Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.
In patients with schizophrenia in a psychotic episode, intra-striatal intrinsic connectivity is increased in the putamen but not ventral striatum. Furthermore, multimodal changes have been observed in the anterior insula that interact extensively with the putamen. We hypothesised that during psychosis, putamen extra-striatal functional connectivity is altered with both the anterior insula and areas normally connected with the ventral striatum (i.e. altered functional connectivity distinctiveness of putamen and ventral striatum). We acquired resting-state functional magnetic resonance images from 21 patients with schizophrenia in a psychotic episode and 42 controls. Patients had decreased functional connectivity: the putamen with right anterior insula and dorsal prefrontal cortex, the ventral striatum with left anterior insula. Decreased functional connectivity between putamen and right anterior insula was specifically associated with patients' hallucinations. Functional connectivity distinctiveness was impaired only for the putamen. Results indicate aberrant extra-striatal connectivity during psychosis and a relationship between reduced putamen-right anterior insula connectivity and hallucinations. Data suggest that altered intrinsic connectivity links striatal and insular pathophysiology in psychosis.


Does Abortion Liberalisation Accelerate Fertility Decline? A Worldwide Time-Series Analysis.
Since WWII, the two most important global trends in family planning have been fertility decline and abortion liberalisation. But are they related? Specifically: Does abortion liberalisation affect changes in fertility rates? The demographic literature has yet to answer this important question and instead offers two opposing predictions. Some studies argue that liberalisation of this medical procedure reduces fertility rates. By contrast, others note that such legal reforms may merely have an average, negligible effect on fertility levels. We adjudicate between the two approaches by conducting, in our view, the most comprehensive global, quantitative analysis of the relationship between those legal reforms and changing fertility rates. The analysis relies on two-way fixed models and three different indicators of abortion policy liberalism created by independent research teams to estimate the relationship between abortion liberalisation and total fertility changes. The data cover 185 independent states between 1970 and 2019. Fertility rates are significantly related to average public education levels and alternative contraceptive use. Using multiple model specifications, however, abortion reforms do not have a robust association with the outcome. Replication materials for this article can be found at https://figshare.com/s/5336a4422f47c8c39228 .


Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600 -Wild-Type Colorectal Cancer.
Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600 -wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600 -wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies. IMPLICATIONS: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600 -wild-type tumors is warranted.


The effect of midazolam premedication on mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures.
To assess the effect of IV midazolam premedication on recovery of cognitive function, 90 geriatric patients (aged 65-81 yr) undergoing brief transurethral procedures were enrolled into this prospective, placebo-controlled, double-blinded study. In all cases, a standard general anesthetic was administered. Thirty minutes before operating room transfer, patients in Group 0.5 mg, Group 2 mg, and Group S received 0.5 mg of midazolam, 2 mg of midazolam, or an equal volume of saline, respectively. Before study-drug administration (baseline), at 15 min thereafter, as well as on arrival in the postanesthesia care unit (PACU), and at 60 min and 120 min, postoperatively, we administered a digit-symbol substitution test, a mini-mental test, a shape-sorter test, and a patient-generated 100-mm visual analog score (0 = minimal and 100 = maximal) for anxiety, sleepiness, and coordination. A 4-point scale was used to assess the degree of patient sedation at 7, 15, and 30 min after study-drug administration. Using a modified Aldrete scoring system, PACU discharge was determined by the PACU staff. Patient anxiety, sleepiness, and coordination scores at baseline and at 15 min after study-drug administration were similar. When compared with saline, midazolam was associated with a significantly (P < 0.05) higher incidence of "deep" sedation. In Group 2 mg, the incidence of a low preoperative Spo2 (<94%) was significantly (P < 0.05) higher when compared with Group S. Emergence, extubation, and orientation times, as well as time to follow commands were unaffected by midazolam premedication. Postoperatively, the digit-symbol substitution test, mini-mental test, and shape-sorter test were similar among the groups. However, time to PACU discharge was significantly (P = 0.03) longer in the two midazolam treatment groups (41 +/-25 min, 60 +/- 32 min, 53 +/- 39 min for Groups S, 0.5 mg, and 2 mg, respectively). Finally, patient satisfaction was unaffected by the randomization schedule. IV premedicant midazolam 0.5 mg or 2 mg does not adversely affect mental and psychomotor recovery in geriatric patients undergoing brief surgical procedures. However, midazolam administration significantly prolonged postanesthesia care unit discharge time. Finally, during the preoperative period, midazolam increases the incidence of a Spo2 <94% in a dose-dependent manner.


Association study between HLA-A, -B, -C, -DRB1 alleles and Psoriatic arthritis in southern France.
Psoriatic arthritis (PsA) is a type of inflammatory arthritis associated with psoriasis. HLA association studies performed in northern Europe, comparing patients with control populations, have shown that the highest risk for PsA is carried by HLA-C*06, HLA-B*57 and HLA-B*27 alleles. This retrospective association study compared HLA-A, -B, -C, and -DR alleles of 500 patients from southern France, who fulfilled the CASPAR criteria for Psoriatic Arthritis (PsA), with 2346 controls from healthy blood donors, using the chi-square test. We classified PsA patients into three different subgroups according to disease: purely axial, purely peripheral and combined axial and peripheral. The 'axial' subgroup was associated with HLA-B*27 (OR = 16.3, p = 2.7 × 10-28) and its haplotypes: HLA- B*27-C*01 (OR = 12.4, p = 1.7 × 10-12) and HLA-B*27-C*02 (OR = 8.7, p = 10 × 10-9). The 'axial and peripheral' and the 'peripheral' subgroups were associated with HLA-C*06 (respectively OR = 1.5, p = 3.6 × 10-10 and OR = 2.4, p = 3.6 × 10-12) and its haplotypes HLA-C*06-B*13 (respectively OR = 2.4, p = 1.2 × 10-6 and OR = 2.8, p = 6.4 × 10-11). This association study on a southern French PsA cohort identifies HLA-C*06 as a marker for peripheral PsA and HLA-B*27 as a marker for purely axial PsA.


Ontogeny of serotonin and serotonin2A receptors in rat auditory cortex.
Maturation of the mammalian cerebral cortex is, in part, dependent upon multiple coordinated afferent neurotransmitter systems and receptor-mediated cellular linkages during early postnatal development. Given that serotonin (5-HT) is one such system, the present study was designed to specifically evaluate 5-HT tissue content as well as 5-HT(2A) receptor protein levels within the developing auditory cortex (AC). Using high performance liquid chromatography (HPLC), 5-HT and the metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was measured in isolated AC, which demonstrated a developmental dynamic, reaching young adult levels early during the second week of postnatal development. Radioligand binding of 5-HT(2A) receptors with the 5-HT(2A/2C) receptor agonist, (125)I-DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; in the presence of SB206553, a selective 5-HT(2C) receptor antagonist, also demonstrated a developmental trend, whereby receptor protein levels reached young adult levels at the end of the first postnatal week (P8), significantly increased at P10 and at P17, and decreased back to levels not significantly different from P8 thereafter. Immunocytochemical labeling of 5-HT(2A) receptors and confocal microscopy revealed that 5-HT(2A) receptors are largely localized on layer II/III pyramidal cell bodies and apical dendrites within AC. When considered together, the results of the present study suggest that 5-HT, likely through 5-HT(2A) receptors, may play an important role in early postnatal AC development.


Lung function in mitral stenosis.
The aim of this study was to look to for a relationship between pulmonary artery pressure (PAP), left atrial pressure (LAP), mitral valve area (MVA) and transmitral gradient (Gr) on the one hand and the spirometric data on the other, in cases of mitral stenosis. The spirometry values measured were forced vital capacity (FVC), forced expiratory volume in one second and as percent of FVC (FEV1, FEV1/FVC%), forced expiratory flow between 25% to 75% of FVC (FEF 25-75%), at 50% of FVC (FEF 50%) 75% of FVC (FEF 75%) and peak expiratory flow rate (PEFR). The PAP, LAP, MVA and Gr were measured at echocardiography and cardiac catheterisation. Analysis of results was done of 60 patients in four groups divided on basis of mean PAP: Group 1 with least and group 4 with highest mean PAP. FVC values were reduced in direct proportion to PAP, LAP, MVA and Gr in three out of four groups. FEV1% as a percent of predicted value showed uniform reduction in all the groups, PEFR was moderately affected in group 1 and most severely in group 4. Values of FEV1/FVC% were within normal range in all the groups. FEF 25-75%, and FEF 50% showed serial reduction in values in keeping with the elevation of the PAP. FEF 75% was also moderately affected in group 1 and most severely in group 4. We found that a moderate restrictive defect and a small airway defect which is found in cases of mitral stenosis, directly correlates to the PAP, LAP, MVA and Gr. There was no significant involvement of the larger airways.


Robotic Surgery Is Less Physically Demanding Than Laparoscopic Surgery: Paired Cross Sectional Study.
To study musculoskeletal workload in experienced surgeons during laparoscopic surgery (LS) compared with robotic assisted laparoscopy (RALS). 70-90% of surgeons who regularly perform LS report musculoskeletal symptoms, mainly in neck and shoulders. Data regarding the potential ergonomic benefits of RALS in a clinical setting is very limited. Twelve surgeons with advanced experience in both LS and RALS each performed 2 hysterectomies on the same day. LS was performed standing, RALS sitting, the latter allowing forearm and head support. Bipolar surface electromyogram (EMG) was recorded from several muscles and was expressed relative to EMG during maximum contractions (%EMGmax). Gaps per minute plus static (p0.1), mean (p0.5), and peak (p0.9) muscle activation were calculated. Perceived exertion was rated before and just after each surgery. Neck muscle activity (p0.1 4.7 vs. 3.0%EMGmax, p0.5 7.4 vs. 5.3%EMGmax, p0.9 11.6 vs. 8.2%EMGmax, all P < 0.05) and static shoulder muscle activity (p0.1 5.7 vs. 2.8%EMGmax, P < 0.05) were higher for LS than for RALS. Both a higher level of gaps during RALS and a lower rating of perceived exertion, also for the legs, after RALS supported these observations. However, low back muscle activity was higher for RALS. RALS is significantly less physically demanding than LS, and also feels less strenuous for the surgeons. However, for both types of surgeries, there still is room for improvement of working conditions. To further optimize these, we suggest a scheme to regularly observe and advise the surgeons.


