The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design.
Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity. T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed. In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1. HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.


Limited joint mobility in subjects with insulin dependent diabetes mellitus: relationship with eye and kidney complications.
Three hundred and fifty seven subjects (178 males and 179 females) with insulin dependent diabetes mellitus were evaluated for the presence of limited joint mobility of the interphalangeal joints. Sixty six subjects (19%) had stage 1 and 26 subjects (7%) had stage 2 involvement of their interphalangeal joints. The presence of contractures was significantly related to mean longitudinal glycated haemoglobin (HbA1) concentrations, duration of diabetes, age of onset, mean longitudinal cholesterol concentrations and blood pressure. Limited joint mobility was also significantly associated with early diabetic retinopathy and raised albumin excretion rates. Limited joint mobility remained a significant factor in the logistic regression model for albuminuria and grade of retinopathy when controlled for smoking, cholesterol concentrations, duration of diabetes, age, gender, and blood pressure. However, limited joint mobility was only significantly associated with diabetic retinopathy when the effect of HbA1 concentrations was included in the multivariate model.


Comparable Minimum 2-Year Patient-Reported Outcome Scores Between Circumferential and Segmental Labral Reconstruction for the Management of Irreparable Labral Tear and Femoroacetabular Impingement Syndrome in the Primary Setting: A Propensity-Matched Study.
To compare minimum 2-year follow-up patient-reported outcome scores (PROs) in patients who underwent primary acetabular circumferential and segmental labral reconstruction for irreparable labral tears and femoroacetabular impingement syndrome (FAIS). Data were reviewed from August 2010 to December 2017. Patients with primary labral reconstruction and minimum 2-year follow-up for the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale (HOS-SSS), and visual analog scale (VAS) for pain were included. Circumferential and segmental reconstruction were selected in each case based on the extent of the labral pathology. Exclusion criteria were previous ipsilateral hip surgery/conditions, dysplasia, or Tönnis grade >1. Patients were propensity matched 1:1 based on age, sex, and body mass index. Secondary surgeries were reported. The P value was set at <.05. In total, 144 hips were eligible, and 17 hips were lost to follow-up, leaving 127 hips (88.2%) for analysis. Eighty hips underwent a segmental reconstruction, and 47 hips underwent a circumferential reconstruction. Forty-seven hips with circumferential reconstruction were matched to 47 hips with segmental reconstruction. The average follow-up and age for the segmental and circumferential groups were 29.0 ± 7.8 and 27.9 ± 7.0 months (P = .732) and 43.1 ± 9.4 and 44.7 ± 10.2 years (P = .442) respectively. The segmental and circumferential groups were 48.9% and 51.1% female, respectively. The groups achieved significant and comparable improvement for all PROs and rates of secondary surgeries. No differences were found for achieving the minimal clinically important difference (MCID) and the patient acceptable symptomatic state (PASS). The MCIDs for the segmental and circumferential groups were 76.7% and 77.8% for the mHHS, 64.9% and 77.8% for the HOS-SSS, 71.1% and 68.9% for the VAS, and 68.9% and 73.9% for the NAHS, respectively. The PASSs for the segmental and circumferential groups were 78.3% and 73.3% for the mHHS, 55.3% and 55.0% for the HOS-SSS, and 75.6% and 71.1% for the International Hip Outcome Tool 12, respectively. At minimum 2-year follow-up, patients who underwent primary hip arthroscopy for either circumferential or segmental labral reconstruction for irreparable labra and FAIS reported significant improvement and similar postoperative scores for all PROs, with no difference in psychometric outcomes and rate of secondary surgeries. A customized approach, using the extent of the irreparable labral tear, seems to be an appropriate strategy. Level III, retrospective comparative therapeutic trial.


Chronic hyperdynamic sepsis in the rat: I. Characterization of the animal model.
We describe a new rat model of chronic hyperdynamic sepsis. After control values for weight gain, and food and water intake of each animal were obtained over a 5-day period, male Sprague-Dawley rats weighing 370-425 g were anesthetized, catheterized to allow chronic cardiac-output measurements, and a sterile subcutaneous cavity was formed over the flank area. The animals were allowed a 3-4 day postoperative recovery period. Body weight, food and water intake, and cardiac output were measured daily. Frequent blood samples were withdrawn for bacterial cultures and white cell counts (WBC). On the third and, in some cases, the fourth postoperative day, the subcutaneous cavity was inoculated with 10(9) colony-forming units of Escherichia coli and Bacteroides fragilis. The resulting sepsis was characterized by loss of body weight in spite of normal food and water intake, increased cardiac output, increased WBC, intermittent bacteremia, decreased muscle mass, and decreased cross-sectional area of skeletal muscle myofibrils. Two levels of septic response emerged--moderate and severe. Based on the above-mentioned measurements, it was possible to categorize all long-term septic animals into these two groups. Both groups exhibited cardiac-output, body-weight, and WBC data significantly different from sham controls. Repeated inoculations of the subcutaneous abscess initiated on the third postoperative day resulted in moderate sepsis with no long-term mortality, severe sepsis with 23% mortality over a 3-week period, or a 100% mortality within 4 days, depending on the virulence of the E. coli organisms used. The new model is ideally suited for pathophysiologic studies of sustained, hyperdynamic sepsis.


Gaps in Knowledge and Understanding of Patients With Metastatic Breast Cancer in Mexico.
There is paucity of data regarding the knowledge and understanding of patients with metastatic breast cancer (MBC) about their disease stage and treatment goals. This study assessed these patients' awareness of MBC incurability, topics reviewed with their oncologist, perceptions of having enough knowledge to participate in treatment decision-making, most helpful information source, and satisfaction with the information they received. For this purpose, 185 patients with MBC who attended follow-up medical appointments at a Mexican referral cancer center completed a survey designed by the Metastatic Breast Cancer Alliance. Clinical data were obtained from medical records. Descriptive statistics were applied, and associations between qualitative and quantitative variables were assessed with χ2 and Mann-Whitney U tests, respectively. Half (52%) of the patients were aware that their disease was incurable, while 31% were not sure, and 17% thought it was curable. Forty percent found it difficult to talk about treatments because they did not understand the options that were available to them. The medical staff was the most helpful information source for 74% of participants, and 64% scored their satisfaction with information ≥9 of 10. A significant association was found between higher satisfaction and knowing that MBC is incurable, as well as being older than 40 years. These results illustrate the significant lack of understanding patients with MBC have regarding their cancer, even when reporting high satisfaction with the provided information, and identify a critical need for improved patient education to enhance their comprehension and promote their participation in decision-making processes, treatment adherence, and, ultimately, outcomes.


Impact of the Y-containing cell line on histological differentiation patterns in dysgenetic gonads.
Gonadal karyotyping is considered a tool for increasing our knowledge of disturbed gonadal development in patients with gonadal dysgenesis and for estimating more accurately the risk for gonadoblastoma formation. The objective was to gain insight into the role of Y chromosome distribution in the histological heterogeneity of gonads of patients with gonadal dysgenesis. Investigation of the possible relationship between peripheral blood karyotype, gonadal karyotype, morphological differentiation patterns of dysgenetic gonads and tumour formation. In total 22 gonadal samples from 19 patients with gonadal dysgenesis (45,X/46,XY and variants n = 14; 46,XY: n = 3; 46,XX: n = 2) were examined. Morphological examination and immunohistochemical staining for testis specific protein, Y encoded (TSPY) and fluorescent and nonfluorescent in situ hybridization directly on gonadal tissue. No correlation was observed between peripheral blood karyotype and gonadal karyotype or between gonadal karyotype and the corresponding differentiation pattern. A Y-containing cell line in Sertoli cells was encountered no more frequently than were other cell types. The distribution of the Y-containing cell line in peripheral blood is not a suitable indicator for predicting the histological differentiation pattern found in the gonads of patients with gonadal dysgenesis. The analysis of Y-containing cell lines in the gonads of such patients could be informative with regard to the specific characteristics of gonadal development in humans as compared to chimeric mouse models. Moreover, it is essential to understand the mechanisms underlying disturbed gonadogenesis in these patients. As the gonadal karyotype is not related to the encountered gonadal differentiation pattern, it does not allow prediction of the risk for gonadoblastoma formation.


The 2017 EULAR standardised procedures for ultrasound imaging in rheumatology.
In 2001, the European League Against Rheumatism developed and disseminated the first guidelines for musculoskeletal (MS) ultrasound (US) in rheumatology. Fifteen years later, the dramatic expansion of new data on MSUS in the literature coupled with technological developments in US imaging has necessitated an update of these guidelines. To update the existing MSUS guidelines in rheumatology as well as to extend their scope to other anatomic structures relevant for rheumatology. The project consisted of the following steps: (1) a systematic literature review of MSUS evaluable structures; (2) a Delphi survey among rheumatologist and radiologist experts in MSUS to select MS and non-MS anatomic structures evaluable by US that are relevant to rheumatology, to select abnormalities evaluable by US and to prioritise these pathologies for rheumatology and (3) a nominal group technique to achieve consensus on the US scanning procedures and to produce an electronic illustrated manual (ie, App of these procedures). Structures from nine MS and non-MS areas (ie, shoulder, elbow, wrist and hand, hip, knee, ankle and foot, peripheral nerves, salivary glands and vessels) were selected for MSUS in rheumatic and musculoskeletal diseases (RMD) and their detailed scanning procedures (ie, patient position, probe placement, scanning method and bony/other landmarks) were used to produce the App. In addition, US evaluable abnormalities present in RMD for each anatomic structure and their relevance for rheumatology were agreed on by the MSUS experts. This task force has produced a consensus-based comprehensive and practical framework on standardised procedures for MSUS imaging in rheumatology.


