Transport mechanism of a new behaviorally highly potent adrenocorticotropic hormone (ACTH) analog, ebiratide, through the blood-brain barrier.
The binding and internalization of a novel adrenocorticotropic hormone (ACTH) analog having a potent neuromodulating effect, ebiratide (H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2), by isolated bovine brain capillaries, were examined. Metabolism of [5-125I-His]ebiratide occurred during a 30-min incubation with bovine brain capillaries at 37 degrees C. In the presence of 20 mM EDTA, added to inhibit this metabolism, the medium, after 30 min of incubation, contained 82.3 +/- 0.5% of the unchanged ebiratide. The total binding and acid-resistant binding of [125I]ebiratide increased with time and reached an equilibrium at about 15 min. The total binding and acid-resistant binding at 30 min (as the cell/medium ratios corrected with [14C]sucrose) were 13.07 +/- 0.86 and 5.00 +/- 0.18 microliters/mg of protein, respectively. The acid-resistant binding showed significant dependence on temperature and medium osmolarity. The [125I]ebiratide binding was significantly inhibited by dansylcadaverine, an endocytosis inhibitor. The saturable acid-resistant binding was obtained by the addition of unlabeled ebiratide (100 nM-5 mM), and the maximal internalization capacity (Bmax) at 30 min was 144.2 pmol/mg of protein, with the half-saturation constant (KD) of 62.1 microM. The nonsaturable acid-resistant binding [cell/medium ratio in the presence of the unlabeled compound (1 mM or more)] was 2.2 microliters/mg of protein. The acid-resistant binding was significantly inhibited by human ACTH, poly-L-lysine, protamine and E-2078, a basic peptide, but was not inhibited by poly-L-glutamate, insulin or transferrin. These results demonstrate that ebiratide is transported through the blood-brain barrier via a basic peptide-specific absorptive-mediated endocytosis.


Do sequence-space synaesthetes have better spatial imagery skills? Yes, but there are individual differences.
People with sequence-space synaesthesia perceive sequences (e.g. numbers, months, letters) as spatially extended forms. Here, we ask whether sequence-space synaesthetes have advantages in visuo-spatial skills such as mental rotation. Previous studies addressing this question have produced mixed results with some showing mental rotation advantages (Simner et al. in Cortex 45:1246-1260, 2009; Brang et al. in Cogn Process, 2013), but one that did not (Rizza and Price in Cogn Process 13:299-303, 2012). We tested this hypothesis again with a new group of sequence-space synaesthetes, and we also tested a range of individual differences that might have caused this conflict across previous studies. Specifically, we tested: years of education, visual imagery ability, nature of forms (2D or 3D representation of sequences), number of forms (e.g. for months, days, numbers), and tendency to project sequences into external space versus the mind's eye. We found yet again that synaesthetes had enhanced abilities in mental rotation compared to controls, but that one individual difference in synaesthetes (the ability to project forms into space) was especially linked to performance. We also found that synaesthetes self-reported higher visual imagery than controls (Price in Cortex 45:1229-1245, 2009; Mann et al. in Conscious Cognit 18:619-627, 2009; Rizza and Price 2012). Overall, our data support previous studies showing superior imagery reports (Price 2009) and mental rotation (Simner et al. 2009; Brang et al. 2013) in sequence-space synaesthetes, and we suggest that one previous failure to replicate (Rizza and Price 2012) might be explained by individual differences among synaesthetes recruited for testing.


Is triple immunostaining with 34betaE12, p63, and racemase in prostate cancer advantageous? A tissue microarray study.
This study aimed to determine the usefulness of a combination of 3 immunohistochemical markers, 34/betaE12, p63 and alpha-methylacyl coenzyme A racemase (AMACR), for the diagnosis of prostate cancer using tissue microarrays (TMAs) constructed from 91 archival radical prostatectomy specimens derived from the Pathology Department files of Singapore General Hospital, Singapore. Triple immunostaining using a cocktail of these 3 antibodies was performed on TMA sections using the streptavidin-biotin method. When compared with immunohistochemical staining using the individual antibodies, we found that the triple cocktail allowed improved evaluation of basal cells in benign glands, and AMACR allowed simultaneous corroboration of malignant prostatic glands in the same section. We achieved a specificity of 100% with the triple cocktail, and sensitivity was acceptable, at 93.8%. In comparison, specificity and sensitivity of the individual antibodies were 95.5% and 97.3%, 93.3% and 93.8%, 97.0% and 95.6% for p63, 34betaE12, and AMACR, respectively. The triple cocktail offers a cost-effective way of evaluating abnormal prostatic glandular foci, in addition to maximizing the use of small tissue samples from prostatic needle biopsies.


Non-pharmacological interventions for assisting the induction of anaesthesia in children.
Induction of general anaesthesia can be distressing for children. Non-pharmacological methods for reducing anxiety and improving co-operation may avoid the adverse effects of preoperative sedation. To assess the effects of non-pharmacological interventions in assisting induction of anaesthesia in children by reducing their anxiety, distress or increasing their co-operation. In this updated review we searched CENTRAL (the Cochrane Library 2012, Issue 12) and searched the following databases from inception to 15 January 2013: MEDLINE, EMBASE, PsycINFO and Web of Science. We reran the search in August 2014. We will deal with the single study found to be of interest when we next update the review. We included randomized controlled trials of a non-pharmacological intervention implemented on the day of surgery or anaesthesia. At least two review authors independently extracted data and assessed risk of bias in trials. We included 28 trials (2681 children) investigating 17 interventions of interest; all trials were conducted in high-income countries. Overall we judged the trials to be at high risk of bias. Except for parental acupuncture (graded low), all other GRADE assessments of the primary outcomes of comparisons were very low, indicating a high degree of uncertainty about the overall findings. Parental presence: In five trials (557 children), parental presence at induction of anaesthesia did not reduce child anxiety compared with not having a parent present (standardized mean difference (SMD) 0.03, 95% confidence interval (CI) -0.14 to 0.20). In a further three trials (267 children) where we were unable to pool results, we found no clear differences in child anxiety, whether a parent was present or not. In a single trial, child anxiety showed no significant difference whether one or two parents were present, although parental anxiety was significantly reduced when both parents were present at the induction. Parental presence was significantly less effective than sedative premedication in reducing children's anxiety at induction in three trials with 254 children (we could not pool results). Child interventions (passive): When a video of the child's choice was played during induction, children were significantly less anxious than controls (median difference modified Yale Preoperative Anxiety Scale (mYPAS) 31.2, 95% CI 27.1 to 33.3) in a trial of 91 children. In another trial of 120 children, co-operation at induction did not differ significantly when a video fairytale was played before induction. Children exposed to low sensory stimulation were significantly less anxious than control children on introduction of the anaesthesia mask and more likely to be co-operative during induction in one trial of 70 children. Music therapy did not show a significant effect on children's anxiety in another trial of 51 children. Child interventions (mask introduction): We found no significant differences between a mask exposure intervention and control in a single trial of 103 children for child anxiety (risk ratio (RR) 0.59, 95% CI 0.31 to 1.11) although children did demonstrate significantly better co-operation in the mask exposure group (RR 1.27, 95% CI 1.06 to 1.51). Child interventions (interactive): In a three-arm trial of 168 children, preparation with interactive computer packages (in addition to parental presence) was more effective than verbal preparation, although differences between computer and cartoon preparation were not significant, and neither was cartoon preparation when compared with verbal preparation. Children given video games before induction were significantly less anxious at induction than those in the control group (mYPAS mean difference (MD) -9.80, 95% CI -19.42 to -0.18) and also when compared with children who were sedated with midazolam (mYPAS MD -12.20, 95% CI -21.82 to -2.58) in a trial of 112 children. When compared with parental presence only, clowns or clown doctors significantly lessened children's anxiety in the operating/induction room (mYPAS MD -24.41, 95% CI -38.43 to -10.48; random-effects, I² 75%) in three trials with a total of 133 children. However, we saw no significant differences in child anxiety in the operating room between clowns/clown doctors and sedative premedication (mYPAS MD -9.67, 95% CI -21.14 to 1.80, random-effects, I² 66%; 2 trials of 93 children). In a trial of hypnotherapy versus sedative premedication in 50 children, there were no significant differences in children's anxiety at induction (RR 0.59, 95% CI 0.33 to 1.04). Parental interventions: Children of parents having acupuncture compared with parental sham acupuncture were less anxious during induction (mYPAS MD -17, 95% CI -30.51 to -3.49) and were more co-operative (RR 1.59, 95% CI 1.01 to 2.53) in a single trial of 67 children. Two trials with 191 parents assessed the effects of parental video viewing but did not report any of the review's prespecified primary outcomes. This review shows that the presence of parents during induction of general anaesthesia does not diminish their child's anxiety. Potentially promising non-pharmacological interventions such as parental acupuncture; clowns/clown doctors; playing videos of the child's choice during induction; low sensory stimulation; and hand-held video games need further investigation in larger studies.


Genotyping as a tool for antibiotic resistance surveillance of Neisseria gonorrhoeae in New Caledonia: evidence of a novel genotype associated with reduced penicillin susceptibility.
Antibiotic resistance in Neisseria gonorrhoeae continues to be a major concern in public health. Resistance of N. gonorrhoeae bacteria to penicillin G is widespread in most developed countries, which has necessitated a change to newer drugs for treatment of gonococcal infections. Recent reports indicate that resistance to these newer drugs is increasing, highlighting the need for accurate therapeutic recommendations. In some countries or communities, however, N. gonorrhoeae isolates are still susceptible to penicillin, so the use of this antibiotic for single-dose treatments of medically under-resourced patients is beneficial. In order to evaluate the adequacy and sustainability of this treatment approach, we explored the presence and prevalence of chromosomally mediated resistance determinants in N. gonorrhoeae isolates collected from 2005 to 2007 in New Caledonia. We developed two new real-time PCR assays targeting the penB and mtrR determinants, to be used together with a previously described duplex assay targeting the penA and ponA determinants. The results of this study provided evidence that neither the most-common mtrR determinants nor the most-resistance-associated penB alleles are currently circulating in New Caledonia, suggesting that penicillin should still be considered a valuable treatment strategy. Additionally, using our genotyping assay, we observed an unexpected penB genotype at a relatively high frequency that was associated with a decreased susceptibility to penicillin (average MIC, 0.15 mug/ml). Sequencing revealed that this genotype corresponded to an A102S mutation in the penB gene. The molecular tools developed in this study can be used successfully for prospective epidemiological monitoring and surveillance of penicillin susceptibility.


