Bisphosphonates for steroid induced osteoporosis.
To assess the effects of bisphosphonates for the prevention and treatment of corticosteroid-induced osteoporosis. We searched the Cochrane Musculoskeletal Group trials register, Medline up to 1997 and Embase1988-1997), and selected hand searching of reference lists was conducted. Hand searching of scientific abstracts from relevant meetings for the last five years was also done. An electronic search in Current Contents was done for the last six months. The Cochrane Controlled Trials Register (CCTR) will be searched for future updates. All languages were included in the search. For practical reasons only those in English were included, but all languages will be retrieved and translated for future updates. All controlled clinical trials (CCTs) dealing with prevention or treatment of corticosteroid-induced osteoporosis with bisphosphonates of any type and reporting the outcomes of interest were assessed. Trials had to involve adults only, and subjects had to be taking a mean steroid dose of 7.5 mg/day or more. All data extraction was performed by two independent reviewers. Outcomes of interest included change in bone mineral density (BMD) at the lumbar spine and femoral neck at six and 12 months. If present, data on number of new fractures and withdrawals due to adverse effects were also extracted. All data extraction was performed by two independent reviewers. Both continuous and dichotomous data were analyzed using fixed effects models. When significant heterogeneity was present, a random effects model was used. A total of 13 trials, including 842 patients are included in this meta-analysis. Results are reported as a weighted mean difference of the percent change in BMD between the treatment and placebo groups, with trials being weighted by the inverse of their variance. The 95% confidence intervals (95% CI) are presented. At the lumbar spine, the weighted mean difference of BMD between the treatment and placebo groups was 4.3% (95% CI 2.7, 5.9). At the femoral neck, the weighted mean difference was 2.1% (95%CI 0. 01, 3.8). Although there was a 24% reduction in odds of spinal fractures [OR 0.76 (95%CI 0.37, 1.53)], this result was not statistically significant. Bisphosphonates are effective at preventing and treating corticosteroid-induced bone loss at the lumbar spine and femoral neck. Efficacy regarding fracture prevention cannot be concluded from this analysis, although bone density changes are correlated with fracture risk.


[Study on energy absorption of mouthguard splints by impact test].
Using impact test to study energy absorption ability of mouthguard splints of different thickness and materials. In this experiment, group 1 was BIOPLAST 5 mm splint, group 2 was BIOPLAST 4 mm splint, group 3 was BIOPLAST 3 mm splint,group 4 was BIOPLAST 2 mm splint and group 7 was BIOPLAST 1 mm splint. Group 5 was ERKOLOC-PRO 2 mm splint, group 6 was DURAN 2 mm splint. Mouthguard splints were clashed by impact head from different heights. Digital Image Correlation System was used to record the process of the test. Images were transferred to data processing software, to analyze incident speed, incident depth and rebound height of the impact head. Absorbed energy and energy absorption ratio were calculated to analyze energy absorption ability of mouthguard splints of different thickness and materials. The data were analyzed using SPSS 22.0 software package for one-way analysis of variance and LSD. The higher impact head fell, the larger energy absorption ratio was. There was significant difference among group 1, 2, 3, 4, 7 in average energy absorption ratio(P<0.05), and group 7 was the largest. There was significant difference among group 4, 5, 6 in average energy absorption ratio(P<0.05), among which group 4 and group 5 were larger. 3 mm splint is good enough to be used to make mouthguard, which is also thinner and more comfortable. Splint of soft material is more suitable for mouthguard than splint of hard material.


Comparative efficiency of commercial and improvised spacer device in acute bronchial asthma.
To compare the efficacy of a commercial spacer device versus an improvised spacer device in delivering aerosolized beta-2 agonist through metered dose inhaler in an acute exacerbation of bronchial asthma. Randomized controlled trial. Urban tertiary care teaching hospital. 60 children between 1 to 12 years of age with acute asthma were prospectively enrolled and randomized into two groups. Detailed history, clinical evaluation and appropriate laboratory investigations were recorded on a pretested proforma. One group received inhaled salbutamol using metered dose inhaler via commercial spacer device (Group 1), while the other received it via improvised spacer device (Group II). The response was sequentially assessed after 20, 40 and 60 minutes of institution of therapy. The two groups were comparable with respect to various parameters at presentation (p > 0.05). All the outcome parameters showed a significant improvement with time in both groups (p < 0.05). There was no statistical difference between the response in the two groups (p< 0.05). Metered dose inhaler with improvised spacer device is equivalent in efficacy and a more cost effective alternative to metered dose inhaler with commercial spacer for administration of beta-2 agonist in acute asthma.


Effects of interactions between intestinal microbiota and intestinal macrophages on health.
Macrophages reside in every tissue of the body and play an important role in maintaining homeostasis. The intestinal mucosa is the largest immune organ and harbors macrophages in abundance. Dysfunction of intestinal macrophages is characteristic of patients with certain inflammatory bowel diseases. Although intestinal macrophages exhibit hyporesponsiveness to foreign substances, including various bacterial products, their physiological functions are unknown, but may be related to the contribution of intestinal bacteria to the maintenance of various physiological functions of the host. Moreover, recent reports suggest that there are associations between intestinal microbiota and the onset of pathologies, such as diverse metabolic syndromes, depression, and cancer. Evidence indicates that the host's immune response to intestinal microbiota may be etiologically-linked to these diseases; however, the mechanisms are poorly understood. In the present review, we discuss the possibility that intestinal microbiota influence health through the function of intestinal macrophages.


Brain/behavior Asymmetry in Schizophrenia: A MEG Study of Cross-modal Semantic Priming.
Semantic priming has long been used to investigate how concepts and ideas are related at the level of language, and has become a convenient tool for assessing conceptual and semantic dysfunction in cognitive disorders, including schizophrenia. The study of semantic priming in schizophrenia has led to diverse results: enhanced priming, reduced priming, and priming equivalent to that found in nonpsychiatric comparison groups. A number of hypotheses have been proposed to explain some of the observed deficits in schizophrenia patients. For example, difficulties in word recognition may be due to hyperactivation of too many lexical representations or to a failure to inhibit lexical competitors. One way to distinguish between these possible explanations is to move beyond reliance on behavior alone and to examine the neural processes involved in lexical recognition. Here we present a magnetoencephalographic study of semantic priming in schizophrenia. Importantly, schizophrenia patients and healthy controls did not differ in performance on a priming task. We show that normal behavioral performance can occur in a context of aberrant neural responses. These findings suggest that normal behavioral responses in schizophrenia can be achieved through neural mechanisms that differ from those seen in the psychiatrically well brain.


[Contact with violence--health professionals and their patients victims of abuse].
Using qualitative methods of collecting data and analysis, this article outlines the way health care professionals, mainly pediatricians, feel about violence and their responsibility in denouncing the cases which they were forced to deal with. Although a typical "case study"--the experience in Instituto Fernandes Figueira/FIOCRUZ--the major concern of this work is to offer material for reflexion about procedures that should or could be taken in face to child morbidity caused by "external causes", making suggestions for a health conduct that enhances the relationship between violence and the medical practice related to child and adolescent abuse.


Feeding the low-birth-weight infant: II. Effects of taurine and cholesterol supplementation on amino acids and cholesterol.
Plasma and urine concentrations of taurine were consistently lower in preterm infants fed unsupplemented formula than those observed in the infants fed human milk or formulas supplemented with taurine alone or with taurine plus cholesterol. Such supplementation of formula restored plasma and urine concentrations of taurine to those observed in the infants fed human milk. Taurine was the only amino acid that was present at lower concentrations in the infants fed unsupplemented formula than in those fed human milk. The other acidic and neutral amino acids were present in higher concentrations in the formula-fed infants than in the group fed human milk either during the early weeks of the study (serine, glutamine, glycine, alanine, tyrosine, and methionine) or consistently higher during the entire study (threonine, glutamate, citrulline, valine, isoleucine, leucine, and phenylalanine). Supplementation of formula with taurine plus cholesterol did not appear to have any effect on the amino acid concentrations in the plasma and urine, other than that on taurine itself. Plasma total cholesterol concentration decreased during the fifth to the 12th postnatal weeks of life in all feeding groups. It then returned to the concentrations found during the first and third postnatal weeks in all feeding groups except in the infants fed formulas supplemented with taurine plus cholesterol which had a greater decrease.


Comparative Study on Different Skin Pruritus Mouse Models.
The animal model is an important tool to study the mechanism of disease formation. Different animal models of pruritus have been adopted based on the purpose of researchers in the study of the itching mechanism. Although the symptoms of various models are quite different, scratching behavior is a key indicator. Therefore, it is necessary to find an animal model that can quickly induce animal scratching and maintain the stability of scratching behavior. In this study, we compared animal models of pruritus induced by four substances and found that the scratching behavior of mice induced by urushiol not only reached the plateau stage quickly but also showed more stability in the plateau phase than that induced by 2,4-dinitrofluorobenzene, oxazolone, and imiquimod. Meanwhile, in the animal model induced by urushiol, the changes of epidermal thickening and inflammatory cell aggregation were also more obvious. In addition, pruritus induced by urushiol is prevalent all over the world, especially in the United States and Europe, involving outdoor groups such as firefighters, forest loggers, and farmers. Therefore, we believe that the urushiol-induced animal model is an ideal choice for the study of the itch formation mechanism and the development of antipruritic drugs.


Psychotropics without borders: ethics and legal implications of internet-based access to psychiatric medications.
Medical practitioners are revisiting many of the ethics and the legal implications surrounding the clinical frameworks within which we operate. In today's world, distinguishing between virtual and physical reality continues to be increasingly difficult. The physician may be found grappling with the decision of whether to continue to treat a patient who may be obtaining psychotropic medications through the Internet. This article approaches some of the clinical and legal implications and the ethics regarding the availability of prescription psychotropics over the Internet.


