Psychological and/or educational interventions for the prevention of depression in children and adolescents.
Depression is the fourth most important disease in the estimation of the burden of disease Murray 1996 and is a common problem with prevalence rates estimated to be as high as 8% in young people. Depression in young people is associated with poor academic performance, social dysfunction, substance abuse, suicide attempts, and completed suicide (NHMRC 1997). This has precipitated the development of programmes aimed at preventing the onset of depression. This review evaluates evidence for the effectiveness of these prevention programmes. To determine whether psychological and/or educational interventions (both universal and targeted) are effective in reducing risk of depressive disorder by reducing depressive symptoms immediately after intervention or by preventing the onset of depressive disorder in children and adolescents over the next one to three years. The Cochrane Depression, Anxiety and Neurosis Group trials register (August 2002), MEDLINE (1966 to December Week 3 2002), EMBASE (1980 to January Week 2 2003), PsychInfo (1886 to January Week 2 2003) and ERIC (1985 to December 2002) were searched. In addition, conference abstracts, the reference lists of included studies, and other reviews were searched and experts in the field were contacted. Each identified study was assessed for possible inclusion by two independent reviewers based on the methods sections. The determinants for inclusion were that the trial include a psychological and/or educational prevention programme for young people aged 5 to 19 years-old, who did not meet DSM or ICD criteria for depression and/or did not fall into the clinical range on standardised, validated, and reliable rating scales of depression. The methodological quality of the included trials was assessed by two independent reviewers according to a list of pre-determined criteria, which were based on quality ratings devised by Moncrieff and colleagues (Moncrieff 2001). Outcome data was extracted and entered into Revman 4.2. Means and standard deviations for continuous outcomes and number of events for dichotomous outcomes were extracted where available. For trials where the required data were not reported or could not be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and described, but not included in the meta-analysis. Results were presented for each type of intervention: targeted or universal interventions; and educational or psychological interventions and if data were provided, by gender. Where possible data were combined in meta-analyses to give a treatment effect across all trials. Sensitivity analysis were conducted on studies rated as "adequate" or "high" quality, that is with a score over 22, based on the scale by Moncrieff et al (Moncrieff 2001). The presence of publication bias was assessed using funnel plots. Studies were divided into those that compared intervention with an active comparison or placebo (i.e. a control condition that resembles the intervention being investigated but which lacks the elements thought to be active in preventing depression) and those that used a "wait-list" or no intervention comparison group. Only two studies fell into the former category and neither showed effectiveness although one study was inadequately powered to show a difference and in the other the "placebo" contained active therapeutic elements, reducing the ability to demonstrate a difference from intervention. Psychological interventions were effective compared with non-intervention immediately after the programmes were delivered with a significant reduction in scores on depression rating scales for targeted (standardised mean difference (SMD) of -0.26 and a 95% confidence interval (CI) of -0.40 to -0.13 ) but not universal interventions (SMD -0.21, 95% CI -0.48, 0.06), with a significant effect maintained on pooling data (SMD -0.26, 95% CI -0.36, -0.15). While small effect sizes were reported, these were associated with a significant reduction in depressive episodes. The overall risk difference after intervention translates to "numbers needed to treat" (NNT) of 10. The most effective study is the targeted programme by Clarke (Clarke 2001) where the initial effect size of -0.46 is associated with an initial risk difference of -0.22 and NNT 5. There was no evidence of effectiveness for educational interventions. Reports of effectiveness for boys and girls were contradictory. The quality of many studies was poor, and only two studies made allocation concealment explicit. Sensitivity analysis of only high quality studies did not alter the results significantly. The only analysis in which there was significant statistical heterogeneity was the sub-group analysis by gender where there was variability in the response to different programmes for both girls and boys. For the most part funnel plots indicate findings are robust for short term effects with no publication bias evident. There are too few studies to comment on whether there is publication bias for studies reporting long-term (12-36 month) follow-up. Although there is insufficient evidence to warrant the introduction of depression prevention programmes currently, results to date indicate that further study would be worthwhile. There is a need to compare interventions with a placebo or some sort of active comparison so that study participants do not know whether they are in the intervention group or not, to investigate the impact of booster sessions to see if effectiveness immediately after intervention can be prolonged, ideally for a year or longer, and to consider practical implementation of prevention programmes when choosing target populations. Until now most studies have focussed on psychological interventions. The potential effectiveness of educational interventions has not been fully investigated. Given the gender differences in prevalence, and the change in these that occurs in adolescence with a disproportionate increase in prevalence rates for girls, it is likely that girls and boys will respond differently to interventions. Although differences have been reported in studies in this review the findings are contradictory and a more definitive delineation of gender specific responses to interventions would be helpful.


Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia.
The neural mechanisms underlying cognitive deficits in schizophrenia are poorly understood. Sub-chronic treatment with the NMDA antagonist phencyclidine (PCP) produces cognitive abnormalities in rodents that reliably model aspects of the neurocognitive alterations observed in schizophrenia. Given that network activity across regions encompassing medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) plays a significant role in motivational and cognitive tasks, we measured activity across cortico-striatal pathways in PCP-treated rats to characterize neural enabling and encoding of task performance in a novel object recognition task. We found that PCP treatment impaired task performance and concurrently (1) reduced tonic NAc neuronal activity, (2) desynchronized cross-activation of mPFC and NAc neurons, and (3) prevented the increase in mPFC and NAc neural activity associated with the exploration of a novel object in relation to a familiar object. Taken together, these observations reveal key neuronal and network-level adaptations underlying PCP-induced cognitive deficits, which may contribute to the emergence of cognitive abnormalities in schizophrenia.


Inula L. Secondary Metabolites against Oxidative Stress-Related Human Diseases.
An imbalance in the production of reactive oxygen species in the body can cause an increase of oxidative stress that leads to oxidative damage to cells and tissues, which culminates in the development or aggravation of some chronic diseases, such as inflammation, diabetes mellitus, cancer, cardiovascular disease, and obesity. Secondary metabolites from Inula species can play an important role in the prevention and treatment of the oxidative stress-related diseases mentioned above. The databases Scopus, PubMed, and Web of Science and the combining terms Inula, antioxidant and secondary metabolites were used in the research for this review. More than 120 articles are reviewed, highlighting the most active compounds with special emphasis on the elucidation of their antioxidative-stress mechanism of action, which increases the knowledge about their potential in the fight against inflammation, cancer, neurodegeneration, and diabetes. Alantolactone is the most polyvalent compound, reporting interesting EC50 values for several bioactivities, while 1-O-acetylbritannilactone can be pointed out as a promising lead compound for the development of analogues with interesting properties. The Inula genus is a good bet as source of structurally diverse compounds with antioxidant activity that can act via different mechanisms to fight several oxidative stress-related human diseases, being useful for development of new drugs.


HLA-DR in Brazilian patients with polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA).
The aim of this study was to evaluate the frequency and clinical associations of HLA-DR alleles in Brazilian Caucasian patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA). We evaluated 29 Caucasian patients with vasculitis classified as PAN or MPA according to the American College of Rheumatology (ACR) 1990 Criteria, Chapel Hill Consensus Conference (CHCC) nomenclature for vasculitis and EULAR recommendations for conducting clinical studies in systemic vasculitis. HLA-DR alleles were typed using polymerase chain reaction-amplified DNA, hybridized with sequence-specific low resolution primers. DNA obtained from 59 Caucasian healthy blood donors were used as control. In order to evaluate if a specific HLA may have influence on the clinical profile of those diseases, we also divided the patients according to Birmingham vasculitis score (BVAS) and Five-Factors Score (FFS) at the time of diagnosis. Increased frequency of HLA-DRB1*16 (p = 0.023) and DRB4*01 (p = 0.048) was found in patients with higher disease activity at the time of diagnosis (BVAS >/=22). Patients with less severe disease (FFS = 0) had a higher frequency of HLA-DRB1*03 (p = 0.011). Patients with gastrointestinal tract involvement had significantly increased frequency of HLA-DRB1*11 or B1*12 (p = 0.046), B1*13 (p = 0.021) and B3 (p = 0.008). In contrast, patients with renal disease, had higher frequency of DRB1*15 or DRB1*16 (p = 0.035) and B5 (p = 0.035). In the subgroup of patients with MPA, increased frequency of HLA-DRB1*15 was found in patients with BVAS >/=22 (p = 0.038) and FFS >/=1 (p = 0.039) suggesting that this allele is associated with more aggressive disease. Antineutrophil cytoplasmic antibodies (ANCA) negative MPA patients had significantly increased frequency of HLA-DRB1*11 or DRB1*12 when compared to ANCA positive patients (p = 0.023). Our results suggest that HLA-DR alleles may influence PAN and MPA clinical expression and outcome and that in MPA they participate in the mechanisms involved in the development to ANCA.


Holographic interferometric microscope on the basis of a Bi(12)TiO(20) crystal.
The applicability of cubic photorefractive crystals in which the recording can be fixed to holographic interferometric studies of microobjects is outlined. The possibility of observing the temporal behavior of the object by a method combining double exposure and real time interferometry is experimentally demonstrated.