Cannabis, the Endocannabinoid System and Immunity-the Journey from the Bedside to the Bench and Back.
The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.


Measurement of specimen-induced aberrations of biological samples using phase stepping interferometry.
Confocal or multiphoton microscopes, which deliver optical sections and three-dimensional (3D) images of thick specimens, are widely used in biology. These techniques, however, are sensitive to aberrations that may originate from the refractive index structure of the specimen itself. The aberrations cause reduced signal intensity and the 3D resolution of the instrument is compromised. It has been suggested to correct for aberrations in confocal microscopes using adaptive optics. In order to define the design specifications for such adaptive optics systems, one has to know the amount of aberrations present for typical applications such as with biological samples. We have built a phase stepping interferometer microscope that directly measures the aberration of the wavefront. The modal content of the wavefront is extracted by employing Zernike mode decomposition. Results for typical biological specimens are presented. It was found for all samples investigated that higher order Zernike modes give only a small contribution to the overall aberration. Therefore, these higher order modes can be neglected in future adaptive optics sensing and correction schemes implemented into confocal or multiphoton microscopes, leading to more efficient designs.


Daily online testing in large classes: boosting college performance while reducing achievement gaps.
An in-class computer-based system, that included daily online testing, was introduced to two large university classes. We examined subsequent improvements in academic performance and reductions in the achievement gaps between lower- and upper-middle class students in academic performance. Students (N = 901) brought laptop computers to classes and took daily quizzes that provided immediate and personalized feedback. Student performance was compared with the same data for traditional classes taught previously by the same instructors (N = 935). Exam performance was approximately half a letter grade above previous semesters, based on comparisons of identical questions asked from earlier years. Students in the experimental classes performed better in other classes, both in the semester they took the course and in subsequent semester classes. The new system resulted in a 50% reduction in the achievement gap as measured by grades among students of different social classes. These findings suggest that frequent consequential quizzing should be used routinely in large lecture courses to improve performance in class and in other concurrent and subsequent courses.


Avian Influenza Virus Detection by Optimized Peptide Termination on a Boron-Doped Diamond Electrode.
The development of a simple detection method with high sensitivity is essential for the diagnosis and surveillance of infectious diseases. Previously, we constructed a sensitive biosensor for the detection of pathological human influenza viruses using a boron-doped diamond electrode terminated with a sialyloligosaccharide receptor-mimic peptide that could bind to hemagglutinins involved in viral infection. Circulation of influenza induced by the avian virus in humans has become a major public health concern, and methods for the detection of avian viruses are urgently needed. Here, peptide density and dendrimer generation terminated on the electrode altered the efficiency of viral binding to the electrode surface, thus significantly enhancing charge-transfer resistance measured by electrochemical impedance spectroscopy. The peptide-terminated electrodes exhibited an excellent detection limit of less than one plaque-forming unit of seasonal H1N1 and H3N2 viruses. Furthermore, the improved electrode was detectable for avian viruses isolated from H5N3, H7N1, and H9N2, showing the potential for the detection of all subtypes of influenza A virus, including new subtypes. The peptide-based electrochemical architecture provided a promising approach to biosensors for ultrasensitive detection of pathogenic microorganisms.


Reverse engineering of Alzheimer's disease based on biomarker pathways analysis.
Alzheimer's disease (AD) poses an increasingly profound problem to society, yet progress toward a genuine understanding of the disease remains worryingly slow. Perhaps, the most outstanding problem with the biology of AD is the question of its mechanistic origins, that is, it remains unclear wherein the molecular failures occur that underlie the disease. We demonstrate how molecular biomarkers could help define the nature of AD in terms of the early biochemical events that correlate with disease progression. We use a novel panel of biomolecules that appears in cerebrospinal fluid of AD patients. As changes in the relative abundance of these molecular markers are associated with progression to AD from mild cognitive impairment, we make the assumption that by tracking their origins we can identify the biochemical conditions that predispose their presence and consequently cause the onset of AD. We couple these protein markers with an analysis of a series of genetic factors and together this hypothesis essentially allows us to redefine AD in terms of the molecular pathways that underlie the disease.


Increased Levels of Genomic Instability and Mutations in Homologous Recombination Genes in Locally Advanced Rectal Carcinomas.
Pre-operative 5-fluoracil-based chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Patients with pathological complete response (pCR-0% of tumor cells in the surgical specimen after nCRT) have better overall survival and lower risk of recurrence in comparison with incomplete responders (pIR). Predictive biomarkers to be used for new therapeutic strategies and capable of stratifying patients to avoid overtreatment are needed. We evaluated the genomic profiles of 33 pre-treatment LARC biopsies using SNP array and targeted-next generation sequencing (tNGS). Based on the large number of identified genomic alterations, we calculated the genomic instability index (GII) and three homologous recombination deficiency (HRD) scores, which have been reported as impaired DNA repair markers. We observed high GII in our LARC cases, which was confirmed in 165 rectal cancer cases from TCGA. Patients with pCR presented higher GII compared with pIR. Moreover, a negative correlation between GII and the fraction of tumor cells remaining after surgery was observed (ρ = -0.382, P = 0.02). High HRD scores were detected in 61% of LARC, of which 70% were incomplete responders. Using tNGS (105 cancer-related genes, 13 involved in HR and 5 in mismatch repair pathways), we identified 23% of cases with mutations in HR genes, mostly in pIR cases (86% of mutated cases). In agreement, the analysis of the TCGA dataset (N = 145) revealed 21% of tumors with mutations in HR genes. The HRD scores were shown to be predictive of better response to PARP-inhibitors and platinum-based chemotherapy in breast and ovarian cancer. Our results suggest that the same strategy could be applied in a set of LARC patients with HRD. In conclusion, we identified high genomic instability in LARC, which was related to alterations in the HR pathway, especially in pIR. These findings suggest that patients with impaired HRD would clinically benefit from PARP-inhibitors and platinum-based therapy.


Efficacy and tolerability of combination therapy with valsartan/hydrochlorothiazide in the initial treatment of severe hypertension.
Most patients with severe hypertension are at high risk for cardiovascular events and require prompt blood pressure (BP)-lowering and combination therapy to achieve BP goals. This study evaluated the therapeutic efficacy and tolerability of initial treatment with the combination of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with severe hypertension. This was a 6-week, randomized, double-blind, multicenter, forced titration study that compared initial therapy with the combination of valsartan/HCTZ 160/12.5 mg (force titrated to 160/25 mg after 2 weeks and to 320/25 mg after 4 weeks) to monotherapy with valsartan 160 mg (force titrated to 320 mg after 2 weeks and sham-titrated to 320 mg after 4 weeks). Eligible patients were 18-80 years old with severe essential hypertension (mean sitting diastolic BP > or = 110 mmHg and < 120 mmHg and mean sitting systolic BP > or = 140 mmHg and < 200 mmHg). The Clinical Trial Registry number was NCT00273299. The primary efficacy variable was the rate of BP control (mean sitting BP < 140/90 mmHg) at Week 4. Tolerability was evaluated by monitoring all adverse events, vital signs, and laboratory tests including hematology and biochemistry. A total of 608 patients were randomized to either valsartan/HCTZ (n = 307) or valsartan monotherapy (n = 301). Significantly more patients achieved overall BP control (< 140/90 mmHg) with valsartan/HCTZ compared to monotherapy at Week 4 (primary efficacy variable and timepoint) (39.6% vs. 21.8%; p < 0.0001) and Week 6 (48.2% vs. 27.2%; p < 0.0001). Mean reductions in BP at Week 4 were significantly greater for valsartan/HCTZ (30.8/22.7 mmHg vs. 21.7/17.5 mmHg; p < 0.0001), with further reductions at Week 6. BP control rates were greater with combination therapy as early as Week 2. The overall incidence of adverse events was comparable between the combination therapy (34.9%) and monotherapy (36.7%) treatment groups. A potential limitation of the forced-titration design is that some patients were titrated to higher doses despite having achieved goal BP. This may impact the interpretation of the incidence of dose-dependent adverse events. Initial therapy with valsartan/HCTZ is effective and well tolerated in patients with severe hypertension.


Hearing in children with fetal alcohol spectrum disorder (FASD).
Alcohol is the most prevalent human teratogen affected by early exposure of the fetus. Although not listed as a major part of the fetal alcohol spectrum disorder (FASD), different texts list hearing loss as a characteristic of the FASD, based on several small studies. To characterize hearing in children with FASD, diagnosed in the Motherisk Program in Toronto. Cross sectional cohort study. Academic referral center. Children 4-16 years of age that met criteria for FASD, with no other known risk factor for sensorineural hearing loss. A consecutive sample of 41 children (13 girls, mean age 8.9 +/-3 years) was collected. Physical examination, audiometry and tympanometry. External and middle ear pathology on physical examination, pure tone average (PTA), speech reception threshold (SRT), discrimination and tympanometry. Results were compared to reference values in the normal population. Hearing loss equal or greater than 16dB hearing-level in each frequency tested was considered to be clinically significant. A total of 5 (11.2%) of children had hearing loss of at least 16dB hearing-level, mostly unilateral. SRT was within the normal range in 40 (98%) of children with FASD and discrimination was normal in all children. None had auricular or external canal dysmorphology. 14.7% of the children had frequent episodes of acute otitis media. Middle ear effusion was detected in 8 ears (9.8%). The prevalence of mild sensorineural hearing loss in children diagnosed with FASD (16dB hearing-level or greater) was not higher than expected in this age group. However, because children with FASD are academically and behaviorally challenged, early detection of hearing loss and early intervention is warranted.