Does the DOSPERT scale predict risk-taking behaviour during travel? A study using smartphones.
Despite the continuing growth of international tourism, very little research has been done on the link between individual risk attitudes and health behaviours during travel. Our study uses a validated risk-taking questionnaire Domain-Specific Risk-Taking Scale (DOSPERT) and data from a smartphone application to study the association between pre-travel risk attitudes and the occurrence of behaviours during travel. A prospective cohort of travellers to Thailand used a smartphone application to answer a daily questionnaire about health behaviours and events. Prior to travel, participants completed the DOSPERT, a validated 30-item scale that assesses risk-taking and perception in five content domains: financial decisions, health/safety, recreational, ethical and social decisions. Multiple linear regression models were used to model the relationship between DOSPERT risk-taking subdomain score and health behaviour. Of the 75 travellers that completed the study, 70 (93.3%) completed the DOSPERT pre-travel. Men, backpackers and young travellers reported a higher willingness to take recreational risks than women, luxury travellers and older travellers. Incidence of drug and alcohol risk behaviours during travel, itching from mosquitoes, smoking and failing to use a seatbelt in automobiles while at home were all significantly associated with an individual's score on the health and safety DOSPERT subdomain. In our study, individual scores on risk-taking in the health and safety subdomain of the DOSPERT questionnaire seem to be predictive of health behaviours both during travel and at home. By pairing new methods of data collection with questionnaires such as DOSPERT that identify key traveller characteristics to intervene on, travel medicine doctors will be able to provide more specialised health advice, ensuring that all travellers receive well-rounded advice about the full range of health challenges they will face during travel.


LncRNA LEF1-AS1 Promotes Ovarian Cancer Development Through Interacting with miR-1285-3p.
Growing evidence indicates that long noncoding RNA (lncRNA) is a group of important regulator in cancer development. However, the correlation between lncRNA and ovarian cancer remains elusive. Here, we aimed to investigate the roles of LEF1-AS1 in ovarian cancer progression. LEF1-AS1 expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survival rate was analyzed by Kaplan-Meier method. Cell Counting Kit-8 (CCK8) and colony formation assays were used for proliferation analysis. Transwell assay was utilized for analyses of migration and invasion. Luciferase reporter assay was performed to test the interaction between LEF1-AS1 and miR-1285-3p. We showed that LEF1-AS1 expression was upregulated in ovarian cancer tissues compared with normal tissues. Besides, LEF1-AS1 level was positively correlated with lymph node metastasis and advanced stage. Enhanced expression of LEF1-AS1 may predict a poor prognosis. Moreover, LEF1-AS1 knockdown suppressed ovarian cancer cell proliferation, migration and invasion. Mechanistically, LEF1-AS1 exerted its oncogenic functions through interacting with miR-1285-3p to inhibit miRNA activity. Rescue assay validated that miR-1285-3p inhibitors abrogated LEF1-AS1-silencer-caused suppression of ovarian cancer progression. Our study revealed that LEF1-AS1 acts as a vital regulation in ovarian cancer progression.


Risk and protective factors for cognitive impairment in persons aged 85 years and older.
To determine risk and protective factors for mild cognitive impairment (MCI) among persons 85 years and older. Participants in the population-based prospective Mayo Clinic Study of Aging were comprehensively evaluated at baseline and at 15 monthly intervals to determine incident MCI. At baseline, lifestyle factors in midlife and late life were assessed by self-reported questionnaire; vascular and comorbid conditions were abstracted from participants' medical records. Of 256 participants who were cognitively normal at enrollment (median age 87.3 years, 62% women), 121 developed MCI at a median 4.1 years of follow-up. Predictors of MCI were APOE ε4 allele (hazard ratio [HR] 1.89; p = 0.008), current depressive symptoms (HR 1.78; p = 0.02), midlife onset of hypertension (HR 2.43; p = 0.005), increasing number of vascular diseases (HR 1.13; p = 0.02), and chronic conditions from the Charlson Comorbidity Index (HR 1.08; p = 0.006). Models were adjusted for sex and education, with age as the time variable. The risk of MCI was reduced for participants who reported engagement in artistic (HR 0.27; p = 0.03), craft (HR 0.55; p = 0.02), and social (HR 0.45; p = 0.005) activities in both midlife and late life, and in the use of a computer in late life (HR 0.47; p = 0.008). Chronic disease burden increases risk of MCI, whereas certain lifestyle factors reduce risk in persons 85 years and older. This implies that preventive strategies for MCI may need to begin in midlife and should persist throughout late life.


Evaluation of the flexural strength of dual-cure composite resin cements.
The aim of this study was to evaluate of flexural strength of some adhesive resin cements. Three dual-cure composite resin cements (Nexus 3; Variolink II, Panavia F) were prepared. The manufacturer's mixing directions for the cements were followed. Adhesive resin cement was mixed, placed in the rectangular portion of the mold. Fifteen specimens were prepared for each cements. The cements were light-activated with light lamp for 40 s on both and top and bottom surfaces. The each cement specimens were divided into three groups according to time of storage and stored in distilled water for 24 h, 15, and 30 days. Total 45 specimens were stored at 37°C (98.6 0F) in distilled water for 24 h, 15, and 30 days prior to tests. The flexural strength was tested wıth a universal testing machine at a crosshead speed of 0.5 mm/min (0.02 in.) The maximum load was recorded as MPa. The results were analyzed by Analysis of Variance and Duncan test. The Panavia F resin cements content Bisphenol A was showed the highest flexural strength (80.80 MPa) (11.71 ksi) for 24 h. The lowest flexural strength was observed in Nexus 3 (51.00 MPa) (7.39 ksi). It was found significant interaction of material and time (p < 0.05). The types of cement and time of storage was statistically significant on the flexural strengths (p < 0.001).


Evaluation of Histomorphometric Changes in Tissue Architecture in Relation to Alteration in Fixation Protocol - An Invitro Study.
Preparation of good tissue specimens for microscopy requires complete fixation. No ideal fixative has been found till date, with every fixative showing advantages and disadvantages. Appropriate fixation is required to maintain clear and consistent morphologic features for histologic examination. Pathologists mostly examine formalin fixed tissue sections and are less used to the morphologic changes induced by other fixatives. Underfixed and overfixed tissue in various fixatives can lead to tissue architectural changes which can affect its diagnostic value. To assess sectioning ability, staining intensity and microscopic details of tissues kept in different fixatives at different time intervals. Fresh tissue specimen i.e., goat tongue was collected and its middle-third portion was used for the study purpose. The tissue was grossed into 10 equal pieces and kept in various fixatives (10% Buffered formalin, Carnoy's solution, Absolute ethyl alcohol, Bouin's fluid) for five different time intervals (6, 12, 18, 24 and 30 hours) and normal tissue processing steps were carried out followed by sectioning and staining. During sectioning, sectioning parameter was assessed. Following sectioning, sections were observed under light microscope and were histologically evaluated for staining and microscopic details. To calculate the sectioning parameter Fisher's exact test was used and to assess parameters for staining and microscopic details Mann-Whitney U test was used. According to the study, 10% buffered formaldehyde is considered as a superior fixative under all parameters followed by Bouin's fluid, Carnoy's solution and Absolute alcohol. In our study, it was concluded that 10% buffered formaldehyde should be continued as a routine fixative however, other fixatives can be used depending upon the non-availability of required fixative or in case of emergencies. Pathologist should be accustomed to histologic and morphologic changes of underfixed and overfixed tissue which can affect its diagnostic value.


Prostate cancer age-standardised incidence increase between 2006 and 2016 in Gauteng Province, South Africa: A laboratory data-based analysis.
Prostate cancer (PCa) is the leading male neoplasm in South Africa (SA) and is the second most frequently diagnosed cancer among men globally. Age-specific incidence rates (ASIRs) vary by up to 189-fold globally, with an ASIR of 68.0 per 100 000 in 2018 in SA. To describe PCa among men undergoing prostate biopsy in Gauteng Province, SA. We undertook a retrospective descriptive study using prostate biopsy data collected from the National Health Laboratory Service (NHLS) database between 2006 and 2016. We extracted the Systematized Nomenclature of Medicine (SNOMED) clinical terms morphology and topography codes to assign histological findings using the International Classification of Diseases for Oncology. PCa was defined as adenocarcinoma with a reported Gleason Score (GS). The new grade group (GG) based on the GS is defined as follows; (i) GG1 for a GS ≤6; (ii) GG2 for a GS of 3 + 4 = 7 ; (iii) GG3 for a GS of 4 + 3 = 7; (iv) GG4 for a GS of 8; and (v) GG5 for a GS ≥9. Higher-grade disease was defined as GG4 and GG5 (GS ≥8), in line with local guidelines. We reported associations of PCa with a GS ≥7 with age and race and used provincial and world standard population data to determine annual ASIRs. We identified 22 937 biopsies referred to the NHLS between 2006 and 2016. Of the 6 448 biopsies (39%) with a PCa finding for black Africans, 46% were diagnosed with high-risk PCa compared with 36 - 40% for other race groups (p<0.0001). Black Africans were more likely than whites to have GG4 or GG5 PCa (odds ratio 1.45; 95% confidence interval 1.27 - 1.67). The ASIR increased from 44.9 per 100 000 in 2006 to 57.3 per 100 000 in 2016. Black African men were significantly more likely to present with PCa with a GS ≥8 (GG4 and GG5) compared with the other racial groups in Gauteng. The ASIR increased dramatically during the study period, perhaps as a result of increased screening and awareness. There is a need for additional research to better understand why black African men present with higher-grade disease.


Selection assisted by a BoLA-DR/DQ haplotype against susceptibility to bovine dermatophilosis.
Bovine dermatophilosis is a severe skin infection of tropical ruminants inducing a severe loss in productivity and a 15% mortality rate. This disease is caused by the actinomycete bacterium Dermatophilus congolensis associated with the tick Amblyomma variegatum. Currently there are no prospects for a vaccine, and acaricide or antibiotic control is hampered by the development of chemoresistance. Animal breeders have observed that dermatophilosis susceptibility seems to be determined genetically, and we previously identified a BoLA-DRB3-DQB class II haplotype marker for high (R2= 0.96) susceptibility to the disease. With this marker, we developed a successful eugenic selection procedure for zebu Brahman cattle in Martinique (FWI). Over a period of five years, a marked reduction in disease prevalence, from 0.76 to 0.02 was achieved, and this low level has been maintained over the last two years. The selection procedure, based on a genetic marker system targeting the highly polymorphic BoLA locus, eliminates only those individuals which are at the highest risk of contracting the disease. In the present work, we discuss the properties of this system, including the "heterozygote advantage" and the "frequency dependence" theories, and examine their involvement in the biological mechanisms at the host/pathogen interface. We speculate on the exact role of the MHC molecules in the control of the disease, how the natural selection pressure imposed by the pathogens selectively maintains MHC diversity, and how our results can be practically applied for integrated control of dermatophilosis in developing countries.