Comparison of Three Fungicide Spray Advisories for Lettuce Downy Mildew.
Lettuce growers in coastal California have relied mainly on protective fungicide sprays to control downy mildew. Thus, timing of sprays before infection is critical for optimal results. A leaf-wetness-driven, infection-based advisory system, previously developed, did not always perform satisfactorily. In this study, the advisory system was modified by incorporating a pathogen survival component (system 1) or both survival and sporulation components (system 2). These systems were then evaluated in commercial lettuce fields in coastal California during 1996-1998. Three or four treatments were carried out in each field: (i) no spray; (ii) sprays as scheduled by the growers; (iii) sprays following modified system 1; and (iv) sprays following the original advisory system (1996) or modified system 2 (1998). Downy mildew incidence was evaluated every 2 to 9 days. In fields with drip irrigation, the number of fungicide applications was reduced by one or two regardless of the advisory system used compared to the grower's calendar-based schedule, although one unnecessary spray was recommended in 1996 at Soledad and 1997 at Salinas. Under all three systems, disease levels were low (incidence <25% and about 1 lesion per plant) for fields with drip irrigation, but not for fields with sprinklers (incidence up to 100% and 5 to 10 lesions per plant). For the first time, we established that survival and sporulation components are not needed for a lettuce downy mildew forecasting system. Instead, a threshold with a shorter period of morning leaf wetness and high temperatures were found to have potential for improving forecasting efficiency.


Cognitive and motor improvement after retesting in normal-pressure hydrocephalus: a real change or merely a learning effect?
The test-retest method is commonly used in the management of patients with normal-pressure hydrocephalus (NPH). One of the most widely used techniques in the diagnosis of this condition is evaluation of the patient's response to CSF evacuation by lumbar puncture (a so-called tap test or spinal tap). However, interpretation of improved results in subsequent evaluations is controversial because higher scores could reflect a real change in specific abilities or could be simply the result of a learning effect. To determine the effect of testing-retesting in patients with NPH, the authors analyzed changes documented on 5 neuropsychological tests (the Toulouse-Pieron, Trail Making Test A, Grooved Pegboard, Word Fluency, and Bingley Memory tests) and several motor ability scales (motor performance test, length of step, and walking speed tests) in a series of 32 patients with NPH who underwent the same battery on 4 consecutive days. The same tests were also applied in 30 healthy volunteers. In both groups, the authors used the generalized least-squares regression method with random effects to test for learning effects. To evaluate possible differences in response depending on the degree of cognitive impairment at baseline, the results were adjusted by using the Mini-Mental State Examination scores of patients and controls when these scores were significant in the model. In patients with NPH there were no statistically significant differences in any of the neuropsychological or motor tests performed over the 4 consecutive days, except in the results of the Toulouse-Pieron test, which were significantly improved on Day 3. In contrast, healthy volunteers had statistically significant improvement in the results of the Toulouse-Pieron test, Trail Making Test A, and Grooved Pegboard test but not in the remaining neuropsychological tests. Patients in the healthy volunteer group also exhibited statistically significant improvement in the motor performance test but not in step length or walking speed. No learning effect was found in patients with NPH on any of the neuropsychological or motor tests. Clinical improvement after retesting in these patients reflects real changes, and this strategy can therefore be used in both the diagnosis and evaluation of surgical outcomes.


Cannabinoids for nausea and vomiting related to chemotherapy: Overview of systematic reviews.
Nausea and vomiting are common and distressing adverse events of chemotherapy. This review focuses on the findings and quality of systematic reviews (SRs) of cannabinoids for chemotherapy-induced nausea and vomiting (CINV). Review of SRs, a systematic literature search, was conducted in several electronic databases and included SRs evaluating cannabinoids for CINV in cancer patients. Methodological quality and quality of reporting were evaluated by AMSTAR and PRISMA, respectively. Initial search retrieved 2,206 records, and 5 SRs were included. On the basis of findings of the sole SR judged as high methodological quality, cannabinoids seem to be more effective than placebo, equal to prochlorperazine for reducing CINV, and to be preferred by patients. The response to different combinations of antiemetic agents seems to be equal to 1 antiemetic alone. The average of AMSTAR score was 5, and the average of PRISMA score was 13.2. Cannabinoids represent a valuable option for treating CINV, despite the adverse events related to treatment, such as drowsiness and cognitive impairment. There is no good quality evidence to recommend or not the use of cannabinoids for CINV. More studies are still needed to evaluate the effectiveness of cannabinoids when compared with modern antiemetics.


Curcumin aggravates CNS pathology in experimental systemic lupus erythematosus.
Complement activation and inflammation are key disease features of systemic lupus erythematosus. Curcumin is an anti-inflammatory agent that inhibits the complement cascade. Therefore, we hypothesized that curcumin will be protective in CNS lupus. To assess the effect of curcumin on CNS-lupus, MRL/lpr mice were used. Brain MRI showed that curcumin (30mg/kg body wt. i.p. from 12-20 weeks) worsened regional brain atrophy. The volumes of the lateral and third ventricles are significantly increased (150%-213% and 107%-140%, without and with treatment respectively compared to MRL+/+ controls). The hippocampus was reduced further (83%-81%) by curcumin treatment. In line with increased brain atrophy, there were edematous cells (41% increase in cell size in MRL/lpr compared to MRL+/+ mice. The cell size was further increased by 28% when treated with curcumin; p<0.02) in the cortex. In line with increased atrophy and edema, there was a significant increase (p<0.02) in the mRNA and protein expression of the water channel protein, aquaporin 4 in these mice. The increase in the matrix proteins, glial fibrillary acidic protein and vimentin in lupus mice in the hippocampus was prevented by curcumin. Curcumin increased IgG deposits and decreased C3 deposits in brain with a corresponding increase in immune complexes and decrease in C3 concentration (by 60% in MRL/lpr mice Vs. MRL+/+ mice and a further 26% decrease when treated with curcumin) in circulation. Decrease in C3 could alter the transport of immune complexes leading to an increase in IgG deposits which could induce inflammatory pathways thereby leading to worsening of the disease. The neurological outcome as measured by maze performance indicates that the curcumin treated mice performed poorly compared to the untreated counterparts. Our results for the first time provide evidence that at the dose used in this study, curcumin aggravates some CNS disease manifestations in experimental lupus brain. Therefore, until a safe dose range is established by additional studies, and the validity of the findings is determined in human patients, caution may be warranted in the use of curcumin, even as adjuvant therapy for CNS lupus.


In situ assembly of active surface-enhanced Raman scattering substrates via electric field-guided growth of dendritic nanoparticle structures.
Surface-enhanced Raman scattering (SERS) can provide ultrasensitive detection of chemical and biological analytes down to the level of a single molecule. The need for costly, nanostructured, noble-metal substrates, however, poses a major obstacle in the widespread application of the method. Here we present for the first time a novel type of metallic nanostructured substrates that, not only exhibit a remarkable SERS activity, but are also produced in a facile, cost-effective and nanofabrication-free manner. The substrates are formed through an electric field-guided assembly process of silver nanocolloids, which results in extended and interconnected dendritic nanoparticle structures with a high density of "hot spots". A unique and significant performance attribute of these nanostructures is their ability to also function as concentration amplification devices, thereby further enhancing their analyte detection efficiency. This major advantage against conventional SERS substrates is illustrated experimentally here with the concentration and detection of proteins from solution. Low limits of detection for illicit drugs, food contaminants and pesticides in relevant matrices are also demonstrated. The SERS-active dendrites are reusable and can be removed and replaced in a few minutes. The SERS substrates presented herein constitute a significant advance towards more effective and less expensive diagnostic tools.


The experiences of older adults in the community dying from cancer and non-cancer causes: a national survey of bereaved relatives.
there is limited understanding of symptoms and care in the last few months of life for adults dying from causes other than cancer. the aim of the study is to compare the experiences in the community in the last 3 months of life of older adults dying from cancer and non-cancer causes. the study employed a retrospective cross-sectional survey of bereaved relatives. the survey took place across eight cancer networks in England. a random sample of 1,266 adults who registered a death occurring in someone aged 65 and over between August 2002 and February 2004 was drawn. VOICES (Views of Informal Carers-Evaluation of Services) questionnaires were sent to sampled informants by the Office for National Statistics 3-9 months after the registration of the death. Differences in the reported experiences of cancer and non-cancer decedents in symptoms, treatment and care were assessed using Pearson's chi square test. cancer decedents were significantly more likely than non-cancer decedents to have had pain (93 vs 79%, P < 0.001), nausea and vomiting (62 vs 40%, P < 0.001) and constipation (74 vs 66%, P = 0.03), whilst a greater proportion of non-cancer decedents experienced breathlessness (74 vs 65%, P = 0.006). Across both groups, less than half of the decedents were reported to have received treatment which completely relieved their symptoms some or all of the time. There were significant variations in the receipt of district nursing, general practitioner care and other health and social care and the reported quality of this care, for decedents dying of cancer and non-cancer causes. Further, informants for cancer deaths reported greater satisfaction with support received. there are important differences in the reported experiences of older adults dying from cancer and non-cancer causes in the last months of life, independent of age.


Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit.
Excessive fluid therapy in patients with sepsis may be associated with risks that outweigh any benefit. We investigated the possible influence of early fluid balance on outcome in a large international database of ICU patients with sepsis. Observational cohort study. Seven hundred and thirty ICUs in 84 countries. All adult patients admitted between May 8 and May 18, 2012, except admissions for routine postoperative surveillance. For this analysis, we included only the 1,808 patients with an admission diagnosis of sepsis. Patients were stratified according to quartiles of cumulative fluid balance 24 hours and 3 days after ICU admission. ICU and hospital mortality rates were 27.6% and 37.3%, respectively. The cumulative fluid balance increased from 1,217 mL (-90 to 2,783 mL) in the first 24 hours after ICU admission to 1,794 mL (-951 to 5,108 mL) on day 3 and decreased thereafter. The cumulative fluid intake was similar in survivors and nonsurvivors, but fluid balance was less positive in survivors because of higher fluid output in these patients. Fluid balances became negative after the third ICU day in survivors but remained positive in nonsurvivors. After adjustment for possible confounders in multivariable analysis, the 24-hour cumulative fluid balance was not associated with an increased hazard of 28-day in-hospital death. However, there was a stepwise increase in the hazard of death with higher quartiles of 3-day cumulative fluid balance in the whole population and after stratification according to the presence of septic shock. In this large cohort of patients with sepsis, higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.