Metagenomic and metatranscriptomic analyses reveal activity and hosts of antibiotic resistance genes in activated sludge.
Wastewater treatment plants (WWTPs) are a source and reservoir for subsequent spread of various antibiotic resistance genes (ARGs). However, little is known about the activity and hosts of ARGs in WWTPs. Here, we utilized both metagenomic and metatranscriptomic approaches to comprehensively reveal the diversity, abundance, expression and hosts of ARGs in activated sludge (AS) from three conventional WWTPs in Taiwan. Based on deep sequencing data and a custom-made ARG database, a total of 360 ARGs associated with 24 classes of antibiotics were identified from the three AS metagenomes, with an abundance range of 7.06 × 10-1-1.20 × 10-4 copies of ARG/copy of 16S rRNA gene. Differential coverage binning analysis revealed that >22 bacterial phyla were the putative hosts of the identified ARGs. Surprisingly, genus Mycobacterium and family Burkholderiaceae were observed as multi-drug resistant harboring 14 and 50 ARGs. Metatranscriptome analysis showed 65.8% of the identified ARGs were being expressed, highlighting that ARGs were not only present, but also transcriptionally active in AS. Remarkably, 110 identified ARGs were annotated as plasmid-associated and displayed a close to two-fold increased likelihood of being transcriptionally expressed compared to those ARGs found exclusively within bacterial chromosomes. Further analysis showed the transcript abundance of aminoglycoside, sulfonamide, and tetracycline resistance genes was mainly contributed by plasmid-borne ARGs. Our approach allowed us to specifically link ARGs to their transcripts and genetic context, providing a comprehensive insight into the prevalence, expression and hosts of ARGs in AS. Overall, results of this study enhance our understanding of the distribution and dissemination of ARGs in WWTPs, which benefits environmental risk assessment and management of ARB and ARGs.


The impact of an indigenous proverb on women's mental health: A phenomenological approach.
Proverbs and idioms represent cultural and societal beliefs and values inherited from the forefathers. An example is lebitla la mosadi ke bogadi. Over many decades African people have used such ancient instructions to counsel women to be resilient in their marriages thus impacting on their mental health. The purpose of this article was to explore and describe that proverb and its impact on women's mental health. Hermeneutic phenomenology was used to explore and describe the prover band its impact on indigenous women's mental health. The population included married, divorced, widowed and single women who were attending social clubs or networks in the cities of Tshwane and Johannesburg. Snowball and purposive sampling was used to select 57 participants. Five face-to-face interviews and eight focus groups interviews were conducted. Colaizzi's data analysis method was used to analyse data. Oppression and stigmatisation of women and their families and harmful effects that may result in death were identified as having an impact on women's mental health. Some women shared that they were oppressed in many ways. In addition, they feared stigmatisation should they wish to divorce. They constantly lived in fear of being harmed or killed by their spouses. There was a need for nurses to develop awareness regarding cultural issues so that women are better served in primary healthcare settings. Women who are suspected of experiencing abuse, should be screened for abuse so that they can be assisted accordingly.


Induction of "infectious" tolerance to MHC-incompatible cardiac allografts in CD4 monoclonal antibody-treated sensitized rat recipients.
LBNF1 heart grafts are rejected in an accelerated manner within 36 h by LEW rats that have been sensitized with Brown Norway rat skin grafts on day -7. Treatment with RIB-5/2, a CD4-nondepleting mAb (10 doses of 5 mg/rat/day, i.v., from day -7 to day +21) abrogated rejection at <36 h and produced indefinite (>200 days) cardiac allograft survival. Transplantation tolerance in this model developed within several weeks, and during the maintenance phase (>100 days) it was associated with diminished host circulating allo-Ab responses and induction of peripheral allospecific T cell unresponsiveness both in vitro and in vivo. Tolerant cells in mAb-treated hosts could disable naive or alloimmune cells, so that they failed to trigger graft rejection. Moreover, donor-specific and organ-nonspecific tolerance could be adoptively transferred by spleen cells alone into new sets of primary (100%) and secondary (>40%) test recipients. CD4+ T cells were instrumental for the induction of such readily transferable tolerance. The first and second generation suppressive regulatory cells were also critical for the inhibition of allograft recognition by normal or even alloimmune cells. Hence, the features of an "infectious" tolerance pathway to minor histocompatibility-mismatched skin grafts, originally described in thymectomized mice, may be applied to the euthymic primed rats rendered tolerant to fully MHC-incompatible vascularized organ allografts. Such reprogramming of host cell-mediated regulatory mechanisms following CD4-targeted therapy adds to our appreciation of the potential utility and applicability of infectious tolerance in transplant recipients treated with a perioperative course of CD4-targeted monotherapy.


Referral patterns after school medical examinations.
The incidence of sensory or language abnormalities and the factors influencing the clinical medical officers' decisions to refer children who failed developmental tests were studied. There were 1259 children examined and referrals for vision, hearing, and language assessment were made for 39(3.1%), 75(6.0%), and 27(2.1%), respectively. About 80% of these problems, however, were not known to the child health services when the children were 3.5 years old, mainly because children had moved to the district after the age of 3.5, and did not attend the 3.5 year screening clinics. Referrals formed only a small percentage of children who failed a test (11.0% failed vision, 19.5% hearing, and 24.6% language assessments). For vision and hearing the most important reason for the discrepancy was the clinical medical officers' wish to reassess children who failed the test before referring them. For the language test the clinical medical officer's often believed that the screening did not reflect the child's skills, which suggests that language screening as currently used in the district is not effective. Evaluation of the examination has highlighted the need to review the tests being used.


Comparison of mandibular movement trajectories and associated patterns of oral muscle electromyographic activity during spontaneous and apomorphine-induced rhythmic jaw movements in the guinea pig.
Vertical and horizontal movements of the lower jaw (mandible) of ketamine-anesthetized guinea pigs were recorded in association with electromyographic (EMG) activity in the anterior digastric, lateral pterygoid, medial pterygoid, and deep masseter muscles during spontaneously occurring rhythmic jaw movements (SRJMs) and during rhythmical jaw movements induced by the intravenous administration of apomorphine (ARJMs). Both ARJMs and SRJMs were near periodic and occurred at frequencies in the 2- to 5-Hz range. However, the profiles of the mandibular movements and associated patterns of jaw muscle EMG activity differed dramatically for SRJMs versus ARJMs. SRJMs were characterized by prominent lateral excursions of the mandible that occurred in association with both the jaw opening and closing movements. The lateral excursions were directed to the left side on some SRJM cycles and to the right side on others. The direction of the lateral component alternated irregularly, but no more than three consecutive cycles with horizontal movements to the same side were observed at any time. Each SRJM cycle was generated by the occurrence of one of two coordinated sequences of EMG activity. One sequence produced right-sided cycles, the other produced left-sided cycles. Each sequence was initiated by an EMG burst in the digastric muscle ipsilateral to the direction of the horizontal excursion of the mandible, followed by EMG bursts in the contralateral digastric, lateral pterygoid, and medial pterygoid muscles. The EMG bursts in the digastrics and contralateral lateral pterygoid muscles were associated with jaw opening and the initial stage of lateral movement. EMG activity in the contralateral medial pterygoid muscle was associated with the onset of closing and a second stage of lateral movement. Masseter muscle activity was also observed during SRJMs, but only in a subset of the animals tested (3 of 12). When present, the masseter activity began well after the onset of jaw closing. No significant horizontal mandibular movements were observed during ARJMs. The mandibular trajectories during opening and closing always remained close to the midline. The opening phase of ARJM cycles was associated with bilaterally synchronized activity in the digastric and lateral pterygoid muscles. The closing phase was associated with bilaterally symmetric activity in the masseter muscles. The medial pterygoid muscles displayed little or no EMG activity during ARJMs. The durations of the EMG bursts recorded in the masseter muscle were correlated with cycle time during SRJMs, as were the burst durations of the digastric and lateral pterygoid muscles during ARJMs.(ABSTRACT TRUNCATED AT 400 WORDS)


Rare-earth-doped glass and LiNbO(3) waveguide lasers and optical amplifiers.
Recently there has been considerable interest in the field of rare-earth-doped integrated optics because of their potential use in compact and efficient monolithic devices combining the rare-earth laser gain and the large range of integrated optical functions already demonstrated. Recent developments in Nd(3+)-doped and Er(3+)-doped glass and LiNbO(3) waveguide lasers and optical amplifiers, their application, and future prospects are reviewed briefly.


Functional responses of uremic single skeletal muscle fibers to redox imbalances.
The exact causes of skeletal muscle weakness in chronic kidney disease (CKD) remain unknown with uremic toxicity and redox imbalances being implicated. To understand whether uremic muscle has acquired any sensitivity to acute redox changes we examined the effects of redox disturbances on force generation capacity. Permeabilized single psoas fibers (N =37) from surgically induced CKD (UREM) and sham-operated (CON) rabbits were exposed to an oxidizing (10 mM Hydrogen Peroxide, H2O2) and/or a reducing [10 mM Dithiothreitol (DTT)] agent, in a blind design, in two sets of experiments examining: A) the acute effect of the addition of H2O2 on maximal (pCa 4.4) isometric force of actively contracting fibers and the effect of incubation in DTT on subsequent re-activation and force recovery (N =9 CON; N =9 UREM fibers); B) the effect of incubation in H2O2 on both submaximal (pCa 6.2) and maximal (pCa 4.4) calcium activated isometric force generation (N =9 CON; N =10 UREM fibers). Based on cross-sectional area (CSA) calculations, a 14 % atrophy in UREM fibers was revealed; thus forces were evaluated in absolute values and corrected for CSA (specific force) values. A) Addition of H2O2 during activation did not significantly affect force generation in any group or the pool of fibers. Incubation in DTT did not affect the CON fibers but caused a 12 % maximal isometric force decrease in UREM fibers (both in absolute force p =0.024, and specific force, p =0.027). B) Incubation in H2O2 during relaxation lowered subsequent maximal (but not submaximal) isometric forces in the Pool of fibers by 3.5 % (for absolute force p =0.033, for specific force p =0.019) but not in the fiber groups separately. Force generation capacity of CON and UREM fibers is affected by oxidation similarly. However, DTT significantly lowered force in UREM muscle fibers. This may indicate that at baseline UREM muscle could have already been at a more reduced redox state than physiological. This observation warrants further investigation as it could be linked to disease-induced effects. HIPPOKRATIA 2017, 21(1): 3-7.