Post-traumatic hydrocephalus: An overview of classification, diagnosis, treatment, and post-treatment imaging evaluation.
The syndrome of post-traumatic hydrocephalus (PTH) has been recognized since Dandy's report in 1914. The pathogenesis of PTH has not been fully clarified. At present, it is believed that the obstacles of cerebrospinal fluid (CSF) secretion, absorption and circulation pathways are the reasons for the development of PTH. However, recent studies have also suggested that the osmotic pressure load of CSF and the pathological changes of CSF dynamics are caused by the development of hydrocephalus. Therefore, a better understanding of the definition, classification, diagnostic criteria, treatment, and evaluation of post-treatment effects of PTH is critical for the effective prevention and treatment of PTH. In this paper, we reviewed the classification and diagnosis of PTH and focused on the treatment and the imaging evaluation of post-treatment effects of PTH. This review might provide a judgment criterion for diagnosis of PTH and a basis for the effective prevention and treatment of PTH in the future.


Changes in Health and Well-Being of Care Aides in Nursing Homes From a Pre-Pandemic Baseline in February 2020 to December 2021.
Nursing homes were profoundly affected by the COVID-19 pandemic, influencing work outcomes of care aides who provide the most direct care. We compared care aides' quality of work life by conducting a repeated cross-sectional analysis of data collected in February 2020 and December 2021 from a stratified random sample of urban nursing homes in two Canadian provinces. We used two-level random-intercept repeated-measures regression models, adjusting for demographics and nursing home characteristics. 2348 and 1116 care aides completed the survey in February 2020 and December 2021, respectively. The 2021 sample had higher odds of reporting worked short-staffed daily to weekly in the previous month than the 2020 sample. The 2021 sample also had a small but significant drop in professional efficacy and mental health. Despite the worsening changes, our findings suggest that this workforce may have withstood the pandemic better than might be expected.


Clinical and economic outcomes associated with low-dose fluticasone propionate versus montelukast in children with asthma aged 4 to 11 years.
Inhaled corticosteroids (ICS) are preferred first-line controller agents for adults and adolescents with asthma. There is limited effectiveness data comparing ICS to leukotriene receptor antagonists (LTRA) in children with asthma aged 4 to 11 years. A retrospective, matched cohort study was conducted using medical and pharmacy claims data. Asthma patients (ICD-9, 493.xx) naïve to any asthma controller therapy, and having ≥1 dispensing of fluticasone propionate 44 mcg (FP44), an ICS, or montelukast any dose (MON), an LTRA, were identified. Drug cohorts were matched (1:2) using propensity scores. Outcomes during follow-up included asthma-related ED visits, composite measure of asthma-related ED/hospital visit, asthma-related costs per month, and monthly rescue medication use. Statistical differences between cohorts were evaluated using multivariate regression models. The final matched sample included 6,636 patients (FP44=2,212; MON=4,424). During follow-up, the FP44 cohort had a 29% significantly lower risk of an asthma-related ED visit (Hazard ratio (95% CI) =0.71 (0.52, 0.96)) compared to the MON cohort. Monthly asthma-related costs were significantly reduced on average by 36% in the FP44 compared to the MON cohort ($48 vs $75, p<0.05). Use of short-acting beta-agonists per month were similar between cohorts but monthly adjusted number of oral corticosteroid prescriptions were significantly lower in the FP44 compared to the MON cohort (0.03 vs 0.04, p<0.001). Initiation of FP44 versus MON in children with asthma aged 4 to 11 years is associated with a significant reduction in asthma-related ED visits, costs, and oral corticosteroid use.


An NMR shielding model for protons above the plane of a carbonyl group.
Covalently bonded hydrogen nuclei located over the plane of a carbonyl group in a strong magnetic field experience magnetic shielding (or deshielding) that results from the combined effect of the magnetic anisotropy of the carbon-oxygen double bond and various other intramolecular shielding effects. GIAO-HF in Gaussian 98 was employed to calculate isotropic shielding values and to predict the net proton NMR shielding increment for a simple model system: the proximate proton of methane held in various positions over formaldehyde. The net shielding increments of the proximate proton of methane, plotted against its Cartesian coordinates relative to the center of the carbon-oxygen double bond, led to the development of a single empirical equation for predicting the NMR shielding experienced by a covalently bonded proton over the plane of a carbonyl group. The predictive capability of this equation has been validated by calculating the shielding increments of protons over the plane of a carbonyl group in known structures, using this as a correction to the chemical shift estimated by subtituent effects and comparing the result to experimentally observed chemical shifts. Shielding is predicted by this equation for protons located in the region from over the center of the carbon-oxygen double bond to beyond the carbon atom; deshielding is predicted for protons located above and beyond the oxygen atom. This prediction differs from those made by the long-held "shielding cone" model found in nearly every textbook on NMR, but is consistent with experimental observations. The algorithm for predicting the shielding increment for a proton over a carbonyl group can be used in a spreadsheet or incorporated into software that estimates chemical shifts using additive substituent constants or a database of structures. Its use can improve the accuracy of the estimated chemical shift of a proton in the vicinity of a carbon-oxygen double bond, and thus assist in spectral assignments and in correct structure determination.


Dual adaptation and adaptive generalization of the human vestibulo-ocular reflex.
In two experiments, we examined the possibility that the human vestibulo-ocular reflex (VOR) is subject to dual adaptation (the ability to adapt to a sensory rearrangement more rapidly and/or more completely after repeated experience with it) and adaptive generalization (the ability to adapt more readily to a novel sensory rearrangement as a result of prior dual adaptation training). In Experiment 1, the subjects actively turned the head during alternating exposure to a visual-vestibular rearrangement (target/head gain = 0.5) and the normal situation (target/head gain = 0.0). These conditions produced both adaptation and dual adaptation of the VOR but no evidence of adaptive generalization when tested with a target/head gain of 1.0. Experiment 2, in which exposure to the 0.5 gain entailed externally controlled (i.e., passive) whole body rotation, resulted in VOR adaptation but no dual adaptation. As in Experiment 1, no evidence of adaptive generalization was found.


Gastro-oesophageal reflux disease.
Gastro-oesophageal reflux disease is the most common cause of indigestion in the community, and is usually chronic. Typical symptoms are recurrent retrosternal burning (heartburn) and regurgitation of sour or bitter fluid. In patients with typical symptoms and no alarm symptoms (pain on swallowing, dysphagia, weight loss or anaemia), treatment may be instituted without investigation. Patients with alarm symptoms and those who respond poorly or relapse after initial treatment require investigation (endoscopy and possibly pH monitoring). About 60% of reflux sufferers have no evidence of mucosal injury; their management aims to relieve symptoms. About 40% of reflux sufferers have oesophagitis and/or complications such as Barrett's oesophagus or oesophageal stricture at endoscopy. Drug therapy consists of H2-receptor antagonists, cisapride or proton-pump inhibitors.


Hepatobiliary complications of polyarteritis nodosa.
Although polyarteritis nodosa (PAN) may result in thrombosis or aneurysm formation in any organ in the body, hepatobiliary complications are unusual. We reviewed seven cases that demonstrated the diagnostic difficulties and therapeutic options available in the management of hepatobiliary PAN. No consistent sign that indicated the severity of hepatobiliary PAN could be identified. In cases of thrombotic PAN, acalculus cholecystitis usually could be diagnosed preoperatively. Early tissue diagnosis and aggressive intervention are required for appropriate patient treatment. If the diagnosis is unclear, a preoperative muscle or skin biopsy specimen is often helpful in establishing a tissue diagnosis of PAN, even if no obvious pathologic condition is evident. Patients who undergo celiotomy for acalculus cholecystitis or peritoneal signs of an unclear origin should have tissue specimens (gallbladder wall, liver, or omentum) submitted for pathologic study. Angiography may be diagnostic preoperatively or when results of biopsies are equivocal. In addition, early angiography can define the extent of visceral involvement and permit control by embolization of hemorrhage secondary to aneurysm rupture. Awareness of the possibilities of thrombotic, ischemic, or bleeding complications from PAN allows more aggressive and rapid management of abdominal complaints, especially in patients who are receiving immunosuppressant therapy.


Intestinal probiotics in relieving clinical symptoms of severe hand, foot, and mouth disease and potential mechanism analysis.
In this prospective cohort study, the efficacy and action mechanism of an intestinal probiotic formulation, Golden Bifid, in severe hand, foot, and mouth disease (HFMD) were determined in 63 consecutively admitted patients successfully treated in the Pediatrics Emergency Department of our hospital. All patients had a persistent fever; 43 patients had rashes on hands, feet, crissum, and hips; and 45 patients had neurological signs and symptoms. Patients were treated with standard supportive therapy along with ventilator-assisted respiration combined with bedside hemofiltration for removal of circulatory toxins and to achieve acid-base equilibrium and electrolyte stability. Golden Bifid was orally administered for 2 weeks, and vaccination was performed after patients were in stable condition. Additional supportive nursing care was also provided. Patients were categorized into the effective treatment (n = 40) and ineffective treatment (n = 23) groups. Serum levels of proinflammatory factors [interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and interferon-γ] were significantly decreased and those of anti-inflammatory factors (IL-13, IL-4, and IL-10) were significantly increased after treatment in the effective treatment group. In contrast, in the ineffective treatment group, serum proinflammatory factor levels were significantly increased and serum anti-inflammatory factor levels were significantly decreased. Between-group difference was significant. After treatment, serum D-lactic acid, diamine oxidase, and endotoxin levels were significantly decreased in the effective group and significantly increased in the ineffective group by intra- and inter-group comparisons. Intestinal probiotics were effective in relieving clinical symptoms of severe HFMD, maintaining intestinal immunity and anti-inflammatory responses, and enhancing intestinal barrier function, with better safety and efficacy, which should be further evaluated for more extensive clinical applications.