Hemosuccus pancreaticus--a rare cause of gastrointestinal bleeding: diagnosis and interventional radiological therapy.
Hemorrhage from the pancreatic duct, i.e. hemosuccus pancreaticus (HP), is a rare cause of gastrointestinal bleeding. Pancreatic hemosuccus is usually due to the rupture of an aneurysm of a visceral artery, most likely the splenic artery, in chronic pancreatitis. Other causes of HP are rare. We present a case of HP in a female patient with no history but with positive findings of chronic calcifying pancreatitis upon ultrasonographic investigation, computed tomography scan, and endoscopic retrograde cholangiopancreatography. With detectable fresh blood in the descending duodenum, angiography of the celiac artery revealed an aneurysm of the splenic artery as the suspected cause of intermittent bleeding from the pancreatic duct. The treatment is traditionally surgical or by interventional radiological means. This is the first case described in the literature in which interventional radiological therapy involved implantation of an uncoated metal Palmaz stent in the splenic artery. In the follow-up of 18 months no relapse of HP was observed.


The state and the development of an information society: Greek policy and experience.
The paper looks into the dynamics of information society policy and its implementation in the Greek context. It argues that information society development is a contested process, influenced by pre-existing state, economy and society relations. Based on this, it looks into the different aspects of the idiosyncratic path which the evolution of the Greek information society has followed, particularly after 2000. Using Bob Jessop's strategic-relational approach (SRA) to the state as an analytical framework and drawing on a number of in-depth interviews with relevant political actors, it provides insights into policy implementation by examining: the public management of information technology projects, how such projects were received in bureaucratic structures and practices, as well as the relationship between the state and the information and communication technology (ICT) sector in public procurement processes. The emphasis is on the period 2000-2008, during which a major operational programme on the information society in Greece was put into effect. The paper also touches upon the post-2008 experience, suggesting that information society developments might include dynamics operating independently and even in contradiction to the state agenda.


Global variation of COVID-19 mortality rates in the initial phase.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation in over 200 countries. Italy, Spain, and the United States (US) were most severely affected by the first wave of the pandemic. The reasons why some countries were more strongly affected than others remain unknown. We identified the most-affected and less-affected countries and states and explored environmental, host, and infrastructure risk factors that may explain differences in the SARS-CoV-2 mortality burden. We identified the top 10 countries/US states with the highest deaths per population until May 2020. For each of these 10 case countries/states, we identified 6 control countries/states with a similar population size and at least 3 times fewer deaths per population. We extracted data for 30 risk factors from publicly available, trusted sources. We compared case and control countries/states using the non-parametric Wilcoxon rank-sum test, and conducted a secondary cluster analysis to explore the relationship between the number of cases per population and the number of deaths per population using a scalable EM (expectation-maximization) clustering algorithm. Statistically significant differences were found in 16 of 30 investigated risk factors, the most important of which were temperature, neonatal and under-5 mortality rates, the percentage of under-5 deaths due to acute respiratory infections (ARIs) and diarrhea, and tuberculosis incidence (p < 0.05). Countries with a higher burden of baseline pediatric mortality rates, higher pediatric mortality from preventable diseases like diarrhea and ARI, and higher tuberculosis incidence had lower rates of coronavirus disease 2019-associated mortality, supporting the hygiene hypothesis.


Study on the effect of digital economy development on carbon emissions: evidence from 30 provinces in China.
Currently, China is moving towards the era of the digital economy, which is gradually becoming a new engine of high-quality development. In the "double carbon" strategy context, the digital economy is characterized by low carbon emissions and high permeability, making it essential for carbon emission reduction. There needs to be more empirical research on the digital economy and carbon emissions. Given this, this study empirically examines the impact of digital economy development on carbon emissions intensity and its mechanisms in a multidimensional way based on the panel data of 30 provincial-level administrative regions in China from 2011 to 2019, utilizing a fixed-effects model, a mediated-effects model, a spatial Durbin model, and other methods. The study results show that (1) the digital economy can significantly reduce carbon emissions intensity. (2) The digital economy can indirectly affect the intensity of carbon emissions through industrial structure, energy structure, and environmental regulation. (3) The development of the local digital economy has a positive spillover effect on the carbon emissions intensity of neighbouring places. However, the overall effect is negative. This paper reveals some new features of the digital economy and carbon emissions intensity, which provides a reference for advancing the country's construction and realizing China's "double carbon" goal.


Prebiotic Peptides: Molecular Hubs in the Origin of Life.
The fundamental roles that peptides and proteins play in today's biology makes it almost indisputable that peptides were key players in the origin of life. Insofar as it is appropriate to extrapolate back from extant biology to the prebiotic world, one must acknowledge the critical importance that interconnected molecular networks, likely with peptides as key components, would have played in life's origin. In this review, we summarize chemical processes involving peptides that could have contributed to early chemical evolution, with an emphasis on molecular interactions between peptides and other classes of organic molecules. We first summarize mechanisms by which amino acids and similar building blocks could have been produced and elaborated into proto-peptides. Next, non-covalent interactions of peptides with other peptides as well as with nucleic acids, lipids, carbohydrates, metal ions, and aromatic molecules are discussed in relation to the possible roles of such interactions in chemical evolution of structure and function. Finally, we describe research involving structural alternatives to peptides and covalent adducts between amino acids/peptides and other classes of molecules. We propose that ample future breakthroughs in origin-of-life chemistry will stem from investigations of interconnected chemical systems in which synergistic interactions between different classes of molecules emerge.


A multimodal MRI study of the neural mechanisms of emotion regulation impairment in women with obesity.
Maladaptive emotion regulation contributes to overeating and impedes weight loss. Our study aimed to compare the voluntary downregulation of negative emotions by means of cognitive reappraisal in adult women with obesity (OB) and female healthy controls (HC) using a data-driven, multimodal magnetic resonance imaging (MRI) approach. Women with OB (n = 24) and HC (n = 25) carried out an emotion regulation task during functional MRI scanning. Seed-to-voxel resting-state connectivity patterns derived from activation peaks identified by this task were compared between groups. Diffusion tensor imaging (DTI) was used to examine white matter microstructure integrity between regions exhibiting group differences in resting-state functional connectivity. Participants in the OB group presented reduced activation in the ventromedial prefrontal (vmPFC) cortex in comparison to the HC group when downregulating negative emotions, along with heightened activation in the extrastriate visual cortex (p < 0.05, AlphaSim-corrected). Moreover, vmPFC peak activity levels during cognitive reappraisal were negatively correlated with self-reported difficulties in emotion regulation. OB patients exhibited decreased functional connectivity between the vmPFC and the temporal pole during rest (peak-pFWE = 0.039). Decreased fractional white-matter track volume in the uncinate fasciculus, which links these two regions, was also found in participants with OB. Taken together, our findings are indicative of emotion regulation deficits in OB being underpinned by dysfunctional hypoactivity in the vmPFC and hyperactivity in the extrastriate visual cortex. Our results provide a potential target circuit for neuromodulatory interventions to improve emotion regulation skills and weight-loss intervention outcomes.


Estimation of global insulin use for type 2 diabetes, 2018-30: a microsimulation analysis.
The amount of insulin needed to effectively treat type 2 diabetes worldwide is unknown. It also remains unclear how alternative treatment algorithms would affect insulin use and disability-adjusted life-years (DALYs) averted by insulin use, given that current access to insulin (availability and affordability) in many areas is low. The aim of this study was to compare alternative projections for and consequences of insulin use worldwide under varying treatment algorithms and degrees of insulin access. We developed a microsimulation of type 2 diabetes burden from 2018 to 2030 across 221 countries using data from the International Diabetes Federation for prevalence projections and from 14 cohort studies representing more than 60% of the global type 2 diabetes population for HbA1c, treatment, and bodyweight data. We estimated the number of people with type 2 diabetes expected to use insulin, international units (IU) required, and DALYs averted per year under alternative treatment algorithms targeting HbA1c from 6·5% to 8%, lower microvascular risk, or higher HbA1c for those aged 75 years and older. The number of people with type 2 diabetes worldwide was estimated to increase from 405·6 million (95% CI 315·3 million-533·7 million) in 2018 to 510·8 million (395·9 million-674·3 million) in 2030. On this basis, insulin use is estimated to increase from 516·1 million 1000 IU vials (95% CI 409·0 million-658·6 million) per year in 2018 to 633·7 million (500·5 million-806·7 million) per year in 2030. Without improved insulin access, 7·4% (95% CI 5·8-9·4) of people with type 2 diabetes in 2030 would use insulin, increasing to 15·5% (12·0-20·3) if insulin were widely accessible and prescribed to achieve an HbA1c of 7% (53 mmol/mol) or lower. If HbA1c of 7% or lower was universally achieved, insulin would avert 331 101 DALYs per year by 2030 (95% CI 256 601-437 053). DALYs averted would increase by 14·9% with access to newer oral antihyperglycaemic drugs. DALYs averted would increase by 44·2% if an HbA1c of 8% (64 mmol/mol) were used as a target among people aged 75 years and older because of reduced hypoglycaemia. The insulin required to treat type 2 diabetes is expected to increase by more than 20% from 2018 to 2030. More DALYs might be averted if HbA1c targets are higher for older adults. The Leona M and Harry B Helmsley Charitable Trust.