The thermal dependence of locomotor performance and muscle contractile function in the salamander Ambystoma tigrinum nebulosum.
The thermal dependence of locomotor performance and in vitro muscle mechanical properties were studied after acclimation at 10 degrees and 20 degrees C in the salamander Ambystoma tigrinum nebulosum Hallowell. Performance measurements included burst and endurance capacities on land and in water. No significant differences in locomotor performance or muscle contractile properties were found between acclimation groups. Locomotor performance had only a slight thermal dependence, with Q10 values of 0.99-1.36 for running and swimming burst capacities (i.e. maximum speed and leg/tail cycling frequency). Running and swimming endurance capacities had thermal ratios of 1.58-1.66. Thermal dependence of muscle contractile rates was higher than that of locomotor performance: rates of force development for both isometric twitch and tetanus and maximal shortening velocity had Q10 values of 1.89-2.01. Maximal power output was also thermally dependent (Q10 = 2.33) and occurred at 38% of maximal (tetanic) force output. Force-generating capacities in isometric twitch and tetanus were relatively temperature-independent.


Impact of synthetic canine cerumen on in vitro penetration of auricular skin of dogs by florfenicol, terbinafine, and betamethasone acetate.
OBJECTIVE To determine the pharmacokinetics of florfenicol, terbinafine, and betamethasone acetate after topical application to canine auricular skin and the influence of synthetic canine cerumen on pharmacokinetics. SAMPLE Auricular skin from 6 euthanized shelter dogs (3 females and 3 neutered males with no visible signs of otitis externa). PROCEDURES Skin adjacent to the external opening of the ear canal was collected and prepared for use in a 2-compartment flow-through diffusion cell system to evaluate penetration of an otic gel containing florfenicol, terbinafine, and betamethasone acetate over a 24-hour period. Radiolabeled 14C-terbinafine hydrochloride and 3H-betamethasone acetate were added to the gel to determine dermal penetration and distribution. Florfenicol absorption was determined by use of high-performance liquid chromatography-UV detection. Additionally, the effect of synthetic canine cerumen on the pharmacokinetics of all compounds was evaluated. RESULTS During the 24-hour experiment, mean ± SD percentage absorption without the presence of synthetic canine cerumen was 0.28 ± 0.09% for 3H-betamethasone acetate, 0.06 ± 0.06% for florfenicol, and 0.06 ± 0.02% for 14C-terbinafine hydrochloride. Absorption profiles revealed no impact of synthetic canine cerumen on skin absorption for all 3 active compounds in the gel or on skin distribution of 3H-betamethasone acetate and 14C-terbinafine hydrochloride. CONCLUSIONS AND CLINICAL RELEVANCE 3H-betamethasone acetate, 14C-terbinafine hydrochloride, and florfenicol were all absorbed in vitro through healthy auricular skin specimens within the first 24 hours after topical application. Synthetic canine cerumen had no impact on dermal absorption in vitro, but it may serve as a temporary reservoir that prolongs the release of topical drugs.


Controversial treatment of a victim of severe head injury complicated by septic shock and acute respiratory distress syndrome.
Pneumonia, severe sepsis, and acute respiratory distress syndrome (ARDS) are frequent complications after head trauma. Recombinant human activated protein C (APC) reportedly improves circulation and respiration in severe sepsis, but is contraindicated after head injury because of increased risk of intracranial bleeding. A 21-year-old man with severe head injury after a car accident was endotracheally intubated, mechanically ventilated, and hemodynamically stabilized before transfer to our university hospital. His condition became complicated with pneumonia, septic shock, ARDS, coagulation dysfunction, and renal failure. In spite of intensive therapy, oxygenation and arterial blood pressure fell to critically low values. Simultaneously, his intracranial pressure peaked and his pupils dilated, displaying no reflexes to light. His antibiotic regimen was changed and ventilation was altered to high frequency oscillations, and despite being ethically problematic, we added APC to his treatment. The patient recovered with modest neurological sequelae.


Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice.
CD8+ islet cell-specific CTL lines and clones were established from lymphocytes infiltrating the pancreatic islets of acutely diabetic nonobese diabetic (NOD) mice from two subcolonies (NOD/Yn and NOD/Lt). CTL from NOD/Yn mice were predominantly cytotoxic against H-2b+ islet cells and to a lesser extent against H-2d+ islet cells. On the other hand, CTL from NOD/Lt mice were cytotoxic against H-2d+ but not against H-2b+ islet cells. Three of four CTL clones derived from NOD/Yn mice were H-2Db restricted, whereas two of two CTL clones derived from NOD/Lt mice were H-2Kd restricted. However, all of the H-2Kd restricted T cell clones expressed the same TCR, regardless of the NOD subcolony from which they were derived, compatible with a restricted repertoire. When two representative CTL clones were transferred into irradiated young NOD mice, neither induced insulitis or diabetes. However, transfer of these clones, together with CD4(+)-rich NOD splenocytes depleted of CD8+ T cells, caused severe insulitis and diabetes. When recipient NOD mice were treated with anti-CD4 mAbs, none of the mice developed insulitis or diabetes. Most of the irradiated NOD mice that received CD8-depleted splenocytes alone did not become diabetic. Through these studies we show that CTL clones can destroy pancreatic beta-cells as final effectors but that these clones require signals from CD4+ T cells to effect beta-cell damage.


Cell death induced by GSM 900-MHz and DCS 1800-MHz mobile telephony radiation.
In the present study, the TUNEL (Terminal deoxynucleotide transferase dUTP Nick End Labeling) assay--a well known technique widely used for detecting fragmented DNA in various types of cells--was used to detect cell death (DNA fragmentation) in a biological model, the early and mid stages of oogenesis of the insect Drosophila melanogaster. The flies were exposed in vivo to either GSM 900-MHz (Global System for Mobile telecommunications) or DCS 1800-MHz (Digital Cellular System) radiation from a common digital mobile phone, for few minutes per day during the first 6 days of their adult life. The exposure conditions were similar to those to which a mobile phone user is exposed, and were determined according to previous studies of ours [D.J. Panagopoulos, A. Karabarbounis, L.H. Margaritis, Effect of GSM 900-MHz mobile phone radiation on the reproductive capacity of D. melanogaster, Electromagn. Biol. Med. 23 (1) (2004) 29-43; D.J. Panagopoulos, N. Messini, A. Karabarbounis, A.L. Philippetis, L.H. Margaritis, Radio frequency electromagnetic radiation within "safety levels" alters the physiological function of insects, in: P. Kostarakis, P. Stavroulakis (Eds.), Proceedings of the Millennium International Workshop on Biological Effects of Electromagnetic Fields, Heraklion, Crete, Greece, October 17-20, 2000, pp. 169-175, ISBN: 960-86733-0-5; D.J. Panagopoulos, L.H. Margaritis, Effects of electromagnetic fields on the reproductive capacity of D. melanogaster, in: P. Stavroulakis (Ed.), Biological Effects of Electromagnetic Fields, Springer, 2003, pp. 545-578], which had shown a large decrease in the oviposition of the same insect caused by GSM radiation. Our present results suggest that the decrease in oviposition previously reported, is due to degeneration of large numbers of egg chambers after DNA fragmentation of their constituent cells, induced by both types of mobile telephony radiation. Induced cell death is recorded for the first time, in all types of cells constituting an egg chamber (follicle cells, nurse cells and the oocyte) and in all stages of the early and mid-oogenesis, from germarium to stage 10, during which programmed cell death does not physiologically occur. Germarium and stages 7-8 were found to be the most sensitive developmental stages also in response to electromagnetic stress induced by the GSM and DCS fields and, moreover, germarium was found to be even more sensitive than stages 7-8.


Arrestin function in inactivation of G protein-coupled receptor rhodopsin in vivo.
Arrestins have been implicated in the regulation of many G protein-coupled receptor signaling cascades. Mutations in two Drosophila photoreceptor-specific arrestin genes, arrestin 1 and arrestin 2, were generated. Analysis of the light response in these mutants shows that the Arr1 and Arr2 proteins are mediators of rhodopsin inactivation and are essential for the termination of the phototransduction cascade in vivo. The saturation of arrestin function by an excess of activated rhodopsin is responsible for a continuously activated state of the photoreceptors known as the prolonged depolarized afterpotential. In the absence of arrestins, photoreceptors undergo light-dependent retinal degeneration as a result of the continued activity of the phototransduction cascade. These results demonstrate the fundamental requirement for members of the arrestin protein family in the regulation of G protein-coupled receptors and signaling cascades in vivo.


Intracranial internal carotid artery stenosis: longterm prognosis.
Sixty-six patients with greater than or equal to 50% stenosis of an intracranial internal carotid artery (IICA) were followed-up for an average of 3.9 years. Eighteen patients (27.3%) experienced ischemic events; 8 (12.1%) had isolated TIA and 10 (15.2%) a stroke. The observed stroke rate for patients 35 years and older are 13 times the expected infarction rate for a normal population. Patients with tandem extracranial stenosis had a greater risk of stroke than patients with isolated IICA stenosis. Thirty-three patients (50%) died during follow-up and 55% of all deaths were cardiac related. The observed 5 year survival rate was 60% compared to an expected rate of 87%. Patients with IICA stenosis had a higher risk of stroke and death compared to a previously reported referral population with ICA occlusion. IICA stenosis is a marker of extensive cerebrovascular and systemic atherosclerotic disease, especially coronary artery disease.


Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study.
Treatment for Hodgkin's disease (HD) is associated with a variety of thyroid abnormalities, including hypothyroidism, hyperthyroidism, and thyroid neoplasms. Due to the small sample size and short follow-up time of most published studies, it has been difficult to appreciate the full extent of the problem and to characterize the interaction between various patient and treatment variables. To overcome these limitations we have assessed thyroid status in 1,791 (959 males) HD survivors from among 13,674 participants in the Childhood Cancer Survivor Study, a cohort of 5-yr survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. Thyroid abnormalities were ascertained as part of a 22-page questionnaire sent to participants. Survivors were a median of 14 yr (range, 2-20 yr) at diagnosis of HD and a median of 30 yr (range, 12-47 yr) at follow-up. Seventy-nine percent of subjects were treated with radiation (median dose of radiation to the thyroid, 3,500 cGy; range, 0.37-5,500 cGy). Control data were available from 2,808 (1,346 males) sibling controls. Thirty-four percent of the entire cohort has been diagnosed with at least one thyroid abnormality. Hypothyroidism was the most common disturbance, with a relative risk of 17.1 (P < 0.0001) compared to sibling controls. Increasing dose of radiation, older age at diagnosis of HD, and female sex were all independently associated with an increased risk of hypothyroidism. Actuarial risk of hypothyroidism for subjects treated with 4,500 cGy or more is 50% at 20 yr from diagnosis. Hyperthyroidism was reported by 5% of survivors, which was 8-fold greater (P < 0.0001) than the incidence reported by the controls. Thyroid dose of 3,500 cGy or more was the only risk factor identified for hyperthyroidism. The risk of thyroid nodules was 27 times (P < 0.0001) that in sibling controls. Female sex and radiation dose to the thyroid of 2,500 cGy or more were independent risk factors for thyroid nodules. The actuarial risk of a female survivor developing a thyroid nodule is 20% at 20 yr from diagnosis. Thyroid cancer was diagnosed in 20 survivors, which is 18 times the expected rate for the general population. After taking into account the possibility that some of the relative risk estimates may be exaggerated due to ascertainment bias, abnormalities of the thyroid are still extremely common in young adult survivors of childhood HD, particularly among females treated with high doses of radiation to the neck.


Extended lifespan and long telomeres in rectal fibroblasts from late-onset ulcerative colitis patients.
Ulcerative colitis (UC) is characterized by damage to the intestinal epithelium and connective tissue. The causes of this damage could include changes in the ability of colonic fibroblasts to heal wounds and maintain epithelial cell proliferation. Telomeres shorten with each cell division and eventually signal senescence. The aim of this study is to investigate whether the impaired function of rectal fibroblasts in UC is due to accelerated telomere shortening, oxidative stress and premature senescence. We isolated rectal fibroblasts from eight UC patients and nine non-colitis controls, and recorded their in-vitro lifespans. Telomere lengths and superoxide dismutase mRNA expression were also measured by real-time polymerase chain reaction and peroxide levels were measured by flow cytometry. The fibroblast lifespan decreased as patient age increased (R2=0.68, P=0.003) in control patients, but this relationship was absent in UC fibroblasts. We identified a group of patients who were diagnosed later in life than a second group (59 versus 35 years, P=0.002). Fibroblasts from these late-onset UC patients underwent significantly more population doublings before senescence than age-matched controls (25 versus 15, P=0.02). Slower in-vitro telomere shortening rates (32 versus 344, P=0.006) and trends towards longer telomeres at explant were also observed in late-onset UC fibroblasts. Peroxide levels correlated positively with telomere shortening rate (r=0.581, P=0.078). Some UC-predisposed individuals may have more efficient antioxidant systems that protect the telomeres from oxidative damage. This may allow their rectal fibroblasts to live longer, function better and thus delay the onset of the disease until later life.


Effects of organic matter on virus transport in unsaturated flow.
The effects of natural humic material and sewage sludge organic matter (SSOM) derived from primary treated sewage sludge on virus transport by unsaturated flow through soil columns were evaluated. Bacteriophage MS-2 was applied to loamy fine sand columns 0.052 m in diameter and 1.05 m long. Virus concentrations in the influent and effluent were measured daily for 7 to 9 days. In the first experiment, virus transport through two fresh soil columns was compared with that through a column previously leached with more than four pore volumes (T) of well water. The soil water organic matter concentrations in the leachate of the fresh soil declined with time. Relative virus concentrations (C/Co) from one fresh soil column reached 0.82 in 0.9 T and then declined to 0.51 by 2.1 T. The other fresh soil column reached and maintained a steady-state relative virus concentration [(C/Co)s] of 0.47 from 1.5 to 2.5 T. The leached column reached and maintained a (C/Co)s of 0.05. Concentrations measured at 0.2-, 0.4-, 0.8-, and 1.05-m depths indicated that most virus particles were removed in the surface 0.2 m. In the second experiment, one leached column was pretreated with SSOM derived from primary treated sewage sludge and the other leached column was untreated. SSOM concentrations declined with depth. A suspension of virus and SSOM in well water was applied to both columns. Although the (C/Co)s values were similar (0.41 for the pretreated column and 0.47 for the untreated column), breakthrough was delayed for the untreated column. Both natural humic material and sewage sludge-derived SSOM increased the unsaturated-flow transport of MS-2.


Effective feature learning and fusion of multimodality data using stage-wise deep neural network for dementia diagnosis.
In this article, the authors aim to maximally utilize multimodality neuroimaging and genetic data for identifying Alzheimer's disease (AD) and its prodromal status, Mild Cognitive Impairment (MCI), from normal aging subjects. Multimodality neuroimaging data such as MRI and PET provide valuable insights into brain abnormalities, while genetic data such as single nucleotide polymorphism (SNP) provide information about a patient's AD risk factors. When these data are used together, the accuracy of AD diagnosis may be improved. However, these data are heterogeneous (e.g., with different data distributions), and have different number of samples (e.g., with far less number of PET samples than the number of MRI or SNPs). Thus, learning an effective model using these data is challenging. To this end, we present a novel three-stage deep feature learning and fusion framework, where deep neural network is trained stage-wise. Each stage of the network learns feature representations for different combinations of modalities, via effective training using the maximum number of available samples. Specifically, in the first stage, we learn latent representations (i.e., high-level features) for each modality independently, so that the heterogeneity among modalities can be partially addressed, and high-level features from different modalities can be combined in the next stage. In the second stage, we learn joint latent features for each pair of modality combination by using the high-level features learned from the first stage. In the third stage, we learn the diagnostic labels by fusing the learned joint latent features from the second stage. To further increase the number of samples during training, we also use data at multiple scanning time points for each training subject in the dataset. We evaluate the proposed framework using Alzheimer's disease neuroimaging initiative (ADNI) dataset for AD diagnosis, and the experimental results show that the proposed framework outperforms other state-of-the-art methods.


Fetal sex and maternal pregnancy outcomes: a systematic review and meta-analysis.
Since the placenta also has a sex, fetal sex-specific differences in the occurrence of placenta-mediated complications could exist. To determine the association of fetal sex with multiple maternal pregnancy complications. Six electronic databases Ovid MEDLINE, EMBASE, Cochrane Central, Web-of-Science, PubMed, and Google Scholar were systematically searched to identify eligible studies. Reference lists of the included studies and contact with experts were also used for identification of studies. Observational studies that assessed fetal sex and the presence of maternal pregnancy complications within singleton pregnancies. Data were extracted by 2 independent reviewers using a predesigned data collection form. From 6522 original references, 74 studies were selected, including over 12,5 million women. Male fetal sex was associated with term pre-eclampsia (pooled OR 1.07 [95%CI 1.06 to 1.09]) and gestational diabetes (pooled OR 1.04 [1.02 to 1.07]). All other pregnancy complications (i.e., gestational hypertension, total pre-eclampsia, eclampsia, placental abruption, and post-partum hemorrhage) tended to be associated with male fetal sex, except for preterm pre-eclampsia, which was more associated with female fetal sex. Overall quality of the included studies was good. Between-study heterogeneity was high due to differences in study population and outcome definition. This meta-analysis suggests that the occurrence of pregnancy complications differ according to fetal sex with a higher cardiovascular and metabolic load for the mother in the presence of a male fetus. None.


Incidence of non-tunnelled central venous catheter-related infections in oncologic patients receiving chemotherapy in an outpatient setting.
Central venous catheters (CVCs) are becoming more popular for delivery of outpatient courses of intravenous therapy such as chemotherapy and long-term antibiotics. The incidence of non-tunnelled type CVC-related infections in patients with solid tumours receiving chemotherapy in an ambulatory setting has not been well studied. We aimed to determine the baseline data on CVC-related infections in this retrospective study conducted from January 2005 to December 2007. Data on cancer patients with CVCs inserted as outpatients at National Cancer Centre Singapore over a three-year period were collected and analysed retrospectively. Data retrieved from medical records included patients' demographics, the number of catheter days, cancer type and other medical illnesses. Definitions from the Centre for Disease Control and Prevention for CVC-related infections were used. For data analysis, graphical and quantitative techniques were employed. A total of 88 CVCs were inserted during the study period, with a total of 11,541 catheter days (median 114; range 2-510 days). Infection rate was 0.87 per 1,000 catheter days. The risk of infection was higher when catheters were left in situ for longer periods of time and in patients with solid tumours. The infection rate for non-tunnelled type CVCs is low in our centre. Hence, its use for chemotherapy on an outpatient basis is relatively safe and convenient in oncologic patients.