Non-neutral role of replicative senescence in tissue homeostasis and tumorigenesis.
Normal somatic cells divide only a limited number of times reaching a state known as replicative senescence. This restraint in reproductive potential has been proposed as a mechanism evolved in higher eukaryotes to protect the organism from developing cancer. However, despite this protection there is a positive correlation between tumor incidence and organism aging when cells are potentially closer to their replication limit. We use simple mathematical models derived from quasispecies theory to analyse the role of senescence in various scenarios with different cell types according to their replicative capacity. The models predict that a situation with cells launching more often the senescence response plays against tissue homeostasis favoring tumor initiation. It is also shown that cancer cells arising early in organism life are more sensitive to genetic instabilities progressing less often toward tissue invasion. The passage of cells through crisis emerges as a mechanism to maintain tissue homeostasis that is weakened in aged individuals. The models introduced, though simple, help to integrate experimental information relating tumorigenesis with cellular and organism aging phenomena.


[Problems of development, production and clinical use of highly effective blood substitutes].
An analysis of biological properties of blood substitutes has shown the expedience of wider clinical use instead of polyglucin of such substitutes as polyglucol, polifer, rondex, neorondex, polyoxidin, volecam; instead of rheopolyglucin--the rheopolyglucin with glucose, rheogluman and rheoglusol prepared for clinical tests; instead of haemodesin--haemodesin-H, neohaemodesin, gluconeodesin; instead of protein hydrolysates--polyamine and purified from peptides infusamine, hydromine, amicin; instead of 0.9% solution of sodium chloride--disol, quintasol, lactasol, mafusol. They have polyfunctional properties and considerably increase the effectiveness of the infusion--transfusion therapy.


Comparison of levels of human immunodeficiency virus type 1 RNA in plasma as measured by the NucliSens nucleic acid sequence-based amplification and Quantiplex branched-DNA assays.
This study compared levels of human immunodeficiency virus type 1 RNA in plasma as measured by the Quantiplex branched-DNA and NucliSens nucleic acid sequence-based amplification assays. RNA was detectable in 118 of 184 samples (64.13%) by the Quantiplex assay and in 171 of 184 samples (92.94%) by the NucliSens assay. Regression analysis indicated that a linear relationship existed between the two sets of values (P < 0.0001), although the Quantiplex and NucliSens values were significantly different (P < 0.001), with the NucliSens values being approximately 0.323 log higher. Spearman correlation analysis indicated that the overall changes in patient viral load patterns were highly correlative between the two assays: r = 0.912, P < 0.0001. The lower limits of sensitivity were determined to be approximately 100 copies/ml and 1,200 to 1,400 copies/ml for the NucliSens and Quantiplex assays, respectively.


Obesity in primary care: evidence for advising weight constancy rather than weight loss in unsuccessful dieters.
In view of the limited success rates of all weight-loss strategies to date, this article hypothesises that in situations where previous dieting attempts have failed, better outcomes and health improvements will arise from advocating weight-stability goals. This means the promotion of weight maintenance (to ensure any reduction in weight is maintained) and weight constancy (where steps are taken to maintain existing weight without attempting weight loss), rather than advocating existing 5-10% weight-loss targets for these patients. The majority of approaches to obesity focus on weight reduction despite poor evidence of effectiveness. Primary care remains reluctant to engage in ineffective approaches, yet is well placed to give advice, and would undoubtedly adopt effective obesity-management approaches if they were developed. Despite guidance for overweight or obese people to aim for a 5-10% weight reduction, current trends demonstrate escalation of average weights and obesity. A literature review found little information about evaluation of weight-stability approaches (either weight maintenance or weight constancy), despite theoretical support for them. Yet taking steps to protect weight reduction where it is achieved, and to promote weight constancy (without weight loss) where further dieting is predicted to fail, would have a beneficial effect on preventing further growth of obesity-related morbidity in the population. Some evidence exists to support simple behavioural approaches to improve weight stability, but these measures do not feature in current advice and hence are not widely advocated.


Aortic Stenosis Risk in Rheumatoid Arthritis.
Although an increased risk of ischemic cardiovascular disease has been associated with rheumatoid arthritis (RA), the risk of aortic stenosis (AS) is unknown. To examine the risk of incident AS, aortic valve intervention, AS-related death, and risk factors for AS development in patients with RA. This cohort study linked data from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services from 2000 to 2019. Patients with RA were matched by age, sex, and VHA enrollment year with up to 10 patients without RA. The cohort was followed until incident AS, aortic valve intervention, or death. Data were analyzed from August 23, 2022, to March 3, 2023. the primary exposure was the presence of RA, defined using validated RA algorithms. Aortic stenosis was defined as a composite of inpatient or outpatient diagnoses, surgical or transcatheter aortic valve replacement, or AS-related death using diagnostic and procedural codes. Risk of AS development was assessed with multivariable Cox proportional hazards models adjusted for race, ethnicity, smoking status, body mass index, rurality, comorbidities, and health care use. The cohort included 73 070 patients with RA (64 008 [87.6%] males; mean [SD] age, 63.0 [11.9] years) matched with 639 268 patients without RA (554 182 [86.7%] males; mean [SD] age, 61.9 [11.7] years) and 16 109 composite AS outcomes that occurred over 6 223 150 person-years. The AS incidence rate was 3.97 (95% CI, 3.81-4.13) per 1000 person-years in patients with RA and 2.45 (95% CI, 2.41-2.49) per 1000 person-years in the control patients (absolute difference, 1.52 per 1000 person-years). Rheumatoid arthritis was associated with an increased risk of composite AS (adjusted hazard ratio [AHR], 1.48; 95% CI, 1.41-1.55), aortic valve intervention (AHR, 1.34; 95% CI, 1.22-1.48), and AS-related death (AHR, 1.26; 95% CI, 1.04-1.54). In this cohort study, RA was associated with a higher risk of developing AS and the subsequent risks of undergoing aortic valve intervention and suffering from AS-related death. Future studies are needed to confirm whether valvular heart disease, specifically AS, may be an overlooked cardiovascular disease complication in RA.


Many multipotential gene-marked progenitor or stem cell clones contribute to hematopoiesis in nonhuman primates.
Retroviral insertion site analysis was used to track the contribution of retrovirally transduced primitive progenitors to hematopoiesis after autologous transplantation in the rhesus macaque model. CD34-enriched mobilized peripheral blood cells were transduced with retroviral marking vectors containing the neo gene and were reinfused after total body irradiation. High-level gene transfer efficiency allowed insertion site analysis of individual myeloid and erythroid colony-forming units (CFU) and of highly purified B- and T-lymphoid populations in 2 animals. At multiple time points up to 1 year after transplantation, retroviral insertion sites were identified by performing inverse polymerase chain reaction and sequencing vector-containing CFU or more than 99% pure T- and B-cell populations. Forty-eight unique insertion sequences were detected in the first animal and also in the second animal, and multiple clones contributed to hematopoiesis at 2 or more time points. Multipotential clones contributing to myeloid and lymphoid lineages were identified. These results support the concept that hematopoiesis in large animals is polyclonal and that individual multipotential stem or progenitor cells can contribute to hematopoiesis for prolonged periods. Gene transfer to long-lived, multipotent clones is shown and is encouraging for human gene therapy applications.


[Characterization of secondary immune deficiency in patients with chronic glomerulonephritis].
A study was made of the nature of secondary immuno-deficiency, peculiarities of disordered function of regulatory T-lymphocytes (helpers and suppressors), and their interrelationships in different clinical variants of chronic glomerulonephritis (CGN). Altogether 94 CGN patients were examined, of them 34 were with urinary syndrome and 60 with nephrotic syndrome. With relation to a clinical variant of disease the absolute amount of T-lymphocytes was significantly lowered, the amount and function of B-lymphocytes showed a tendency to an increase. Function of nonspecific Concanavalin A-induced T-suppressors using PHA as a mitogenic indicator (T-T-suppression) was insignificantly raised, and when lipopolysaccharide (T-B-suppression) was used it was considerably suppressed. T-lymphocyte helper activity in CGN patients was on an increase.


Audiological findings after stereotactic radiosurgery in acoustic neurinomas.
Stereotactic radiosurgery was used in the treatment of 126 patients with acoustic neurinomas up to 30 mm in diameter from 1969 to 1984. Adequate follow-up data (mean follow-up period 4.7 years) were available for 111 (116 ears) of these 126 patients; of these 111 patients, 64 (65 ears) had a pure-tone threshold of less than 90 dB before the treatment and were followed up audiologically. Preserved hearing was found in 26% of the ears one year postoperatively. Shrinkage of the tumour was obtained in 44% and arrest of its growth in 42%. There was no mortality related to the radiosurgical treatment. Transitory facial weakness was noted in 15% of the patients (3% in 1983-84). Eighteen per cent of the patients had some, usually transitory, trigeminal dysfunction. The stapedius reflex threshold was improved in 13 ears (20%). In one patient the audiological tests became pathological in the contralateral ear during growth of a new tumour. Initially the stapedius reflex threshold was elevated, and 11 months later the BRA pattern also became abnormal.


Synthesis of oligonucleotides containing 2-N-heteroarylguanine residues and their effect on duplex/triplex stability.
To systematically understand the effect of 2-N-heteroarylguanine (GHA) modification on the stability of higher-order DNA structures, nucleoside derivatives and oligodeoxyribonucleotides containing guanine residues modified with four kinds of hereroaryl groups on the 2-amino group were synthesized. The stabilities of the DNA duplex and the parallel-oriented DNA triplex containing these GHAs were studied by measuring their melting temperatures (Tm). Tm experiments and DFT calculations of the modified guanine nucleobases suggested that the base pair formation energy and stability of the two conformations, i.e., the open- and closed-type conformations, are key to determining the stability of the DNA duplex. Finally, the DNA triplex was destabilized when modified guanine residues were introduced into triplex-forming oligonucleotides.


Infection after total elbow arthroplasty.
Deep sepsis occurred after fourteen (9 per cent) of 156 elbow-replacement procedures in 140 patients. This high frequency of infection was attributed to several factors. First, the patients were drawn from a population that was at high risk of infection, because rheumatoid arthritis and post-traumatic arthritis were the indications for arthroplasty. Second, many of the patients had had prior surgery, which significantly (p less than 0.02) increased the risk of sepsis in those with rheumatoid arthritis. Third, some patients had surgery after the arthroplasty, which also seemed to predispose to deep infection (p less than 0.05). In one patient the elbow was salvaged by early débridement, and in two others reimplantation of a total joint replacement was successful after removal of the first prosthesis and control of the infection. Resection arthroplasty was required to arrest the infection in ten patients, eight of whom had a satisfactory result. The high incidence of this significant complication attests to the hazardous nature of the elbow-replacement procedure and should warn orthopaedic surgeons to be cautious when recommending this form of treatment.