Formation of an alpha-helix in human tumor necrosis factor-alpha by guanidine hydrochloride-induced unfolding.
Human tumor necrosis factor-alpha (TNF-alpha) is a trimeric protein consisting primarily of beta-sheet. GdnHCl-induced unfolding of TNF-alpha was investigated at room temperature by circular dichroism (CD) and size exclusion chromatography. The secondary and tertiary structure of TNF-alpha persisted up to 0.9N GdnHCl regardless of incubation time, but, in the range of 1.2 N to 2.1 N GdnHCl, there was loss of tertiary structure accompanied by the formation of an alpha-helix, as revealed by far- and near-UV CD spectra. The structural changes occurred gradually in 1.2 and 2.1 N GdnHCl, but were rapid in 1.5 and 1.8 N GdnHCl. The GdnHCl-induced state of TNF-alpha is an unfolded, alpha-helical aggregate of about 130 monomers, as shown by size exclusion chromatography. We suggest the most likely pathway for the transition from beta-sheet to alpha-helix.


Algorithm for the treatment of chronic depression.
Chronic depression, which is marked by a course of illness lasting 2 years or more, encompasses 4 subtypes of depressive illness: (1) chronic major depressive disorder, (2) dysthymic disorder, (3) dysthymic disorder with major depressive disorder ("double depression"), and (4) major depressive disorder with poor interepisodic recovery (i.e., in incomplete remission). In the 1990s, chronic depression had a reported prevalence rate of 3% to 5% and accounted for 30% to 35% of all cases of depression in the United States. The authors present an algorithm modified from the Texas Medication Algorithm Project for patients with chronic depression. This treatment algorithm recommends a progression of steps or stages in treating chronic depression. The first stage is monotherapy with the selective serotonin reuptake inhibitors, nefazodone, bupropion sustained release, venlafaxine extended release, mirtazapine, or psychotherapy. Later options include combination therapy, electroconvulsive therapy, atypical antipsychotics, and novel treatments. Utilization of a comprehensive treatment algorithm for chronic major depression should encourage efficient, efficacious treatment.


[High ratio of omega 6/omega 3 ratio children with neuropathies; cause or effect].
The n-3 and n-6 fatty acids compete for the same elongases and desaturases, still highly deficient synthesis of polyunsaturated fatty acids from n-3 linolenic acid. The n-3 polyunsaturated prevent disease and are important in the development and maintenance of neuronal activities, necessitating a proper relationship with their antagonists n-6. This paper studies the proportion of these fatty acids. We analyzed the fatty acids of n- 3 and n-6 in sera and membrane phospholipid with 374 children neuropathies and 34 healthy children, using gas chromatography with mass detector. It has made the relevant statistical study. The n-3 (EPA and DHA) in serum and their corresponding membrane phospholipids correlate better than the n-6 family. The major n-6 (LA and ARA) are equally in serum, being significantly higher in phospholipids of healthy children. The n-3 (EPA and DHA) have higher values in healthy children, both in serum and phospholipids, their sum is equal to the membrane phospholipids. The n-6/n-3 ratio is higher in children with neurological disorder in both samples. Not being the cause of the high rate n-6/n- 3 neuropathy, however it is advisable to increase the intake of n-3, DHA particularly across the population, especially in children with neurological disorders.


Trends in snakebite envenomation therapy: scientific, technological and public health considerations.
The therapy of snakebite envenomation has been based on the parenteral administration of animal-derived antivenoms. Despite the success of this treatment at reducing the impact of snakebite mortality and morbidity, mostly due to their capacity to neutralize systemically-acting toxins, antivenoms are of relatively low efficacy in the prevention of venom-induced local tissue damage, which often leads to permanent disability. The issue of safety also remains a concern, particularly for some antivenoms which induce a relatively high incidence of adverse reactions. Consequently, there is a need to improve the therapy of snakebite envenomations on the following lines: (a) the technologies to produce antivenoms require improvements aimed at obtaining more refined preparations of higher efficacy and safety, while being affordable for the public health systems of developing countries. (b) The growing knowledge on the biochemistry and toxicology of snake venoms should pave the way for the identification of natural and synthetic inhibitors of venom toxins, particularly of those involved in local tissue pathology. Such inhibitors might become a highly effective therapeutic tool for the abrogation of venom-induced local tissue damage. (c) A better knowledge of the inflammatory events secondary to venom actions may open the possibility of modulating such response, in order to prevent further tissue damage and to promote successful tissue repair and regeneration. A global partnership, involving many participants and combining scientific, technological and public health actions, is required to achieve a leap forward in the treatment of snakebite envenomations world-wide.


Albumin-corrected or ionized calcium in renal failure? What to measure?
Secondary hyperparathyroidsm is frequently observed in patients with chronic renal failure, and clinical treatment guidelines have been published. Despite this, a large proportion of patients do not reach the target levels for calcium, phosphorus, calcium x phosphorus product, or intact parathyroid hormone. The use of albumin-corrected calcium is recommended as calcium measurement, but it is the concentration of ionized calcium that is biologically active. We hypothesized that in clinical practice, the use of ionized calcium rather than albumin-corrected calcium would influence the calcium classification of the individual patient. Blood samples from 34 patients in chronic haemodialysis were analysed for evaluation of mineral metabolism according to K/DOQI guidelines. Blood for analysis of total and ionized calcium was drawn simultaneously. As ionized calcium is pH dependent, samples were analysed at the actual pH of the individual patient. For both methods, a similar number of patients were characterized as normocalcaemic. The use of albumin-corrected calcium caused one patient (3%) to be classified as hypocalcaemic, and 10 patients (26%) as hypercalcaemic whereas with ionized calcium, five (15%) and three patients (9%) were classified as hypo- and hypercalcaemic, respectively. According to present guidelines, the difference in calcium classification of patients might have clinical implications for the prescription of vitamin D, and on the choice of phosphate binders.


Amyloid fibril formation by a partially structured intermediate state of alpha-chymotrypsin.
Here we investigated the effects of 2,2,2-trifluoroethanol (TFE) on the structure of alpha-chymotrypsin. The protein aggregates maximally in 35% (v/v) TFE. Congo red and thioflavin-T binding experiments suggest that the aggregates induced by TFE have amyloid-like properties, and transmission electron microscopy data show that these aggregates have a fibrilar morphology. Fluorescence, circular dichroism, anilino-8-napthalene sulfonate binding, and Fourier-transformed infrared spectroscopy data suggest that formation of a partially structured intermediate state precedes the onset of the aggregation process. The native beta-barrel structure of alpha-chymotrypsin appears to be disrupted in the partially structured intermediate state in favour of a non-native extended beta-sheet conformation with exposed hydrophobic surfaces. The protein becomes "sticky" under these conditions and aggregates into amyloid-like structures. The data support the hypothesis that amyloid formation involves the ordered self-assembly of partially folded species that are critical soluble precursors of fibrilar aggregates.


Managing heart failure in a specialist clinic.
Patients with heart failure are often inadequately investigated and treated in general practice. To improve the management of heart failure locally we initiated a specialist clinic in 1994. After its first 18 months, we audited the outcome of general practitioners' referrals to the clinic to examine its effectiveness in improving the diagnosis and treatment of heart failure. Eighty-five patients were referred with suspected heart failure. However, only 48% had echocardiographic evidence of left ventricular systolic dysfunction. Following referral, 80% of these patients were given a trial of angiotensin-converting enzyme inhibitors compared with 27% before referral. Six patients were receiving angiotensin-converting enzyme inhibitors unnecessarily, and five patients had significant structural cardiac disorders. Referral to a specialist clinic improved the accuracy of diagnosis and the number of patients on appropriate treatment. Greater use of open access echocardiography prior to referral might have allowed a more selective (and cost-effective) utilisation of the clinic.


The intake assessment of diverse dietary patterns on childhood hypertension: alleviating the blood pressure and lipidemic factors with low-sodium seafood rich in omega-3 fatty acids.
Childhood hypertension (CH) is related to the dietary intake and diversity of children. The study aimed to assess the critical role of dietary diversity, and seafood long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) in reducing CH among the Iranian community. A cross-sectional two-phase study with 7-12-year-old Iranian students was designed. In the initial phase, the socio-demographic characteristics, and blood pressure status (normal, pre-hypertension, and hypertension) based on systolic (SBP) and diastolic (DBP) blood pressure data were assessed. The 24-h dietary recall questionnaire was used to generate the dietary diversity score (DDS, count of consumed food groups) and dietary variety score (DVS, the cumulative number of daily consumed food items). In the second phase, the association between CH reduction and changes in serum 25-hydroxyvitamin D (25OHD), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) levels of schoolchildren intervened by a seafood diet rich in omega-3 fatty acids were assessed using the regression analyses. The pre-hypertension and hypertension prevalence rates were 7.8 and 9.15%, respectively. CH was significantly associated with age, gender, and DDS. A significant inverse association was found between the high intake of seafood and CH (P = 0.032). The gas-chromatography analysis showed the high presence of α-linolenic (ALA, 6.72%), eicosapentaenoic (EPA, 7.62%), docosapentaenoic (DPA, 5.88%), and docosahexaenoic (DHA, 18.52%) acids in the seafood-based diet (p < 0.05). The low blood pressure levels with regular consumption of this healthy-functional diet were significantly associated with a reduction in BMI, LDL, TC, and TG, and a remarkable increase in 25OHD and HDL levels. The multiple linear regression showed that the SBP was highly associated with the TC (p < 0.001; β = 0.464). The age and DDS were efficient predictors for the different CH status. A regular seafood-rich dietary pattern due to the high LC n-3 PUFAs contents could significantly reduce the obesity-related cardiovascular risk factors.