A proposed refinement of the mitochondrial free radical theory of aging.
Over recent years, evidence has been accumulating in favour of the free radical theory of aging, first proposed by Harman. Despite this, an understanding of the mechanism by which cells might succumb to the effects of free radicals has proved elusive. This paper proposes such a mechanism, based on a previously unexplored hypothesis for the proliferation of mutant mitochondrial DNA: that mitochondria with reduced respiratory function, due to a mutation or deletion affecting the respiratory chain, suffer less frequent lysosomal degradation, because they inflict free radical damage more slowly on their own membranes. Once such a mutation occurs in a mitochondrion of a non-dividing cell, therefore, mitochondria carrying it will rapidly populate that cell, thereby destroying the cell's respiratory capability. The accumulation of cells that have undergone this transition results in aging at the organismal level. The consistency of the hypothesis with known facts is discussed, and technically feasible tests are suggested, of both the proposed mechanism and its overall contribution to mammalian aging.


Characterization of 43 non-protein-coding mRNA genes in Arabidopsis, including the MIR162a-derived transcripts.
Messenger RNAs that do not contain a long open reading frame (ORF) or non-protein-coding RNAs (npcRNAs) are an emerging novel class of transcripts. Their functions may involve the RNA molecule itself and/or short ORF-encoded peptides. npcRNA genes are difficult to identify using standard gene prediction programs that rely on the presence of relatively long ORFs. Here, we used detailed bioinformatic analyses of expressed sequence tag/cDNA databases to detect a restricted set of npcRNAs in the Arabidopsis (Arabidopsis thaliana) genome and further characterized these transcripts using a combination of bioinformatic and molecular approaches. Compositional analyses revealed strong nucleotide strand asymmetries in the npcRNAs, as well as a biased GC content, suggesting the existence of functional constraints on these RNAs. Thirteen of these transcripts display tissue-specific expression patterns, and three are regulated in conditions affecting root architecture. The npcRNA 78 gene contains the miR162 sequence in an alternative intron and corresponds to the MIR162a locus. Although DICER-LIKE 1 (DCL1) mRNA is known to be regulated by miR162-guided cleavage, its level does not change in a mir162a mutant. Alternative splicing of npcRNA 78 leads to several transcript isoforms, which all accumulate in a dcl1 mutant. This suggests that npcRNA 78 is a genuine substrate of DCL1 and that splicing of this microRNA primary transcript and miR162 processing are competitive nuclear events. Our results provide new insights into Arabidopsis npcRNA biology and the potential roles of these genes.


Angle determination and scattering suppression in polarization-enhanced two-dimensional infrared spectroscopy in the pump-probe geometry.
The signal to noise in two-dimensional spectra recorded in the pump-probe geometry can be significantly improved with a quasi-crossed polarizer configuration, often employed in linear dichroism measurements. Here we examine this method in detail and demonstrate how to analyse and interpret the amplified signals. The angle between transition dipole moments can be determined with better accuracy than in conventional anisotropy measurements, and the method can be used to selectively suppress individual peaks and to efficiently remove scattering contributions. We present spectra of the coupled CO-stretch modes of a Ruthenium-carbonyl complex in DMSO for experimental illustration.


The dynamics of cancer chromosomes and genomes.
A key feature of cancer chromosomes and genomes is their high level of dynamics and the ability to constantly evolve. This unique characteristic forms the basis of genetic heterogeneity necessary for cancer formation, which presents major obstacles to current cancer diagnosis and treatment. It has been difficult to integrate such dynamics into traditional models of cancer progression. In this conceptual piece, we briefly discuss some of the recent exciting progress in the field of cancer genomics and genome research. In particular, a re-evaluation of the previously disregarded non-clonal chromosome aberrations (NCCAs) is reviewed, coupled with the progress of the detection of sub-chromosomal aberrations with array technologies. Clearly, the high level of genetic heterogeneity is directly caused by genome instability that is mediated by stochastic genomic changes, and genome variations defined by chromosome aberrations are the driving force of cancer progression. In addition to listing various types of non-recurrent chromosomal aberrations, we discuss the likely mechanism underlying cancer chromosome dynamics. Finally, we call for further examination of the features of dynamic genome diseases including cancer in the context of systems biology and the need to integrate this new knowledge into basic research and clinical applications. This genome centric concept will have a profound impact on the future of biological and medical research.


Macrophage type 3 complement receptors mediate serum-independent binding of Leishmania donovani. Detection of macrophage-derived complement on the parasite surface by immunoelectron microscopy.
In this study, direct visual evidence for local opsonization of L. donovani by macrophage (M phi)-derived complement components was obtained using immunoelectron microscopy. C3 deposition was detected on the surface of both promastigotes and amastigotes after 20 min serum-free incubation with murine resident peritoneal M phi (RPM), followed by fixation and incubation first with specific antibody directed against C3 and then with gold-labelled protein A. Gold deposition was not observed around either form of the parasite if the anti-C3 antibody was omitted. For promastigotes, the degree of C3 deposition under serum-free conditions was comparable with that observed in the presence of an exogenous (serum) source of C3, but did not result in the same severe damage to the parasite as did the latter. Addition of sodium salicyl hydroxamate, which prevents covalent binding of C3 to activator surfaces, abrogated promastigote binding. Hence, although the anti-C3 antibody did not distinguish between native C3 and its breakdown product iC3b, these data support our earlier conclusion that promastigote binding to the CR3 of murine RPM is complement dependent. For amastigotes, gold deposition and binding to murine RPM were not eliminated by sodium salicyl hydroxamate. The presence of normal mouse serum resulted in increased gold deposition, but did not mediate either enhanced binding to M phi or damage to the amastigote. These data suggest that a proportion of C3 binding to the amastigote surface may be via noncovalent linkages, and that the C3 bound may not be in the correct form to mediate binding to CR3.


Requirements of Slm proteins for proper eisosome organization, endocytic trafficking and recycling in the yeast Saccharomyces cerevisiae.
Eisosomes are large immobile assemblies at the cortex of a cell under the membrane compartment of Can1 (MCC) in yeast. Slm1 has recently been identified as an MCC component that acts downstream of Mss4 in a pathway that regulates actin cytoskeleton organization in response to stress. In this study, we showed that inactivation of Slm proteins disrupts proper localization of the primary eisosome marker Pil1, providing evidence that Slm proteins play a role in eisosome organization. Furthermore, we found that slm ts mutant cells exhibit actin defects in both the ability to polarize cortical F-actin and the formation of cytoplasmic actin cables even at the permissive temperature (30 degrees C). We further demonstrated that the actin defect accounts for the slow traffic of FM4-64- labelled endosome in the cytoplasm, supporting the notion that intact actin is essential for endosome trafficking. However, our real-time microscopic analysis of Abp1-RFP revealed that the actin defect in slm ts cells was not accompanied by a noticeable defect in actin patch internalization during receptor-mediated endocytosis. In addition, we found that slm ts cells displayed impaired membrane recycling and that recycling occurred in an actin-independent manner. Our data provide evidence for the requirement of Slm proteins in eisosome organization and endosome trafficking and recycling.


The ADAM metalloproteinases.
The ADAMs (a disintegrin and metalloproteinase) are a fascinating family of transmembrane and secreted proteins with important roles in regulating cell phenotype via their effects on cell adhesion, migration, proteolysis and signalling. Though all ADAMs contain metalloproteinase domains, in humans only 13 of the 21 genes in the family encode functional proteases, indicating that at least for the other eight members, protein-protein interactions are critical aspects of their biological functions. The functional ADAM metalloproteinases are involved in "ectodomain shedding" of diverse growth factors, cytokines, receptors and adhesion molecules. The archetypal activity is shown by ADAM-17 (tumour necrosis factor-alpha convertase, TACE), which is the principal protease involved in the activation of pro-TNF-alpha, but whose sheddase functions cover a broad range of cell surface molecules. In particular, ADAM-17 is required for generation of the active forms of Epidermal Growth Factor Receptor (EGFR) ligands, and its function is essential for the development of epithelial tissues. Several other ADAMs have important sheddase functions in particular tissue contexts. Another major family member, ADAM-10, is a principal player in signalling via the Notch and Eph/ephrin pathways. For a growing number of substrates, foremost among them being Notch, cleavage by ADAM sheddases is essential for their subsequent "regulated intramembrane proteolysis" (RIP), which generates cleaved intracellular domains that translocate to the nucleus and regulate gene transcription. Several ADAMs play roles in spermatogenesis and sperm function, potentially by effecting maturation of sperm and their adhesion and migration in the uterus. Other non-catalytic ADAMs function in the CNS via effects on guidance mechanisms. The ADAM family are thus fundamental to many control processes in development and homeostasis, and unsurprisingly they are also linked to pathological states when their functions are dysregulated, including cancer, cardiovascular disease, asthma, Alzheimer's disease. This review will provide an overview of current knowledge of the human ADAMs, discussing their structure, function, regulation and disease involvement.


