dysfunction LH furnishes the androgen substrate necessary for FSH for estrogen synthesis, but excess LH is a less reliable index than free androgen level to predict the absence of response to ovarian stimulation. LH and ovarian stimulation


Mind on Canvas: anatomy, signs and neurosurgery in art.
Throughout the ages, art and neuroscience have had a delicate yet definite relationship with reciprocal influence. By virtue of their superior power of observation, artists have often preserved neurological signs through detailed brush strokes or meticulous carvings long before it is described in scientific literature. There has been an increasing tendency to use paintings and drawings as independent sources for investigation of scientific history. In neuroanatomy, these tools have helped reveal the complex interrelation between arts and neurosciences that on the surface often appear as highly polarized worlds. In this article we begin by giving a brief introduction to the general relationship between neuroscience and art as depicted in paintings and drawings, and describe the artistic tendencies of the early neuroanatomists. We aim to highlight the existence of neurosurgical themes within paintings and drawings from different eras.


Comparison and differentiation of potyvirus isolates and identification of strain-, virus-, subgroup-specific and potyvirus group-common epitopes using monoclonal antibodies.
A panel of monoclonal antibodies (MAbs) generated against an admixture of 12 potyvirus isolates was used to compare and differentiate diverse potyviruses. Both native and denatured virions of strains of bean yellow mosaic (BYMV), potato virus Y, tobacco etch, pea seed-borne mosaic, iris severe mosaic, iris mild mosaic and asparagus virus-1 potyviruses were used as immunogen and as antigen for screening of the hybridoma cell lines. Thirty cell lines secreting potyvirus-specific antibodies reactive in indirect antigen-coated plate (ACP-) ELISA were selected for detailed analysis. All 30 MAbs reacted with at least one strain of BYMV; 11 MAbs reacted with between one and eight of the nine BYMV strains and an additional three MAbs reacted only with isolates within the BYMV subgroup (BYMV, pea mosaic virus and clover yellow vein virus). The remaining 16 MAbs reacted with a BYMV isolate and with at least one of the other 43 potyvirus isolates tested. MAb PTY 1 reacted with all 55 potyvirus isolates tested (representing at least 33 different and distinct aphid-transmissible potyviruses). The potyvirus cross-reactive MAbs generally gave higher reactivity values in ACP-ELISA with dissociated virus than with polyclonal antibody-trapped intact virions in triple antibody sandwich ELISA (i.e. were cryptotope-specific). The BYMV strain- and virus-specific MAbs reacted strongly with both types of antigens (i.e. were metatope-specific). At least 25 distinct epitopes (12 cryptotopes and 13 metatopes) could be identified from the MAb-antigen reactivity patterns. The distribution of these epitopes between virus isolates can be used to detect and differentiate potyviruses in infected plant extracts and to examine virus architectures. Some of these epitopes are shared by potyvirus isolates not previously shown to be serologically related. The broad spectrum-reacting MAb PTY 1 recognizes a cryptotope conserved on all of the aphid-transmissible potyviruses examined and should be a valuable tool for the detection and assay of these potyviruses.


Update on molecular epidemiology of H1, H5, and H7 influenza virus infections in poultry in North America.
Avian influenza is endemic in wild birds in North America, and the virus routinely has been transmitted from this reservoir to poultry. Influenza, once introduced into poultry, can become endemic within the poultry population. It may be successfully eradicated by human intervention, or the virus may fail to successfully spread on its own. In the last 5 yr, influenza virus has been isolated from poultry in the United States on numerous occasions, and, with the use of molecular epidemiology, the relationships of these different viruses can be determined. There are 15 different hemagglutinin subtypes of avian influenza viruses, but infections with virus of H5 and H7 subtypes are of the most concern because of the potential for these viruses to mutate to the highly pathogenic form of the virus. Most of the influenza isolations in the United States have been associated with the live-bird markets (LBMs) in the Northeast. This has included primarily H7N2 influenza viruses, but also H7N3, H5N2, and other subtypes. Most of the H7N2 viruses were part of a single lineage that was first observed in 1994, but new introductions of H7N2 and H7N3 were also observed. The predominant H7N2 LBM lineage of virus spread to large commercial poultry operations on at least three occasions since 1997, with the largest outbreak occurring in Virginia in 2002. The H5N2 viruses in the LBMs included viruses from domestic ducks, gamebirds, and environmental samples. Some H5N2 viruses isolated in different years and in different locations had a high degree of sequence relatedness, although the reservoir source, if it is endemic, has not been identified. Finally, an H1N2 virus, associated with a drop in egg production, was isolated from turkeys in Missouri in 1999. This virus was a complex reassortant with swine, human, and avian influenza genes that was similar to recent swine isolates from the Midwest. Additional serologic evidence suggests that flocks in other states were infected with a H1N2 virus.