Functional gastrointestinal disorders in children: an Italian prospective survey.
To assess the prevalence and natural history of functional gastrointestinal disorders (FGIDs) in children using the Rome Criteria. Thirteen primary care pediatricians were randomly selected from the Campania region of the Italian National Health Service. Each pediatrician completed a detailed FGID questionnaire on consecutive patients seen during a 3-month period. A total of 9660 patients aged birth to 12 years were enrolled prospectively during this 3-month period. Follow-up was performed at 1-, 3-, and 12-month intervals. A total of 194 children initially met strict criteria for at least 1 FGID. A total of 72 (37.1%) children had infant regurgitation, 26 (13.4%) had functional dyspepsia, 27 (13.9%) had irritable bowel syndrome, and 66 (34.1%) had functional constipation or other defecation disorders. All children who had a diagnosis of FGIDs were reevaluated at 1, 3, and 12 months to study the natural history of the illnesses. Additional evaluation revealed 5 children who had developed an organic diagnosis. Therefore, 5 (2.5%) of 194 children who had a diagnosis of FGIDs by the Rome criteria had a change in diagnosis to an organic disease during the study period, none of whom experienced permanent sequelae. Of 194 children who received a prospective diagnosis of FGIDs using the Rome criteria, 97.5% continued to satisfy the diagnostic criteria or were improved at follow-up. The low prevalence of functional dyspepsia and irritable bowel syndrome in our population is most likely explained by the lack of adolescents in our sample.


Amino acid composition and the evolutionary rates of protein-coding genes.
Based on the rates of amino acid substitution for 60 mammalian genes of 50 codons or more, it is shown that the rate of amino acid substitution of a protein is correlated with its amino acid composition. In particular, the content of glycine residues is negatively correlated with the rate of amino acid substitution, and this content alone explains about 38% of the total variation in amino acid substitution rates among different protein families. The propensity of a polypeptide to evolve fast or slowly may be predicted from an index or indices of protein mutability directly derivable from the amino acid composition. The propensity of an amino acid to remain conserved during evolutionary times depends not so much on its being featured prominently in active sites, but on its stability index, defined as the mean chemical distance [R. Grantham (1974) Science 185:862-864] between the amino acid and its mutational derivatives produced by single-nucleotide substitutions. Functional constraints related to active and binding sites of proteins play only a minor role in determining the overall rate of amino acid substitution. The importance of amino acid composition in determining rates of substitution is illustrated with examples involving cytochrome c, cytochrome b5, ras-related genes, the calmodulin protein family, and fibrinopeptides.


Activity of Tedizolid in Methicillin-Resistant Staphylococcus aureus Experimental Foreign Body-Associated Osteomyelitis.
We compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (n = 14), tedizolid plus rifampin (n = 11), rifampin (n = 16), or vancomycin plus rifampin (n = 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 μg/ml and 60 μg · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid- plus rifampin-treated animals were not significantly different from those in the vancomycin- plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 μg/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin.


[Effect of injuries of the median forebrain bundle and the preoptic area on the activity of the strychnine-induced epileptiform focus (concerning the phenomenon of the hyperactive determinant transmission center)].
It was shown in experiments on cats that a lesion of the medial forebrain bundle (MFB) and partly of the preoptic region (RPO) at the side of local strychnine application of the cortex (g. suprasylvius medius) resulted in depression of the epileptiform activity in the strychnine-induced focus, as well as in the second "mirror" focus appearing in the symmetrical cortical area of the other hemisphere. This effect could also be obtained under conditions of injury of the MFB alone. The lesion of the MFB and partly of the RPO at the side of the "Mirror" focus leads to depression of the spike potentials in this focus only and does not influence the activity in the primary epileptiform focus. The described effects are considered from the aspect of conceptions of the role played by the determinant dispatch station (DDS) in the central nervous system activity: the primary epileptiform focus plays the role of the hyperactive DDS which induces the development of the secondary foci and maintaines and determines the character of their activity. The results of these studies suggest the participation of the MFB in the modulation of the epileptiform activity in the cortex.


Advances in NMR Methods To Map Allosteric Sites: From Models to Translation.
The last five years have witnessed major developments in the understanding of the allosteric phenomenon, broadly defined as coupling between remote molecular sites. Such advances have been driven not only by new theoretical models and pharmacological applications of allostery, but also by progress in the experimental approaches designed to map allosteric sites and transitions. Among these techniques, NMR spectroscopy has played a major role given its unique near-atomic resolution and sensitivity to the dynamics that underlie allosteric couplings. Here, we highlight recent progress in the NMR methods tailored to investigate allostery with the goal of offering an overview of which NMR approaches are best suited for which allosterically relevant questions. The picture of the allosteric "NMR toolbox" is provided starting from one of the simplest models of allostery (i.e., the four-state thermodynamic cycle) and continuing to more complex multistate mechanisms. We also review how such an "NMR toolbox" has assisted the elucidation of the allosteric molecular basis for disease-related mutations and the discovery of novel leads for allosteric drugs. From this overview, it is clear that NMR plays a central role not only in experimentally validating transformative theories of allostery, but also in tapping the full translational potential of allosteric systems.


Efficacy and Prediction Model Construction of Drug-Coated Balloon Combined with Cutting Balloon Angioplasty in the Treatment of Drug-Eluting Stent In-Stent Restenosis.
To investigate the efficacy of drug-coated balloon (DCB) combined with cutting balloon angioplasty (CBA) in the treatment of drug-eluting stent in-stent restenosis (DES-ISR) and to construct a predictive model for the occurrence of DES-ISR. According to the criteria of diagnosis, inclusion, and exclusion, DES-ISR patients who were treated in the outpatient and inpatient departments of cardiovascular medicine of Second People's Hospital of Guangdong Province from July 2021 to December 2021 were included. A total of 72 cases were planned to be enrolled, including 36 cases in the control group and 36 cases in the experimental group. The control group was treated with DCB, and the experimental group was combined with CBA. The treatment success rate, coronary angiography results before and after surgery, and the incidence of major adverse cardiovascular events during the follow-up period were compared between the two groups. Seventy-two DES-ISR patients were divided into ISR group and 59 non-ISR patients were divided into non-ISR group. The clinical data of the two groups were compared to analyze the risk factors affecting the occurrence of DES-ISR, and the prediction model was established. The surgical success rate of the experimental group was 94.44% (34/36), which was higher than the 77.78% (28/36) of the control group (P < 0.05). The minimum lumen diameter (MLD) of the experimental group 6 months after operation was greater than that of the control group, the late lumen loss (LL) and lumen stenosis rate were higher than those in the control group, and the incidence of major adverse cardiovascular events was lower than that in the control group (P < 0.05). In the ISR group, the proportion of patients with abnormal BMI, smoking, hypertension, diabetes, and family history of coronary heart disease and multivessel coronary artery disease was higher than that in the non-ISR group, the degree of stenosis target lesion was higher than that in the non-ISR group, the diameter of target lesion and stent diameter were smaller than those in the non-ISR group, and the length of target lesion and stent length were longer than those in the non-ISR group; the number of stents was more than that in the non-ISR group (P < 0.05). Combined hypertension, multiple coronary artery lesions, stenosis target lesion degree ≥85.05%, and target lesion length ≥36.88 mm were risk factors for DES-ISR, and target lesion diameter ≥3.15 mm and stent diameter ≥3.15 mm were protective factors (P < 0.05). The prediction model of DES-ISR was obtained by multiple logistic regression analysis, P = 1[1 + e (2.281 + 3.321Xhypertension + 3.427Xumber of arterial lesions + 3.359Xstenosis target lesion degree - 3.143Xtarget lesion diameter + 0.650Xtarget lesion length - 10.159Xstent diameter)]. The Hosmer-Lemeshow test showed that Hosmer-Lemeshow χ 2 = 0.925, P =0.413; the ROC curve analysis showed that the AUC of the prediction model for the occurrence of DES-ISR was 0.924, the SE value was 0.022, and the 95% CI was 0.880-0.967. DCB combined with CBA has good clinical efficacy in the treatment of DES-ISR, which can reduce the rate of lumen stenosis and the incidence of adverse cardiovascular events. The prediction model established according to risk factors has high predictive value for the occurrence of DES-ISR.


Fronto-orbitonasal intradiploic meningioma in a child.
Intradiploic meningioma, which may be classified as a subgroup of intraosseous meningioma, is a rarely encountered disorder. To date, less than 10 cases have been reported. Here, we report a case of fronto-orbitonasal intradiploic meningioma. A 12-year-old female with exophthalmos and diplopia was operated on for a cranial intradiploic mass lesion. Histopathological evaluation of the specimen confirmed the diagnosis of intradiploic psammomatous meningioma. Her exophthalmos did not change, but the diplopia disappeared. This case is unique in that it is an extensive case of intradiploic meningioma of the orbital roof and frontal base in a child. Intradiploic meningiomas generally are of psammomatous type. Especially tumors adjacent to the orbita cause exophthalmos; cases located on the other side of the calvarium may not cause any symptom or sign other than headache or sometimes a mass on the scalp. Treatment, as with meningiomas located in the intracranial cavity, is total resection of the lesion.


Expression of trypsin-like activity by the genera Corynebacterium and Actinomyces in canine periodontitis.
Trypsin-like activity (TLA), clinical parameters and TLA-positive bacteria were examined in periodontitis and healthy sites in dogs. TLA was markedly higher in periodontitis than at healthy sites. There was good correlation between TLA positivity and severity of periodontal disease. The proportions of TLA-positive bacteria to total isolates in periodontitis and healthy sites were 21.1% and 2.1%, respectively. Among TLA-positive bacteria in periodontitis sites, 4.4% showed strong TLA activity, 35.3% showed moderate and 60.3% showed weak activity. In the healthy sites, all the TLA-positive bacteria showed weak activity. In all, 90% of the total number of TLA-positive bacteria were identified as belonging to the family Actinomycetaceae; 40% of bacteria belonging to the family Actinomycetaceae were identified as genus Corynebacterium with moderate trypsin-like activity and the remaining 60% were identified as genus Actinomyces with weak activity. Obligately anaerobic bacteria accounted for only 5.9% of the total population of TLA-positive bacteria; they were gram-negative coccobacilli, gram-positive rods and gram-positive cocci. These observations suggested that bacteria in the family Actinomycetaceae may play an important role in periodontitis and that measurement of TLA is a clinically reliable marker for the diagnosis of periodontitis in dogs.