Significant Chondrocyte Viability Is Present in Acetabular Chondral Flaps Associated With Femoroacetabular Impingement.
Patients presenting with cam deformity of the femoral head and neck sustain repeated trauma to the articular cartilage of the superior acetabulum, with chondral delamination injuries found during hip arthroscopy. Two previous studies reveal conflicting chondrocyte viability data in these traumatic cartilage injuries. The full-thickness nature of flaps may suggest that chondrocytes residing in the cartilage flap matrix in the joint environment would remain viable despite shear trauma. Hypothesis/Purpose: The purpose of this study is to determine the in vivo tissue viability of acetabular chondral flaps in patients with femoroacetabular impingement (FAI) when samples are analyzed immediately after biopsy. We hypothesize that the majority of the tissue in acetabular chondral flaps is viable in the joint microenvironment. Descriptive laboratory study. Partially detached cartilage flaps from 10 patients undergoing arthroscopic hip surgery for FAI were biopsied in a minimally traumatic manner before chondroplasty and microfracture. Samples were placed in cold Hank's Balanced Salt Solution without phenol red solution and immediately transported on ice to our laboratory. The edge of the samples was trimmed and further cut into 3 separate, 1-mm-thick sections. Sections were stained using a live/dead staining kit. Images were obtained with confocal microscopy, and the percentage of live cells was quantified. Patients averaged 36 ± 11 years (range, 18-48 years), and 2 patients were female. The mean body mass index was 28.9 ± 5.6 kg/m2. The total proportion of live cells from all sections analyzed was 85.8%. The proportion of live cells per patient was 87% ± 10%. We determined that acetabular chondral flaps are approximately 87% live cells when analyzed immediately after biopsy, with 6 of 10 patients having greater than 90% live cells. These data point to the importance of laboratory techniques in making viability judgments in biologic systems. Full-thickness cartilage loss is a difficult problem for all active people but particularly in the young population in whom joint preservation is key. We describe the viability of chondrocytes present in full-thickness acetabular-based chondral flaps encountered during hip arthroscopy. Identification of greater than 85% chondrocyte viability supports a foundation for evaluation and creation of novel clinical innovations for repair and replacement techniques using the flap as donor tissue, as alternatives to chondroplasty and microfracture.


[Mitochondrial DNA mutations in lung cancer].
Mitochondiral DNA (mtDNA) mutations has been identified in various cancers, but their significance was unknown. This study aimed to detect mtDNA mutations in lung cancer, and to investigate their roles in the carcinogenesis of human lung. Total DNA (including nuclear DNA and mtDNA) was extracted from the tumor tissues, corresponding distal non-cancerous lung tissues, and peripheral lymphocytes derived from 58 patients with lung cancer. Fifty-eight overlapping fragments and covering complete sequence of mtDNA were amplified by nested PCR, and the PCR products were sequenced directly with the cycle sequencing methods. The mtDNA mutations in the tumor tissue were determined by comparing with corresponding and peripheral lymphocytes. Sixty-six mutations were identified in 36 cases (62.1%) of lung cancer, including 58 point mutations, 4 insertions, and 4 deletions. These mutations were dispersedly distributed in the full length of mtDNA. The frequency of mutation in D-loop is the highest, in which 18 mutations were detected. No mutation hot spot was found in peptide-coding regions. Among 43 point mutations identified in protein-coding region, 20 were silent mutations. In 8 patients, identical mutations were detected both in the tumor tissues and corresponding distal non-cancerous tissues. Most of mtDNA mutations in the lung cancers investigated were occurred randomly and might have no impact on carcinogenesis; whereas the homoplasmic mutations may provide a potential diagnostic marker for lung cancer.


COordination of Standards in MetabOlomicS (COSMOS): facilitating integrated metabolomics data access.
Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative 'coordination of standards in metabolomics' (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities' participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards.


Hypnotic analgesia reduces brain responses to pain seen in others.
Brain responses to pain experienced by oneself or seen in other people show consistent overlap in the pain processing network, particularly anterior insula, supporting the view that pain empathy partly relies on neural processes engaged by self-nociception. However, it remains unresolved whether changes in one's own pain sensation may affect empathic responding to others' pain. Here we show that inducing analgesia through hypnosis leads to decreased responses to both self and vicarious experience of pain. Activations in the right anterior insula and amygdala were markedly reduced when participants received painful thermal stimuli following hypnotic analgesia on their own hand, but also when they viewed pictures of others' hand in pain. Functional connectivity analysis indicated that this hypnotic modulation of pain responses was associated with differential recruitment of right prefrontal regions implicated in selective attention and inhibitory control. Our results provide novel support to the view that self-nociception is involved during empathy for pain, and demonstrate the possibility to use hypnotic procedures to modulate higher-level emotional and social processes.


FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBP alpha.
Fms interacting protein (FMIP) is a substrate for Fms tyrosine kinase, and a nuclear/cytoplasm shuttling protein with a leucine zipper. As the phosphorylation of FMIP is observed in insulin-stimulated preadipocytes, we examined the role of FMIP in adipocyte differentiation, using the mesenchymal multipotent stem cells, C2C12 cells, that can differentiate into adipocytes, muscle cells and osteoblasts. Ectopic expression of FMIP in C2C12 impairs the adipocyte differentiation induced by treatment with insulin, dexamethasone and 3-isobutyl-1-methylxanthine. These cells exhibit muscle phenotype with multinuclear morphology. Furthermore, knockdown of endogenous FMIP expression by small interfering RNA improves adipocytic lineage commitment of C2C12 cells, while impairing muscle differentiation. Upon stimulation with insulin, CCAAT/enhancer binding protein (C/EBP)beta, but not C/EBPalpha, is upregulated in cells expressing ectopic FMIP, whereas in FMIP knockdown cells, C/EBPalpha is constitutively expressed. Ectopic expression of C/EBPalpha counteracts the effects of FMIP, whereas C/EBPalpha knockdown partially mimics the effects of FMIP in this system. Northern blot analysis and reverse transcriptase-polymerase chain reaction study reveal that ectopic FMIP-expressing cells do not contain the polyadenylated C/EBPalpha mRNA, but contain the C/EBPalpha pre-mRNA, suggesting that FMIP plays a role in RNA processing and/or export. Indeed, a member of the THO complex that plays a role in mRNA export, THOC1, is co-precipitated with FMIP. The data we have acquired on FMIP suggest that it is a target for tyrosine kinase receptors that potentiate mRNA export.


Inflammation-induced increase in hyperpolarization-activated, cyclic nucleotide-gated channel protein in trigeminal ganglion neurons and the effect of buprenorphine.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are active at resting membrane potential and thus contribute to neuronal excitability. Their increased activity has recently been demonstrated in models of nerve injury-induced pain. The major aim of the current study was to investigate altered HCN channel protein expression in trigeminal sensory neurons following inflammation of the dura. HCN1 and HCN2 channel immunoreactivity was observed on the membranes of medium- to large-sized trigeminal ganglion neurons with 76% and 85% of HCN1 and HCN2 expressing neurons also containing the 200 kDa neurofilament protein (associated with myelinated fibers). Western immunoblots of lysates from rat trigeminal ganglia also showed bands with appropriate molecular weights for HCN1 and HCN2. Three days after application of complete Freund's adjuvant (CFA) to the dura mater, Western blot band densities were significantly increased; compared to control, to 166% for HCN1 and 284% for HCN2 channel protein. The band densities were normalized against alpha-actin. In addition, the number of retrogradely labeled neurons from the dura expressing HCN1 and HCN2 was significantly increased to 247% (HCN1) and 171% (HCN2), three days after inflammation. When the opioid receptor partial agonist, buprenorphine, was given systemically, immediately after CFA, the inflammation-induced increase in HCN protein expression in both Western blot and immunohistochemical experiments was not observed. These results suggest that HCN1 and HCN2 are involved in inflammation-induced sensory neuron hyperexcitability, and indicate that an opioid receptor agonist can reverse the protein upregulation.


Pharmaceutical Clinical Educators: A Resource for Advanced Practice Providers.
One of the main challenges within clinical practice today involves attaining the knowledge necessary to treat patients safely and effectively. The explosion of scientific breakthroughs within the health-care setting has created a new challenge for today's practitioners: staying informed. In turn, the pharmaceutical industry has been challenged with providing information that is accurate, meaningful, and compliant with US Food and Drug Administration guidelines. In this article, we review how the pharmaceutical industry has tried to fill this need through the role of the pharmaceutical clinical educator (PCE). We describe the PCE role and the different forms of education and support that can be provided to advanced practice providers (APPs). We also address the conflict of interest issues surrounding a collaborative relationship between APPs and pharmaceutical industry APPs.


Influence of testosterone on breathing during sleep.
Apneas and hypopneas during sleep occur more frequently in men than women. Disordered breathing is also reported to increase in hypogonadal men following testosterone administration. This suggests a hormonal influence on sleeping respiratory pattern. We therefore studied respiratory rhythm during sleep in 11 hypogonadal males both on and off testosterone-replacement therapy. In four subjects the anatomy (computerized tomography) and airflow resistance of the upper airway were also determined on both occasions. Sleep stage distribution and duration were unchanged following androgen administration. However, both apneas and hypopneas increased significantly during testosterone replacement so that the total number of disordered breathing events (apneas + hypopneas) per hour of sleep rose from 6.4 +/- 2.1 to 15.4 +/- 7.0 (P less than 0.05). This was a highly variable event with some subjects demonstrating large increases in apneas and hypopneas when androgen was replaced, whereas others had little change in respiration during sleep. Upper airway dimensions, on the other hand, were unaffected by testosterone. These results suggest that testosterone contributes to sleep-disordered breathing through mechanisms independent of anatomic changes in the upper airway.