Contributions of feature shapes and surface cues to the recognition and neural representation of facial identity.
A full understanding of face recognition will involve identifying the visual information that is used to discriminate different identities and how this is represented in the brain. The aim of this study was to explore the importance of shape and surface properties in the recognition and neural representation of familiar faces. We used image morphing techniques to generate hybrid faces that mixed shape properties (more specifically, second order spatial configural information as defined by feature positions in the 2D-image) from one identity and surface properties from a different identity. Behavioural responses showed that recognition and matching of these hybrid faces was primarily based on their surface properties. These behavioural findings contrasted with neural responses recorded using a block design fMRI adaptation paradigm to test the sensitivity of Haxby et al.'s (2000) core face-selective regions in the human brain to the shape or surface properties of the face. The fusiform face area (FFA) and occipital face area (OFA) showed a lower response (adaptation) to repeated images of the same face (same shape, same surface) compared to different faces (different shapes, different surfaces). From the behavioural data indicating the critical contribution of surface properties to the recognition of identity, we predicted that brain regions responsible for familiar face recognition should continue to adapt to faces that vary in shape but not surface properties, but show a release from adaptation to faces that vary in surface properties but not shape. However, we found that the FFA and OFA showed an equivalent release from adaptation to changes in both shape and surface properties. The dissociation between the neural and perceptual responses suggests that, although they may play a role in the process, these core face regions are not solely responsible for the recognition of facial identity.


Contrasting the use of 2 vision-specific quality of life questionnaires in subjects with open-angle glaucoma.
To compare 2 vision-specific functional status measures to each other and to clinical parameters in the Collaborative Initial Glaucoma Treatment Study (CIGTS). CIGTS participants completed the Visual Activities Questionnaire (VAQ) and the National Eye Institute-Visual Function Questionnaire (NEI-VFQ) and were tested for visual field (VF) and visual acuity (VA). In all, 426 subjects contributed the VAQ and NEI-VFQ scores at 54 months. Pearson correlations were used to assess associations. The VAQ subscales (range, 0 to 100) that assessed light-dark adaptation (mean=66.1), glare disability (66.4), and acuity/spatial vision (67.7) indicated vision-related functions that CIGTS participants found most difficult. On the NEI-VFQ, subjects reported high levels of visual functioning, with mean >/=90 (out of 100) on the total score and in 9 of 12 subscales. General vision (mean=82.6) received the lowest subscale score. Two subscales common to both questionnaires were highly correlated: VA (r=0.68) and peripheral vision (r=0.77) (both P<0.0001). Correlations between participants' perceptions and clinical measures of visual function were in the expected direction, but weaker. Stronger associations were found between clinical measures and the NEI-VFQ than the VAQ. Better eye VF and worse eye VA had the highest number of significant correlations with subjects' perceptions of their visual function. Increasing VF loss was associated with a significant decrease in the overall and peripheral vision subscale scores from both questionnaires, and also several other subscales. CIGTS patients reported excellent visual function on both the NEI-VFQ and VAQ. These findings will help researchers interested in assessing patients' perceptions of their visual function make an informed selection when choosing between the VAQ and the NEI-VFQ.


Discovery of a body-wide photosensory array that matures in an adult-like animal and mediates eye-brain-independent movement and arousal.
The ability to respond to light has profoundly shaped life. Animals with eyes overwhelmingly rely on their visual circuits for mediating light-induced coordinated movements. Building on previously reported behaviors, we report the discovery of an organized, eye-independent (extraocular), body-wide photosensory framework that allows even a head-removed animal to move like an intact animal. Despite possessing sensitive cerebral eyes and a centralized brain that controls most behaviors, head-removed planarians show acute, coordinated ultraviolet-A (UV-A) aversive phototaxis. We find this eye-brain-independent phototaxis is mediated by two noncanonical rhabdomeric opsins, the first known function for this newly classified opsin-clade. We uncover a unique array of dual-opsin-expressing photoreceptor cells that line the periphery of animal body, are proximal to a body-wide nerve net, and mediate UV-A phototaxis by engaging multiple modes of locomotion. Unlike embryonically developing cerebral eyes that are functional when animals hatch, the body-wide photosensory array matures postembryonically in "adult-like animals." Notably, apart from head-removed phototaxis, the body-wide, extraocular sensory organization also impacts physiology of intact animals. Low-dose UV-A, but not visible light (ocular-stimulus), is able to arouse intact worms that have naturally cycled to an inactive/rest-like state. This wavelength selective, low-light arousal of resting animals is noncanonical-opsin dependent but eye independent. Our discovery of an autonomous, multifunctional, late-maturing, organized body-wide photosensory system establishes a paradigm in sensory biology and evolution of light sensing.