Maximal sum of metabolic exchange fluxes outperforms biomass yield as a predictor of growth rate of microorganisms.
Growth rate has long been considered one of the most valuable phenotypes that can be measured in cells. Aside from being highly accessible and informative in laboratory cultures, maximal growth rate is often a prime determinant of cellular fitness, and predicting phenotypes that underlie fitness is key to both understanding and manipulating life. Despite this, current methods for predicting microbial fitness typically focus on yields [e.g., predictions of biomass yield using GEnome-scale metabolic Models (GEMs)] or notably require many empirical kinetic constants or substrate uptake rates, which render these methods ineffective in cases where fitness derives most directly from growth rate. Here we present a new method for predicting cellular growth rate, termed SUMEX, which does not require any empirical variables apart from a metabolic network (i.e., a GEM) and the growth medium. SUMEX is calculated by maximizing the SUM of molar EXchange fluxes (hence SUMEX) in a genome-scale metabolic model. SUMEX successfully predicts relative microbial growth rates across species, environments, and genetic conditions, outperforming traditional cellular objectives (most notably, the convention assuming biomass maximization). The success of SUMEX suggests that the ability of a cell to catabolize substrates and produce a strong proton gradient enables fast cell growth. Easily applicable heuristics for predicting growth rate, such as what we demonstrate with SUMEX, may contribute to numerous medical and biotechnological goals, ranging from the engineering of faster-growing industrial strains, modeling of mixed ecological communities, and the inhibition of cancer growth.


Weighted Joint Sparse Representation for Removing Mixed Noise in Image.
Joint sparse representation (JSR) has shown great potential in various image processing and computer vision tasks. Nevertheless, the conventional JSR is fragile to outliers. In this paper, we propose a weighted JSR (WJSR) model to simultaneously encode a set of data samples that are drawn from the same subspace but corrupted with noise and outliers. Our model is desirable to exploit the common information shared by these data samples while reducing the influence of outliers. To solve the WJSR model, we further introduce a greedy algorithm called weighted simultaneous orthogonal matching pursuit to efficiently approximate the global optimal solution. Then, we apply the WJSR for mixed noise removal by jointly coding the grouped nonlocal similar image patches. The denoising performance is further improved by incorporating it with the global prior and the sparse errors into a unified framework. Experimental results show that our denoising method is superior to several state-of-the-art mixed noise removal methods.


Hemocyanin from the Australian freshwater crayfish Cherax destructor. Oxygen binding studies of major components.
Oxygen binding curves have been obtained for unfractionated hemocyanin from Cherax destructor and it major components, the 25S and 17S forms. In all cases the binding was characterized by positive cooperativity at pH 7.8 with a P50 of approximately 4 mmHg and a Hill coefficient, nH, of approximately 3. There was no evidence of concentration dependence of the binding curves in the range 0.6-6 mg/mL, a finding which excludes a dynamic equilibrium between polymeric forms of different oxygen affinity as a source of the cooperative binding. A positive Bohr effect operates between pH 6.8 and pH 7.8 and removal of calcium ions from the 25S and 17S aggregates markedly reduces their affinities for oxygen. Cooperativity is retained in these circumstances though nH drops to about 2.5 in the case of the 25S and 2.0 in the case of the 17S form. The two major monomers M1 and M2, from which the 25S and 17S complexes are constructed, may be reconstituted into the hexamers (M1)6 and (M2)6. These show oxygen binding behavior perfectly consistent with that expected of native hexamers as studied in the 17S fraction, a mixed population of hexamers. The monomer M1 can also be studied in monomeric form and was found to show indistinguishable oxygen binding at pH 7.8 and pH 10, the curve being a rectangular hyperbola as expected. The oxygen binding curve of the single subunit hexamer (M1)6 was fitted adequately by a polynomial expression of order 6 as required for a molecule with six binding sites. Further interpretation in terms of a particular binding model was not attempted because available knowledge of the structures of arthropod hemocyanin aggregates and their oxygen binding sites does not yet justify it.


Effects of the epipodophyllotoxin VP-16-213 on herpes simplex virus type 2 replication.
It has been recently shown that VP-16-213, a semi-synthetic derivative of podophyllotoxin, inhibits the function of mammalian DNA topoisomerase II. In the present study, we examined the effects of VP-16-213 on the replication of herpes simplex virus type 2 (HSV-2). The compound did not inhibit the synthesis of early viral polypeptides at concentrations at which viral DNA synthesis was strongly suppressed, but induced double-strand breaks in newly synthesized HSV DNA. Electron microscopic examination of treated cells revealed the presence of a number of capsids with empty or partial cores. The level of topoisomerase II activity remained unaltered after infection, and all attempts to isolate VP-16-213-resistant mutants of HSV-2 have failed in spite of extensive efforts. It is suggested therefore that the mode of action of VP-16-213 may be inhibition of viral DNA synthesis by impairing the function of host cell topoisomerase II.


Purification and characterization of the inactive MoFe protein (NifB-Kp1) of the nitrogenase from nifB mutants of Klebsiella pneumoniae.
The inactive MoFe protein of nitrogenase, NifB-Kp1, from two distinct nifB mutants of Klebsiella pneumoniae, Kp5058 (a nifB point mutant) and UNF1718 (a nifB, nifJ double mutant) has been purified and characterized. NifB-Kp1 can be activated by reaction with the iron-molybdenum cofactor, FeMoco, extracted from active MoFe protein. NifB-Kp1 purified from either source had similar properties and was contaminated with an approximately equimolar amount of protein of mol.wt. 21 000. Like active wild-type Kp1, it was an alpha 2 beta 2 tetramer, but it was far less stable than Kp1, deteriorating rapidly at temperatures above 8 degrees C or on mild oxidation. NifB-Kp1 preparations contained 0.4-0.9 Mo and 9.0 +/- 0.9 Fe atoms . mol-1 and, when activated by FeMoco, had a specific activity of approx. 500 units . mg-1. The Mo in our preparations was not associated with the e.p.r. signal normally observed from FeMoco. All preparations exhibited a weak gav. = 1.95 e.p.r. signal which was probably not associated with activatable protein.


Predictors of longterm mortality in patients with and without systemic lupus erythematosus on maintenance dialysis: a comparative study.
To compare the prognosis of patients with and without systemic lupus erythematosus (SLE) on dialysis and to determine the factors that affect survival after dialysis. We used the Taiwan National Health Insurance Research Database (NHRI-NHIRD-99182) and collected data on patients who started maintenance dialysis between 2001 and 2003. Patients were followed from the initiation of dialysis until death, discontinuation of dialysis, or the end of 2008. We did a Kaplan-Meier analysis of the cohort and used multivariate Cox regression analysis to identify significant predictors of survival. Of the 22,394 dialysis patients studied, 303 (1.35%) had SLE. Hypertension and diabetes were the 2 most common comorbidities associated with dialysis for patients with and without SLE. After adjusting for age, sex, dialysis modality, and comorbidities, we found no significant survival difference between the 2 patient groups after 8 years of followup. Multivariate analysis showed that increased mortality in the patient group without SLE (p < 0.05) was associated with older age (≥ 45 years), male sex, initial choice of hemodialysis, diabetes mellitus, heart failure, coronary artery disease, cerebrovascular disease, and malignancy. In the patient group with SLE, independent predictors of mortality (p < 0.05) were older age (≥ 65 years), male sex, and diabetes mellitus. The longterm survival outcome was similar between patients with and without SLE who were on dialysis. The factors affecting patient mortality were not identical in these 2 groups.


Patient and Spousal Health and Outcomes in Heart Failure.
A diagnosis of heart failure (HF) often requires a comprehensive lifestyle change to maintain disease stability. When patients with HF are married, the spouse frequently assumes the caregiving role. Our objectives were to describe the health of spouses of married patients with HF, and examine whether the health of a spouse impacts patient outcomes. We identified 905 patients that were married at the time of incident HF diagnosis in Olmsted County, MN, from 2000 to 2012. Using Rochester Epidemiology Project resources, the patient and their spouse's comprehensive longitudinal health histories were linked. Spousal health at patient HF diagnosis was assessed by comorbidity burden, self-reported difficulty with activities of daily living and prior hospitalizations. The associations of spousal health with patient outcomes and patient death with spousal outcomes were examined using Cox and Andersen-Gill models. Spouses of patients with HF were elderly (mean age, 71 years), often had comorbid conditions, and 16% had difficulty with ≥1 activities of daily living. After adjustment for patient age, sex, and comorbidity, there were no independent associations of spousal health and patient risk of death or hospitalization after HF diagnosis. However, the risk of hospitalization (adjusted hazard ratio, 1.34; 95% confidence interval, 1.11-1.60; P=0.002) and death (hazard ratio, 2.10; 95% confidence interval, 1.60-2.75; P<0.001) increased in the surviving spouse after patient death. We found no evidence that the health of a spouse impacts patient outcomes after HF diagnosis. However, after a patient with HF dies, their surviving spouse's risk of hospitalization and death increases.