Infection Control for Drug-Resistant Tuberculosis: Early Diagnosis and Treatment Is the Key.
Multidrug-resistant (MDR) tuberculosis, "Ebola with wings," is a significant threat to tuberculosis control efforts. Previous prevailing views that resistance was mainly acquired through poor treatment led to decades of focus on drug-sensitive rather than drug-resistant (DR) tuberculosis, driven by the World Health Organization's directly observed therapy, short course strategy. The paradigm has shifted toward recognition that most DR tuberculosis is transmitted and that there is a need for increased efforts to control DR tuberculosis. Yet most people with DR tuberculosis are untested and untreated, driving transmission in the community and in health systems in high-burden settings. The risk of nosocomial transmission is high for patients and staff alike. Lowering transmission risk for MDR tuberculosis requires a combination approach centered on rapid identification of active tuberculosis disease and tuberculosis drug resistance, followed by rapid initiation of appropriate treatment and adherence support, complemented by universal tuberculosis infection control measures in healthcare facilities. It also requires a second paradigm shift, from the classic infection control hierarchy to a novel, decentralized approach across the continuum from early diagnosis and treatment to community awareness and support. A massive scale-up of rapid diagnosis and treatment is necessary to control the MDR tuberculosis epidemic. This will not be possible without intense efforts toward the implementation of decentralized, ambulatory models of care. Increasing political will and resources need to be accompanied by a paradigm shift. Instead of focusing on diagnosed cases, recognition that transmission is driven largely by undiagnosed, untreated cases, both in the community and in healthcare settings, is necessary. This article discusses this comprehensive approach, strategies available, and associated challenges.


The effects of partitioning on phylogenetic inference.
Partitioning is a commonly used method in phylogenetics that aims to accommodate variation in substitution patterns among sites. Despite its popularity, there have been few systematic studies of its effects on phylogenetic inference, and there have been no studies that compare the effects of different approaches to partitioning across many empirical data sets. In this study, we applied four commonly used approaches to partitioning to each of 34 empirical data sets, and then compared the resulting tree topologies, branch-lengths, and bootstrap support estimated using each approach. We find that the choice of partitioning scheme often affects tree topology, particularly when partitioning is omitted. Most notably, we find occasional instances where the use of a suboptimal partitioning scheme produces highly supported but incorrect nodes in the tree. Branch-lengths and bootstrap support are also affected by the choice of partitioning scheme, sometimes dramatically so. We discuss the reasons for these effects and make some suggestions for best practice.


Psychosocial functioning in the balance between autism and psychosis: evidence from three populations.
Functional impairment is a core feature of both autism and schizophrenia spectrum disorders. While diagnostically independent, they can co-occur in the same individual at both the trait and diagnostic levels. The effect of such co-occurrence is hypothesized to worsen functional impairment. The diametric model, however, suggests that the disorders are etiologically and phenotypically diametrical, representing the extreme of a unidimensional continuum of cognition and behavior. A central prediction of this model is that functional impairment would be attenuated in individuals with mixed symptom expressions or genetic liability to both disorders. We tested this hypothesis in two clinical populations and one healthy population. In individuals with chronic schizophrenia and in individuals with first episode psychosis we evaluated the combined effect of autistic traits and positive psychotic symptoms on psychosocial functioning. In healthy carriers of alleles of copy number variants (CNVs) that confer risk for both autism and schizophrenia, we also evaluated whether variation in psychosocial functioning depended on the combined risk conferred by each CNV. Relative to individuals with biased symptom/CNV risk profiles, results show that functional impairments are attenuated in individuals with relatively equal levels of positive symptoms and autistic traits-and specifically stereotypic behaviors-, and in carriers of CNVs with relatively equal risks for either disorder. However, the pattern of effects along the "balance axis" varied across the groups, with this attenuation being generally less pronounced in individuals with high-high symptom/risk profile in the schizophrenia and CNV groups, and relatively similar for low-low and high-high individuals in the first episode psychosis group. Lower levels of functional impairments in individuals with "balanced" symptom profile or genetic risks would suggest compensation across mechanisms associated with autism and schizophrenia. CNVs that confer equal risks for both disorders may provide an entry point for investigations into such compensatory mechanisms. The co-assessment of autism and schizophrenia may contribute to personalized prognosis and stratification strategies.


The natural course of Hashimoto's thyroiditis in children and adolescents.
Hashimoto's thyroiditis (HT) is the most common cause of thyroid disease in children and adolescents, but little is known about the long-term follow-up of HT. The aim of this study was to analyze the clinical and laboratory characteristics and to observe the natural course of HT in children and adolescents. We retrospectively reviewed 153 patients with HT diagnosed before 18 years of age. Subjects were grouped into euthyroid, subclinical hypothyroidism, overt hypothyroidism, and hyperthyroidism on the basis of the thyroid function test. Of the 153 subjects, 133 were followed up (range 6∼181 months) at our clinic every 6 months for evaluation of goiter size, thyroid function, thyroid peroxidase antibodies (TPO Ab), and thyroglobulin antibodies (TG Ab) serum concentration. Thyroid function tests at the time of presentation revealed euthyroid in 72 patients (47.1%), subclinical hypothyroidism in 48 (31.4%), overt hypothyroidism in 22 (14.4%), and hyperthyroidism in 11 (7.2%). Serum TPO Ab and TG Ab significantly decreased in the subclinical hypothyroidism group with levothyroxine treatment. Also, there was a significant decrease in the mean serum TG Ab levels among the overt hypothyroid patients during the follow-up period, although TPO Ab levels were not significantly different when compared to their baseline TPO Ab levels. Most children with HT were euthryoid and remained euthyroid during follow-up. However, thyroid function should still be monitored periodically for early detection and treatment of overt hypothyroidism. Our data also showed that levothyroxine treatment may have beneficial effects on the thyroid antibody titers.


Hydration characteristics of alpha-tricalcium phosphates: Comparison of preparation routes.
Alpha tricalcium phosphate ( á -TCP) cement powders were obtained by solid state reaction and milling (M1) and by precipitation from aqueous solution followed by heating (M2). The materials were hydrated to form calcium-deficient hydroxyapatite (CDHA) with a 2.5 wt% solution of Na2 HPO4 (liquid to powder ratio = 0.34 ml/g, temperature = 37.5 degrees C) and subjected to isothermal calorimetry, mechanical compression tests, X-ray powder diffraction, at various times during hydration, as well as scanning electron microscopy (SEM), laser diffraction and gas adsorption. The particle characteristics of the two powders were similar, but M2 exhibited two reaction events in the thermal power curve, while M1 showed a single event. Both reaction events were attributed to á -TCP dissolution and CDHA recipitation. The minimum in the reaction rate response of M2 was probably due to the formation of a passivating product layer. No such layer was formed on the milled M1 due to its rougher surfaces. Both preparations reached a compressive strength of 30-40 MPa after 24 hr.


Patient, Clinician, and Communication Factors Associated with Colorectal Cancer Screening.
Screening for colorectal cancer is beneficial. Yet, screening remains suboptimal, and underserved populations are at greater risk for not being appropriately screened. Although many barriers to screening are understood, less is known about how the decision-making process on whether to receive colonoscopy or stool testing influences screening. As part of a randomized controlled trial to test engaging underserved populations in preventive care through online, personalized, educational material, 2417 patients aged 50 to 74 years were randomly selected from the 70,998 patients with an office visit the year prior and mailed a survey to assess decision-making for colorectal cancer screening. Twenty practices in practice-based research networks from 5 diverse states participated. Survey data were supplemented with electronic health record data. Among respondents, 64% were or became up to date with screening within 3 months of their office visit. The main factor associated with being up to date was the length of the patient-clinician relationship (<6 months vs 5+ years: odds ratio [OR], 0.49; 95% CI, 0.30-0.80). Sharing the decision about screening options with the clinician was a predictor for being up to date compared with patients who made the decision for themselves (OR, 1.75; 95% CI, 1.27-2.44). Only 36% of patients reported being given a choice about screening options. Traditional factors like race, employment, insurance, and education were not associated with screening. Having a long-term relationship with a primary care clinician and sharing decisions may be key drivers to ensure evidence-based preventive care for underserved populations.


Protein antigens of Streptococcus mutans: purification and properties of a double antigen and its protease-resistant component.
A surface protein antigen of Streptococcus mutans having two sets of antigenic determinants (antigens I and II) was purified by column chromatography from culture supernatants of S. mutans serotype c. The protease-resistant component, antigen II, was purified from pronase-digested antigen I/II. The antigens were analyzed chemically and immunologically, and their physicochemical properties were investigated. Antigen I/II consisted of more than 80% protein, and its peptide chain molecular weight was estimated to be 185,000. Antigen II consisted of approximately 60% protein, with a peptide chain molecular weight of 48,000. Antisera to antigens I/II and II were raised in rabbits and used to investigate the presence of the antigens in cells of other streptococci. This indicated that not only serotype c but also serotypes e and f possessed antigen I and II determinants, whereas serotypes a, d, and g possessed a determinant related to antigen I but not one related to antigen II.


Secretory cells of the peripheral pulmonary epithelium as targets for toxic agents.
The extracellular lining of the pulmonary peripheral airways is of vital importance to the lung. In this report, some aspects of the pulmonary extracellular lining and the epithelial cells believed to be responsible for its formation and secretion have been briefly reviewed. The influence of a number of toxic agents on the extracellular lining either directly or via those cells involved in its formation indicates that the extracellular lining may be important in understanding numerous toxic agent interactions with the lung.