Defects of the fetal forebrain in mice with hereditary agenesis of the corpus callosum.
Inbred BALB/c mice are genetically the same, yet less than half of adults show absent or small corpus callosum. Is this because only a minority has prenatal defects of the sling at the telencephalic midline, or do most fetuses have a defective sling but some are able to form a corpus callosum via some other substrate pathway? This question was addressed by comparing large samples of BALB/c fetuses at 17, 18, and 19 days after conception with a series of normal C57BL/6 and hybrid fetuses matched for body size. At 17 days postconception almost all BALB/c fetuses show an unusual widening or bulge in the interhemispheric fissure anterior to the hippocampal commissure. Furthermore, formation of the hippocampal commissure is greatly retarded, although it eventually attains a normal size in adult mice. At 17 days, when mice of normal strains all have a corpus callosum at midplane, almost every BALB/c fetus lacks the structure, but 1 day later 67% of fetuses show delayed formation of this structure and by 19 days all but 7% of fetuses have some callosal axons crossing the midsagittal plane. Many BALB/c fetuses are able to form a corpus callosum without the benefit of a normal sling. The degree of delay of axon crossing is strongly correlated with the severity of sling defects. An unusually small adult corpus callosum occurs because fetal axons are able to follow unusual pathways and actively compensate for absence of the sling, not because of arrested midline development.


Electrocardiographic Left Atrial Abnormality and B-Type Natriuretic Peptide in a General Japanese Population: NIPPON DATA2010.
P-wave terminal force in lead V1 (PTFV1) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV1 and BNP concentrations in a contemporary representative Japanese population. Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines. In total, 125 (4.9%) participants had PTFV1. Participants with PTFV1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 [6.9, 22.8] versus 7.8 [4.4, 14.5] pg/mL; P<0.001). After adjustment for confounders, PTFV1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05-2.62; P=0.030). This correlation was consistent among various subgroups and was particularly evident in those aged <65 years or those without a history of hypertension. In the contemporary general population cohort, PTFV1 was independently related to high BNP concentration. PTFV1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.


Adaptive algorithm utilizing acceptance rate for eliminating noisy epochs in block-design functional near-infrared spectroscopy data: application to study in attention deficit/hyperactivity disorder children.
Functional near-infrared spectroscopy (fNIRS) signals are prone to problems caused by motion artifacts and physiological noises. These noises unfortunately reduce the fNIRS sensitivity in detecting the evoked brain activation while increasing the risk of statistical error. In fNIRS measurements, the repetitive resting-stimulus cycle (so-called block-design analysis) is commonly adapted to increase the sample number. However, these blocks are often affected by noises. Therefore, we developed an adaptive algorithm to identify, reject, and select the noise-free and/or least noisy blocks in accordance with the preset acceptance rate. The main features of this algorithm are personalized evaluation for individual data and controlled rejection to maintain the sample number. Three typical noise criteria (sudden amplitude change, shifted baseline, and minimum intertrial correlation) were adopted. Depending on the quality of the dataset used, the algorithm may require some or all noise criteria with distinct parameters. Aiming for real applications in a pediatric study, we applied this algorithm to fNIRS datasets obtained from attention deficit/hyperactivity disorder (ADHD) children as had been studied previously. These datasets were divided for training and validation purposes. A validation process was done to examine the feasibility of the algorithm regardless of the types of datasets, including those obtained under sample population (ADHD or typical developing children), intervention (nonmedication and drug/placebo administration), and measurement (task paradigm) conditions. The algorithm was optimized so as to enhance reproducibility of previous inferences. The optimum algorithm design involved all criteria ordered sequentially (0.047 mM mm of amplitude change, 0.029 mM mm / s of baseline slope, and 0.6 × interquartile range of outlier threshold for each criterion, respectively) and presented complete reproducibility in both training and validation datasets. Compared to the visual-based rejection as done in the previous studies, the algorithm achieved 71.8% rejection accuracy. This suggests that the algorithm has robustness and potential to substitute for visual artifact-detection.


Maternal bereavement in the antenatal period and oral cleft in the offspring.
Is maternal bereavement (emotional stress) due to loss of a close relative in the antenatal period associated with the risk of oral cleft in the offspring? Our study suggests prenatal maternal bereavement is associated with an increased risk of oral cleft in the offspring, especially when the bereavement was due to a sudden death or death of a child. The aetiology of oral cleft is unknown but includes both genetic and environmental causes. We performed a population-based cohort study based on several national registers in Denmark from 1978 to 2008. Our final study population consisted of 1 771 663 children. Of these 35 118 (2%) were born to mothers who experienced bereavement in the exposure window from 1 year before pregnancy to the end of the first trimester. In total, 3043 children were diagnosed with a cleft; 968 with cleft lip, 1206 with cleft lip and palate and 869 with a cleft palate. For overall bereavement the prevalence was 1.7 per 1 000 live born in the unexposed children and 2.2 per 1 000 live born in the exposed children. Overall, maternal bereavement due to the death of a close relative from 1 year before conception to the end of the first trimester was associated with a significantly increased risk of oral cleft [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.01; 1.61). When mothers lost a relative due to a sudden death, the risk of oral cleft in the offspring was higher (OR: 1.76, 95% CI: 1.06; 2.94). Losing a relative in the time period before pregnancy and during the first trimester showed a tendency to an increased risk. The risk increase was 77% when the mother was bereaved due to sudden death and the estimation was robust in different analytical strategies. It is a limitation that we only studied live born children, but most children with isolated oral cleft would survive their pregnancy and birth. Since oral cleft are rare and despite the large study population, we still had a relatively small number of cases, which results in limited power to detect small differences. We did not have actual measurements of the maternal cortisol concentration, but we believe that bereavement due to death of a close relative produces a strong stress reaction in most people. Also we did not have the opportunity to adjust for intake of folic acid and use of anti-depressant; however, analysis in a subset of the data showed no difference in these intakes between exposed and unexposed mothers. With this study we add a large-scale human cohort study to the body of literature on stress and birth defects. Our study is in agreement with previously published results and can be generalized to similar populations like the native Danish population. Severe stress may be added to the list of potential causes for oral cleft.


Robust quantification of fish early life CO2 sensitivities via serial experimentation.
Despite the remarkable expansion of laboratory studies, robust estimates of single species CO2 sensitivities remain largely elusive. We conducted a meta-analysis of 20 CO2 exposure experiments conducted over 6 years on offspring of wild Atlantic silversides (Menidia menidia) to robustly constrain CO2 effects on early life survival and growth. We conclude that early stages of this species are generally tolerant to CO2 levels of approximately 2000 µatm, likely because they already experience these conditions on diel to seasonal timescales. Still, high CO2 conditions measurably reduced fitness in this species by significantly decreasing average embryo survival (-9%) and embryo+larval survival (-13%). Survival traits had much larger coefficients of variation (greater than 30%) than larval length or growth (3-11%). CO2 sensitivities varied seasonally and were highest at the beginning and end of the species' spawning season (April-July), likely due to the combined effects of transgenerational plasticity and maternal provisioning. Our analyses suggest that serial experimentation is a powerful, yet underused tool for robustly estimating small but true CO2 effects in fish early life stages.


Familial and nutritional risk factors for p53 overexpression in colorectal cancer.
Although familial and dietary factors are recognized as important risk determinants for colorectal tumorigenesis, the specific causes of colorectal cancer remain unclear. Studies of p53 genetic alterations have provided clues concerning the etiology of many cancers. This study was designed to determine whether overexpression of the p53 protein is associated with familial and dietary risk factors. Epidemiological data were obtained from 163 colorectal cancer cases and 326 healthy controls. Tumors of all patients were analyzed immunohistochemically for p53 overexpression using an avidin-biotin immunoperoxidase procedure and polyclonal anti-p53 antibody CM1. Of patient tumors, 44.8% showed p53 nuclear reactivity. Colorectal cases versus controls were three times more likely to report a family history of colorectal cancer [odds ratio (OR), 3.12; 95% confidence interval (CI), 1.77-5.52]. Only cruciferous vegetables exhibited a significant inverse association (OR, 0.59; 95% CI, 0.34-1.02; trend test, P = 0.03) for the highest versus lowest quartiles. Both meat and beef displayed an elevated increase in risk. When cases with p53 overexpression (p53 positive) were compared with cases without p53 overexpression (p53 negative), etiological heterogeneity was suggested for family history of colorectal cancer (OR, 0.39; 95% CI, 0.16-0.93), cruciferous vegetables (trend test, P = 0.12), and beef consumption (trend test, P = 0.08). To estimate the individual relative risks for p53-dependent and p53-independent pathways, each p53 subtype was compared with controls. Cruciferous vegetables exhibited a significant association (OR, 0.37; 95% CI, 0.17-0.82; trend test, P = 0.03) when p53 positive cases were compared with controls. When p53 negative cases were compared with controls, a significant increase in risk was observed for family history of cancer (OR, 4.46; 95% CI, 2.36-8.43) and beef (OR, 3.17; 95% CI, 1.83-11.28; trend test, P = 0.006). The p53 (positive) dependent pathway was characterized by an inverse association with cruciferous vegetables, and p53-independent tumors were characterized by family history and beef consumption. These data may indicate the significance of linking epidemiology and molecular biology in assessing specific etiological pathways.