Noninvasive detection of regional myocardial ischemia using rubidium-81 and the scintillation camera: comparison with stress electrocardiography in patients with arteriographically documented coronary stenosis.
The sensitivity of rest and stress myocardial perfusion studies using scintillation camera imaging of intravenously administered rubidium-81 (81Rb) in the detection of myocardial ischemia was compared to that of stress electrocardiography by relating results in 40 patients to the degree of stenosis delineated by coronary arteriography. Of 33 patients with greater than 75% stenosis of at least one of the three major coronary vessels (significant stenosis), rest and stress 81Rb imaging detected ventricular ischemia in 29 (88%) whereas simultaneous stress electrocardiography was positive (1 mm or greater horizontal ST-segment depression) in only 19 (58%) of the same patients. Five of the 29 patients who developed stress-induced scintigraphic evidence of ischemia did not develop angina or a positive electrocardiogram with stress. In 31 of the 33 patients with significant coronary stenosis, either the stress scintigram or the stress electrocardiogram was positive. In seven patients with less than 50% narrowing of a major coronary vessel on coronary arteriography, the stress scinitigrams were negative, whereas the stress electrocardiograms were positive in the two of these patients with the syndrome of angina with normal coronary arteriograms. It is concluded that high resolution images of the myocardium can be obtained with 81Rb using the scintillation camera with special shielding, and that rest and stress 81Rb scintigraphy appears to provide greater sensitivity and specificity when compared to stress electrocardiography in the nininvasive identification of significant coronary stenosis.


Mimicking nature with synthetic macromolecules capable of recognition.
Nature has, through billions of years of evolution, assembled a multitude of polymeric macromolecules capable of exquisite molecular recognition. This functionality arises from the precise control exerted over their biosynthesis that results in key residues being anchored in the appropriate positions to interact with target substrates. Developing 'wholly synthetic' macromolecular analogues that can mimic this behaviour presents a considerable challenge to chemists, who lack the 'biological machinery' used in nature to assemble polymers with such precision. In addressing this challenge, familiar chemical concepts, such as combinatorial methods and supramolecular interactions, have been adapted for application in the macromolecular arena. Working from a limited set of residues, synthetic macromolecules have been produced that display surprisingly high binding affinities towards target proteins, even possessing useful in vivo activities. These observations are all the more surprising when one considers the heterogeneity inherent within these synthetic macromolecular receptors, and provoke intriguing questions regarding our assumptions about the design of receptors.


An overview of approaches and challenges for retrieving marine inherent optical properties from ocean color remote sensing.
Ocean color measured from satellites provides daily global, synoptic views of spectral waterleaving reflectances that can be used to generate estimates of marine inherent optical properties (IOPs). These reflectances, namely the ratio of spectral upwelled radiances to spectral downwelled irradiances, describe the light exiting a water mass that defines its color. IOPs are the spectral absorption and scattering characteristics of ocean water and its dissolved and particulate constituents. Because of their dependence on the concentration and composition of marine constituents, IOPs can be used to describe the contents of the upper ocean mixed layer. This information is critical to further our scientific understanding of biogeochemical oceanic processes, such as organic carbon production and export, phytoplankton dynamics, and responses to climatic disturbances. Given their importance, the international ocean color community has invested significant effort in improving the quality of satellite-derived IOP products, both regionally and globally. Recognizing the current influx of data products into the community and the need to improve current algorithms in anticipation of new satellite instruments (e.g., the global, hyperspectral spectroradiometer of the NASA Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission), we present a synopsis of the current state of the art in the retrieval of these core optical properties. Contemporary approaches for obtaining IOPs from satellite ocean color are reviewed and, for clarity, separated based their inversion methodology or the type of IOPs sought. Summaries of known uncertainties associated with each approach are provided, as well as common performance metrics used to evaluate them. We discuss current knowledge gaps and make recommendations for future investment for upcoming missions whose instrument characteristics diverge sufficiently from heritage and existing sensors to warrant reassessing current approaches.


Prevalence and risk factors for Extended-Spectrum Beta-Lactamase-producing- Enterobacteriaceae in French military and civilian travelers: A cross-sectional analysis.
International travel is a risk factor for colonization with Extended-Spectrum Beta-Lactamase-producing- Enterobacteriaceae (ESBL-E). We describe the prevalence of and risk-factors for ESBL-E colonization in civilian and military travelers. Patients hospitalized in the infectious diseases department of Bégin Military Hospital (France) from May 2012 to November 2015, who had traveled abroad over the past two months, were screened for intestinal colonization with ESBL-E. Forty-one out of 166 travelers (24.7%) had ESBL-E colonization, predominantly Escherichia coli. The risk factors for ESBL-E colonization in the univariate analysis were a treatment with any antibiotic in the last two months (OR 4.19, 95% CI 1.91-9.16) or with a beta-lactam in the same period (OR 3.35, 95% CI 1.44-7.82), and an hospitalization in the last two months (OR 3.96, 95% CI 1.91-9.16). The military status, military mission or military accommodation were not associated with an increased risk of ESBL-E colonization. In the multivariate analysis, a treatment with any antibiotic in the last two months was significantly associated with ESBL-E colonization (OR 6.71, 95% CI 3.36-19.08). Antibiotic treatment in the two previous months is strongly predictive of ESBL-E colonization in international travelers, while the military status and its specific living conditions are not.


Cleavage of the bovine herpesvirus glycoprotein B is not essential for its function.
Herpes simplex virus glycoprotein B (HSVgB) and its bovine herpesvirus homologue (BHVgB) share similar primary structures. These glycoproteins are present in the envelope of the virion and are believed to initiate infection by fusing the virus envelope with a host cell membrane. BHVgB, like the membrane-fusing glycoproteins of most enveloped viruses, is normally cleaved and is present as a disulphide-linked complex in the virus envelope and host cell membranes. HSVgB, however, remains uncleaved, presumably because it lacks a similar protease recognition sequence. To determine whether the cleavage of BHVgB is essential for its role in initiating infection, we altered the coding sequence of this glycoprotein by removing the protease cleavage site and making this region similar to that of HSVgB. The mutant BHVgB gene was expressed by an HSV recombinant virus in mouse L cells and produced an uncleaved BHVgB. The uncleaved BHVgB could complement the function of HSVgB which had been neutralized by monoclonal antibody H233. When expressed in mouse L cells, the uncleaved mutant BHVgB retained its ability to fuse membranes.


Harnessing biodiversity: the Malagasy Institute of Applied Research (IMRA).
Biopiracy - the use of a people's long-established medical knowledge without acknowledgement or compensation - has been a disturbing historical reality and exacerbates the global rich-poor divide. Bioprospecting, however, describes the commercialization of indigenous medicines in a manner acceptable to the local populace. Challenges facing bioprospectors seeking to develop traditional medicines in a quality-controlled manner include a lack of skilled labor and high-tech infrastructure, adapting Northern R&D protocols to Southern settings, keeping products affordable for the local population, and managing the threat of biopiracy. The Malagasy Institute of Applied Research (IMRA) has employed bioprospecting to develop new health treatments for conditions such as diabetes and burns. Because of its integration of Western science and Malagasy cultural traditions, IMRA may provide a useful example for African and other organizations interested in bioprospecting. IMRA's approach to drug development and commercialization was adapted from the outset to Malagasy culture and Southern economic landscapes. It achieved a balance between employing Northern R&D practices and following local cultural norms through four guiding principles. First, IMRA's researchers understood and respected local practices, and sought to use rather than resist them. Second, IMRA engaged the local community early in the drug development process, and ensured that local people had a stake in its success. Third, IMRA actively collaborated with local and international partners to increase its credibility and research capacity. Fourth, IMRA obtained foreign research funds targeting the "diseases of civilization" to cross-fund the development of drugs for conditions that affect the Malagasy population. These principles are illustrated in the development of IMRA products like Madeglucyl, a treatment for diabetes management that was developed from a traditional remedy. By combining local and international research interests, IMRA has been able to keep its treatments affordable for the Malagasy population. Our analysis of IMRA's history, strategy, and challenges suggests that other developing world institutions seeking to use bioprospecting to address issues of local access to medicines would be well-advised to treat traditional medical knowledge with respect and humility, share its benefits with the local community, and pursue strategic partnerships.


Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization.
In humans, invading pathogens are recognized by Toll-like receptors (TLRs). Upon recognition of lipopolysaccharide (LPS) derived from the cell wall of Gram-negative bacteria, TLR4 dimerizes and can stimulate two different signaling pathways, the proinflammatory, MyD88-dependent pathway and the antiviral, MyD88-independent pathway. The balance between these two pathways is ligand-dependent, and ligand composition determines whether the invading pathogen activates or evades the host immune response. We investigated the dimerization behavior of TLR4 in intact cells in response to different LPS chemotypes through quantitative single-molecule localization microscopy. Quantitative superresolved data showed that TLR4 was monomeric in the absence of its co-receptors MD2 and CD14 in transfected HEK 293 cells. When TLR4 was present together with MD2 and CD14 but in the absence of LPS, 52% of the receptors were monomeric and 48% were dimeric. LPS from Escherichia coli or Salmonella minnesota caused the formation of dimeric TLR4 complexes, whereas the antagonistic LPS chemotype from Rhodobacter sphaeroides maintained TLR4 in monomeric form at the cell surface. Furthermore, we showed that LPS-dependent dimerization was required for the activation of NF-κB signaling. Together, these data demonstrate ligand-dependent dimerization of TLR4 in the cellular environment, which could pave the way for a molecular understanding of biased signaling downstream of the receptor.


The lived experience of engaging in everyday occupations in persons with mild to moderate aphasia.
Impairment of language ability, aphasia, can cause barriers to communication and hence impact on participation in many life situations. This study aimed to describe and explore how persons with aphasia following stroke experience engaging in everyday occupations. Six persons from Southwest Finland who had aphasia due to stroke one to four years previously were interviewed for the study. A modified form of the empirical phenomenological psychological method was used for data analysis. Three main characteristics of experiences of engaging in everyday occupations were identified: (1) encountering new experiences in everyday occupations, (2) striving to handle everyday occupations and (3) going ahead with life. The participants had experienced an altering life-world. Engagement in occupations affected their perceptions of competence and identity, and experiences of belonging and well-being. It was also through engagement in everyday occupations that they had discovered and learnt to handle changes in their everyday life. Aphasia can have a long-term impact on engagement in everyday occupations and participation in society, but conversely, engagement in meaningful occupations can also contribute to adaptation to disability and life changes. Aphasia can have a long-term impact on engagement in everyday occupations and participation in society. Health care professionals need to determine what clients with aphasia think about their occupations and life situations in spite of difficulties they may have verbalizing their thoughts. Experiences of engaging in meaningful occupations can help clients with aphasia in reconstructing their life stories, thereby contributing to adaptation to disability and life changes.