Linear Support Tensor Machine With LSK Channels: Pedestrian Detection in Thermal Infrared Images.
Pedestrian detection in thermal infrared images poses unique challenges because of the low resolution and noisy nature of the image. Here, we propose a mid-level attribute in the form of the multidimensional template, or tensor, using local steering kernel (LSK) as low-level descriptors for detecting pedestrians in far infrared images. LSK is specifically designed to deal with intrinsic image noise and pixel level uncertainty by capturing local image geometry succinctly instead of collecting local orientation statistics (e.g., histograms in histogram of oriented gradients). In order to learn the LSK tensor, we introduce a new image similarity kernel following the popular maximum margin framework of support vector machines facilitating a relatively short and simple training phase for building a rigid pedestrian detector. Tensor representation has several advantages, and indeed, LSK templates allow exact acceleration of the sluggish but de facto sliding window-based detection methodology with multichannel discrete Fourier transform, facilitating very fast and efficient pedestrian localization. The experimental studies on publicly available thermal infrared images justify our proposals and model assumptions. In addition, the proposed work also involves the release of our in-house annotations of pedestrians in more than 17 000 frames of OSU color thermal database for the purpose of sharing with the research community.


Exhaled Breath Analysis Using Selected Ion Flow Tube Mass Spectrometry and Disease Severity in Heart Failure.
Exhaled breath volatile organic compounds (VOCs) are elevated in heart failure (HF). The ability of VOCs to predict long term cardiovascular mortality and morbidity has not been independently verified. In 55 patients admitted with acute decompensated heart failure (ADHF), we measured exhaled breath acetone and pentane levels upon admission and after 48 h of diuresis. In a separate cohort of 51 cardiac patients undergoing cardiopulmonary exercise testing (CPET), we measured exhaled breath acetone and pentane levels before and at peak exercise. In the ADHF cohort, admission acetone levels correlated with lower left ventricular ejection fraction (LVEF, r = -0.297, p = 0.035). Greater weight loss with diuretic therapy correlated with a greater reduction in both acetone levels (r = -0.398, p = 0.003) and pentane levels (r = -0.309, p = 0.021). In patients with above-median weight loss (≥4.5 kg), patients demonstrated significantly greater percentage reduction in acetone (59% reduction vs. 7% increase, p < 0.001) and pentane (23% reduction vs. 2% reduction, p = 0.008). In the CPET cohort, admission acetone and pentane levels correlated with higher VE/VCO2 (r = 0.39, p = 0.005), (r = 0.035, p = 0.014). However, there were no significant correlations between baseline or peak exercise acetone and pentane levels and peak VO2. In longitudinal follow-up with a median duration of 33 months, patients with elevated exhaled acetone and pentane levels experienced higher composite adverse events of death, ventricular assist device implantation, or orthotopic heart transplantation. In patients admitted with ADHF, higher exhaled breath acetone levels are associated with lower LVEF and poorer outcomes, and greater reductions in exhaled breath acetone and pentane tracked with greater weight loss. Exhaled acetone and pentane may be novel biomarkers in heart failure worthy of future investigation.


Design considerations in a clinical trial of a cognitive behavioural intervention for the management of low back pain in primary care: Back Skills Training Trial.
Low back pain (LBP) is a major public health problem. Risk factors for the development and persistence of LBP include physical and psychological factors. However, most research activity has focused on physical solutions including manipulation, exercise training and activity promotion. This randomised controlled trial will establish the clinical and cost-effectiveness of a group programme, based on cognitive behavioural principles, for the management of sub-acute and chronic LBP in primary care. Our primary outcomes are disease specific measures of pain and function. Secondary outcomes include back beliefs, generic health related quality of life and resource use. All outcomes are measured over 12 months. Participants randomised to the intervention arm are invited to attend up to six weekly sessions each of 90 minutes; each group has 6-8 participants. A parallel qualitative study will aid the evaluation of the intervention. In this paper we describe the rationale and design of a randomised evaluation of a group based cognitive behavioural intervention for low back pain.


Chronic Stress Does Not Influence the Survival of Mouse Models of Glioblastoma.
The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain tumors is not known. Glioblastoma (GBM) is a highly malignant primary brain cancer, for which effective treatments do not exist. Understanding how chronic stress, or its effector hormones glucocorticoids (GCs), may modulate GBM aggressiveness is of great importance. To address this, we used both syngeneic and xenograft in vivo orthotopic mouse models of GBM, in immunocompetent C57BL/6J or immunodeficient NSG mice, respectively, to evaluate how different paradigms of stress exposure could influence GBM aggressiveness and animals' overall survival (OS). Our results demonstrated that a previous exposure to exogenous corticosterone administration, chronic restraint stress, or chronic unpredictable stress do not impact the OS of these mice models of GBM. Concordantly, ex vivo analyses of various GBM-relevant genes showed similar intra-tumor expression levels across all experimental groups. These findings suggest that corticosterone and chronic stress do not significantly affect GBM aggressiveness in murine models.


Prevalence of the Different Types of Palmar Creases Among Medical and Dental Students in Addis Ababa, Ethiopia.
Studies have suggested that identification of aberrant palmar creases may give clues for an early and noninvasive method of diagnosis of certain disease conditions. Toward this purpose, awareness of the normal variants of palmar creases must be first recognized. Accordingly, this study aimed to investigate the patterns of palmar creases in healthy Ethiopian population among Medical and Dental Students in Addis Ababa. Right and left palm pictures from 318 (177 females and 141 males) participants were taken using a mobile camera, and evaluated qualitatively. Observations were analyzed by Fisher's exact test, and significance levels for comparisons were set at p<0.05. Aberrant creases were observed in 13.8% of the palms. Simian crease was the most common among the aberrant crease types, followed by Suwon and Sydney. Palmar creases with two and three points of origin were significantly more common, respectively, in males and the females. Minor variants as accessory to the radial longitudinal crease and middle longitudinal crease were also observed. This study suggests that aberrant crease types at the observed frequencies may not be indicative of known disease conditions as they occurred in apparently healthy Ethiopians. However, the results of this study, besides revealing the patterns of palmar creases among Ethiopians, could give a baseline for studies aimed at diagnosis of disease conditions based on palmar crease configurations. Further qualitative and quantitative studies of palmar creases in wider populations with various conditions, including ethno-geographic factors, are recommended.


A critical review of adolescent problem gambling assessment instruments.
The field of youth gambling assessment is in its infancy. Currently four youth problem gambling instruments have been used to identify adolescent problem gamblers: a) South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA); b) DSM-IV-Juvenile (DSM-IV-J) and the related DSM-IV-Multiple Response-Juvenile (DSM-IV-MR-J); c) Massachusetts Gambling Screen (MAGS) and d) Canadian Adolescent Gambling Inventory (CAGI). Three of the four instruments are adaptations of adult instruments, and none of the four have undergone rigorous psychometric evaluation. While these instruments are used with varying populations in divergent settings, the psychometric properties for their use in these populations and settings are unknown. This review provides information about the instruments and makes suggestions for further instrument development and refinement. Each instrument is described in terms of its development, content, intended purpose, psychometric properties, administration method, scoring instructions, and interpretation. Strengths and limitations of each instrument are compared for both research and clinical purposes. Existing instruments are used to make clinical, scientific, and public policy decisions, and therefore, it is critical that these instruments demonstrate evidence of reliability, validity and accuracy. It is recommended that the field adopt testing standards for the development and use of adolescent problem gambling scales, and generate a body of rigorous psychometric research that demonstrates reliability, validity, and classification accuracy. Ultimately, the goal is to improve measurement precision in identifying youth problem gamblers.


Metabolomics of Endurance Capacity in World Tour Professional Cyclists.
The study of elite athletes provides a unique opportunity to define the upper limits of human physiology and performance. Across a variety of sports, these individuals have trained to optimize the physiological parameters of their bodies in order to compete on the world stage. To characterize endurance capacity, techniques such as heart rate monitoring, indirect calorimetry, and whole blood lactate measurement have provided insight into oxygen utilization, and substrate utilization and preference, as well as total metabolic capacity. However, while these techniques enable the measurement of individual, representative variables critical for sports performance, they lack the molecular resolution that is needed to understand which metabolic adaptations are necessary to influence these metrics. Recent advancements in mass spectrometry-based analytical approaches have enabled the measurement of hundreds to thousands of metabolites in a single analysis. Here we employed targeted and untargeted metabolomics approaches to investigate whole blood responses to exercise in elite World Tour (including Tour de France) professional cyclists before and after a graded maximal physiological test. As cyclists within this group demonstrated varying blood lactate accumulation as a function of power output, which is an indicator of performance, we compared metabolic profiles with respect to lactate production to identify adaptations associated with physiological performance. We report that numerous metabolic adaptations occur within this physically elite population (n = 21 males, 28.2 ± 4.7 years old) in association with the rate of lactate accumulation during cycling. Correlation of metabolite values with lactate accumulation has revealed metabolic adaptations that occur in conjunction with improved endurance capacity. In this population, cycling induced increases in tricarboxylic acid (TCA) cycle metabolites and Coenzyme A precursors. These responses occurred proportionally to lactate accumulation, suggesting a link between enhanced mitochondrial networks and the ability to sustain higher workloads. In association with lactate accumulation, altered levels of amino acids before and after exercise point to adaptations that confer unique substrate preference for energy production or to promote more rapid recovery. Cyclists with slower lactate accumulation also have higher levels of basal oxidative stress markers, suggesting long term physiological adaptations in these individuals that support their premier competitive status in worldwide competitions.


Coding accuracy is not fully determined by the neuronal model.
It is automatically assumed that the accuracy with which a stimulus can be decoded is entirely determined by the properties of the neuronal system. We challenge this perspective by showing that the identification of pure tone intensities in an auditory nerve fiber depends on both the stochastic response model and the arbitrarily chosen stimulus units. We expose an apparently paradoxical situation in which it is impossible to decide whether loud or quiet tones are encoded more precisely. Our conclusion reaches beyond the topic of auditory neuroscience, however, as we show that the choice of stimulus scale is an integral part of the neural coding problem and not just a matter of convenience.