Creating an objective structured clinical examination for the internal medicine clerkship: pitfalls and benefits.
The objective-structured clinical examination (OSCE) is a useful tool in evaluating clinical competence. Traditional clinical-evaluation measures have been criticized as arbitrary and lacking reliability, whereas written exams test primarily cognitive aspects. The OSCE focuses on learner actions rather than abstract knowledge and evaluates in a uniform fashion. A 15-station OSCE was created for an internal medicine junior clerkship, based on predetermined skill and content goals. The exams then were scored by a single, blinded reviewer, again in a predetermined fashion. The OSCE has been studied in terms of reliability, content validity, and construct validity. The exam has become accepted by the department and has guided the continuing curricular development. The OSCE is not designed to measure all the domains of a learner's educational process. However, when used in conjunction with other evaluating mechanisms, it provides an objective outcome measure of the medical education process.


Endoglin haploinsufficiency promotes fibroblast accumulation during wound healing through Akt activation.
Accurate regulation of dermal fibroblast function plays a crucial role in wound healing. Many fibrotic diseases are characterized by a failure to conclude normal tissue repair and the persistence of fibroblasts inside lesions. In the present study we demonstrate that endoglin haploinsufficiency promotes fibroblast accumulation during wound healing. Moreover, scars from endoglin-heterozygous (Eng(+/-)) mice show persisting fibroblasts 12 days after wounding, which could lead to a fibrotic scar. Endoglin haploinsufficiency results in increased proliferation and migration of primary cultured murine dermal fibroblasts (MDFs). Moreover, Eng(+/-) MDF have diminished responses to apoptotic signals compared with control cells. Altogether, these modifications could explain the augmented presence of fibroblasts in Eng(+/-) mice wounds. We demonstrate that endoglin expression regulates Akt phosphorylation and that PI3K inhibition abolishes the differences in proliferation between endoglin haploinsufficient and control cells. Finally, persistent fibroblasts in Eng(+/-) mice wound co-localize with a greater degree of Akt phosphorylation. Thus, endoglin haploinsufficiency seems to promote fibroblast accumulation during wound healing through the activation of the PI3K/Akt pathway. These studies open new non-Smad signaling pathway for endoglin regulating fibroblast cell function during wound healing, as new therapeutic opportunities for the treatment of fibrotic wounds.


Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors.
Activation of signaling dependent on the mammalian target of rapamycin (mTOR) has been demonstrated in a variety of human malignancies, and our previous work suggests that mTOR complex (mTORC) 1 and mTORC2 may play unique roles in skin tumorigenesis. The purpose of these studies was to investigate the function of mTORC2-dependent pathways in skin tumor development and the maintenance of established tumors. Using mice that allow spatial and temporal control of mTORC2 in epidermis by conditional knockout of its essential component Rictor, we studied the effect of mTORC2 loss on both epidermal proliferation and chemical carcinogenesis. The results demonstrate that mTORC2 is dispensable for both normal epidermal proliferation and the hyperproliferative response to treatment with tetradecanoyl phorbol acetate (TPA). In contrast, deletion of epidermal Rictor prior to initiation in DMBA/TPA chemical carcinogenesis was sufficient to dramatically delay tumor development and resulted in reduced tumor number and size compared with control groups. Silencing of Rictor expression in tumor-bearing animals triggered regression of established tumors and increased caspase-3 cleavage without changes in proliferation. In vitro experiments demonstrate an increased sensitivity to caspase-dependent apoptosis in the absence of rictor, which is dependent on mTORC2 signaling. These studies demonstrate that mTORC2 activation is essential for keratinocyte survival, and suggest that inhibition of mTORC2 has value in chemoprevention by eliminating carcinogen-damaged cells during the early stages of tumorigenesis, and in therapy of existing tumors by restricting critical pro-survival pathways.