Biometric verification with correlation filters.
Using biometrics for subject verification can significantly improve security over that of approaches based on passwords and personal identification numbers, both of which people tend to lose or forget. In biometric verification the system tries to match an input biometric (such as a fingerprint, face image, or iris image) to a stored biometric template. Thus correlation filter techniques are attractive candidates for the matching precision needed in biometric verification. In particular, advanced correlation filters, such as synthetic discriminant function filters, can offer very good matching performance in the presence of variability in these biometric images (e.g., facial expressions, illumination changes, etc.). We investigate the performance of advanced correlation filters for face, fingerprint, and iris biometric verification.


Functional interaction of p53 and BLM DNA helicase in apoptosis.
The Bloom syndrome (BS) protein, BLM, is a member of the RecQ DNA helicase family that also includes the Werner syndrome protein, WRN. Inherited mutations in these proteins are associated with cancer predisposition of these patients. We recently discovered that cells from Werner syndrome patients displayed a deficiency in p53-mediated apoptosis and WRN binds to p53. Here, we report that analogous to WRN, BLM also binds to p53 in vivo and in vitro, and the C-terminal domain of p53 is responsible for the interaction. p53-mediated apoptosis is defective in BS fibroblasts and can be rescued by expression of the normal BLM gene. Moreover, lymphoblastoid cell lines (LCLs) derived from BS donors are resistant to both gamma-radiation and doxorubicin-induced cell killing, and sensitivity can be restored by the stable expression of normal BLM. In contrast, BS cells have a normal Fas-mediated apoptosis, and in response to DNA damage normal accumulation of p53, normal induction of p53 responsive genes, and normal G(1)-S and G(2)-M cell cycle arrest. BLM localizes to nuclear foci referred to as PML nuclear bodies (NBs). Cells from Li-Fraumeni syndrome patients carrying p53 germline mutations and LCLs lacking a functional p53 have a decreased accumulation of BLM in NBs, whereas isogenic lines with functional p53 exhibit normal accumulation. Certain BLM mutants (C1055S or Delta133-237) that have a reduced ability to localize to the NBs when expressed in normal cells can impair the localization of wild type BLM to NBs and block p53-mediated apoptosis, suggesting a dominant-negative effect. Taken together, our results indicate both a novel mechanism of p53 function by which p53 mediates nuclear trafficking of BLM to NBs and the cooperation of p53 and BLM to induce apoptosis.


Patterned dextran ester films as a tailorable cell culture platform.
The elucidation of cell-surface interactions and the development of model platforms to help uncover their underlying mechanisms remains vital to the design of effective biomaterials. To this end, dextran palmitates with varying degrees of substitution were synthesised with a multipurpose functionality: an ability to modulate surface energy through surface chemistry, and an ideal thermal behaviour for patterning. Herein, dextran palmitate films are produced by spin coating, and patterned by thermal nanoimprint lithography with nano-to-microscale topographies. These films of moderately hydrophobic polysaccharide esters with low nanoscale roughness performed as well as fibronectin coatings in the culture of bovine aortic endothelial cells. Upon patterning, they display distinct regions of roughness, restricting cell adhesion to the smoothest surfaces, while guiding multicellular arrangements in the patterned topographies. The development of biomaterial interfaces through topochemical fabrication such as this could prove useful in understanding protein and cell-surface interactions.


A review of physical activity patterns in pregnant women and their relationship to psychological health.
Regular physical activity contributes positively to physical and psychological health. Adverse consequences of inactivity may be an especially important problem among pregnant women. Up to 60% are inactive during pregnancy. This review found consistent evidence that physical activity is reduced during pregnancy; however, few investigators have sought to quantify physical activity patterns among pregnant women using well validated measures. Some of the barriers to physical activity during pregnancy, such as depression, anxiety and fatigue, have been shown to be attenuated by regular exercise performed by non-pregnant samples. There is a need to better understand the relationships between these factors and physical activity during pregnancy. Available retrospective and prospective results suggest that both leisure time and work-related physical activities are decreased across pregnancy. Intensity and duration decrease both during pregnancy compared with pre-pregnancy and in the third trimester compared with the first. There is a need for well designed longitudinal investigations that document pregnancy-related changes in physical activity at frequent intervals during pregnancy using validated and more precise measures of physical activity. Reductions in physical activity and a worsening mood are common during pregnancy. If the relationship between physical inactivity and mood disturbances is indeed observed and maintained during pregnancy, then decreases in physical activity in the third trimester would be expected to result in a worsening mood. In recent years, increased attention has been paid to antenatal mood disturbances, and this research has yielded a host of important findings. Prior correlational and experimental research with non-pregnant samples has demonstrated a consistent relationship between physical inactivity and mood disturbances. Whether this relationship occurs among pregnant women and/or is maintained as women progress during pregnancy is uncertain. Prior investigations have revealed that there is higher rate of mood disturbance during pregnancy than following pregnancy but little is known about the mechanisms that cause these mood disturbances. It is important to better understand changes in mood with pregnancy because mood disturbances can have major negative consequences for a pregnant woman. The major adverse consequences of depression among pregnant women are largely the same as those of non-pregnant individuals. Only six investigations have quantified the relationship between changes in physical activity and changes in mood during pregnancy. The available evidence suggests that inactivity is associated with worse mood. Additional research into this topic is warranted due to the limited number of published papers and the design and methodology limitations of these investigations.


Clinical strategies for esthetic excellence in anterior tooth restorations: understanding color and composite resin selection.
Direct composite resin restorations have become a viable alternative for patients that require anterior restorative procedures to be integrated to the other teeth that compose the smile, especially for presenting satisfactory esthetic results and minimum wear of the dental structure. Technological evolution along with a better understanding of the behavior of dental tissues to light incidence has allowed the development of new composite resins with better mechanical and optical properties, making possible a more artistic approach for anterior restorations. The combination of the increasing demand of patients for esthetics and the capacity to preserve the dental structure resulted in the development of different incremental techniques for restoring fractured anterior teeth in a natural way. In order to achieve esthetic excellence, dentists should understand and apply artistic and scientific principles when choosing color of restorative materials, as well as during the insertion of the composite resin. The discussion of these strategies will be divided into two papers. In this paper, the criteria for color and material selection to obtain a natural reproduction of the lost dental structures and an imperceptible restoration will be addressed.


Activating positive memory engrams suppresses depression-like behaviour.
Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders. Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia. The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments, although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus-amygdala-nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.


Implementing and integrating a clinically driven electronic medical record for radiation oncology in a large medical enterprise.
While our department is heavily invested in computer-based treatment planning, we historically relied on paper-based charts for management of Radiation Oncology patients. In early 2009, we initiated the process of conversion to an electronic medical record (EMR) eliminating the need for paper charts. Key goals included the ability to readily access information wherever and whenever needed, without compromising safety, treatment quality, confidentiality, or productivity. In February, 2009, we formed a multi-disciplinary team of Radiation Oncology physicians, nurses, therapists, administrators, physicists/dosimetrists, and information technology (IT) specialists, along with staff from the Duke Health System IT department. The team identified all existing processes and associated information/reports, established the framework for the EMR system and generated, tested and implemented specific EMR processes. Two broad classes of information were identified: information which must be readily accessed by anyone in the health system versus that used solely within the Radiation Oncology department. Examples of the former are consultation reports, weekly treatment check notes, and treatment summaries; the latter includes treatment plans, daily therapy records, and quality assurance reports. To manage the former, we utilized the enterprise-wide system, which required an intensive effort to design and implement procedures to export information from Radiation Oncology into that system. To manage "Radiation Oncology" data, we used our existing system (ARIA, Varian Medical Systems.) The ability to access both systems simultaneously from a single workstation (WS) was essential, requiring new WS and modified software. As of January, 2010, all new treatments were managed solely with an EMR. We find that an EMR makes information more widely accessible and does not compromise patient safety, treatment quality, or confidentiality. However, compared to paper charts, time required by clinicians to access/enter patient information has substantially increased. While productivity is improving with experience, substantial growth will require better integration of the system components, decreased access times, and improved user interfaces. $127K was spent on new hardware and software; elimination of paper yields projected savings of $21K/year. One year after conversion to an EMR, more than 90% of department staff favored the EMR over the previous paper charts. Successful implementation of a Radiation Oncology EMR required not only the effort and commitment of all functions of the department, but support from senior health system management, corporate IT, and vendors. Realization of the full benefits of an EMR will require experience, faster/better integrated software, and continual improvement in underlying clinical processes.