Active and passive vaccination against hantavirus pulmonary syndrome with Andes virus M genome segment-based DNA vaccine.
Hantavirus pulmonary syndrome (HPS) is a rapidly progressing human disease with one of the highest case fatality rates (30 to 50%) of any acute viral disease known. There are no vaccines, effective antiviral drugs, or immunologics to prevent or treat HPS. In an attempt to develop HPS medical countermeasures, we constructed an expression plasmid, pWRG/AND-M, that contains the full-length M genome segment of Andes virus (ANDV), a South American hantavirus. Transfection experiments in cell culture indicated that both the G1 and G2 glycoproteins are expressed from pWRG/AND-M. Rhesus macaques vaccinated by gene gun with pWRG/AND-M developed remarkably high levels of neutralizing antibodies that not only neutralized ANDV but also cross-neutralized other HPS-associated hantaviruses, including Sin Nombre virus. To determine if the antibodies elicited in the monkeys could confer protection, we performed a series of passive-transfer experiments using a recently described lethal HPS animal model (i.e., adult Syrian hamsters develop HPS and die within 10 to 15 days after challenge with ANDV). When injected into hamsters 1 day before challenge, sera from the vaccinated monkeys either provided sterile protection or delayed the onset of HPS and death. When injected on day 4 or 5 after challenge, the monkey sera protected 100% of the hamsters from lethal disease. These data provide a proof of concept for a gene-based HPS vaccine and also demonstrate the potential value of a postexposure immunoprophylactic to treat individuals after exposure, or potential exposure, to these highly lethal hantaviruses.


Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex.
Mouse MT-I (metallothionein-I) transcription is regulated by MTF-1 (metal-response-element-binding transcription factor-1) which is recruited to the promoter in response to zinc. Cr(VI) [chromium(VI)] pretreatment blocks zinc-activation of the endogenous MT-I gene and attenuates zinc-activation of MT-I-promoter-driven luciferase reporter genes in transient transfection assays. Chromatin immunoprecipitation assays revealed that Cr(VI) only modestly reduces recruitment of MTF-1 to the MT-I promoter in response to zinc, but drastically reduces the recruitment of RNA polymerase II. These results suggest that Cr(VI) inhibits the ability of MTF-1 to transactivate this gene in response to zinc. Zinc has recently been shown to induce the formation of a co-activator complex containing MTF-1 and the histone acetyltransferase p300 which plays an essential role in the activation of MT-I transcription. In the present study, co-immunoprecipitation assays demonstrated that Cr(VI) pretreatment blocks the zinc-induced formation of this co-activator complex. Thus Cr(VI) inhibits mouse MT-I gene expression in response to zinc by interfering with the ability of MTF-1 to form a co-activator complex containing p300 and recruiting RNA polymerase II to the promoter.


Mediterranean diet and other lifestyle factors in relation to 20-year all-cause mortality: a cohort study in an Italian population.
The aim of the present analysis was to evaluate the association of the Mediterranean diet (MeDi), smoking habits and physical activity with all-cause mortality in an Italian population during a 20-year follow-up study. A total of 1693 subjects aged 40-74 who enrolled in the study in 1991-5 were asked about dietary and other lifestyle information at baseline. Adherence to the MeDi was evaluated by the Mediterranean dietary score (MedDietScore). A healthy lifestyle score was computed by assigning 1 point each for a medium or high adherence to the MedDietScore, non-smoking and physical activity. Cox models were used to assess the associations between lifestyle factors and healthy lifestyle scores and all-cause mortality, adjusting for potential confounders. The final sample included 974 subjects with complete data and without chronic disease at baseline. During a median of 17·4 years of follow-up, 193 people died. Subjects with high adherence to the MedDietScore (hazard ratio (HR) 0·62, 95 % CI 0·43, 0·89)), non-smokers (HR 0·71, 95 % CI 0·51, 0·98) and physically active subjects (HR 0·55, 95 % CI 0·36, 0·82) were at low risk of death. Each point increase in the MedDietScore was associated with a significant 5 % reduction of death risk. Subjects with 1, 2 or 3 healthy lifestyle behaviours had a significantly 39, 56, and 73 % reduced risk of death, respectively. A high adherence to MeDi, non-smoking and physical activity were strongly associated with a reduced risk of all-cause mortality in healthy subjects after long-term follow-up. This reduction was even stronger when the healthy lifestyle behaviours were combined.


Adaptive Control of an Artificial Pancreas Using Model Identification, Adaptive Postprandial Insulin Delivery, and Heart Rate and Accelerometry as Control Inputs.
People with type 1 diabetes (T1D) have varying sensitivities to insulin and also varying responses to meals and exercise. We introduce a new adaptive run-to-run model predictive control (MPC) algorithm that can be used to help people with T1D better manage their glucose levels using an artificial pancreas (AP). The algorithm adapts to individuals' different insulin sensitivities, glycemic response to meals, and adjustment during exercise as a continuous input during free-living conditions. A new insulin sensitivity adaptation (ISA) algorithm is presented that updates each patient's insulin sensitivity during nonmeal periods to reduce the error between the actual glucose levels and the process model. We further demonstrate how an adaptive learning postprandial hypoglycemia prevention algorithm (ALPHA) presented in the previous work can complement the ISA algorithm, and the algorithm can adapt in several days. We further show that if physical activity is incorporated as a continuous input (heart rate and accelerometry), performance is improved. The contribution of this work is the description of the ISA algorithm and the evaluation of how ISA, ALPHA, and incorporation of exercise metrics as a continuous input can impact glycemic control. Incorporating ALPHA, ISA, and physical activity into the MPC improved glycemic outcome measures. The adaptive learning postprandial hypoglycemia prevention algorithm combined with ISA significantly reduced time spent in hypoglycemia by 71.7% and the total number of rescue carbs by 67.8% to 0.37% events/day/patient. Insulin sensitivity adaptation significantly reduced model-actual mismatch by 12.2% compared to an AP without ISA. Incorporating physical activity as a continuous input modestly improved time in the range 70 to 180 mg/dL during high physical activity days from 84.4% to 84.9% and reduced the percentage time in hypoglycemia by 23.8% from 2.1% to 1.6%. Adapting postprandial insulin delivery, insulin sensitivity, and adapting to physical exercise in an MPC-based AP systems can improve glycemic outcomes.


Resistance-breaking profiling and gene expression analysis on an organometallic ReI-phenanthridine complex reveal parallel activation of two apoptotic pathways.
Emerging resistances of tumors against multiple anti-cancer agents are a major concern in the chemotherapeutical treatment of various cancers. Clearly, this raises the need for novel therapeutics with new modes of action. Herein, we report on the favorable in vitro anti-proliferative properties of a phenanthridine-containing ReI(CO)3 complex (compound 1, also abbreviated LR-166) and identify major contributions to its mode of action. The complex induces apoptosis in low micromolar concentrations even in drug-resistant Burkitt-like lymphoma (BJAB) and leukemia (Nalm-6) cell lines with known overexpression of p-glycoproteins as was confirmed by measuring the amount of hypodiploid DNA via FACS Scan analysis. Importantly, a gene expression analysis in combination with toxicity studies on a number of modified cell lines (leukemia: NALM-6, lymphoma: BJAB, melanoma: MelHO) and the reduction of mitochondrial membrane potential (determined by adding JC-1 dye, followed by FACS analysis) confirmed the activation of both, the extrinsic and the intrinsic apoptotic pathway. Finally, the mechanism of action was shown not to be influenced by overexpression of the anti-apoptotic factor Bcl-2 in Mel-HO cells which are known to be resistant to a variety of drugs. All taken together, our experiments underscore the unique opportunities inherent in this novel lead structure of Re complexes to act as an effective chemotherapeutic agent in a combination therapy to overcome documented drug resistances in tumors.


Keratinization of the adult male foreskin and implications for male circumcision.
The theory that a more thinly keratinized inner foreskin leads to increased HIV-1 susceptibility has been based on relatively little published data. We sought to quantify the keratin thicknesses of the inner and outer foreskin to determine the plausibility of this hypothesis. We took repeated measurements of the keratin layer of 16 adult male foreskins to determine whether differences existed between the inner and outer foreskin. Adult foreskins were collected from consenting donors undergoing elective male circumcision for unknown medical indications in Chicago, Illinois, USA. Specimens were processed, sectioned and stained for keratin using antifilaggrin fluorescent antibodies. Slides stained with hematoxylin and eosin were used as controls and compared with results from previously published studies using this method. Keratin layers were measured in a standardized fashion for each specimen. Comparing our fluorescence-based analysis with previously published immunohistochemical methods revealed that our method was highly accurate for measuring foreskin keratin thickness. There was significant heterogeneity in the keratin thickness of the inner and outer aspects of the male foreskin within and between the different donors. There was no significant difference between the inner and outer foreskin keratin thickness (25.37 +/- 12.51 and 20.54 +/- 12.51 microm, respectively; P = 0.451). We found no difference between the keratinization of the inner and outer aspects of the adult male foreskin. Keratin layers alone are unlikely to explain why uncircumcised men are at higher risk for HIV infection.


Enrichment of oligonucleotide sets with transcription control signals. II: Mammalian DNA.
We studied the frequency distribution of oligonucleotides 10 bp long in a sample of 1.6 Mb of mammalian genes, containing 579 sequences from GenBank(R) 55.0, with the aim of detecting transcription control signals. 2216 decamers had a frequency higher than 10 times the mean and were subjected to further statistical analysis. For each of the 2216 decamers (parents), we counted the individual frequencies of the 30 decamers differing from the parent by one base mutation (progeny) and then calculated two variance/mean chi squares for the progeny, with and without the parent. We then studied the distribution of the ratio between the two chi squares. Out of 2216 decamers, 346 had a chi square ratio of 1.9 or larger. In this final set, which corresponds to less than 0.033 per cent of all possible decamers, 18 were found to contain 23 eukaryotic transcription control elements 5-10 bp of length, such as Sp1 and others. Furthermore, when compared to 210 random sets containing 346 decamers, this set contains a highly significant excess of the longer signals.