Vision-related quality of life according to location of visual field loss in patients with glaucoma.
To assess influence of the location of visual field (VF) loss on vision-related quality of life (VRQOL) in patients with glaucoma. We included 826 patients with primary open-angle glaucoma (POAG) enrolled in the prospectively designed Life Quality of Glaucoma Patients Who Underwent Treatment (LIGHT) study organized by the Korean Glaucoma Society. We divided the integrated binocular visual field (IVF) into four regions and evaluated the associations between Rasch-analysed 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and location of the IVF using univariate and hierarchical multivariable linear regression. Mean deviation (MD) of the IVF at superior centre showed the lowest value among the four regions. Multivariable linear regression analysis revealed significant correlation of the composite score and all subscales of the NEI VFQ-25 except ocular pain and near activities at each of four IVF regions. Mean deviation at superior centre showed significant correlation with composite score (R2 = 0.181), near activities (R2 = 0.175), and social functioning (R2 = 0.166); MD at superior periphery showed highest correlation with role difficulties (R2 = 0.137); MD at inferior centre showed highest correlation with driving (R2 = 0.145); and MD at inferior periphery showed significant correlation with distance activities (R2 = 0.214) and dependency (R2 = 0.119). Four different regions of the IVF had a similarly important impact on subscales of the NEI VFQ-25 in glaucoma patients. Preservation of the superior field should be considered as much as that of the inferior field for maintaining a good VRQOL in patients with glaucoma.


Video gaming in school children: How much is enough?
Despite extensive debate, the proposed benefits and risks of video gaming in young people remain to be empirically clarified, particularly as regards an optimal level of use. In 2,442 children aged 7 to 11 years, we investigated relationships between weekly video game use, selected cognitive abilities, and conduct-related problems. A large subgroup of these children (n = 260) was further examined with magnetic resonance imaging approximately 1 year later to assess the impact of video gaming on brain structure and function. Playing video games for 1 hour per week was associated with faster and more consistent psychomotor responses to visual stimulation. Remarkably, no further change in motor speed was identified in children playing >2 hours per week. By comparison, the weekly time spent gaming was steadily associated with conduct problems, peer conflicts, and reduced prosocial abilities. These negative implications were clearly visible only in children at the extreme of our game-playing distribution, with 9 hours or more of video gaming per week. At a neural level, changes associated with gaming were most evident in basal ganglia white matter and functional connectivity. Significantly better visuomotor skills can be seen in school children playing video games, even with relatively small amounts of use. Frequent weekly use, by contrast, was associated with conduct problems. Further studies are needed to determine whether moderate video gaming causes improved visuomotor skills and whether excessive video gaming causes conduct problems, or whether children who already have these characteristics simply play more video games. Ann Neurol 2016;80:424-433.


Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease.
Polycystic kidney disease (PKD) is the most common genetic cause of renal failure in humans. Several proteins that are encoded by genes associated with PKD have recently been identified in primary cilia in renal tubular epithelia. These findings have suggested that abnormalities in cilia formation and function may play a role in the pathogenesis of PKD. To directly determine whether cilia are essential to maintain tubular integrity, we conditionally inactivated KIF3A, a subunit of kinesin-II that is essential for cilia formation, in renal epithelia. Constitutive inactivation of KIF3A produces abnormalities of left-right axis determination and embryonic lethality. Here we show that tissue-specific inactivation of KIF3A in renal tubular epithelial cells results in viable offspring with normal-appearing kidneys at birth. Cysts begin to develop in the kidney at postnatal day 5 and cause renal failure by postnatal day 21. The cyst epithelial cells lack primary cilia and exhibit increased proliferation and apoptosis, apical mislocalization of the epidermal growth factor receptor, increased expression of beta-catenin and c-Myc, and inhibition of p21(CIP1). These results demonstrate that the absence of renal cilia produces both the clinical and cell biological findings associated with PKD. Most generally, the phenotype of Kif3a mutant mice suggests a role for primary cilia in the maintenance of lumen-forming epithelial differentiation.


Free-standing three-dimensional hollow bacterial cellulose structures with controlled geometry via patterned superhydrophobic-hydrophilic surfaces.
Bacteria can produce cellulose, one of the most abundant biopolymer on earth, and emerge as an interesting candidate to fabricate advanced materials. Cellulose produced by Komagataeibacter Xylinus, a bacterial strain, is a pure water insoluble biopolymer, without hemicellulose or lignin. Bacterial cellulose (BC) exhibits a nanofibrous porous network microstructure with high strength, low density and high biocompatibility and it has been proposed as cell scaffold and wound healing material. The formation of three dimensional (3D) cellulose self-standing structures is not simple. It either involves complex multi-step synthetic procedures or uses chemical methods to dissolve cellulose and remold it. Here we present an in situ single-step method to produce self-standing 3D-BC structures with controllable wall thickness, size and geometry in a reproducible manner. Parameters such as hydrophobicity of the surfaces, volume of the inoculum and time of culture define the resulting 3D-BC structures. Hollow spheres and convex domes can be easily obtained by changing the surface wettability. The potential of these structures as a 3D cell scaffold is exemplified supporting the growth of mouse embryonic stem cells within a hollow spherical BC structure, indicating its biocompatibility and future prospective.


Crystal structure of a human rhinovirus neutralizing antibody complexed with a peptide derived from viral capsid protein VP2.
The three-dimensional structure of the complex between the Fab fragment of an anti-human rhinovirus neutralizing antibody (8F5) and a cross-reactive synthetic peptide from the viral capsid protein VP2 has been determined at 2.5 A resolution by crystallographic methods. The refinement is presently at an R factor of 0.18 and the antigen-binding site and viral peptide are well defined. The peptide antigen adopts a compact fold by two tight turns and interacts through hydrogen bonds, some with ionic character, and van der Waals contacts with antibody residues from the six hypervariable loops as well as several framework amino acids. The conformation adopted by the peptide is closely related to the corresponding region of the viral protein VP2 on the surface of human rhinovirus 1A whose three-dimensional structure is known. Implications for the cross-reactivity between peptides and the viral capsid are discussed. The peptide-antibody interactions, together with the analysis of mutant viruses that escape neutralization by 8F5 suggest two different mechanisms for viral escape. The comparison between the complexed and uncomplexed antibody structures shows important conformational rearrangements, especially in the hypervariable loops of the heavy chain. Thus, it constitutes a clear example of the 'induced fit' molecular recognition mechanism.


Reduction of snoring with a plasma-mediated radiofrequency-based ablation (Coblation) device.
We evaluated the effectiveness of using a plasma-mediated radiofrequency-based ablation (Coblation) device to perform volumetric tissue reduction of the soft palate as a means of controlling snoring in 23 patients with loud snoring and mild or no sleep apnea. Tissue reduction was achieved by performing a channeling procedure designed to shrink the tissue surrounding the treatment zone. The soft palate was treated at three separate sites, and each channel was completed in approximately 11 seconds. Data regarding the primary outcome--that is, pre- and postoperative subjective assessments of snoring intensity provided by the patients' bed partners--were available for comparison for 21 of the 23 patients. Of the 21 patients, treatment was deemed successful in 10 (48%). Postoperatively, the overall mean intensity of snoring on a scale of 0 (no snoring) to 10 (terrible snoring) fell by 4 points (p < 0.05). Likewise, the loudness of snoring was also significantly reduced on objective SNAP recordings; the mean intensity fell from 12 to 8 dB (p < 0.05). Of the 10 successfully treated patients, 2 required only one procedure, 5 were improved after two treatments, and 3 underwent three operations. Seventeen of the 23 patients (74%) reported an improvement in quality of life. Surgical complications were mild to moderate, and pain was easily manageable in most cases. Our findings suggest that this procedure can be an effective treatment for socially unacceptable snoring. We hope that in future studies, investigators will evaluate outcomes over a longer term.


TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists.
Quinoxalinedione compounds such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) are the most commonly used alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. However, we find that in the presence of transmembrane AMPA receptor regulatory proteins (TARPs), which are AMPA receptor auxiliary subunits, CNQX acts as a partial agonist. CNQX induced small depolarizing currents in neurons of the central nervous system, and reconstitution of this agonist activity required coexpression of TARPs. A crystal structure of CNQX bound to the TARP-less AMPA receptor ligand-binding domain showed that, although CNQX induces partial domain closure, this movement is not transduced into linker separation, suggesting that TARPs may increase agonist efficacy by strengthening the coupling between domain closure and channel opening. Our results demonstrate that the presence of an auxiliary subunit can determine whether a compound functions as an agonist or antagonist.


GDP-L-fucose is required for boundary definition in plants.
The CUP-SHAPED COTYLEDON (CUC) transcription factors control plant boundary formation, thus allowing the emergence of novel growth axes. While the developmental roles of the CUC genes in different organs and across species are well characterized, upstream and downstream events that contribute to their function are still poorly understood. To identify new players in this network, we performed a suppressor screen of CUC2g-m4, a line overexpressing CUC2 that has highly serrated leaves. We identified a mutation that simplifies leaf shape and affects MURUS1 (MUR1), which is responsible for GDP-L-fucose production. Using detailed morphometric analysis, we show that GDP-L-fucose has an essential role in leaf shape acquisition by sustaining differential growth at the leaf margins. Accordingly, reduced CUC2 expression levels are observed in mur1 leaves. Furthermore, genetic analyses reveal a conserved role for GDP-L-fucose in different developmental contexts where it contributes to organ separation in the same pathway as CUC2. Taken together, our results reveal that GDP-L-fucose is necessary for proper establishment of boundary domains in various developmental contexts.