Flexner 3.0-Democratization of Medical Knowledge for the 21st Century: Teaching Medical Science Using K-12 General Pathology as a Gateway Course.
A medical school general pathology course has been reformatted into a K-12 general pathology course. This new course has been implemented at a series of 7 to 12 grade levels and the student outcomes compared. Typically, topics covered mirrored those in a medical school general pathology course serving as an introduction to the mechanisms of diseases. Assessment of student performance was based on their score on a multiple-choice final examination modeled after an examination given to medical students. Two Tucson area schools, in a charter school network, participated in the study. Statistical analysis of examination performances showed that there were no significant differences as a function of school (F = 0.258, P = .6128), with students at school A having an average test scores of 87.03 (standard deviation = 8.99) and school B 86.00 (standard deviation = 8.18; F = 0.258, P = .6128). Analysis of variance was also conducted on the test scores as a function of gender and class grade. There were no significant differences as a function of gender (F = 0.608, P = .4382), with females having an average score of 87.18 (standard deviation = 7.24) and males 85.61 (standard deviation = 9.85). There were also no significant differences as a function of grade level (F = 0.627, P = .6003), with 7th graders having an average of 85.10 (standard deviation = 8.90), 8th graders 86.00 (standard deviation = 9.95), 9th graders 89.67 (standard deviation = 5.52), and 12th graders 86.90 (standard deviation = 7.52). The results demonstrated that middle and upper school students performed equally well in K-12 general pathology. Student course evaluations showed that the course met the student's expectations. One class voted K-12 general pathology their "elective course-of-the-year."


Increased brain atrophy and lesion load is associated with stronger lower alpha MEG power in multiple sclerosis patients.
In multiple sclerosis, the interplay of neurodegeneration, demyelination and inflammation leads to changes in neurophysiological functioning. This study aims to characterize the relation between reduced brain volumes and spectral power in multiple sclerosis patients and matched healthy subjects. During resting-state eyes closed, we collected magnetoencephalographic data in 67 multiple sclerosis patients and 47 healthy subjects, matched for age and gender. Additionally, we quantified different brain volumes through magnetic resonance imaging (MRI). First, a principal component analysis of MRI-derived brain volumes demonstrates that atrophy can be largely described by two components: one overall degenerative component that correlates strongly with different cognitive tests, and one component that mainly captures degeneration of the cortical grey matter that strongly correlates with age. A multimodal correlation analysis indicates that increased brain atrophy and lesion load is accompanied by increased spectral power in the lower alpha (8-10 Hz) in the temporoparietal junction (TPJ). Increased lower alpha power in the TPJ was further associated with worse results on verbal and spatial working memory tests, whereas an increased lower/upper alpha power ratio was associated with slower information processing speed. In conclusion, multiple sclerosis patients with increased brain atrophy, lesion and thalamic volumes demonstrated increased lower alpha power in the TPJ and reduced cognitive abilities.


Catalase catalyzes nitrotyrosine formation from sodium azide and hydrogen peroxide.
Sodium azide (NaN3) is known as an inhibitor of catalase, and a nitric oxide (NO) donor in the presence of catalase and H2O2. We showed here that catalase-catalyzed oxidation of NaN3 can generate reactive nitrogen species which contribute to tyrosine nitration in the presence of H2O2. The formation of free-tyrosine nitration and protein-bound tyrosine nitration by the NaN3/catalase/H2O2 system showed a maximum level at pH 6.0. Free-tyrosine nitration induced by peroxynitrite was inhibited by ethanol and dimethylsulfoxide (DMSO), and augmented by superoxide dismutase (SOD). However, free-tyrosine nitration induced by the NaN3/catalase/H2O2 system was not affected by ethanol, DMSO and SOD. NO2- and NO donating agents did not affect free-tyrosine nitration by the NaN3/catalase/H2O2 system. The reaction of NaN3 with hydroxyl radical generating system showed free-tyrosine nitration, but no formation of nitrite and nitrate. The generation of nitrite (NO2-) and nitrate (NO3-) by the NaN3/catalase/H2O2 system was maximal at pH 5.0. These results suggested that the oxidation of NaN3 by the catalase/H2O2 system generates unknown peroxynitrite-like reactive nitrogen intermediates, which contribute to tyrosine nitration.


Slum upgrading strategies involving physical environment and infrastructure interventions and their effects on health and socio-economic outcomes.
Slums are densely populated, neglected parts of cities where housing and living conditions are exceptionally poor. In situ slum upgrading, at its basic level, involves improving the physical environment of the existing area, such as improving and installing basic infrastructure like water, sanitation, solid waste collection, electricity, storm water drainage, access roads and footpaths, and street lighting, as well as home improvements and securing land tenure. To explore the effects of slum upgrading strategies involving physical environment and infrastructure interventions on the health, quality of life and socio-economic wellbeing of urban slum dwellers in low and middle income countries (LMIC). Where reported, data were collected on the perspectives of slum dwellers regarding their needs, preferences for and satisfaction with interventions received. We searched for published and unpublished studies in 28 bibliographic databases including multidisciplinary (for example Scopus) and specialist databases covering health, social science, urban planning, environment and LMIC topics. Snowballing techniques included searching websites, journal handsearching, contacting authors and reference list checking. Searches were not restricted by language or publication date. We included studies examining the impact of slum upgrading strategies involving physical environment or infrastructure improvements (with or without additional co-interventions) on the health, quality of life and socio-economic wellbeing of LMIC urban slum dwellers. Randomised controlled trials (RCTs), controlled before and after studies (CBAs) and interrupted time series (ITS) were eligible for the main analysis. Controlled studies with only post-intervention data (CPI) and uncontrolled before and after (UBA) studies were included in a separate narrative to examine consistency of results and to supplement evidence gaps in the main analysis. Two authors independently extracted data and assessed risk of bias for each study. Differences between the included study interventions and outcomes precluded meta-analysis so the results were presented in a narrative summary with illustrative harvest plots. The body of evidence for outcomes within the main analysis was assessed according to GRADE as very low, low, moderate or high quality. We identified 10,488 unique records, with 323 screened as full text. Five studies were included for the main analysis: one RCT with a low risk, two CBAs with a moderate risk and two CBAs with a high risk of bias. Three CBAs evaluated multicomponent slum upgrading strategies. Road paving only was evaluated in one RCT and water supply in one CBA. A total of 3453 households or observations were included within the four studies reporting sample sizes.Most health outcomes in the main studies related to communicable diseases, for which the body of evidence was judged to be low quality. One CBA with a moderate risk of bias found that diarrhoeal incidence was reduced in households which received water connections from a private water company (risk ratio (RR) 0.53; 95% confidence interval (CI) 0.27 to 1.04) and the severity of diarrhoeal episodes (RR 0.48; 95% CI 0.19 to 1.22). There was no effect for duration of diarrhoea. Road paving did not result in changes in parasitic infections or sickness in one RCT. After multicomponent slum upgrading, claims for a waterborne disease as opposed to a non-waterborne disease reduced (RR 0.64; 95% CI 0.27 to 0.98) in one CBA with a high risk of bias but there was no change in sanitation-related mortality in a CBA with a moderate risk of bias.The majority of socio-economic outcomes reported within the main studies related to financial poverty, for which the body of evidence was of very low quality. Results were mixed amongst the main studies; one RCT and two CBAs reported no effect on the income of slum dwellers following slum upgrading. One further CBA found significant reduction in monthly water expenditure (mean difference (MD) -17.11 pesos; 95% CI -32.6 to -1.62). One RCT also showed mixed results for employment variables, finding no effect on unemployment levels but increased weekly worked hours (MD 4.68; 95% CI -0.46 to 9.82) and lower risk of residents intending to migrate for work (RR 0.78; 95% CI 0.60 to 1.01).There was no evidence available to assess the impact of slum upgrading on non-communicable diseases or social capital. Maternal and perinatal conditions, infant mortality, nutritional deficiencies, injuries, self-reported quality of life, education and crime were evaluated in one study each.Nine supporting studies were included that measured varying outcomes (6794 households or observations within eight studies reporting sample sizes). One CPI evaluated cement flooring only while three UBAs and five CPIs evaluated multicomponent slum upgrading strategies. All studies but one had a high risk of bias.The studies reinforced main study findings for diarrhoea incidence and water-related expenditure. Findings for parasitic infections and financial poverty were inconsistent with the main studies. In addition, supporting studies reported a number of disparate outcomes that were not evaluated in the main studies.Five supporting studies included some limited information on slum dweller perspectives. They indicated the importance of appropriate siting of facilities, preference for private facilities, delivering synergistic interventions together, and ensuring that infrastructure was fit for purpose and systems were provided for cleaning, maintenance and repair. A high risk of bias within the included studies, heterogeneity and evidence gaps prevent firm conclusions on the effect of slum upgrading strategies on health and socio-economic wellbeing. The most common health and socio-economic outcomes reported were communicable diseases and indicators of financial poverty. There was a limited but consistent body of evidence to suggest that slum upgrading may reduce the incidence of diarrhoeal diseases and water-related expenditure. The information available on slum dwellers' perspectives provided some insight to barriers and facilitators for successful implementation and maintenance of interventions.The availability and use of reliable, comparable outcome measures to determine the effect of slum upgrading on health, quality of life and socio-economic wellbeing would make a useful contribution to new research in this important area. Given the complexity in delivering slum upgrading, evaluations should look to incorporate process and qualitative information alongside quantitative effectiveness data to determine which particular interventions work (or don't work) and for whom.


The effect of orientation on prehension movement time.
We explored the relationship between hand orientation and movement time. Three groups of participants (n = 8 per group) were asked to grasp an object rotated in one of the following planes: (1) coronal; (2) sagittal; (3) horizontal. In the coronal plane, the rotational requirements directly mapped onto the neuromuscular demands associated with a single joint-level degree of freedom movement. A simple lawful relationship was found between the extent of rotation (pronation or supination) and duration. Reach-to-grasp movements to objects rotated in the sagittal and horizontal plane produced different movement patterns. These patterns increased the muscle level degrees of freedom recruited (higher neuromuscular demands) and movement duration increased correspondingly though not in a simple manner. The results of the present study show unambiguously that object orientation influences the duration of reach-to-grasp movements.


Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide.
Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). The finding that the amyloid beta protein (Abeta) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of Abeta. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.


Changes in cardiac gene expression after pig-to-primate orthotopic xenotransplantation.
Gene profiling methods have been widely useful for delineating changes in gene expression as an approach for gaining insight into the mechanism of rejection or disease pathology. Herein, we use gene profiling to compare changes in gene expression associated with different orthotopic cardiac xenotransplantation (OCXTx) outcomes and to identify potential effects of OCXTx on cardiac physiology. We used the Affymetrix GeneChip Porcine Genomic Array to characterize three types of orthotopic cardiac xenograft outcomes: 1) rejected hearts that underwent delayed xenograft rejection (DXR); 2) survivor hearts in which the xenograft was not rejected and recipient death was due to model complications; and 3) hearts which failed to provide sufficient circulatory support within the first 48 h of transplant, termed "perioperative cardiac xenograft dysfunction" (PCXD). Gene expression in each group was compared to control, not transplanted pig hearts, and changes in gene expression > 3 standard deviations (±3SD) from the control samples were analyzed. A bioinformatics analysis was used to identify enrichments in genes involved in Kyoto Encyclopedia of Genes and Genomes pathways and gene ontogeny molecular functions. Changes in gene expression were confirmed by quantitative RT-PCR. The ±3SD data set contained 260 probes, which minimally exhibited a 3.5-fold change in gene expression compared to control pig hearts. Hierarchical cluster analysis segregated rejected, survivor and PCXD samples, indicating a unique change in gene expression for each group. All transplant outcomes shared a set of 21 probes with similarly altered expression, which were indicative of ongoing myocardial inflammation and injury. Some outcome-specific changes in gene expression were identified. Bioinformatics analysis detected an enrichment of genes involved in protein, carbohydrate and branched amino acid metabolism, extracellular matrix-receptor interactions, focal adhesion, and cell communication. This is the first genome wide assessment of changes in cardiac gene expression after OCXTx. Hierarchical cluster analysis indicates a unique gene profile for each transplant outcome but additional samples will be required to define the unique classifier probe sets. Quantitative RT-PCR confirmed that all transplants exhibited strong evidence of ongoing inflammation and myocardial injury consistent with the effects of cytokines and vascular antibody-mediated inflammation. This was also consistent with bioinformatic analysis suggesting ongoing tissue repair in survivor and PCXD samples. Bioinformatics analysis suggests for the first time that xenotransplantation may affect cardiac metabolism in survivor and rejected samples. This study highlights the potential utility of molecular analysis to monitor xenograft function, to identify new molecular markers and to understand processes, which may contribute to DXR.


The role of linguistic and indexical information in improved recognition of dysarthric speech.
This investigation examined perceptual learning of dysarthric speech. Forty listeners were randomly assigned to one of two identification training tasks, aimed at highlighting either the linguistic (word identification task) or indexical (speaker identification task) properties of the neurologically degraded signal. Twenty additional listeners served as a control group, passively exposed to the training stimuli. Immediately following exposure to dysarthric speech, all three listener groups completed an identical phrase transcription task. Analysis of listener transcripts revealed remarkably similar intelligibility improvements for listeners trained to attend to either the linguistic or the indexical properties of the signal. Perceptual learning effects were also evaluated with regards to underlying error patterns indicative of segmental and suprasegmental processing. The findings of this study suggest that elements within both the linguistic and indexical properties of the dysarthric signal are learnable and interact to promote improved processing of this type and severity of speech degradation. Thus, the current study extends support for the development of a model of perceptual processing in which the learning of indexical properties is encoded and retained in conjunction with linguistic properties of the signal.


Improving a consensus approach for protein structure selection by removing redundancy.
In protein tertiary structure prediction, a crucial step is to select near-native structures from a large number of predicted structural models. Over the years, extensive research has been conducted for the protein structure selection problem with most approaches focusing on developing more accurate energy or scoring functions. Despite significant advances in this area, the discerning power of current approaches is still unsatisfactory. In this paper, we propose a novel consensus-based algorithm for the selection of predicted protein structures. Given a set of predicted models, our method first removes redundant structures to derive a subset of reference models. Then, a structure is ranked based on its average pairwise similarity to the reference models. Using the CASP8 data set containing a large collection of predicted models for 122 targets, we compared our method with the best CASP8 quality assessment (QA) servers, which are all consensus based, and showed that our QA scores correlate better with the GDT-TSs than those of the CASP8 QA servers. We also compared our method with the state-of-the-art scoring functions and showed its improved performance for near-native model selection. The GDT-TSs of the top models picked by our method are on average more than 8 percent better than the ones selected by the best performing scoring function.


Bayesian independent component analysis recovers pathway signatures from blood metabolomics data.
Interpreting the complex interplay of metabolites in heterogeneous biosamples still poses a challenging task. In this study, we propose independent component analysis (ICA) as a multivariate analysis tool for the interpretation of large-scale metabolomics data. In particular, we employ a Bayesian ICA method based on a mean-field approach, which allows us to statistically infer the number of independent components to be reconstructed. The advantage of ICA over correlation-based methods like principal component analysis (PCA) is the utilization of higher order statistical dependencies, which not only yield additional information but also allow a more meaningful representation of the data with fewer components. We performed the described ICA approach on a large-scale metabolomics data set of human serum samples, comprising a total of 1764 study probands with 218 measured metabolites. Inspecting the source matrix of statistically independent metabolite profiles using a weighted enrichment algorithm, we observe strong enrichment of specific metabolic pathways in all components. This includes signatures from amino acid metabolism, energy-related processes, carbohydrate metabolism, and lipid metabolism. Our results imply that the human blood metabolome is composed of a distinct set of overlaying, statistically independent signals. ICA furthermore produces a mixing matrix, describing the strength of each independent component for each of the study probands. Correlating these values with plasma high-density lipoprotein (HDL) levels, we establish a novel association between HDL plasma levels and the branched-chain amino acid pathway. We conclude that the Bayesian ICA methodology has the power and flexibility to replace many of the nowadays common PCA and clustering-based analyses common in the research field.


NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment.
NDEL1 is a binding partner of LIS1 that participates in the regulation of cytoplasmic dynein function and microtubule organization during mitotic cell division and neuronal migration. NDEL1 preferentially localizes to the centrosome and is a likely target for cell cycle-activated kinases, including CDK1. In particular, NDEL1 phosphorylation by CDK1 facilitates katanin p60 recruitment to the centrosome and triggers microtubule remodeling. Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation. In addition, NDEL1 is required for centrosome targeting of TACC3 through the interaction with TACC3. The expression of Aurora-A phosphorylation-mimetic mutants of NDEL1 efficiently rescued the defects of centrosomal maturation and separation which are characteristic of Aurora-A-depleted cells. Our findings suggest that Aurora-A-mediated phosphorylation of NDEL1 is essential for centrosomal separation and centrosomal maturation and for mitotic entry.


Silver-Impregnated Dressings for Sternotomy Incisions to Prevent Surgical Site Infections in Children.
The consequences of surgical site infections can be severe and range from short-term delays in discharge from the hospital to life-threatening infections such as mediastinitis. To evaluate the effectiveness of silver-impregnated dressings in decreasing surgical site infections in children after cardiac surgery. A randomized, controlled trial was used to compare silver-impregnated dressings (59 participants) with standard dressings (58 participants). The study team supervised all dressing changes after a sternotomy and ensured adherence with the hospital's bundle for reduction of surgical site infections. The ASEPSIS tool was used to evaluate sternal wounds for evidence of infection. The 2 groups had comparable Risk Adjustment for Congenital Heart Surgery scores, age, sex, weight, height, operating room characteristics, and number of chest tubes and/or pacemaker wires. No surgical site infections occurred in any study participant. Infections did occur, however, during the same period, in cardiac surgical patients who were not enrolled in the study. The evidence did not support the superiority of silver-impregnated dressings for prevention of surgical site infections in children after cardiac surgery. Adherence to a bundle for prevention of surgical site infections may have decreased the incidence of such infections in the study population during the study period.


Efficacy of cortico/cancellous composite allograft in treatment of cervical spondylosis.
This was a prospective comparative study.The aim of this study was to compare the clinical and radiologic outcomes of patients treated with cortico/cancellous composite allograft or autoiliac bone graft in anterior cervical discectomy and fusion.Several methods have been developed to fuse the cervical spine for treatment of cervical spondylosis. Cortico/cancellous composite allograft might be another alternative.A total of 46 patients who underwent surgery for treatment of cervical spondylosis were evaluated between September 2010 and January 2015. The duration of operation, blood loss, perioperative complications, neck disability index (NDI), visual analogue scale (VAS), and fusion rates were compared between the 2 groups.There were no significant differences in clinical or radiologic outcomes between the patients treated with cortico/cancellous composite allograft and those treated with autoiliac bone graft. The 2 groups showed similar improvements in clinical symptoms and fusion rates. Although not statistically significant, the subsidence rate was lower in the cortico/cancellous composite group.Cortico/cancellous composite allograft is an effective alternative to conventional allograft or autograft in anterior cervical discectomy and fusion.