Diagnosis and Treatment of Severe Traumatic Brain Injury in Idiopathic Intracranial Hypertension Syndrome.
A topic of current research is the development of a new approach to the diagnosis and treatment of severe brain injury taking into consideration its main pathophysiological mechanism-idiopathic intracranial hypertension syndrome. The goal of this study was to identify Doppler patterns of unfavorable craniocerebral injury conditions to form a consistent algorithm of treatment measures to reduce secondary brain damage in patients with severe craniocerebral trauma. Transcranial Doppler imaging is a prospective method, which allows quick and noninvasive assessment of the intracerebral blood flow dynamics right at the patient's bedside. Due to the operator-dependent nature of this method, clinical interpretation can often be contradictory. As a result, no clear criteria for therapy correction have yet been formulated based on this neuroimaging method. Analysis of the therapy performed allowed us to specify the options for the hyperosmolar solutions for the correction of idiopathic intracranial hypertension syndrome. No statistically significant difference in effectiveness was shown between mannitol and hypertonic saline solutions.


A carob-inspired nanoscale design of yolk-shell Si@void@TiO2-CNF composite as anode material for high-performance lithium-ion batteries.
Silicon (Si) is an attractive anode material for lithium-ion batteries due to its high gravimetric and volumetric capacity. However, the challenges for Si anodes are low conductivity, unstable solid electrolyte interphase (SEI) layer and big volume expansion during the charge/discharge process. Inspired by the structure of carob, we propose a yolk-shell structured Si anode which tackles all the problems mentioned above. The non-filling Si clusters protected by atomic layer-deposited TiO2 are embedded in highly conductive one-dimensional carbon nanofibers, which leaves enough space for the expansion and contraction of Si during lithiation/delithiation. Moreover, the SEI layer will form at the outer surface of carbon nanofibers instead of on individual Si nanoparticles and can remain stable and spatially confined. Therefore, the yolk-shell composite electrode exhibits good electrochemical performance and reversible capacities of 1156 mA h g-1 at a current density of 600 mA g-1 after 500 cycles and 485 mA h g-1 at the current density of 9600 mA g-1 after 2000 cycles are obtained.


Histological differences between preoperative chemoradiotherapy and chemotherapy for rectal cancer: a clinicopathological study.
Pathological studies on the different histological effects between neoadjuvant chemotherapy (NAC) and preoperative chemoradiation therapy (preoperative CRT) have not been performed. The purpose of this study is to elucidate the histological differences in tissue received from NAC and preoperative CRT for rectal cancer to evaluate whether a pathological assessment method used after CRT can be applied for NAC. One hundred and thirty-eight patients were enrolled in this study; 88 patients underwent their operations after preoperative CRT or NAC, and 50 patients underwent surgery only. Residual tumor area was measured using morphometry software and we compared the stromal component of myofibroblasts, immune cells, and vasculature to elucidate the difference of therapeutic effect between them. The grade of reduction after preoperative CRT was more prominent than that seen in NAC. Also, ypT downstaging was more prominent in preoperative CRT than in NAC, and ypN downstaging was more frequent in NAC than in preoperative CRT. Preoperative CRT showed more marked myofibroblasts and fewer immune cells than did NAC, which indicates different effects on the cancer microenvironment. Our histological results suggest different effects between NAC and preoperative CRT on tumor tissue. The best assessment method available for a variable therapeutic protocol should be further investigated.


A biokinetic and dosimetric model for ionic indium in humans.
This paper reviews biokinetic data for ionic indium, and proposes a biokinetic model for systemic indium in adult humans. The development of parameter values focuses on human data and indium in the form of ionic indium(III), as indium chloride and indium arsenide. The model presented for systemic indium is defined by five different pools: plasma, bone marrow, liver, kidneys and other soft tissues. The model is based on two subsystems: one corresponding to indium bound to transferrin and one where indium is transported back to the plasma, binds to red blood cell transferrin and is then excreted through the kidneys to the urinary bladder. Absorbed doses to several organs and the effective dose are calculated for 111In- and 113mIn-ions. The proposed biokinetic model is compared with previously published biokinetic indium models published by the ICRP. The absorbed doses are calculated using the ICRP/ICRU adult reference phantoms and the effective dose is estimated according to ICRP Publication 103. The effective doses for 111In and 113mIn are 0.25 mSv MBq-1 and 0.013 mSv MBq-1 respectively. The updated biokinetic and dosimetric models presented in this paper take into account human data and new animal data, which represent more detailed and presumably more accurate dosimetric data than that underlying previous models for indium.