Growth of acid fast L forms from the blood of patients with sarcoidosis.
Acid fast cell wall deficient forms (CWDF) of bacteria have been grown from blood, bronchial washings, and ocular anterior chamber fluid from patients with sarcoidosis. A monoclonal antibody raised against Mycobacterium tuberculosis whole cell antigen (H37RV) was used to characterise further CWDF grown from the blood of patients with sarcoidosis. Blood from 20 patients with active sarcoidosis and from 20 controls was cultured using methods favourable for the growth of CWDF. Isolates were further characterised by indirect fluorescent antibody analysis using a monoclonal antibody highly reactive with M tuberculosis. CWDF were grown from the blood of 19 of 20 subjects with sarcoidosis. All isolates stained positively with the monoclonal antibody and with a modified Kinyoun stain. No organisms were grown from the blood of controls. These data demonstrate that CWDF can be grown from the blood of nearly all patients with active sarcoidosis. The results confirm that the organisms are mycobacterial in origin and are similar, if not identical, to M tuberculosis. Their role in the pathogenesis of sarcoidosis is unknown.


Washout policies in long-term indwelling urinary catheterisation in adults.
People requiring long-term bladder draining with an indwelling catheter can experience catheter blockage. Regimens involving different solutions can be used to wash out catheters with the aim of preventing blockage. This is an update of a review published in 2010. To determine if certain washout regimens are better than others in terms of effectiveness, acceptability, complications, quality of life and critically appraise and summarise economic evidence for the management of long-term indwelling urinary catheterisation in adults. We searched the Cochrane Incontinence Group Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings to 23 May 2016. We also examined all reference lists of identified trials and contacted manufacturers and researchers in the field. All randomised and quasi-randomised trials comparing catheter washout policies (e.g. washout versus no washout, different washout solutions, frequency, duration, volume, concentration, method of administration) in adults (aged 16 years and above) in any setting (i.e. hospital, nursing/residential home, community) with an indwelling urethral or suprapubic catheter for more than 28 days. Two review authors independently extracted data. Disagreements were resolved by discussion. Data were assessed and analysed as described in the Cochrane Handbook. If data in trials were not fully reported, clarification was sought from the study authors. For categorical outcomes, the numbers reporting an outcome were related to the numbers at risk in each group to derive a risk ratio (RR). For continuous outcomes, means and standard deviations were used to derive mean differences (MD). We included seven trials involving a total of 349 participants, 217 of whom completed the studies. Three were cross-over and four were parallel-group randomised controlled trials (RCTs). Of these, two trials were added for this update (one parallel-group RCT with 40 participants and one cross-over RCT with 67 participants). Analyses of three cross-over trials yielded suboptimal results because they were based on between-group differences rather than individual participants' differences for sequential interventions. Two parallel-group trials had limited clinical value: one combined results for suprapubic and urethral catheters and the other provided data for only four participants. Only one trial was free of significant methodological limitations, but there were difficulties with recruitment and maintaining participants in this study.The included studies reported data on six of the nine primary and secondary outcome measures. None of the trials addressed: number of catheters used, washout acceptability measures (including patient satisfaction, patient discomfort, pain and ease of use), or health status/measures of psychological health; very limited data were collected for health economic outcomes. Trials assessed only three of the eight intervention comparisons identified. Two trials reported in more than one comparison group.Four trials compared washout (either saline or acidic solution) with no washout. We are uncertain if washout solutions (saline or acidic), compared to no washout solutions, has an important effect on the rate of symptomatic urinary tract infection or length of time each catheter was in situ because the results are imprecise.Four trials compared different types of washout solution; saline versus acidic solutions (2 trials); saline versus acidic solution versus antibiotic solution (1 trial); saline versus antimicrobial solution (1 trial). We are uncertain if type of washout solution has an important effect on the rate of symptomatic urinary tract infection or length of time each catheter was in situ because the results are imprecise.One trial compared different compositions of acidic solution (stronger versus weaker solution). We are uncertain if different compositions of acidic solutions has an important effect on the rate of symptomatic urinary tract infection or length of time each catheter was in situ because only 14 participants (of 25 who were recruited) completed this 12 week, three arm trial.Four studies reported on possible harmful effects of washout use, such as blood in the washout solution, changes in blood pressure and bladder spasms.There were very few small trials that met the review inclusion criteria. The high risk of bias of the included studies resulted in the evidence being graded as low or very low quality. Data from seven trials that compared different washout policies were limited, and generally, of poor methodological quality or were poorly reported. The evidence was not adequate to conclude if washouts were beneficial or harmful. Further rigorous, high quality trials that are adequately powered to detect benefits from washout being performed as opposed to no washout are needed. Trials comparing different washout solutions, washout volumes, and frequencies or timings are also needed.


Complete artifact removal for EEG recorded during continuous fMRI using independent component analysis.
The simultaneous recording of EEG and fMRI is a promising method for combining the electrophysiological and hemodynamic information on cerebral dynamics. However, EEG recordings performed in the MRI scanner are contaminated by imaging, ballistocardiographic (BCG) and ocular artifacts. A number of processing techniques for the cancellation of fMRI environment disturbances exist: the most popular is averaged artifact subtraction (AAS), which performs well for the imaging artifact, but has some limitations in removing the BCG artifact, due to the variability in cardiac wave duration and shape; furthermore, no processing method to attenuate ocular artifact is currently used in EEG/fMRI, and contaminated epochs are simply rejected before signal analysis. In this work, we present a comprehensive method based on independent component analysis (ICA) for simultaneously removing BCG and ocular artifacts from the EEG recordings, as well as residual MRI contamination left by AAS. The ICA method has been tested on event-related potentials (ERPs) obtained from a visual oddball paradigm: it is very effective in attenuating artifacts in order to reconstruct clear brain signals from EEG acquired in the MRI scanner. It performs significantly better than the AAS method in removing the BCG artifact. Furthermore, since ocular artifacts can be completely suppressed, a larger number of trials is available for analysis. A comparison of ERPs inside the magnetic environment with those obtained out of the MRI scanner confirms that no systematic bias in the ERP waveform is produced by the ICA method.


Involvement of peroxisome proliferator-activated receptor gamma in gonadal steroidogenesis and steroidogenic acute regulatory protein expression.
Peroxisome proliferator-activated receptor (PPAR) gamma belongs to the PPAR family of nuclear transcription factors whose ligands, such as eicosanoids, fatty acids and prostaglandins, are known to affect gonadal function. Although several of these enhance the expression of the steroidogenic acute regulatory protein (STAR) and steroid production, the role of PPARgamma in regulating STAR-mediated steroidogenesis remains unclear. In the present study, we used ciglitazone to selectively activate PPARgamma and examine its role in STAR-mediated steroidogenesis in immortalised KK1 mouse granulosa cells and MA-10 mouse Leydig tumour cells. Cotreatment with both dibutyryl-cAMP and ciglitazone revealed a dose-dependent, significant increase in progesterone synthesis, Star promoter activity, Star mRNA and STAR protein relative to either compound alone. The overexpression of PPARgamma further increased Star-promoter activity. The ciglitazone-induced activity of the Star-promoter appears to be mediated through the cAMP-response element half-sites located within its proximal 151 bp. Combined treatment with ciglitazone and dibutyryl-cAMP significantly increased the expression and activity of transcriptional pathways impacted by the activator protein-1 family member c-JUN. The present study demonstrates that ciglitazone and dibutyryl-cAMP synergistically enhance STAR expression in MA-10 and KK1 cells. Ciglitazone-activated PPARgamma appears to increase the sensitivity of Leydig and granulosa cells to cAMP stimulation, possibly via upregulation of c-JUN expression.


Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity.
Nitric oxide (NO), essential for maintaining vascular tone, is produced from arginine by nitric oxide synthase. Plasma arginine levels are low in sickle cell anemia, and it is reported here that low plasma arginine is also found in our sickle transgenic mouse model that expresses human alpha, human beta(S), and human beta(S-Antilles) and is homozygous for the mouse beta(major) deletion (S+S-Antilles). S+S-Antilles mice were supplemented with a 4-fold increase in arginine that was maintained for several months. Mean corpuscular hemoglobin concentration (MCHC) decreased and the percent high-density red cells was reduced. Deoxy K(+) efflux is characteristic of red cells in sickle cell disease and contributes to the disease process by increasing the MCHC and rendering the cells more susceptible to polymer formation. This flux versus the room air flux was reduced in S+S-Antilles red cells from an average value of 1.6 +/- 0.3 mmol per liter of red cells x minute (FU) in nonsupplemented mice to 0.9 +/- 0.3 FU (n = 4, P < .02, paired t test) in supplemented mice. In room air, V(max) of the Ca(++)-activated K(+) channel (Gardos) was reduced from 4.1 +/- 0.6 FU (off diet) to 2.6 +/- 0.4 FU (n = 7 and 8, P < .04, t test) in arginine-supplemented mice versus clotrimazole. In conclusion, the major mechanism by which arginine supplementation reduces red cell density (MCHC) in S+S-Antilles mice is by inhibiting the Ca(++)-activated K(+) channel.


The effects of bathing in hot springs on the absorption of green tea catechin: a pilot study.
Japan is a major tea producing country, and green tea is known for its health benefits which are believed to be due to catechins. However, difficulties in maintaining an adequate amount of catechins in the blood have been reported. Another important health-promoting activity among the Japanese is bathing in hot springs. This pilot study examined whether the combined effects of green tea consumption and hot spring bathing improved absorption of green tea catechins. The study, with a comparative within-subject design involving two different intervention trials--green tea consumption with hot spring bathing and only green tea consumption--was conducted on 2 separate days. Plasma levels of catechin; (-)-epigallocatechin-3-O-gallate (EGCG) were analyzed from four volunteers. Plasma EGCG concentration was found to be higher for the combined trial of green tea consumption and hot spring bathing.


Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers.
In recent years, the molecular underpinnings of the long-observed resemblance between neoplastic and immature tissue have begun to emerge. Genome-wide transcriptional profiling has revealed similar gene expression signatures in several tumor types and early developmental stages of their tissue of origin. However, it remains unclear whether such a relationship is a universal feature of malignancy, whether heterogeneities exist in the developmental component of different tumor types and to which degree the resemblance between cancer and development is a tissue-specific phenomenon. We defined a developmental landscape by summarizing the main features of ten developmental time courses and projected gene expression from a variety of human tumor types onto this landscape. This comparison demonstrates a clear imprint of developmental gene expression in a wide range of tumors and with respect to different, even non-cognate developmental backgrounds. Our analysis reveals three classes of cancers with developmentally distinct transcriptional patterns. We characterize the biological processes dominating these classes and validate the class distinction with respect to a new time series of murine embryonic lung development. Finally, we identify a set of genes that are upregulated in most cancers and we show that this signature is active in early development. This systematic and quantitative overview of the relationship between the neoplastic and developmental transcriptome spanning dozens of tissues provides a reliable outline of global trends in cancer gene expression, reveals potentially clinically relevant differences in the gene expression of different cancer types and represents a reference framework for interpretation of smaller-scale functional studies.


Biomechanical and histologic evaluation of non-washed resorbable blasting media and alumina-blasted/acid-etched surfaces.
To compare the biomechanical fixation and histomorphometric parameters between two implant surfaces: non-washed resorbable blasting media (NWRBM) and alumina-blasted/acid-etched (AB/AE), in a dog model. The surface topography was assessed by scanning electron microscopy, optical interferometry and chemistry by X-ray photoelectron spectroscopy (XPS). Six beagle dogs of ∼1.5 years of age were utilized and each animal received one implant of each surface per limb (distal radii sites). After a healing period of 3 weeks, the animals were euthanized and half of the implants were biomechanically tested (removal torque) and the other half was referred to nondecalcified histology processing. Histomorphometric analysis considered bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). Following data normality check with the Kolmogorov-Smirnov test, statistical analysis was performed by paired t-tests at 95% level of significance. Surface roughness parameters S(a) (average surface roughness) and S(q) (mean root square of the surface) were significantly lower for the NWRBM compared with AB/AE. The XPS spectra revealed the presence of Ca and P in the NWRBM. While no significant differences were observed for both BIC and BAFO parameters (P>0.35 and P>0.11, respectively), a significantly higher level of torque was observed for the NWRBM group (P=0.01). Bone morphology was similar between groups, which presented newly formed woven bone in proximity with the implant surfaces. A significant increase in early biomechanical fixation was observed for implants presenting the NWRBM surface.


High normotension is associated with future metabolic syndrome but not cardiovascular disease: A 10-year longitudinal study.
Hypertension and prehypertension can increase the risk of developing cardiovascular disease (CVD) and diabetes. However, whether the harmful effects of high blood pressure (BP) are also seen with high normotension remains unknown. This 10-year longitudinal follow-up study aimed to investigate the relationships among normal-range BP, metabolic syndrome (MetS), and CVD.A total of 9133 nonmedicated normotensive participants, 4634 males and 4499 females, aged 60 years or older were enrolled in a standard health examination program at 2 academic hospitals and a health screening center in Taiwan. The study subjects were divided into 3 groups according to their BP. The systolic BP (SBP) ranges of groups 1, 2, and 3 were 91 to 100, 101 to 110, and 111 to 119 mmHg, whereas the diastolic BP (DBP) ranges of groups 1, 2, and 3 were 51 to 60, 61 to 70, and 71 to 79 mmHg, respectively.In the SBP3 group, both sexes had a higher odds ratio (OR) for having MetS or abnormal MetS components, except for triglycerides. Females in the DBP3 group had a higher OR for having MetS at baseline. After the follow-up period, the SBP3 group had a significantly higher hazard ratio (HR) for developing MetS. Males in the DBP3 group and females in the DBP2 and DBP3 groups had a significantly higher HR for developing MetS. Neither the SBP3 group nor the DBP3 group had a higher HR for developing nonfatal CVD. In the Kaplan-Meier analysis, SBP and DBP in both sexes showed statistical significance as predictors of MetS, but not of nonfatal CVD.High normotensive elderly individuals have an elevated risk of developing MetS at baseline and within 10 years of follow-up, but they are not at increased risk of CVD. Preventive interventions, such as life-style modification, should be offered early even to the apparently healthy elderly.


RING box protein-1 gene involved in flagellar disassembly of Dunaliella salina.
Ring box protein-1 (RBX1), also called Regulator of Cullins-1 (ROC1), is a key component of SCF (Skp-1, cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting protein substrates for degradation. Although RBX1 plays an important role in ubiquitination machinery of both prokaryotes and eukaryotes, studies on the RBX1 have not been involved in the unicellular green alga Dunaliella salina. In this study, a full-length RBX1 cDNA fragment of 817 bp was cloned using rapid amplification of cDNA end (RACE) technique. The full-length sequence contained an open reading frame of 411 bp encoding 136 amino acids. The predicted protein had a molecular molar mass of 14.8 kDa and pI of 5.9 with a high degree of homology to RBX1 from Chlamydomonas reinhardtii (92 %). Recombinant RBX1 was expressed in Escherichia coli BL21 and was purified and characterized. The apparent molecular mass of the recombinant protein was approximately 17 kDa, and the optimal induction time and concentration were 3 h and 0.1 mmol/L IPTG, respectively. The predicted 3D structures of RBX1 proteins contained RING-H2 finger domain including "Cys59-X2-Cys62-X30-Cys93-X1-His95-X2-His98-X2-Cys101-X10-Cys112-X2-Cys115." The expression of RBX1 protein was increased by 132 % during flagellar disassembly and decreased by 76 % during flagellar assembly of D. salina. The expression of RBX1 mRNA had a similar tendency with the expression of RBX1 protein. The results indicated that RBX1 responded to flagellar disassembly of D. salina.


Operative correction of adolescent idiopathic scoliosis in male patients. A radiographic and functional outcome comparison with female patients.
The outcomes following surgical treatment of adolescent idiopathic scoliosis have traditionally been assessed on the basis of radiographic parameters and, more recently, functional outcome measures. However, we know of no published studies in which radiographic and functional outcomes following surgery were compared between male and female patients. Fifty-two male patients who had had surgery for adolescent idiopathic scoliosis were compared retrospectively with two groups of female patients: a random sample of 130 female patients who had had surgical treatment for adolescent idiopathic scoliosis during the same time period and a subgroup of fifty-two of these female patients who had been matched to the male patients with regard to curve type and magnitude. Radiographic parameters were compared between the male and female patients, and the Scoliosis Research Society outcome questionnaire was used to compare functional results between the male patients and the matched female group. Compared with the random sample of female patients, the male patients were older at the time of presentation (average [and standard deviation], 13.9 +/- 1.9 compared with 12.8 +/- 1.4 years) and at the time of surgery (average, 15.9 +/- 2.0 compared with 14.2 +/- 1.4 years) (p < 0.05). The male and female patients presented with primary coronal curves of similar magnitudes (average, 48 degrees +/- 19 degrees compared with 47 degrees +/- 13 degrees ), but the male patients had larger curves at the time of surgery (average, 62 degrees +/- 11 degrees compared with 56 degrees +/- 10 degrees ) with greater coronal plane imbalance. Compared with the subset of female patients matched for curve type and magnitude, the male patients had, on average, a longer surgical time (263 +/- 61 compared with 202 +/- 40 minutes), greater intraoperative blood loss (1148 +/- 660 compared with 944 +/- 408 mL), and less curve correction in the coronal plane (from 62 degrees +/- 11 degrees to 31 degrees +/- 11 degrees compared with from 59 degrees +/- 10 degrees to 23 degrees +/- 9 degrees ) (p < 0.05). The loss of coronal plane correction, the final coronal balance, all measured sagittal plane parameters, and the prevalence of complications were the same in these two groups. With regard to functional outcome, the scores were similar with the exception that the male patients had lower scores in the category of "function from back condition" when compared with the matched female patients (3.8 +/- 0.2 compared with 4.3 +/- 0.3 points) (p < 0.05). Adolescent idiopathic scoliosis is identified at a later age in male patients than in female patients with similar curve types. The curve magnitudes in the male patients are greater at the time of surgery. When surgeons are planning operative correction of adolescent idiopathic scoliosis in male patients, they should expect longer operative time, greater blood loss, and less coronal plane correction of the primary curve. However, balance in the coronal and sagittal planes should be achieved and complication rates and functional outcomes can be expected to be similar to those in female patients.


Iron overload among a psychiatric outpatient population.
Iron overload has been suggested to be an unrecognized cause of psychiatric morbidity. This study sought to estimate the prevalence of iron overload in a large outpatient psychiatric clinic. A retrospective review of screening blood chemistries was conducted on 661 active outpatients at a large, university outpatient psychiatric clinic to identify elevated iron status results (plasma iron, percentage of iron saturation) suggestive of iron overload. Patients with positive profiles were asked to undergo a subsequent blood chemistry to confirm positive results (plasma iron, percentage of iron saturation, plus plasma ferritin). Patients with positive repeated iron chemistry results were considered likely candidates for iron overload. Twenty-one patients (3.2%) were identified as meeting one of the criteria suggestive of iron overload on initial screening reports. Thirty-one percent of those who underwent subsequent, confirmatory testing (5/16) continued to meet one of the criteria. On the basis of these results, we estimated a 1% (3.2 x 0.31) prevalence rate of likely candidates for iron overload. A review of these patients' charts indicated that they carried an unexpectedly high rate of bipolar affective disorder (80%) as a diagnosis and were, without exception, atypical in that they were resistant to conventional psychiatric treatment and lacked a family history for this disorder. The prevalence of positive iron overload profiles on a routine blood chemistry was similar to the prevalence of positive thyroid abnormalities based on TSH results in this population. Blood chemistry profiles suggestive of iron overload may be associated with a small portion of treatment-resistant psychiatric patients. Routine screening for iron abnormalities, especially in treatment-resistant patients, should be considered. Further studies are required to determine the causal association, if any, between iron excess and primary psychiatric illnesses.