Attitudes towards mental illness in Sweden: adaptation and development of the Community Attitudes towards Mental Illness questionnaire.
The main purpose for the expansion of supported community care for persons with serious mental illness in Sweden was to ensure the right for these persons to live as citizens in the community. However, earlier research shows that negative attitudes towards mental illness present an obstacle for social integration of persons with serious mental illness. The aim of this study, conducted in Sweden, was to evaluate an existing instrument's (Community Attitudes towards Mental Illness, CAMI), validity and reliability. An additional aim was to adapt and develop the questionnaire to Swedish circumstances. After translation and modification of the original CAMI, the Swedish version of the questionnaire (CAMI-S) was distributed to all student nurses at three different universities in Sweden. The overall Cronbach's alpha coefficient was 0.90 of the original CAMI-S. A corrected inter-item total correlation excluded 20 items because they showed loading <0.43. The overall Cronbach's alpha coefficient on the 20 items (new CAMI-S) that showed loading, >0.43, was 0.903. A factor analysis of these items revealed that the data could be extracted in three factors labelled as: open-minded and pro-integration, fear and avoidance and community mental health ideology. Finally, in order to reach reliable results in attitude research, it is important to measure the respondent's attitude towards the object in common as well as the respondent's attitude to interact with the object. Accordingly, it is important to add behavioural intention items to the 'new CAMI-S'. Statements exemplifying how something 'ought to be' in an impersonal way have a good degree of stability over time and place.


Influenza A viruses use multivalent sialic acid clusters for cell binding and receptor activation.
Influenza A virus (IAV) binds its host cell using the major viral surface protein hemagglutinin (HA). HA recognizes sialic acid, a plasma membrane glycan that functions as the specific primary attachment factor (AF). Since sialic acid alone cannot fulfill a signaling function, the virus needs to activate downstream factors to trigger endocytic uptake. Recently, the epidermal growth factor receptor (EGFR), a member of the receptor-tyrosine kinase family, was shown to be activated by IAV and transmit cell entry signals. However, how IAV's binding to sialic acid leads to engagement and activation of EGFR remains largely unclear. We used multicolor super-resolution microscopy to study the lateral organization of both IAV's AFs and its functional receptor EGFR at the scale of the IAV particle. Intriguingly, quantitative cluster analysis revealed that AFs and EGFR are organized in partially overlapping submicrometer clusters in the plasma membrane of A549 cells. Within AF domains, the local AF concentration reaches on average 10-fold the background concentration and tends to increase towards the cluster center, thereby representing a multivalent virus-binding platform. Using our experimentally measured cluster characteristics, we simulated virus diffusion on a flat membrane. The results predict that the local AF concentration strongly influences the distinct mobility pattern of IAVs, in a manner consistent with live-cell single-virus tracking data. In contrast to AFs, EGFR resides in smaller clusters. Virus binding activates EGFR, but interestingly, this process occurs without a major lateral EGFR redistribution, indicating the activation of pre-formed clusters, which we show are long-lived. Taken together, our results provide a quantitative understanding of the initial steps of influenza virus infection. Co-clustering of AF and EGFR permit a cooperative effect of binding and signaling at specific platforms, thus linking their spatial organization to their functional role during virus-cell binding and receptor activation.


Rotary replication for freeze-etching.
Rotary replication has been adapted to freeze-etching and evaluated using T4 polyheads, erythrocyte ghosts, and chloroplast membranes. Conventional electron microscopy, electron diffraction, and optical diffraction and filtering indicate that platinum-carbon rotary replication renders radially symmetrical contrast and 25 A resolution to freeze-etched specimens so as to clarify subunit structure not normally evident in unidirectional shadow replicas.


The CXC chemokine cCAF stimulates precocious deposition of ECM molecules by wound fibroblasts, accelerating development of granulation tissue.
During wound repair, fibroblasts orchestrate replacement of the provisional matrix formed during clotting with tenascin, cellular fibronectin and collagen III. These, in turn, are critical for migration of endothelial cells, keratinocytes and additional fibroblasts into the wound site. Fibroblasts are also important in the deposition of collagen I during scar formation. The CXC chemokine chicken Chemotactic and Angiogenic Factor (cCAF), is highly expressed by fibroblasts after wounding and during development of the granulation tissue, especially in areas where extracellular matrix (ECM) is abundant. We hypothesized that cCAF stimulates fibroblasts to produce these matrix molecules. Here we show that this chemokine can stimulate precocious deposition of tenascin, fibronectin and collagen I, but not collagen III. Studies in culture and in vivo show that tenascin stimulation can also be achieved by the N-terminal 15 aas of the protein and occurs at the level of gene expression. In contrast, stimulation of fibronectin and collagen I both require the entire molecule and do not involve changes in gene expression. Fibronectin accumulation appears to be linked to tenascin production, and collagen I to decreased MMP-1 levels. In addition, cCAF is chemotactic for fibroblasts and accelerates their migration. These previously unknown functions for chemokines suggest that cCAF, the chicken orthologue of human IL-8, enhances healing by rapidly chemoattracting fibroblasts into the wound site and stimulating them to produce ECM molecules, leading to precocious development of granulation tissue. This acceleration of the repair process may have important application to healing of impaired wounds.


[The China Kadoorie Biobank: related methodology and baseline characteristics of the participants].
To study the separate and combined effects of environment, lifestyle, physical characteristics, blood biomarkers and genetic factors on aetiology of major chronic diseases in adult Chinese. China Kadoorie Biobank (CKB) is a large blood-based prospective cohort study. The baseline survey took place in 5 urban and 5 rural areas across China during 2004-2008, with collection of data through questionnaire, physical examination and blood samples. Following the baseline survey, 5% of the randomly selected participants were surveyed in 2008, and repeated every 4-5 years. All participants would be followed for cause-specific mortality and morbidity through registries and for any hospital admission through linkages with health insurance databases. Overall, 512 891 adults aged 30-79 years (mean 51.5) were recruited, including 41.0% men and 55.9% from rural areas. Blood collection was successfully done in 99.98% of the participants. The prevalence of current regular smoking was 61.3% in men and 2.4% in women. The prevalence of regular alcohol consumption (i.e., weekly) was 33.4% in men and 2.1% in women. At the baseline, 41.8% of men and 45.3% of women were overweight or obese (i.e., BMI≥24.0 kg/m2) and 32.2% of men and 30.2% of women were hypertensive (i.e., SBP≥140 mm Hg or DBP≥90 mm Hg). For each of the main baseline variables, there were large variations on age, sex and areas of study. CKB seemed to be a powerful and rich resource in studying the environmental and genetic determinants of major chronic diseases in the Chinese population.


Personality disorder in marriage and partnership - a narrative review.
Partner conflicts are the most common precipitating factors of decompensation of psychiatric disorders, including personality disorders. Personal characteristics play a fundamental role in both the prediction of marital satisfaction of the individual as well as the satisfaction of the couple as a whole. Narrative Review of the articles, books and book chapters within the period 1956 - 2016 using PubMed, Web of Science, and Scopus databases with keywords "personality disorder," "partnership," marital problems," "marital conflicts." Additional references were found using reviews of relevant articles. It is evident that patients with personality disorders can have problems with meeting the criteria that contribute to the marital satisfaction and, on the other hand, easily fulfill the criteria that are related to the causes of the relationship breakups. People with personality disorders have substantial problems with starting and continuing a relationship with a partner. They have an unintentional ability to create and maintain problematic relationships. The association between the dysfunctional marriage and personality problems of the partners may have the basis in the insufficient understanding of the behavior of one or both partners. People with personality disorder experience numerous misunderstandings, misinterpretations, communicate poorly, and they are more alert to verbal and physical aggression in the interpersonal relations. They do not recognize that the basis of experienced struggles has a source in their intrapersonal processes and their relationship with the world. Persons with certain personality disorders tend to seek and create a pathologically stable partnership. To understand the dynamics of such relationships, examining personality traits first should be essential. Understanding the maladaptive personality patterns in the context of the relationship should be beneficial for both partners.


Diurnal cortisol patterns are associated with physical performance in the Caerphilly Prospective Study.
Cross-sectional studies have suggested that elevated cortisol is associated with worse physical performance, a surrogate of ageing. We examined the relationship between repeat cortisol measures over 20 years and physical performance in later life. Middle-aged men (45-59 years) were recruited between 1979 and 1983 (Phase 1) from the Caerphilly Prospective Study (CaPS) and re-examined 20 years later at 65-83 years of age (Phase 5). Participants included 750 and 898 subjects with either Phase 1 and/or Phase 5 data on exposure and outcomes. Outcome measures were walking speed and balance time and exposures included morning fasting serum cortisol (Phase 1) and four salivary samples on 2 consecutive days (Phase 5). Faster walking speed was associated with higher morning cortisol at Phase 1 [coefficient per standard deviation (SD) increase 0.68, 95% confidence interval (95% CI) 0.09-1.27; P=0.02] though this was attenuated after adjustment for covariates (coefficient per SD increase 0.45; 95% CI -0.16 to 1.07; P=0.15). Higher night-time cortisol at Phase 5 was associated with slower speed (coefficient per SD increase -1.06; 95% CI -1.60 to -0.52; P<0.001) and poorer balance (odds ratio of top tertile vs bottom 2.49; 95% CI 1.63-3.81; P<0.001). Worst performance was seen for men with a poor morning response (Phase 1) and less nocturnal decline (Phase 5). Dysregulation of the hypothalamic pituitary adrenal (HPA) axis is associated with worse physical performance in later life. This may reflect a causal effect of the HPA axis on ageing or that ageing itself is associated with reduced HPA reactivity.