Challenges faced by trainee psychiatrists working towards competency in psychotherapies.
This paper explores the challenges that trainees of the Royal Australian and New Zealand College of Psychiatrists face as they work towards competency in psychotherapy during basic training. The state of training programs in other countries including the trainee and supervisor perspectives on the outcomes of the shift to competency-based assessment is reviewed, and the limited literature examining the systemic problems impacting on the quality of the training experience in psychotherapies for Australian and New Zealand trainees is considered. The risk of an increasing gap between the ideals and the reality of training expectations and experiences is discussed. The importance of auditing the adherence of training services to College guidelines and formally evaluating the training outcomes in the future is emphasised.


The molecular architecture of Drosophila melanogaster defense against Beauveria bassiana explored through evolve and resequence and quantitative trait locus mapping.
Little is known about the genetic architecture of antifungal immunity in natural populations. Using two population genetic approaches, quantitative trait locus (QTL) mapping and evolve and resequence (E&R), we explored D. melanogaster immune defense against infection with the fungus Beauveria bassiana. The immune defense was highly variable both in the recombinant inbred lines from the Drosophila Synthetic Population Resource used for our QTL mapping and in the synthetic outbred populations used in our E&R study. Survivorship of infection improved dramatically over just 10 generations in the E&R study, and continued to increase for an additional nine generations, revealing a trade-off with uninfected longevity. Populations selected for increased defense against B. bassiana evolved cross resistance to a second, distinct B. bassiana strain but not to bacterial pathogens. The QTL mapping study revealed that sexual dimorphism in defense depends on host genotype, and the E&R study indicated that sexual dimorphism also depends on the specific pathogen to which the host is exposed. Both the QTL mapping and E&R experiments generated lists of potentially causal candidate genes, although these lists were nonoverlapping.


Initial analysis of the dosimetric benefit and clinical resource cost of CBCT-based online adaptive radiotherapy for patients with cancers of the cervix or rectum.
This provides a benchmark of dosimetric benefit and clinical cost of cone-beam CT-based online adaptive radiotherapy (ART) technology for cervical and rectal cancer patients. An emulator of a CBCT-based online ART system was used to simulate more than 300 treatments for 13 cervical and 15 rectal cancer patients. CBCT images were used to generate adaptive replans. To measure clinical resource cost, the six phases of the workflow were timed. To evaluate the dosimetric benefit, changes in dosimetric values were assessed. These included minimum dose (Dmin) and volume receiving 95% of prescription (V95%) for the planning target volume (PTV) and the clinical target volume (CTV), and maximum 2 cc's (D2cc) of the bladder, bowel, rectum, and sigmoid colon. The average duration of the workflow was 24.4 and 9.2 min for cervical and rectal cancer patients, respectively. A large proportion of time was dedicated to editing target contours (13.1 and 2.7 min, respectively). For cervical cancer patients, the replan changed the Dmin to the PTVs and CTVs for each fraction 0.25 and 0.25 Gy, respectively. The replan changed the V95% by 9.2 and 7.9%. The D2cc to the bladder, bowel, rectum, and sigmoid colon for each fraction changed -0.02, -0.08, -0.07, and -0.04 Gy, respectively. For rectal cancer patients, the replan changed the Dmin to the PTVs and CTVs for each fraction of 0.20 and 0.24 Gy, respectively. The replan changed the V95% by 4.1 and 1.5%. The D2cc to the bladder and bowel for each fraction changed 0.02 and -0.02 Gy, respectively. Dosimetric benefits can be achieved with CBCT-based online ART that is amenable to conventional appointment slots. The clinical significance of these benefits remains to be determined. Managing contours was the primary factor affecting the total duration and is imperative for safe and effective adaptive radiotherapy.


Evaluating Pelvis Response During Simulated Underbody Blast Loading.
In recent conflicts, blast injury from landmines and improvised explosive devices (IEDs) has been the main mechanism of wounding and death. When a landmine or IED detonates under a vehicle, (an under-body blast), the seat acceleration rapidly transmits a high load to the pelvis of the occupants, resulting in torso and pelvic injury. Pelvic fractures have high mortality rates, yet their injury mechanism has been poorly researched. Three (3) fresh-frozen male pelvic specimens were tested under axial impact loading. The pelvis was impacted mounted upside down by dropping a 12 kg mass at target impact velocities ranging from 1 to 8.6 m/s with time to peak velocity ranging from 3.8 to 5.8 ms. Resulting fractures were broadly categorised as involving a bilateral pubis rami fracture, a bilateral ischium fracture and sacroiliac joint disruption. The study provides insights into the type and severity of pelvic injury that may occur over a range of UBB-relevant loading profiles.


The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile.
The formation of spores is critical for the survival of Clostridium difficile outside the host gastrointestinal tract. Persistence of C. difficile spores greatly contributes to the spread of C. difficile infection (CDI), and the resistance of spores to antimicrobials facilitates the relapse of infection. Despite the importance of sporulation to C. difficile pathogenesis, the molecular mechanisms controlling spore formation are not well understood. The initiation of sporulation is known to be regulated through activation of the conserved transcription factor Spo0A. Multiple regulators influence Spo0A activation in other species; however, many of these factors are not conserved in C. difficile and few novel factors have been identified. Here, we investigated the function of a protein, CD1492, that is annotated as a kinase and was originally proposed to promote sporulation by directly phosphorylating Spo0A. We found that deletion of CD1492 resulted in increased sporulation, indicating that CD1492 is a negative regulator of sporulation. Accordingly, we observed increased transcription of Spo0A-dependent genes in the CD1492 mutant. Deletion of CD1492 also resulted in decreased toxin production in vitro and in decreased virulence in the hamster model of CDI. Further, the CD1492 mutant demonstrated effects on gene expression that are not associated with Spo0A activation, including lower sigD and rstA transcription, suggesting that this protein interacts with factors other than Spo0A. Altogether, the data indicate that CD1492 negatively affects sporulation and positively influences motility and virulence. These results provide further evidence that C. difficile sporulation is regulated differently from that of other endospore-forming species.


Clinical potential of neuropeptide Y receptor ligands in the treatment of epilepsy.
A substantial amount of experimental evidence implicates neuropeptide Y (NPY) in the pathophysiology of epilepsy. Over the past 20 years, remarkable progress has been made in unraveling the mechanisms and receptors involved in the anticonvulsant effect of this abundantly expressed neuropeptide. Activation of Y(2) and/or Y(5) receptors and blockade of Y(1) receptors in the central nervous system suppresses seizures in a variety of animal seizure models. Orally available, brain penetrating Y(2) and/or Y(5) agonists, and possibly Y(1) antagonists, may therefore constitute a novel class of antiepileptic drugs, which could greatly benefit patients with medically refractory epilepsy. Significant progress has been made in identifying non-peptidergic Y(1) antagonists that fulfill these criteria, but suitable Y(2) and/or Y(5) agonists have proven to be more elusive. Innovative oral and parental drug delivery strategies which are currently under development may offer a means of using the more readily available peptidergic NPY receptor ligands in a clinical setting. Finally, gene therapy, antisense probes or RNA interference strategies which alter the expression of NPY or its receptors in specific brain regions may also be of use in the treatment of epilepsy, but will probably benefit a smaller subgroup of epilepsy patients, since they typically require an invasive procedure.


Vitamin E trafficking.
The alpha-tocopherol transfer protein (alpha-TTP) is required to prevent vitamin E deficiency in humans and in alpha-TTP null mice. Whereas alpha-TTP is not required to facilitate intestinal absorption of vitamin E, it is required to maintain normal alpha-tocopherol concentrations in plasma and extrahepatic tissues. alpha-Tocopherol secretion from the liver in very low density lipoproteins (VLDLs) is impaired in humans with a defect in the alpha-TTP gene. In perfusions of isolated cynomolgus monkey livers, VLDLs were preferentially enriched in RRR-alpha-tocopherol. The mechanism by which alpha-TTP incorporates alpha-tocopherol into nascent VLDLs is the topic of this report. VLDL assembly is a multistep secretory process that occurs within the membrane compartments of the endoplasmic reticulum and Golgi apparatus. Thus, we postulated that alpha-TTP might transfer alpha-tocopherol onto nascent VLDLs either in the endoplasmic reticulum or in the Golgi apparatus. To test these possibilities, we isolated nascent VLDLs from highly purified RER and Golgi apparatus membrane fractions from livers of rats fed equimolar ratios of RRR- and SRR-alpha-tocopherols labeled with different amounts of deuterium. Although the plasma was enriched in RRR-alpha-tocopherol 14 hours after the dose, no enrichment of nascent VLDL precursors from either of the secretory compartments was detected, indicating that VLDL enrichment with alpha-tocopherol may occur as a post-VLDL secretory process. Therefore, we hypothesize that alpha-TTP may facilitate movement of alpha-tocopherol to the hepatocyte plasma membrane (by unknown mechanisms) where newly secreted, nascent VLDLs could acquire both alpha-tocopherol and unesterified cholesterol while within the space of Disse. Clearly, critical information is lacking in our understanding of the mechanism by which alpha-TTP facilitates the preferential enrichment of VLDLs with alpha-tocopherol.