Global Sequestration Potential of Increased Organic Carbon in Cropland Soils.
The role of soil organic carbon in global carbon cycles is receiving increasing attention both as a potentially large and uncertain source of CO2 emissions in response to predicted global temperature rises, and as a natural sink for carbon able to reduce atmospheric CO2. There is general agreement that the technical potential for sequestration of carbon in soil is significant, and some consensus on the magnitude of that potential. Croplands worldwide could sequester between 0.90 and 1.85 Pg C/yr, i.e. 26-53% of the target of the "4p1000 Initiative: Soils for Food Security and Climate". The importance of intensively cultivated regions such as North America, Europe, India and intensively cultivated areas in Africa, such as Ethiopia, is highlighted. Soil carbon sequestration and the conservation of existing soil carbon stocks, given its multiple benefits including improved food production, is an important mitigation pathway to achieve the less than 2 °C global target of the Paris Climate Agreement.


Evaluation of heat shock protein 70 as a biomarker of environmental stress in Fucus serratus and Lemna minor.
Heat shock proteins (Hsps) are known to be induced in response to short-term stress. The present study aimed to evaluate the potential of Hsp70 as a biomarker of stress produced by increased temperature, osmotic pressure, and exposure to cadmium and sodium chloride in marine macroalgae and fresh water plant species. An indirect competitive enzyme-linked immunosorbent assay (IC-ELISA) was developed with a working range of 0.025-10 microg ml(-1) using a monoclonal antibody raised against purified Hsp70 of Phaseolus aureus (mung bean). Fucus serratus (toothed wrack), Chondrus crispus (Stackhouse or Carrageen moss), Ulva lactuca (sea lettuce) and Lemna minor (common duckweed) sample extracts were stressed for up to 24 h and then tested in the IC-ELISA. The presence of Hsp70 and cross-reactivity of the monoclonal antibody was confirmed by Western blot. The heat shock response was confirmed in each species using a 2-h 42 degrees C treatment. Following heat shock, Hsp70 concentrations increased to a peak at 2 h (F. serratus) or 4 h (L. minor), after which concentrations decreased. Osmotic and cadmium stresses also resulted in elevated Hsp70 concentrations in samples of F. serratus and L. minor when compared with unstressed controls. In both, osmotic and metal stress, the production of Hsp70 increased to a maximum and subsequently decreased as the stressor levels increased. Results suggest that Hsp70 IC-ELISA could potentially be applied to the detection of stress in these aquatic species, although it would probably be most effective when used in conjunction with other measurements to provide a stressor-specific biomarker profile or fingerprint.


Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials.
Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m2, or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria. We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3-4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13-1·70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R2 0·47, 95% BCI 0·02-0·96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R2 0·72, 0·05-0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. US National Kidney Foundation.


A High Amount of Local Adipose Tissue Is Associated With High Cortical Porosity and Low Bone Material Strength in Older Women.
Obesity is associated with increased risk of fractures, especially at skeletal sites with a large proportion of cortical bone, such as the humerus and ankle. Obesity increases fracture risk independently of BMD, indicating that increased adipose tissue could have negative effects on bone quality. Microindentation assesses bone material strength index (BMSi) in vivo in humans. The aim of this study was to investigate if different depots of adipose tissue were associated with BMSi and cortical bone microstructure in a population based group of 202 women, 78.2 ± 1.1 (mean ± SD) years old. Bone parameters and subcutaneous (s.c.) fat were measured at the tibia with an XtremeCT device. BMSi was assessed using the OsteoProbe device, and based on at least 11 valid reference point indentations at the mid-tibia. Body composition was measured with dual X-ray absorptiometry. BMSi was inversely correlated to body mass index (BMI) (r = -0.17, p = 0.01), whole body fat mass (r = -0.16,p = 0.02), and, in particular, to tibia s.c. fat (r = -0.33, p < 0.001). Tibia s.c. fat was also correlated to cortical porosity (Ct.Po; r = 0.19, p = 0.01) and cortical volumetric BMD (Ct.vBMD; r = -0.23, p = 0.001). Using linear regression analyses, tibia s.c. fat was found to be independent of covariates (age, height, log weight, bisphosphonates or glucocorticoid use, smoking, calcium intake, walking speed, and BMSi operator) and associated with BMSi (β = -0.34,p < 0.001), Ct.Po (β = 0.18, p = 0.01), and Ct.vBMD (β = -0.32, p < 0.001). BMSi was independent of covariates associated with cortical porosity (β = -0.14, p = 0.04) and cortical volumetric BMD (β = 0.21, p = 0.02) at the distal tibia, but these bone parameters could only explain 3.3% and 5.1% of the variation in BMSi, respectively. In conclusion, fat mass was independently and inversely associated with BMSi and Ct.vBMD, but positively associated with Ct.Po, indicating a possible adverse effect of adipose tissue on bone quality and bone microstructure. Local s.c. fat in tibia was most strongly associated with these bone traits, suggesting a local or paracrine, rather than systemic, negative effect of fat on bone.


N-Difluoromethyl-triazole as a constrained scaffold in peptidomimetics.
The N-difluoromethyl triazolo-β-aza-ε-amino acid present in the core of peptides led to constrained conformations due to CH-F and NH-F interactions. Pseudotetrapeptides were obtained in excellent yields directly by click chemistry between azidodifluoroacetamides and alkynes, both linked to an amino acid. This work demonstrates that the N-difluoromethyltriazole scaffold can induce extended structures to β-strand mimics.


Bioinspired remora adhesive disc offers insight into evolution.
Remoras are a family of fishes that can attach to other swimming organisms via an adhesive disc evolved from dorsal fin elements. However, the factors driving the evolution of remora disc morphology are poorly understood. It is not possible to link selective pressure for attachment to a specific host surface because all known hosts evolved before remoras themselves. Fortunately, the fundamental physics of suction and friction are mechanically conserved. Therefore, a morphologically relevant bioinspired model can be used to examine performance of hypothetical evolutionary intermediates. Using a bioinspired remora disc, we experimentally investigated the performance of increased lamellar number on shear adhesion. Herein, we translated fundamental biological principles into engineering design rules and show that a passive model system can autonomously achieve adhesive forces measured in live remoras in any environment. Our experimental results show that an increase in lamellar number resulted in an increase in shear adhesive performance, supporting the phylogenetic trend observed in extant remoras. The greatest pull-off forces measured for our model were on surface roughness on the order of shark skin and exceeded those measured for live remoras attached to shark skin by almost 60%. Overall, relative to fossil remoras and their closest ancestor, extant remoras exhibit a morphology indicative of selection for enhanced shear adhesive performance.


The Use of the Lateral Tibial Line to Assess Ankle Alignment: A Preliminary Investigation.
Although the medial clear space (MCS) is commonly used to assess talar alignment and ankle stability, its measurement is variable with multiple reported normal values. We have observed that the lateral tibial shaft is a reliable landmark to assess talar alignment. The objective of the current investigation was to determine the normal relationship of the lateral tibia to the superolateral talus using a tangent drawn inferiorly from the lateral tibial shaft, which we refer to as the "lateral tibial line" (LTL). The relationship of the LTL to the superolateral talus was assessed by three reviewers on 99 standing ankle mortise radiographs in uninjured patients. This relationship was quantified by measuring the distance (in millimeters) between the LTL and the superolateral talus. In addition, the interobserver reliability of the LTL measurement was recorded and compared with that of the MCS. The median value for the distance between the superolateral talus and LTL was -0.50 mm with an interquartile range of -1.4 to 0.0 mm. The LTL was within 1 mm of the lateral talus in 176 of 297 reviewer measurements (59.3%). Moreover, it was either lateral to or at most 1 mm medial to the lateral talus in 90.9% of cases. The LTL measurement also demonstrated good interobserver reliability (0.764, 95% confidence interval, 0.670 to 0.834), similar to the measurement of MCS (0.742, 95% confidence interval, 0.539 to 0.846). The relationship between the LTL and superolateral talus is easily measured with good reliability for assessing the anatomic relationship of the tibia and talus. The LTL uncommonly fell more than 1 mm medial to the superolateral talus, as might be seen with displaced ankle fractures. These findings will hopefully serve as a basis for future studies evaluating its role in assessing lateral displacement and stability of isolated fibula fractures. Level III, retrospective review.


Batch distillation employing cyclic rectification and stripping operations.
Several strategies have been proposed to increase the operating efficiency of batch distillation. In this study, conventional batch rectification and inverted batch stripping are used cyclically to promote high product flow rates for a binary fractionation. Process controls are implemented to maintain constant product purity specifications by varying the slope of the operating line. While rectifying, the light component is removed as distillate, concentrating the heavy component in the reboiler. As a result, the distillate rate decreases with time. The column is then changed from rectification to stripping modes, and the heavy component is removed as bottoms product, concentrating the light component in the distillate drum. This causes the bottoms rate to diminish with time, and the column is once again converted back to rectifying mode. Cyclic operation, transitioning from batch rectifying to stripping back to rectifying, continues until all of the initial charge is fractionated or is combined with a new charge. The fractionation of ethanol and 1-propanol using the proposed operating strategy is shown to provide several advantages including energy and time savings when compared to conventional batch or inverted batch distillation alone.