Mixed crystal formation of two gold isocyanide complexes with various ratios for continuous tuning of photophysical properties.
Mixed crystals composed of two distinct gold isocyanide complexes are reported. Characterization of the mixed crystal formation and mixing ratios are performed by single-crystal X-ray diffraction and nuclear magnetic resonance spectroscopy analyses. By changing the mixing ratio, we achieve continuous changes in the emission lifetimes and the emission quantum yields.


The impact of trauma-focused group therapy upon HIV sexual risk behaviors in the NIDA Clinical Trials Network "Women and trauma" multi-site study.
Women in drug treatment struggle with co-occurring problems, including trauma and post-traumatic stress disorder (PTSD), which can heighten HIV risk. This study examines the impact of two group therapy interventions on reduction of unprotected sexual occasions (USO) among women with substance use disorders (SUD) and PTSD. Participants were 346 women recruited from and receiving treatment at six community-based drug treatment programs participating in NIDA's Clinical Trials Network. Participants were randomized to receive 12-sessions of either seeking safety (SS), a cognitive behavioral intervention for women with PTSD and SUD, or women's health education (WHE), an attention control psychoeducational group. Participants receiving SS who were at higher sexual risk (i.e., at least 12 USO per month) significantly reduced the number of USO over 12-month follow up compared to WHE. High risk women with co-occurring PTSD and addiction may benefit from treatment addressing coping skills and trauma to reduce HIV risk.


Near-field digital holography: a tool for plasmon phase imaging.
The knowledge of the phase distribution of the near electromagnetic field has become very important for many applications. However, its experimental observation is still technologically a very demanding task. In this work, we propose a novel method for the measurement of the phase distribution of the near electric field based on the principles of phase-shifting digital holography. In contrast to previous methods the holographic interference occurs already in the near field and the phase distribution can be determined purely from the scanning near-field optical microscopy measurements without the need for additional far-field interferometric methods. This opens a way towards on-chip phase imaging. We demonstrate the capabilities of the proposed method by reconstruction of the phase difference between interfering surface plasmon waves and by imaging the phase of a single surface plasmon wave. We also demonstrate a selectivity of the method towards individual components of the field.


[Integration of the plasmid carrying the genes for tryptophan metabolism of Bacillus mesentericus into the chromosome of Bacillus subtilis].
Integration of several tryptophan operon genes from Bacillus mesentericus into the chromosome of Bac. subtilis was carried out. The genetic material exchange between these two species is usually impossible in the process of transformation, because of poor homology. The integration only took place after the genes of Bac. mesentericus were introduced in Bac. subtilis cells on a hybrid plasmid. Plasmid markers also integrated into the chromosome, together with heterologous DNA. The integration occurred in the region of Bac. subtilis tryptophan operon, which is likely to be due to retained homology between corresponding DNAs. The integration acts occurred during prolonged maintenance of chimeric plasmid in autonomously replicating form. We suggest to designate this phenomenon "retarded homologous recombination".


Duration of stable disease is associated with overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib.
Sorafenib is a molecular-targeting agent showing improved overall survival (OS) for advanced hepatocellular carcinoma (HCC). Although tumor dormancy, characterized by stable tumor status or stable disease (SD) without tumor regression, is a unique feature of sorafenib treatment, the contribution of SD to OS remains debatable. This study aimed to clarify the correlation between SD periods and OS in patients with HCC treated with sorafenib. From May 2009 to January 2013, 269 patients with advanced-stage HCC were treated with sorafenib at the Kinki University Hospital. The antitumor response of sorafenib was evaluated in 158 patients using the modified Response Evaluation Criteria in Solid Tumors, and patients with SD were divided into two subgroups according to the median duration of SD: short SD (<3 months) and long SD (≥3 months). The relationship between the duration of SD and OS was analyzed among patients with complete (CR) and partial response (PR), and long and short SD using the Kaplan-Meier method. The median OS was 5.7 months in the short SD, 20.8 months in the long SD and 17.9 months in the CR + PR group. Although the duration of OS was significantly longer in the long SD group than the short SD group, no difference in OS was detected between the patients with CR + PR and patients with long SD. The impact of long SD on OS could be as strong as that of CR + PR. Achievement of long SD is one of the important goals for improving survival in patients with HCC treated with sorafenib.


Identification of proteins of Francisella tularensis induced during growth in macrophages and cloning of the gene encoding a prominently induced 23-kilodalton protein.
The adaptation of facultative intracellular bacteria to host macrophages involves regulation of the synthesis of bacterial proteins. We analyzed the protein synthesis of Francisella tularensis LVS growing intracellularly in the macrophage-like murine cell line J774 and extracellularly in culture medium. After pulse-labeling with [35S] methionine and separation by one- and two-dimensional polyacrylamide gel electrophoresis, induction of a few proteins during intracellular growth was demonstrated. One of them, a 23-kDa protein, was prominently induced in the macrophages and also when extracellularly growing F. tularensis was exposed to hydrogen peroxide. After isolation of the 23-kDa protein from a preparative two-dimensional gel, a 22-amino-acid N-terminal peptide and two peptides obtained by trypsin digestion were sequenced. Based on the sequences, degenerate oligonucleotides were constructed for use as primers in a PCR. Hybridization of amplified DNA to XbaI-digested LVS DNA identified the gene of the 23-kDa protein in a 1.3-kb DNA fragment. Nucleotide sequence analysis revealed an open reading frame encoding a putative protein of a calculated molecular mass of 22.2 kDa. The open reading frame was preceded by a sequence typical of ribosome-binding sites in Escherichia coli. The amplified gene was successfully expressed by the pTrc99A vector in E. coli under control of the trc promoter. The gene product showed the same mobility and immunoreactivity as the 23-kDa protein of F. tularensis. The deduced amino acid sequence showed no significant homology with protein sequences in current data banks. Thus, intracellular growth of F. tularensis in macrophages was associated with prominent upregulation of a novel 23-kDa protein.


Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels.
Mu-conotoxins are small peptide inhibitors of muscle and neuronal tetrodotoxin (TTX)-sensitive voltage-gated sodium channels (VGSCs). Here we report the isolation of mu-conotoxins SIIIA and SIIIB by (125)I-TIIIA-guided fractionation of milked Conus striatus venom. SIIIA and SIIIB potently displaced (125)I-TIIIA from native rat brain Na(v)1.2 (IC(50) values 10 and 5 nm, respectively) and muscle Na(v)1.4 (IC(50) values 60 and 3 nm, respectively) VGSCs, and both inhibited current through Xenopus oocyte-expressed Na(v)1.2 and Na(v)1.4. An alanine scan of SIIIA-(2-20), a pyroglutamate-truncated analogue with enhanced neuronal activity, revealed residues important for affinity and selectivity. Alanine replacement of the solvent-exposed Trp-12, Arg-14, His-16, Arg-18 resulted in large reductions in SIIIA-(2-20) affinity, with His-16 replacement affecting structure. In contrast, [D15A]SIIIA-(2-20) had significantly enhanced neuronal affinity (IC(50) 0.65 nm), while the double mutant [D15A/H16R]SIIIA-(2-20) showed greatest Na(v)1.2 versus 1.4 selectivity (136-fold). (1)H NMR studies revealed that SIIIA adopted a single conformation in solution comprising a series of turns and an alpha-helical motif across residues 11-16 that is not found in larger mu-conotoxins. The structure of SIIIA provides a new structural template for the development of neuronally selective inhibitors of TTX-sensitive VGSCs based on the smaller mu-conotoxin pharmacophore.


Diagnostic imaging in Canada.
In Ontario, between 1993 and 2003, the annual number of MRI scans performed increased by more than 600 percent (Iron et al. 2003), and the number of CT scans increased threefold (Tu et al. 2005). Despite these massive increases, the Fraser Institute reported a median wait of five weeks for CT and thirteen weeks for MRI scanning in 2004 (Esmail and Walker 2004), and Canadians are increasingly concerned about the length of time they wait for diagnostic imaging. Because of this, politicians have made decreasing wait times for diagnostic imaging one of their top priorities (Health Canada 2004). This raises several interesting questions. Have the indications for CT and MRI really expanded that rapidly, or was there just a huge pent-up demand because Canada had fallen so far behind in acquiring modern imaging machines? Are physicians relying more on diagnostic imaging technologies and less on clinical skills? Are an increasing number of patients undergoing scans when there is a small likelihood that the results will change their management or improve their outcomes? Supporters of the view that Canada needs to expand its diagnostic imaging capacity point to the fact that we rank well behind many developed countries in terms of the number of diagnostic imaging machines per population (Canadian Institute for Health Information 2003: 33), and that improvements in imaging quality have expanded the indication for imaging. Supporters of the view that there is an increased and inappropriate reliance on technology over clinical skill point to the findings of a recent American study showing that the regions that spent the most on healthcare did not have better outcomes than the regions that spent less--indeed, the trend was toward poorer outcomes in the highest-spending regions (Fisher et al. 2003a, 2003b). One of the greatest differences between the highest- and lowest-spending regions was their expenditure on a variety of diagnostic tests, suggesting that more testing did not lead to better outcomes on a population basis. It may in fact have led to iatrogenic illnesses because of the workup of false positive results, and diverted attention away from simple interventions that have been shown to be effective (Fisher et al. 2003a). The truth is likely a combination of many factors. Some patients with clear indications for diagnostic imaging undoubtedly wait too long for their tests in Canada. At the same time, a number of patients undergo tests whose results have a very small likelihood of changing their management, which itself contributes to the access problem. Unfortunately there are no evidence-based benchmarks for the appropriate rate of diagnostic testing that can be used to determine the optimal supply of diagnostic machines and radiological personnel. In this article we discuss the reasons it has been so difficult to determine the optimal imaging capacity needed for a population, describe some factors that are "inappropriately" increasing the rate of imaging and suggest some solutions. Although many of our examples deal with CT and MRI scanning, our remarks apply more broadly to many other diagnostic tests.