Insulin augmentation of glucose-stimulated insulin secretion is impaired in insulin-resistant humans.
Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin's effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologically from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. Insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications.


A method for removal of low frequency components associated with head movements from dual-axis swallowing accelerometry signals.
Head movements can greatly affect swallowing accelerometry signals. In this paper, we implement a spline-based approach to remove low frequency components associated with these motions. Our approach was tested using both synthetic and real data. Synthetic signals were used to perform a comparative analysis of the spline-based approach with other similar techniques. Real data, obtained data from 408 healthy participants during various swallowing tasks, was used to analyze the processing accuracy with and without the spline-based head motions removal scheme. Specifically, we analyzed the segmentation accuracy and the effects of the scheme on statistical properties of these signals, as measured by the scaling analysis. The results of the numerical analysis showed that the spline-based technique achieves a superior performance in comparison to other existing techniques. Additionally, when applied to real data, we improved the accuracy of the segmentation process by achieving a 27% drop in the number of false negatives and a 30% drop in the number of false positives. Furthermore, the anthropometric trends in the statistical properties of these signals remained unaltered as shown by the scaling analysis, but the strength of statistical persistence was significantly reduced. These results clearly indicate that any future medical devices based on swallowing accelerometry signals should remove head motions from these signals in order to increase segmentation accuracy.


Synthetic circuits integrating logic and memory in living cells.
Logic and memory are essential functions of circuits that generate complex, state-dependent responses. Here we describe a strategy for efficiently assembling synthetic genetic circuits that use recombinases to implement Boolean logic functions with stable DNA-encoded memory of events. Application of this strategy allowed us to create all 16 two-input Boolean logic functions in living Escherichia coli cells without requiring cascades comprising multiple logic gates. We demonstrate long-term maintenance of memory for at least 90 cell generations and the ability to interrogate the states of these synthetic devices with fluorescent reporters and PCR. Using this approach we created two-bit digital-to-analog converters, which should be useful in biotechnology applications for encoding multiple stable gene expression outputs using transient inputs of inducers. We envision that this integrated logic and memory system will enable the implementation of complex cellular state machines, behaviors and pathways for therapeutic, diagnostic and basic science applications.


The Clinical Uses of Electrocochleography.
The clinical uses of electrocochleography are reviewed with some technical notes on the apparatus needed to get clear recordings under different conditions. Electrocochleography can be used to estimate auditory thresholds in difficult to test children and a golf club electrode is described. The same electrode can be used to obtain electrical auditory brainstem responses (EABR). Diagnostic testing in the clinic can be performed with a transtympanic needle electrode, and a suitable disposable monopolar electrode is described. The use of tone bursts rather than click stimuli gives a better means of diagnosis of the presence of endolymphatic hydrops. Electrocochleography can be used to monitor the cochlear function during surgery and a long coaxial cable, which can be sterilized, is needed to avoid electrical artifacts. Recently electrocochleography has been used to monitor cochlear implant insertion and to record residual hearing using an electrode on the cochlear implant array as the non-inverting (active) electrode.


[Immunoglobin subclasses and determination of specific antibodies. What role in the study of children with recurrent pneumonias?].
Recurrent pyogenic infections, including pneumonia, are known to occur in children with a defective immune system. Until recently, diagnosis was made by measuring major immunoglobulin isotypes and IgG subclasses. Recent reports show that in some cases all these measurements are normal, but that there is a defect in the production of specific protein or polysaccharide antibodies. To study immune function in children with recurrent pneumonia to determine the most appropriate immunologic studies for the evaluation of recurrent infections in children. Forty-three children (ages 2 to 12 years; mean 5.3 years, 29 male) who were referred to our pulmonology clinic because of recurrent lower respiratory tract infections. Major causes of recurrent infections were excluded by clinical, radiological or laboratory studies. Immunologic studies included serum immunoglobulins, IgG subclasses, IgA subclasses, isohemagglutinins and antibody responsiveness to vaccination with tetanus, rubella, H. influenza b conjugate and pneumococcal polysaccharide. The majority of children had normal or elevated serum immunoglobulin and subclass levels. Three patients had low levels of IgG2 and IgA, alone or simultaneously. Eleven patients failed to respond to Hib or rubella vaccination and one failed to respond to pneumococcal immunisation. Our preliminary results seem to indicate that a high proportion of children with recurrent pneumonia have a demonstrable immunologic abnormality. There is no direct relationship between low levels of IgG subclass and the child's capacity to form antibodies to several antigens. Defects in antibody production are very specific and an extended panel is necessary. Examination of the antibody-forming capacity seems important in the initial evaluation of children with recurrent pneumonia.


Cocoa, blood pressure, and vascular function.
The consumption of a high amount of fruits and vegetables was found to be associated with a lower risk of coronary heart disease and stroke. Epidemiologically, a similar relationship has been found with cocoa, a naturally polyphenol-rich food. Obviously, double blind randomized studies are difficult to perform with cocoa and chocolate, respectively. However, intervention studies strongly suggest that cocoa has several beneficial effects on cardiovascular health, including the lowering of blood pressure, the improvement of vascular function and glucose metabolism, and the reduction of platelet aggregation and adhesion. Several potential mechanisms through which cocoa might exert its positive effects have been proposed, among them activation of nitric oxide synthase, increased bioavailability of nitric oxide as well as antioxidant, and anti-inflammatory properties. It is the aim of this review to summarize the findings of cocoa and chocolate on blood pressure and vascular function.


Validity of four pain intensity rating scales.
The Visual Analogue Scale (VAS), Numerical Rating Scale (NRS), Verbal Rating Scale (VRS), and the Faces Pain Scale-Revised (FPS-R) are among the most commonly used measures of pain intensity in clinical and research settings. Although evidence supports their validity as measures of pain intensity, few studies have compared them with respect to the critical validity criteria of responsivity, and no experiment has directly compared all 4 measures in the same study. The current study compared the relative validity of VAS, NRS, VRS, and FPS-R for detecting differences in painful stimulus intensity and differences between men and women in response to experimentally induced pain. One hundred twenty-seven subjects underwent four 20-second cold pressor trials with temperature order counterbalanced across 1°C, 3°C, 5°C, and 7°C and rated pain intensity using all 4 scales. Results showed statistically significant differences in pain intensity between temperatures for each scale, with lower temperatures resulting in higher pain intensity. The order of responsivity was as follows: NRS, VAS, VRS, and FPS-R. However, there were relatively small differences in the responsivity between scales. A statistically significant sex main effect was also found for the NRS, VRS, and FPS-R. The findings are consistent with previous studies supporting the validity of each scale. The most support emerged for the NRS as being both (1) most responsive and (2) able to detect sex differences in pain intensity. The results also provide support for the validity of the scales for use in Portuguese samples.


Asbestos as a possible major cause of malignant lung tumors (including small cell carcinoma, adenocarcinoma & mesothelioma), brain tumors (i.e. astrocytoma & glioblastoma multiforme), many other malignant tumors, intractable pain including fibromyalgia, & some cardio-vascular pathology: Safe & effective methods of reducing asbestos from normal & pathological areas.
High incidences of Small Cell Carcinoma & Adenocarcinoma of the lung, Astrocytoma & Glioblastoma Multiforme of the brain and Mesothelioma of the lung were found in those who had a high accumulation of Asbestos in the eyes and upper respiratory system (nose, larynx, trachea, etc.). When measured non-invasively using the Bi-Digital O-Ring Test (BDORT), brain tumors had the highest concentration of Asbestos (0.2 approximately 2.1 mg BDORT units). Relatively high levels of Asbestos (0.2 approximately 0.6 mg BDORT units) were found in: Squamous Cell Carcinoma of the lungs & esophagus, Adenocarcinoma of the larynx & breast, myelogenic leukemia, arteries of these cancers, left ventricle of failing heart, myocardial infarction, some of the narrowed arteries, varicose veins, cataracts, balding heads, hot flashes, Alzheimer's Disease and Autism. A small, round or ellipsoidal area, with diameter of 5 mm or less, was found near the center of every cancer tissue with a higher level of Asbestos (1 approximately 3 mg), As, Zn, Cr and Se, than in the rest of the tumor; this small area may be where the cancer initiated. Among areas of intractable pain with frequent recurrence and gradual worsening, about 0.2 approximately 0.5 mg BDORT units (or higher) of Asbestos were found. The author found that in the Astrocytoma and many other cancer patients, the optimal dose of DHEA produced very significant reductions of cancer cell telomere from over 1400 ng in the brain tumors (and over 900 ng in other cancers) to close to or less than 1 yg (=10(-24) g), with circulatory improvement by reduction of TXB2. Unlike the standard, widely used treatment with DHEA 25 approximately 50 mg daily, which is an overdose; we only gave one optimal dose (1.5 approximately 12.5 mg) and the beneficial effects usually lasted anywhere between 3-6 months, unless inhibiting factors were introduced. In addition, once one optimal dose of DHEA was given, the amount of Asbestos from these tumors decreased very significantly (30 approximately 99% reduction) with marked increase in urine Asbestos. One optimal dose of special Cilantro tablet reduced more Asbestos than DHEA or (+) Qi Gong Energy Stored Paper. In addition, the application of (+) Solar Energy Stored Paper often reduces 70 approximately 99% of the Asbestos, while (+) Qi Gong Energy Stored Paper reduces 50 approximately 99% of the Asbestos.