Video game playing increases food intake in adolescents: a randomized crossover study.
Video game playing has been linked to obesity in many observational studies. However, the influence of this sedentary activity on food intake is unknown. The objective was to examine the acute effects of sedentary video game play on various components of energy balance. With the use of a randomized crossover design, 22 healthy, normal-weight, male adolescents (mean ± SD age: 16.7 ± 1.1 y) completed two 1-h experimental conditions, namely video game play and rest in a sitting position, followed by an ad libitum lunch. The endpoints were spontaneous food intake, energy expenditure, stress markers, appetite sensations, and profiles of appetite-related hormones. Heart rate, systolic and diastolic blood pressures, sympathetic tone, and mental workload were significantly higher during the video game play condition than during the resting condition (P < 0.05). Although energy expenditure was significantly higher during video game play than during rest (mean increase over resting: 89 kJ; P < 0.01), ad libitum energy intake after video game play exceeded that measured after rest by 335 kJ (P < 0.05). A daily energy surplus of 682 kJ (163 kcal) over resting (P < 0.01) was observed in the video game play condition. The increase in food intake associated with video game play was observed without increased sensations of hunger and was not compensated for during the rest of the day. Finally, the profiles of glucose, insulin, cortisol, and ghrelin did not suggest an up-regulation of appetite during the video game play condition. A single session of video game play in healthy male adolescents is associated with an increased food intake, regardless of appetite sensations. The trial was registered at clinicaltrials.gov as NCT01013246.


National spending on health by source for 184 countries between 2013 and 2040.
A general consensus exists that as a country develops economically, health spending per capita rises and the share of that spending that is prepaid through government or private mechanisms also rises. However, the speed and magnitude of these changes vary substantially across countries, even at similar levels of development. In this study, we use past trends and relationships to estimate future health spending, disaggregated by the source of those funds, to identify the financing trajectories that are likely to occur if current policies and trajectories evolve as expected. We extracted data from WHO's Health Spending Observatory and the Institute for Health Metrics and Evaluation's Financing Global Health 2015 report. We converted these data to a common purchasing power-adjusted and inflation-adjusted currency. We used a series of ensemble models and observed empirical norms to estimate future government out-of-pocket private prepaid health spending and development assistance for health. We aggregated each country's estimates to generate total health spending from 2013 to 2040 for 184 countries. We compared these estimates with each other and internationally recognised benchmarks. Global spending on health is expected to increase from US$7·83 trillion in 2013 to $18·28 (uncertainty interval 14·42-22·24) trillion in 2040 (in 2010 purchasing power parity-adjusted dollars). We expect per-capita health spending to increase annually by 2·7% (1·9-3·4) in high-income countries, 3·4% (2·4-4·2) in upper-middle-income countries, 3·0% (2·3-3·6) in lower-middle-income countries, and 2·4% (1·6-3·1) in low-income countries. Given the gaps in current health spending, these rates provide no evidence of increasing parity in health spending. In 1995 and 2015, low-income countries spent $0·03 for every dollar spent in high-income countries, even after adjusting for purchasing power, and the same is projected for 2040. Most importantly, health spending in many low-income countries is expected to remain low. Estimates suggest that, by 2040, only one (3%) of 34 low-income countries and 36 (37%) of 98 middle-income countries will reach the Chatham House goal of 5% of gross domestic product consisting of government health spending. Despite remarkable health gains, past health financing trends and relationships suggest that many low-income and lower-middle-income countries will not meet internationally set health spending targets and that spending gaps between low-income and high-income countries are unlikely to narrow unless substantive policy interventions occur. Although gains in health system efficiency can be used to make progress, current trends suggest that meaningful increases in health system resources will require concerted action. Bill & Melinda Gates Foundation.


[Intravenous anesthesia in surgical interventions in ambulatory practice].
Intravenous anesthesia with calipsol and diprivan was used in 297 gynecological patients subjected to various short-term interventions. The course of anesthesia was monitored (arterial pressure, respiration rate, SaO2, Fet CO2) and time course of recovery of attention, thinking, and motor activity in the postoperative period after different types of anesthesia was assessed. Diprivan and fentanyl (0.7-0.8 microgram/kg) anesthesia is preferable for surgical interventions in an outpatient setting due to a smooth and uneventful course of the postoperative period and its slight effect on the cardiovascular system.


Toll-Interacting Protein in Resolving and Non-Resolving Inflammation.
Innate leukocytes manifest dynamic and distinct inflammatory responses upon challenges with rising dosages of pathogen-associated molecular pattern molecules such as lipopolysaccharide (LPS). To differentiate signal strengths, innate leukocytes may utilize distinct intracellular signaling circuitries modulated by adaptor molecules. Toll-interacting protein (Tollip) is one of the critical adaptor molecules potentially playing key roles in modulating the dynamic adaptation of innate leukocytes to varying dosages of external stimulants. While Tollip may serve as a negative regulator of nuclear factor κ of activated B cells signaling pathway in cells challenged with higher dosages of LPS, it acts as a positive regulator for low-grade chronic inflammation in leukocytes programmed by subclinical low-dosages of LPS. This review aims to discuss recent progress in our understanding of complex innate leukocyte dynamics and its relevance in the pathogenesis of resolving versus non-resolving chronic inflammatory diseases.


Confident assignment of intact mass tags to human salivary cystatins using top-down Fourier-transform ion cyclotron resonance mass spectrometry.
A hybrid linear ion-trap Fourier-transform ion cyclotron resonance mass spectrometer was used for top-down characterization of the abundant human salivary cystatins, including S, S1, S2, SA, SN, C, and D, using collisionally activated dissociation (CAD) after chromatographic purification of the native, disulfide intact proteins. Post-translational modifications and protein sequence polymorphisms arising from single nucleotide polymorphisms (SNPs) were assigned from precursor and product ion masses at a tolerance of 10 ppm, allowing confident identification of individual intact mass tags. Cystatins S, S1, S2, SA, and SN were cleaved of a N-terminal 20 amino acid signal peptide and cystatin C a 26-residue peptide, to yield a generally conserved N-terminus. In contrast, cystatin D isoforms with 24 and 28 amino acid residue N-terminal truncations were found such that their N-termini were not conserved. Cystatin S1 was phosphorylated at Ser3, while S2 was phosphorylated at Ser1 and Ser3, in agreement with previous work. Both cystatin D isoforms carried the polymorphism C46R (SNP: rs1799841). The 14,328 Da isoform of cystatin SN previously assigned with polymorphism P31L due to a SNP (rs2070856) was found only in whole saliva. Parotid secretions contained no detectable cystatins while whole saliva largely mirrored the contents of submandibular/sublingual (SMSL) secretions. With fully characterized cystatin intact mass tags it will now be possible to examine the correlation between the abundance of these molecules and human health and disease.


[Eptifibatide in patients with percutaneous coronary intervention in clinical practice. Results of a prospective registry].
The use of potent platelet inhibitors has been shown to reduce the rate of ischemic complications in patients with percutaneous coronary intervention (PCI) in randomized clinical trials. Eptifibatide is a small-molecule glycoprotein (GP) IIb/IIIa receptor inhibitor. Eptifibatide given with a double bolus of 180 microg/kg 10 min apart followed by an infusion of 2.0 microg/kg/h achieves a high grade of platelet inhibition, which was associated with a highly significant clinical benefit in the randomized ESPRIT Study. The aim of the present prospective registry was to evaluate the efficacy and safety of eptifibatide in clinical practice. A total of 673 patients who received eptifibatide during PCI were prospectively enrolled in the registry between January 2001 and November 2002 in 31 clinical centers. The intervention was performed for stable angina in 283 patients (42.1%), for unstable angina in 70 patients (10.4%), for non-ST elevation myocardial infarction in 120 patients (17.8%), and for acute ST elevation myocardial infarction in 200 patients (29.7%). Therapy with eptifibatide was predominantly initiated in the catheter laboratory before or during the intervention and maintained for a mean of 20 h. Major bleeding complications, in 50% of the patients at the catheter insertion site, were observed in 1.2% of the patients. A thrombocytopenia < 100,000/microl was not reported. The total mortality rate was < 1%, a myocardial infarction or reinfarction was observed in up to 3%, depending on the clinical indication for PCI. These data are comparable to the results reported in randomized clinical trials with eptifibatide and document the safety and efficacy of this small-molecule GP IIb/IIIa inhibitor in clinical practice in a wide range of patients undergoing PCI.


Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes.
Cullin-RING E3 ligase (CRL) is the largest family of E3 ubiquitin ligase, responsible for ubiquitylation of ∼20% of cellular proteins. CRL plays an important role in many biological processes, particularly in cancers due to abnormal activation. CRL activation requires neddylation, an enzymatic cascade transferring small ubiquitin-like protein NEDD8 to a conserved lysine residue on cullin proteins. Recent studies have validated that neddylation is an attractive anticancer target. In this study, we report the establishment of an Alpha-Screen-based high throughput screen (HTS) assay for in vitro CUL5 neddylation, and screened a library of 17,000 compounds including FDA approved drugs, natural products and synthetic drug-like small-molecule compounds. Gossypol, a natural compound derived from cotton seed, was identified as an inhibitor of cullin neddylation. Biochemical studies showed that gossypol blocked neddylation of both CUL5 and CUL1 through direct binding to SAG-CUL5 or RBX1-CUL1 complex, and CUL5-H572 plays a key role for gossypol binding. On cellular level, gossypol inhibited cullin neddylation in a variety of cancer cell lines and selectively caused accumulation of NOXA and MCL1, the substrates of CUL5 and CUL1, respectively, in multiple cancer cell lines. Combination of gossypol with specific MCL1 inhibitor synergistically suppress growth of human cancer cells. Our study revealed a previously unknown anti-cancer mechanism of gossypol with potential to develop a new class of neddylation inhibitors.


Process-driven and biological characterisation and mapping of seabed habitats sensitive to trawling.
The increase of anthropogenic pressures on the marine environment together with the necessity of a sustainable management of marine living resources have underlined the need to map and model coastal environments, particularly for the purposes of spatial planning and for the implementation of integrated ecosystem-based management approach. The present study compares outputs of a process-driven benthic habitat sensitivity (PDS) model to the structure, composition and distribution of benthic invertebrates in the Eastern English Channel and southern part of the North Sea. Trawl disturbance indicators (TDI) computed from species biological traits and benthic community composition were produced from samples collected with a bottom trawl. The TDI was found to be highly correlated to the PDS further validating the latter's purpose to identify natural process-driven pattern of sensitivity. PDS was found to reflect an environmental potential that may no longer be fully observable in the field and difference with in situ biological observations could be partially explained by the spatial distribution of fishery pressure on the seafloor. The management implication of these findings are discussed and we suggest that, used in conjunction with TDI approaches, PDS may help monitor management effort by evaluating the difference between the current state and the presumed optimal environmental status of marine benthic habitats.