Administration of aspirin tablets using a novel gel-based swallowing aid: an open-label randomised controlled cross-over trial.
To ease administration of medicines to people with dysphagia we developed and patented a gel formulation within which whole tablets could be inserted. The aim was to determine whether the gel would affect bioequivalence of uncoated aspirin tablet. A gel containing gelatin, hydroxypropylmethylcellulose, citric acid, potassium sorbate and water was developed to maintain structure on tablet insertion and increase saliva production to lubricate the swallow.In an open-label cross-over trial 12 healthy male volunteers were administered a 300 mg uncoated aspirin tablet with and without gel with a 7-day washout period. Blood salicylate levels, platelet activity and patient satisfaction were measured over 2 hours. Analysis was based on a random effects cross-over model. The estimated mean ratio (90% CI) of effect on salicylate levels when comparing administration with and without gel was 0.77 (90% CI 0.40 to 1.47) for amount absorbed and 0.76 (90% CI 0.44 to 1.31) and on total ASP-arachidonic acid platelet activity 1.16 (90% CI 0.88 to 1.53) and maximum ASP-arachidonic platelet activity 0.98 (90% CI 0.79 to 1.22). These results are outside of the range allowable for the assumption of bioequivalence. Participants rated the taste of aspirin tablets significantly better when encapsulated in the gel (p<0.05). We cannot assume that uncoated aspirin administration with and without gel is bioequivalent. Administration with gel resulted in reduced salicylate levels and therefore increased platelet function. Further research is required to determine the exact reason for this result. The results bring into question current processes for providing marketing authorisation for medical devices which are designed to aid swallowing.


Thyroid function and the risk of Alzheimer disease: the Framingham Study.
Clinical hypothyroidism and hyperthyroidism are recognized causes of reversible dementia, but previous studies relating thyrotropin levels to cognitive performance in clinically euthyroid persons have yielded inconsistent results. We related serum thyrotropin concentrations measured at baseline (March 1977-November 1979) to the risk of Alzheimer disease (AD) in 1864 cognitively intact, clinically euthyroid Framingham original cohort participants (mean age, 71 years; 59% women). Sex-specific Cox proportional hazards models were constructed using tertiles of thyrotropin concentration (tertile 2 as the referent) and adjusting for age, apolipoprotein E epsilon4 allele status, educational level, plasma homocysteine level, current smoking, body mass index, prevalent stroke, and atrial fibrillation. During a mean follow-up of 12.7 years (range, 1-25 years), 209 participants (142 women) developed AD. Women in the lowest (<1.0 mIU/L) and highest (>2.1 mIU/L) tertiles of serum thyrotropin concentration were at increased risk for AD (multivariate-adjusted hazard ratio, 2.39 [95% confidence interval, 1.47-3.87] [P < .001] and 2.15 [95% confidence interval, 1.31-3.52] [P = .003], respectively) compared with those in the middle tertile. Thyrotropin levels were not related to AD risk in men. Analyses excluding individuals receiving thyroid supplementation did not significantly alter these relationships. In analyses limited to participants with serum thyrotropin levels of 0.1 to 10.0 mIU/L, the U-shaped relationship between thyrotropin level and AD risk was maintained in women but not when analyses were limited to those with thyrotropin levels of 0.5 to 5.0 mIU/L. Low and high thyrotropin levels were associated with an increased risk of incident AD in women but not in men.


Streptococcus mutans glucan-binding protein-A affects Streptococcus gordonii biofilm architecture.
The glucan-binding protein-A (GbpA) of Streptococcus mutans has been shown to contribute to the architecture of glucan-dependent biofilms formed by this species and influence virulence in a rat model. As S. mutans synthesizes multiple glucosyltransferases and nonglucosyltransferase glucan-binding proteins (GBPs), it is possible that there is functional redundancy that overshadows the full extent of GbpA contributions to S. mutans biology. Glucan-associated properties such as adhesion, aggregation, and biofilm formation were examined independently of other S. mutans GBPs by cloning the gbpA gene into a heterologous host, Streptococcus gordonii, and derivatives with altered or diminished glucosyltransferase activity. The presence of GbpA did not alter dextran-dependent aggregation nor the initial sucrose-dependent adhesion of S. gordonii. However, expression of GbpA altered the biofilm formed by wild-type S. gordonii as well as the biofilm formed by strain CH107 that produced primarily alpha-1,6-linked glucan. Expression of gbpA did not alter the biofilm formed by strain DS512, which produced significantly lower quantities of parental glucan. These data are consistent with a role for GbpA in facilitating the development of biofilms that harbor taller microcolonies via binding to alpha-1,6-linkages within glucan. The magnitude of the GbpA effect appears to be dependent on the quantity and linkage of available glucan.


Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development.
Fibroblast growth factor 8 (Fgf8) is expressed in many domains of the developing embryo. Globally decreased FGF8 signaling during murine embryogenesis results in a hypomorphic phenotype with a constellation of heart, outflow tract, great vessel and pharyngeal gland defects that phenocopies human deletion 22q11 syndromes, such as DiGeorge. We postulate that these Fgf8 hypomorphic phenotypes result from disruption of local FGF8 signaling from pharyngeal arch epithelia to mesenchymal cells populating and migrating through the third and fourth pharyngeal arches. To test our hypothesis, and to determine whether the pharyngeal ectoderm and endoderm Fgf8 expression domains have discrete functional roles, we performed conditional mutagenesis of Fgf8 using novel Crerecombinase drivers to achieve domain-specific ablation of Fgf8 gene function in the pharyngeal arch ectoderm and endoderm. Remarkably, ablating FGF8 protein in the pharyngeal arch ectoderm causes failure of formation of the fourth pharyngeal arch artery that results in aortic arch and subclavian artery anomalies in 95% of mutants; these defects recapitulate the spectrum and frequency of vascular defects reported in Fgf8 hypomorphs. Surprisingly, no cardiac, outflow tract or glandular defects were found in ectodermal-domain mutants, indicating that ectodermally derived FGF8 has essential roles during pharyngeal arch vascular development distinct from those in cardiac, outflow tract and pharyngeal gland morphogenesis. By contrast, ablation of FGF8 in the third and fourth pharyngeal endoderm and ectoderm caused glandular defects and bicuspid aortic valve, which indicates that the FGF8 endodermal domain has discrete roles in pharyngeal and valvar development. These results support our hypotheses that local FGF8 signaling from the pharyngeal epithelia is required for pharyngeal vascular and glandular development, and that the pharyngeal ectodermal and endodermal domains of FGF8 have separate functions.


Proton transfer to charged platinum electrodes. A molecular dynamics trajectory study.
A recently developed empirical valence bond (EVB) model for proton transfer on Pt(111) electrodes (Wilhelm et al 2008 J. Phys. Chem. C 112 10814) has been applied in molecular dynamics (MD) simulations of a water film in contact with a charged Pt surface. A total of seven negative surface charge densities σ between -7.5 and -18.9 µC cm(-2) were investigated. For each value of σ, between 30 and 84 initial conditions of a solvated proton within a water slab were sampled, and the trajectories were integrated until discharge of a proton occurred on the charged surfaces. We have calculated the mean rates for discharge and for adsorption of solvated protons within the adsorbed water layer in contact with the metal electrode as a function of surface charge density. For the less negative values of σ we observe a Tafel-like exponential increase of discharge rate with decreasing σ. At the more negative values this exponential increase levels off and the discharge process is apparently transport limited. Mechanistically, the Tafel regime corresponds to a stepwise proton transfer: first, a proton is transferred from the bulk into the contact water layer, which is followed by transfer of a proton to the charged surface and concomitant discharge. At the more negative surface charge densities the proton transfer into the contact water layer and the transfer of another proton to the surface and its discharge occur almost simultaneously.


Limitation of the Use of the Absorption Angstrom Exponent for Source Apportionment of Equivalent Black Carbon: a Case Study from the North West Indo-Gangetic Plain.
Angstrom exponent measurements of equivalent black carbon (BCeq) have recently been introduced as a novel tool to apportion the contribution of biomass burning sources to the BCeq mass. The BCeq is the mass of ideal BC with defined optical properties that, upon deposition on the aethalometer filter tape, would cause equal optical attenuation of light to the actual PM2.5 aerosol deposited. The BCeq mass hence is identical to the mass of the total light-absorbing carbon deposited on the filter tape. Here, we use simultaneously collected data from a seven-wavelength aethalometer and a high-sensitivity proton-transfer reaction mass spectrometer installed at a suburban site in Mohali (Punjab), India, to identify a number of biomass combustion plumes. The identified types of biomass combustion include paddy- and wheat-residue burning, leaf litter, and garbage burning. Traffic plumes were selected for comparison. We find that the combustion efficiency, rather than the fuel used, determines αabs, and consequently, the αabs can be ∼1 for flaming biomass combustion and >1 for older vehicles that operate with poorly optimized engines. Thus, the absorption angstrom exponent is not representative of the fuel used and, therefore, cannot be used as a generic tracer to constrain source contributions.


Word embeddings quantify 100 years of gender and ethnic stereotypes.
Word embeddings are a powerful machine-learning framework that represents each English word by a vector. The geometric relationship between these vectors captures meaningful semantic relationships between the corresponding words. In this paper, we develop a framework to demonstrate how the temporal dynamics of the embedding helps to quantify changes in stereotypes and attitudes toward women and ethnic minorities in the 20th and 21st centuries in the United States. We integrate word embeddings trained on 100 y of text data with the US Census to show that changes in the embedding track closely with demographic and occupation shifts over time. The embedding captures societal shifts-e.g., the women's movement in the 1960s and Asian immigration into the United States-and also illuminates how specific adjectives and occupations became more closely associated with certain populations over time. Our framework for temporal analysis of word embedding opens up a fruitful intersection between machine learning and quantitative social science.