Transcranial magnetic stimulation to the angular gyrus modulates the temporal dynamics of the hippocampus and entorhinal cortex.
Transcranial magnetic stimulation (TMS) delivered to the angular gyrus (AG) affects hippocampal function and associated behaviors (Thakral PP, Madore KP, Kalinowski SE, Schacter DL. Modulation of hippocampal brain networks produces changes in episodic simulation and divergent thinking. 2020a. Proc Natl Acad Sci U S A. 117:12729-12740). Here, we examine if functional magnetic resonance imaging (fMRI)-guided TMS disrupts the gradient organization of temporal signal properties, known as the temporal organization, in the hippocampus (HPC) and entorhinal cortex (ERC). For each of 2 TMS sessions, TMS was applied to either a control site (vertex) or to a left AG target region (N = 18; 14 females). Behavioral measures were then administered, and resting-state scans were acquired. Temporal dynamics were measured by tracking change in the fMRI signal (i) "within" single voxels over time, termed single-voxel autocorrelation and (ii) "between" different voxels over time, termed intervoxel similarity. TMS reduced AG connectivity with the hippocampal target and induced more rapid shifting of activity in single voxels between successive time points, lowering the single-voxel autocorrelation, within the left anteromedial HPC and posteromedial ERC. Intervoxel similarity was only marginally affected by TMS. Our findings suggest that hippocampal-targeted TMS disrupts the functional properties of the target site along the anterior/posterior axis. Further studies should examine the consequences of altering the temporal dynamics of these medial temporal areas to the successful processing of episodic information under task demand.


Enhanced external counterpulsation improves endothelial function and exercise capacity in patients with ischaemic left ventricular dysfunction.
Enhanced external counterpulsation (EECP) therapy decreases angina episodes and improves quality of life in patients with left ventricular (LV) dysfunction (LVD). However, studies have not elucidated the mechanisms of action and overall effects of EECP in patients with LVD. The purpose of the present study was to investigate the effects of EECP on endothelial function in peripheral conduit arteries and exercise capacity (peak Vo2 ) in patients with LVD. Patients with ischaemic LVD (ejection fraction (EF) 34.5 ± 4.2%; n = 9) and patients with symptomatic coronary artery disease (CAD) and preserved LV function (EF 53.5 ± 6.6%; n = 15) were studied before and after 35 sessions (1 h) of EECP. Brachial and femoral artery flow-mediated dilation (bFMD and fFMD, respectively) were evaluated using high-resolution ultrasound. Enhanced external counterpulsation elicited similar significant improvements in the following FMD parameters in the CAD and LVD groups (P ≥ 0.05 between groups for all): absolute bFMD (+53% and +70%, respectively), relative bFMD (+50% and +74%, respectively), bFMD normalized for shear rate (+70% and +61%, respectively), absolute fFMD (+33% and +21%, respectively) and relative fFMD (+32% and +17%, respectively). In addition, EECP significantly improved plasma levels of nitrate/nitrite (+55% and +28%) and prostacyclin (+50% and +70%), as well as peak Vo2 (+36% and +21%), similarly in both the CAD and LVD groups (P ≥ 0.05 between groups for all). Despite reduced LV function, EECP therapy significantly improves peripheral vascular function and functional capacity in CAD patients with ischaemic LVD to a similar degree to that seen in CAD patients with preserved LV function.


Transcriptomic and genomic profiling of multiple primary colorectal cancers reveals intratumor heterogeneity and a distinct immune microenvironment.
This study reported on the intratumor genomic and immunological heterogeneity of different tumor lesions from a single patient with multiple primary colorectal cancer (MPCC). The goal of this study was to explore the molecular and microenvironment characteristics of tumor lesions from different primary sites in a patient with MPCC. A total of three tumor lesions located in the hepatic flexure of the transverse colon, sigmoid colon, and rectum were collected from a 72-year-old male patient with MPCC. All three tumor samples were examined by using whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). The transcriptome data of The Cancer Genome Atlas (TCGA) colon cancer (COAD) dataset were explored to characterize the biological impacts of certain immune cells. Only three nonsynonymous mutations were shared by all of the tumor lesions, whereas a number of single nucleotide variant (SNV) and copy number variation (CNV) mutations were shared by tumor samples from the sigmoid colon and rectum. Transcriptomic analysis showed that tumor lesions derived from the transverse colon had decreased levels of RTK, ERK, and AKT pathway activity, thus suggesting lower oncogenic properties in the transverse lesion compared to the other two samples. Further immune landscape evaluation by using single-cell transcriptomic analysis displayed significant intratumor heterogeneity in MPCC. Specifically, more abundant mucosal-associated invariant T (MAIT) cell infiltration was found in transverse colon tumor lesions. Afterwards, we found that higher MAIT cell infiltration may correlate with a better prognosis of patients with colon cancer (immunohistochemical status was MSI-L/pMMR) by using a publicly available TCGA dataset.