Comparing the predictive ability of the Edmonton Obesity Staging System with the body mass index for use of health services and pharmacotherapies in Australian adults: A nationally representative cross-sectional study.
We assessed the value of the Edmonton Obesity Staging System (EOSS) compared with the body mass index (BMI) for determining associations with use of health services and pharmacotherapies in a nationally representative sample of participants in the 2011-2013 Australian Health Survey. A subsample of participants aged 18 years or over, with at least overweight (BMI ≥ 25 kg/m2 ) or central obesity (waist measurement of ≥102 cm for men; ≥88 cm for women), and who had provided physical measurements (n = 9730) were selected for analysis. For statistical significance of each predictor, we used logistic regression for model comparisons with the BMI and EOSS separately, and adjusted for covariates. For relative explanatory ability, we used the Nagelkerke pseudo R2 , receiver operating characteristic curve, and area under curve statistic. The EOSS was significantly better than the BMI for predicting polypharmacy and most of the health service use variables. Conversely, the BMI was significantly better than the EOSS for predicting having discussed lifestyle changes relevant to weight loss with the primary care physician. Clinicians, health care professionals, consumers, and policy makers should consider the EOSS a more accurate predictor of polypharmacy and health service use than the BMI in adults with overweight or obesity.


The emotional brain, fear, and the amygdala.
1. Considerable progress has been made over the past 20 years in relating specific circuits of the brain to emotional functions. Much of this work has involved studies of Pavlovian or classical fear conditioning, a behavioral procedure that is used to couple meaningless environmental stimuli to emotional (defense) response networks. 2. The major conclusion from studies of fear conditioning is that the amygdala plays critical role in linking external stimuli to defense responses. 3. Before describing research on the role of the amygdala in fear conditioning, though, it will be helpful to briefly examine the historical events that preceded modern research on conditioned fear.


Conditioned place-preference analysis in the goldfish with the H1 histamine antagonist chlorpheniramine.
The aim of this study was to investigate whether the histamine H1-receptor blocker, chlorpheniramine (CPA), has a reinforcing effect in goldfish. We used a place-preference procedure in an aquarium with two chambers colored black and white. On day 1, the animals were placed in the test chamber for 10 min for habituation. On day 2, they were placed in the start compartment for 30 s, the sliding doors were opened, and the time spent in each compartment was recorded over the 10 min to determine the natural compartment preference for each animal. On day 3, they were injected either with 0.1, 0.4, 1.0, or 4.0 mg/kg of CPA or only with vehicle and placed in the less preferred compartment for 25 min. On day 4, the animals were placed in the start compartment and the time spent in each compartment during the 10-min test period was recorded again. The groups treated with 1.0 and 4.0 mg/kg of CPA, spent significantly more time in the compartment in which they experienced the drug effect than the group treated with vehicle. On the other hand, the group treated with 0.4 mg/kg spent significantly less time in the drug-paired compartment. The results indicate a biphasic effect of CPA. Considering that there is evidence that low doses of CPA can also block H3-receptors, we suggest that in goldfish the histaminergic neural system has an inhibitory role in the reinforcing process.


Exponential-family random graph models for valued networks.
Exponential-family random graph models (ERGMs) provide a principled and flexible way to model and simulate features common in social networks, such as propensities for homophily, mutuality, and friend-of-a-friend triad closure, through choice of model terms (sufficient statistics). However, those ERGMs modeling the more complex features have, to date, been limited to binary data: presence or absence of ties. Thus, analysis of valued networks, such as those where counts, measurements, or ranks are observed, has necessitated dichotomizing them, losing information and introducing biases. In this work, we generalize ERGMs to valued networks. Focusing on modeling counts, we formulate an ERGM for networks whose ties are counts and discuss issues that arise when moving beyond the binary case. We introduce model terms that generalize and model common social network features for such data and apply these methods to a network dataset whose values are counts of interactions.


Observing copepods through a genomic lens.
Copepods outnumber every other multicellular animal group. They are critical components of the world's freshwater and marine ecosystems, sensitive indicators of local and global climate change, key ecosystem service providers, parasites and predators of economically important aquatic animals and potential vectors of waterborne disease. Copepods sustain the world fisheries that nourish and support human populations. Although genomic tools have transformed many areas of biological and biomedical research, their power to elucidate aspects of the biology, behavior and ecology of copepods has only recently begun to be exploited. The extraordinary biological and ecological diversity of the subclass Copepoda provides both unique advantages for addressing key problems in aquatic systems and formidable challenges for developing a focused genomics strategy. This article provides an overview of genomic studies of copepods and discusses strategies for using genomics tools to address key questions at levels extending from individuals to ecosystems. Genomics can, for instance, help to decipher patterns of genome evolution such as those that occur during transitions from free living to symbiotic and parasitic lifestyles and can assist in the identification of genetic mechanisms and accompanying physiological changes associated with adaptation to new or physiologically challenging environments. The adaptive significance of the diversity in genome size and unique mechanisms of genome reorganization during development could similarly be explored. Genome-wide and EST studies of parasitic copepods of salmon and large EST studies of selected free-living copepods have demonstrated the potential utility of modern genomics approaches for the study of copepods and have generated resources such as EST libraries, shotgun genome sequences, BAC libraries, genome maps and inbred lines that will be invaluable in assisting further efforts to provide genomics tools for copepods. Genomics research on copepods is needed to extend our exploration and characterization of their fundamental biological traits, so that we can better understand how copepods function and interact in diverse environments. Availability of large scale genomics resources will also open doors to a wide range of systems biology type studies that view the organism as the fundamental system in which to address key questions in ecology and evolution.


Nonlinear, near photo-realistic caricatures using a parametric facial appearance model.
A mathematical model previously developed for use in computer vision applications is presented as an empirical model for face space. The term appearance space is used to distinguish this from previous models. Appearance space is a linear vector space that is dimensionally optimal, enables us to model and describe any human facial appearance, and possesses characteristics that are plausible for the representation of psychological face space. Randomly sampling from a multivariate distribution for a location in appearance space produces entirely plausible faces, and manipulation of a small set of defining parameters enables the automatic generation of photo-realistic caricatures. The appearance space model leads us to the new concept of nonlinear caricatures, and we show that the accepted linear method for caricature is only a special case of a more general paradigm. Nonlinear methods are also viable, and we present examples of photographic quality caricatures, using a number of different transformation functions. Results of a simple experiment are presented that suggest that nonlinear transformations can accurately capture key aspects of the caricature effect. Finally, we discuss the relationship between appearance space, caricature, and facial distinctiveness. On the basis of our new theoretical framework, we suggest an experimental approach that can yield new evidence for the plausibility of face space and its ability to explain processes of recognition.


An interprofessional health assessment program in rural amateur sport.
Effective interprofessional learning (IPL) in multisectoral collaborations such as those linking health services within communities can provide an authentic experience for students and also appears to be the most effective way to achieve health changes in targeted population groups. The aim of this study was to facilitate the IPL of students at a rural university in a multisectoral health assessment programme and to promote health in players of rural amateur sport. Two rural rugby league teams took part in three pre-season health assessments conducted by general medical practitioners, practice nurses, and nursing, osteopathy, and exercise science students. The Readiness for Interprofessional Learning Scale questionnaire and a series of focus groups were used to evaluate participants' experiences of the programme. Results indicated that students saw the benefits for patients and 93% valued the opportunity to improve interprofessional communication, problem-solving and team skills. Some students felt they needed to learn more about their own professional role before learning about others, and instances of stereotyping were identified. The programme also enabled early detection of potential health risks and referral for medical care, management of musculoskeletal conditions, and health promotion. These health assessments would be readily transferred to other multisectoral sporting settings.


Role of Cbl-PI3K Interaction during Skeletal Remodeling in a Murine Model of Bone Repair.
Mice in which Cbl is unable to bind PI3K (YF mice) display increased bone volume due to enhanced bone formation and repressed bone resorption during normal bone homeostasis. We investigated the effects of disrupted Cbl-PI3K interaction on fracture healing to determine whether this interaction has an effect on bone repair. Mid-diaphyseal femoral fractures induced in wild type (WT) and YF mice were temporally evaluated via micro-computed tomography scans, biomechanical testing, histological and histomorphometric analyses. Imaging analyses revealed no change in soft callus formation, increased bony callus formation, and delayed callus remodeling in YF mice compared to WT mice. Histomorphometric analyses showed significantly increased osteoblast surface per bone surface and osteoclast numbers in the calluses of YF fractured mice, as well as increased incorporation of dynamic bone labels. Furthermore, using laser capture micro-dissection of the fracture callus we found that cells lacking Cbl-PI3K interaction have higher expression of Osterix, TRAP, and Cathepsin K. We also found increased expression of genes involved in propagating PI3K signaling in cells isolated from the YF fracture callus, suggesting that the lack of Cbl-PI3K interaction perhaps results in enhanced PI3K signaling, leading to increased bone formation, but delayed remodeling in the healing femora.


Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine.
The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of depletion was reversible because cortical serotonin concentrations had recovered to control levels by 24 hr. However, transmitter concentrations were reduced significantly 1 week later, indicating a second phase of depletion. The latter phase of depletion was associated with a decrease in synaptosomal [3H]serotonin uptake due to a loss in the number of uptake sites with no change in the affinity of the carrier for serotonin. This neurotoxic effect of MDMA was found to be a property of the (+)-stereoisomer of the drug as only this enantiomer produced the depletion of cortical serotonin and the decrease in synaptosomal serotonin uptake at 1 week. In contrast to this, both stereoisomers of the drug could produce the acute depletion of cortical serotonin measured 3 hr after drug administration. Coadministration of the selective serotonin uptake inhibitor, fluoxetine, completely blocked the reduction in cortical serotonin concentrations 1 week after MDMA. Administration of fluoxetine at various times after MDMA revealed that the long-term effects of the drug developed independently of the acute depletion of serotonin and could be partially blocked by the uptake inhibitor as long as 6 hr after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Medication management for nurses working in long-term care.
In long-term care (LTC), the complexity of residents' conditions and their treatment requirements present challenges for nurses managing medications. The purpose of this qualitative descriptive study was to explore medication management as described by licensed nurses working in LTC. A total of 22 licensed nurses from 2 LTC facilities located in the Canadian province of Ontario participated in 4 focus groups. Thematic content analysis was used to organize data into themes and a conceptual model was developed. The overarching theme was that nurses are "racing against time" to manage medications and 3 subthemes described how they coped with this important care process: preparing to race, running the race, and finishing the race. Barriers to safe medication management included time restraints, knowledge limitations, interruptions and distractions, and poor communication. The findings can be used to better inform health-care providers and to guide future research. They also have the potential to directly impact outcomes related to safe medication management in LTC.


Differential regulation of 3-aminomethylindole/N-methyl-3-aminomethylindole N-methyltransferase and gramine in barley by both biotic and abiotic stress conditions.
The expression of NMT (3-aminomethylindole/N-methyl-3-aminomethylindole N-methyltransferase; EC 2.1.1.), involved in the biosynthesis of the indole alkaloid gramine, was investigated in aphid-infested barley (Hordeum vulgare L.). NMT is induced by methyl jasmonate and it was hypothesized that the gene would be more strongly upregulated in aphid-resistant barley. We examined the effects of feeding by three aphid species; Russian wheat aphid (Diuraphis noxia Mordvilko), rose-grain aphid (Metopolophium dirhodum Walker) and bird cherry-oat aphid (Rhopalosiphum padi L.) on barley genotypes with varying resistance characteristics. The barley genotypes selected included the cultivar Libra, known to upregulate gramine after feeding by Schizaphis graminum. Infestation by R. padi and M. dirhodum resulted in higher NMT expression in the doubled haploid line 5172-28:4 (DH28:4), which has moderate resistance against R. padi, but not in other aphid-barley combinations. None of the aphid-plant combinations had however increased gramine, suggesting that aphid-induction of gramine is specific to S. graminum. The increased abundance of NMT transcript in aphid-infested DH28:4 did not lead to higher amounts of NMT protein or NMT enzyme activity, neither did 200 times upregulation of NMT transcript in cotyledons incubated with methyl jasmonate, illustrating that even large differences measured at transcript level may have no metabolic consequences. Drought stress or treatments with abscisic acid did lead to higher gramine concentrations in several barley cultivars, but without any concomitant increase of NMT transcripts. Thus, the regulation of the biosynthetic pathway to gramine at transcript and metabolite level diverges during two different stress conditions.


Normal functional capacity in circulating myeloid and plasmacytoid dendritic cells in patients with chronic hepatitis C.
Initial reports analyzing dendritic cell (DC) function in patients with hepatitis C virus (HCV) infection have been controversial. Here, we enumerate and characterize the function of circulating myeloid and plasmacytoid DCs. The results show lower percentages of myeloid DCs (0.62 vs. 0.83; P = .05) and plasmacytoid DCs (0.11 vs. 0.34; P = .004) in patients with chronic HCV infection than in healthy, non-HCV-infected individuals. Despite the lower numbers of circulating myeloid DCs present, no phenotypic or functional defects were identified. The lower percentage of plasmacytoid DCs resulted in decreased absolute interferon (IFN)-alpha production; however, when analyzed on a per-cell basis, plasmacytoid DCs from HCV-infected patients generated levels of IFN-alpha equivalent to those generated by DCs from healthy, non-HCV-infected individuals. Contrary to data from previous models (which attributed HCV pathogenesis to defects in the DC compartment), our data reveal functional DC subsets in patients with chronic HCV infection. These results are encouraging for DC-based HCV immunotherapy trials.


The histological features of anteromedial gonarthrosis--the comparison of two grading systems in a human phenotype of osteoarthritis.
Anteromedial gonarthrosis (AMG) displays a well recognised pattern of cartilage damage on the medial tibial plateau. Anteriorly there is a full thickness cartilage defect, with transition to a partial thickness defect, becoming full thickness cartilage in the posterior third of the tibial plateau. The retained posterior cartilage is macroscopically normal. This study characterises the histological changes of AMG and examines the usefulness of two histological assessment tools. Sixteen unicompartmental resection specimens of patients with primary AMG were assessed. Samples were stained with Haematoxylin and Eosin and Safranin-O stains and scored using the modified Mankin grade, and the OOCHAS assessment tool. Each specimen was assessed at five regions along the antero-posterior axis starting from the exposed bone to the region of macroscopically normal cartilage. From anterior to posterior the staining showed a consistent increase in structural integrity and cellularity of the cartilage, matched by a qualitative increase in GAG content. Mean modified Mankin and OOCHAS scores showed a progressive decrease in grade (p < 0.001). The OOCHAS grade had a good correlation with the modified Mankin grade (ρ = 0.886) and there was good intra- and inter-observer variability with both assessment tools. We conclude that there is progressive decrease in histological score from anterior to posterior in AMG and that the macroscopically normal cartilage seen posteriorly is histologically normal. Both the modified Mankin and OOOCHAS assessment tools are useful in histological grading but we found the OOCHAS easier and quicker to use. We propose that AMG represents a spatial model of progressive cartilage damage.


Large-scale replicated field study of maize rhizosphere identifies heritable microbes.
Soil microbes that colonize plant roots and are responsive to differences in plant genotype remain to be ascertained for agronomically important crops. From a very large-scale longitudinal field study of 27 maize inbred lines planted in three fields, with partial replication 5 y later, we identify root-associated microbiota exhibiting reproducible associations with plant genotype. Analysis of 4,866 samples identified 143 operational taxonomic units (OTUs) whose variation in relative abundances across the samples was significantly regulated by plant genotype, and included five of seven core OTUs present in all samples. Plant genetic effects were significant amid the large effects of plant age on the rhizosphere microbiome, regardless of the specific community of each field, and despite microbiome responses to climate events. Seasonal patterns showed that the plant root microbiome is locally seeded, changes with plant growth, and responds to weather events. However, against this background of variation, specific taxa responded to differences in host genotype. If shown to have beneficial functions, microbes may be considered candidate traits for selective breeding.


Intoeing gait in children.
OBJECTIVE: To review the aetiology and management of intoeing. DATA SOURCES: Medline and non-Medline literature search, and personal experience. STUDY SELECTION: Studies that provided evidence-based information about the aetiology and management of paediatric intoeing gait were selected. DATA EXTRACTION: Data were extracted and reviewed independently by both authors. DATA SYNTHESIS: An intoeing gait affects many children and, as with flexible flatfoot, bowleg, and knock-knee, it falls into the category of physiological problems that occur in normal children. The usual causes are excessive femoral anteversion, internal tibial torsion, and metatarsus adductus. Management is based on understanding the causes and the natural course of the condition and the effectiveness of various treatment modalities. Unfortunately, due to poor understanding of the condition, intoeing is commonly overtreated with braces or special footwear. CONCLUSIONS: Intoeing is one of the most common conditions encountered in paediatric orthopaedic practice. It is important to make an early diagnosis of pathological causes of intoeing such as cerebral palsy and developmental dysplasia of the hips so that treatment can be commenced as soon as possible.


Mango-bagasse functional-confectionery: vehicle for enhancing bioaccessibility and permeability of phenolic compounds.
Functional confectionery can be exploited as a vehicle for the protection of phenolic compounds (PCs) and for enhancing absorption during the gastrointestinal (GI) process. In this study, a confection containing 20% of mango bagasse (MB), gelatin and pectin was formulated. The PC profile, antioxidant capacity, in vitro bioaccessibility and apparent permeability (Papp) during mouth-stomach-intestine digestion (15, 30, 60, 120 min) and in vitro colonic fermentation (6, 12, 24 h) were evaluated for MB and the mango bagasse confection (MBC). HPLC-DAD analysis showed that mangiferin (830.69 μg g-1) was the most abundant compound in MBC. Total PCs (4.14 mg g-1), quercetin (244.83 μg g-1), and gallic acid (GA) (285.43 μg g-1) were highly bioaccessible mainly at the intestine at 60-120 min of digestion. GA was the most bioaccessible compound. Total flavonoids (TFs) and condensed tannins (CTs) had the maximum bioaccessibility in the mouth and stomach, respectively. For the permeability studies, PCs showed efflux rather than uptake in the intestine. Those compounds that exhibited intestinal absorption were mangiferin > GA > total PCs > TFs, whereas quercetin and CT absorption was negligible. The antioxidant capacity remained unchanged along the GI, mangiferin and quercetin being the most likely compounds to exert this activity. Overall results indicate that MBC has higher bioaccessibility, absorption and antioxidant capacity than MB, suggesting an effective protective role of gelatin and pectin, giving insight into the potential of MBC as a functional food.


Socio-demographic and drug use factors associated with HIV-1 recombinants and dual infections in Northern Thai drug users: associations of risk with genetic complexity.
Dual infection with diverse HIV strains can foster the emergence of recombinants. The resulting increase in viral genetic diversity is a major challenge for vaccine development HIV treatment. In this study we aim to investigate the socio demographic factors associated with an increasing level of genetic diversity among HIV strains in a population of drug-users in Northern Thailand. From 1999 through 2000, 2231 volunteers were enrolled in the Opiate-Users Research in Chiang Mai, Thailand. HIV subtype analysis was conducted among those HIV-1 seropositive (n=347) using a multi-region hybridization assay. Social and demographic variables were assessed using a structured questionnaire. Overall, 336/347 (96.8%) of the samples could be typed. 81.8% were CRF01_AE, 3.9% were subtype B, 9.2% were recombinants (mostly between CRF01_AE and B) and 5.1% were dual infections. Dual infections were more frequent among those with a lower education level (AOR: 5.2; 95% CI 1.4-20.3), those who have initiated injecting in the last 3 years (AOR: 3.9; 95% CI 1.1-14.6), and those reporting frequent needle sharing in the last 3 months (AOR: 7.0; 95% CI 1.5-34.1). Both recombinant strains and dual infection were more frequent among those reporting frequent needle sharing in the last 3 months (AOR: 5.3; 95% CI 1.6-17.1). To limit the expanding complexity of HIV-1 strains, early intervention should be aimed at reduction in needle sharing, especially among new intravenous drug users.