Cowden Syndrome with a Novel PTEN Mutation Presenting with Partial Epilepsy Related to Focal Cortical Dysplasia.
Cowden syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas of the ectoderm and brain. A 36-year-old Japanese man presented with right facial seizure during sleep and was admitted to our hospital. He showed cobblestoning over the tongue and palmar pitting but no neurological abnormalities while he was not having a seizure. Brain magnetic resonance imaging showed focal cortical dysplasia in the left frontal lobe. Electroencephalography showed sharp waves over the left frontal lesion. A genetic analysis revealed a novel mutation of PTEN. The administration of carbamazepine ended the seizures. This is the first Japanese case of Cowden syndrome with a novel PTEN gene mutation and cortical dysplasia.


Proteomics reveals new salt responsive proteins associated with rice plasma membrane.
The signaling processes in plants that initiate cellular responses to biotic and abiotic factors are believed to be located in the plasma membrane (PM). A better understanding of the PM proteome response to environmental stresses might lead to new strategies for improving stress-tolerant crops. A sub-cellular proteomics approach was applied to monitor changes in abundance of PM-associated protein in response to salinity, a key abiotic stress affecting rice productivity worldwide. Proteome was extracted from a root plasma-membrane-rich fraction of a rice salt tolerant variety, IR651, grown under saline and normal conditions. Comparative two-dimensional electrophoresis revealed that 24 proteins were differentially expressed in response to salt stress. From these, eight proteins were identified by mass spectrometry analysis. Most of the proteins identified are likely to be PM-associated and are known to be involved in several important mechanisms of plant adaptation to salt stress. These include regulation of PM pumps and channels, membrane structure, oxidative stress defense, signal transduction, protein folding, and the methyl cycle. To investigate the correlation between mRNA and protein level in response to salinity, we performed quantitative Real-Time PCR analysis of three genes that were salt responsive at the protein level, including 1,4-Benzoquinone reductase, a putative remorin and a hypersensitive induced response protein. No concordance was detected between the changes in levels of gene and protein expression. Our results indicate that the proteomics approach is suitable for expression analysis of membrane associated proteins under salt stress.


Steroid 21-hydroxylase gene mutational spectrum in 50 Tunisian patients: characterization of three novel polymorphisms.
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease of steroid biosynthesis in humans. More than 90% of all CAH cases are caused by mutations of the 21-hydroxylase gene (CYP21A2), and approximately 75% of the defective CYP21A2 genes are generated through an intergenic recombination with the neighboring CYP21A1P pseudogene. In this study, the CYP21A2 gene was genotyped in 50 patients in Tunisia with the clinical diagnosis of 21-hydroxylase deficiency. CYP21A2 mutations were identified in 87% of the alleles. The most common point mutation in our population was the pseudogene specific variant p.Q318X (26%). Three novel single nucleotide polymorphism (SNP) loci were identified in the CYP21A2 gene which seems to be specific for the Tunisian population. The overall concordance between genotype and phenotype was 98%. With this study the molecular basis of CAH has been characterized, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling.


Interpersonal perception and pathological personality features: consistency across peer groups.
This study investigated the consistency of interpersonal perceptions regarding people who exhibit features of personality disorders. The participants (N=82) were college students who were assessed for features of personality disorders, using both self-report and peer nominations at Time 1. Two years later, participants attended four meetings in groups of 7 to 12 people for a total of 2 hours. Group discussions were designed to encourage interaction and give participants an opportunity to behave in ways that might be expected from people with personality problems. After Meetings 1 and 4, group members ranked their impressions of each other with regard to several personality traits and behavioral attributes. We observed important consistencies between the peer nominations collected at Time 1 and personality rankings made by a different peer group at Time 2. There was considerable convergence between personality disorder features and negative evaluations by others, with participants high in detachment eliciting the most negative reactions from peers in the lab.


Tunable synthesis of self-assembled cyclic peptide nanotubes and nanoparticles.
While tremendous efforts have been made in investigating scalable approaches for fabricating nanoparticles, less progress has been made in scalable synthesis of cyclic peptide nanoparticles and nanotubes, despite their great potential for broader biomedical applications. In this paper, tunable synthesis of self-assembled cyclic peptide nanotubes and nanoparticles using three different methods, phase equilibrium, pH-driven, and pH-sensitive methods, were proposed and investigated. The goal is scalable nanomanufacturing of cyclic peptide nanoparticles and nanotubes with different sizes in large quality by controlling multiple process parameters. Cyclo-(L-Gln-D-Ala-L-Glu-D-Ala-)2 was applied to illustrate the proposed ideas. In the study, mass spectrometry and high performance liquid chromatography were employed to verify the chemical structures and purity of the cyclic peptides. Morphology and size of the synthesized nanomaterials were characterized using atomic force microscopy and dynamic light scattering. The dimensions of the self-assembled nanostructures were found to be strongly influenced by the cyclic peptide concentration, side chain modification, pH values, reaction time, stirring intensity, and sonication time. This paper proposed an overall strategy to integrate all the parameters to achieve optimal synthesis outputs. Mechanisms of the self-assembly of the cyclic peptide nanotubes and nanoparticles under variable conditions and tunable parameters were discussed. This study contributes to scalable nanomanufacturing of cyclic peptide based self-assembled nanoparticles and nanotubes for broader biomedical applications.


Immunohistochemical investigation of cytokine expression levels as biomarkers in transrectal ultrasound-guided needle biopsy specimens of prostate adenocarcinoma.
Cytokines influence the biological behaviour of prostate cancer (PC) and may influence patient outcome and serve as useful prognostic biomarkers. The aim of the present study was to evaluate cytokine expression levels in prostatic needle biopsy specimens and the association with clinicopathological characteristics of patients with PC. A total of 18 patients with PC who underwent transrectal ultrasound (TRUS) guided prostate biopsy were included in the clinical study. These patients were naïve to radiotherapy (RT) or androgen deprivation therapy prior to TRUS biopsy and clinical follow up data was collected. Cytokine expression levels were analysed by using immunohistochemistry and Spearman's correlation test was used to determine the correlation between cytokine expression and clinicopathological characteristics. Expression levels of pro-inflammatory TNF-α and IL-6 decreased as Gleason score (GS) increased; however, a statistically significant difference was not detected. A statically significant correlation was observed between needle biopsy specimen and pre-RT plasma sample expression levels of pro-inflammatory TNF-α and IL-6 (P=0.01 and P=0.05, respectively) and anti-inflammatory TGF-β1 (P=0.05). However, further studies are needed to confirm these results using a larger sample size to confirm the prognostic value of pro-inflammatory TNF-α and IL-6 and anti-inflammatory TGF-β1 in patients with PC.


[Use of methods of pattern recognition to analyze the EEG of patients with different forms of epilepsy].
The electrophysiological aspects of the pathogenesis of Kozhevnikov's epilepsy associated with tick-borne encephalitis were investigated. The study involved computerization of 114 scalp EEGs obtained from patients with this form of epilepsy who were observed in the Primorye Territory. In order to receive control data, the analogous methods were used in processing EEGs of healthy age-matched subjects and also of patients with petit mal epilepsy and with Jackson's epilepsy. The computerized analysis was carried out by means of the image recognition method. The results of this study revealed distinctive features in the nature of the spectrograms of the test subjects and showed that apart from the dependence of the power spectra on the severity of the clinical manifestations of the disease, there are some elements of homogeneity between the spectrograms of patients suffering from Kozhewnikov's epilepsy and petit mal epilepsy. This similarity appears to suggest the sommon level of the localization of the pathological impulsation foci in the patients of both groups, with objective findings supporting this assumption.


A TLR2-Activating Fraction From Mycobacterium abscessus Rough Variant Demonstrates Vaccine and Diagnostic Potential.
Mycobacterium abscessus is a prevalent pathogenic mycobacterium in cystic fibrosis (CF) patients and one of the most highly drug resistant mycobacterial species to antimicrobial agents. It possesses the property to transition from a smooth (S) to a rough (R) morphotype, thereby influencing the host innate immune response. This transition from the S to the R morphotype takes place in patients with an exacerbation of the disease and a persistence of M. abscessus. We have previously shown that the exacerbation of the Toll-like receptor 2 (TLR2)-mediated inflammatory response, following this S to R transition, is essentially due to overproduction of bacilli cell envelope surface compounds, which we were able to extract by mechanical treatment and isolation by solvent partition in a fraction called interphase. Here, we set up a purification procedure guided by bioactivity to isolate a fraction from the R variant of M. abscessus cells which exhibits a high TLR2 stimulating activity, referred to as TLR2-enriched fraction (TLR2eF). As expected, TLR2eF was found to contain several lipoproteins and proteins known to be stimuli for TLR2. Vaccination with TLR2eF showed no protection toward an M. abscessus aerosol challenge, but provided mild protection in ΔF508 mice and their FVB littermates when intravenously challenged by M. abscessus. Interestingly however, antibodies against TLR2eF compounds were detected during disease in CF patients. In conclusion, we show the potential for compounds in TLR2eF as vaccine and diagnostic candidates, in order to enhance diagnosis, prevent and/or treat M. abscessus-related infections.


Colorimetric determination of zirconium in antiperspirant aerosols.
A rapid direct dilution procedure for the estimation of soluble zirconium and a fusion procedure for the determination of total zirconium (soluble and insoluble forms) in cream base concentrates prepared from antiperspirant aerosols are described. The direct dilution procedure involves extraction of soluble zirconium with HCl (55 + 45). The filtered extract is reacted with alizarin red S to form a stable colored complex which is measured spectrophotometrically. The fusion procedure involves ashing the aerosol concentrate followed by fusion of the ash with potassium pyrosulfate to form an acid-soluble melt. Zirconium is precipitated from solution as the hydroxide and washed to eliminate interfering ions, particularly sulfate. After redissolving in HCl (55 + 45) and reacting with alizarin red S, total zirconium is measured. Zirconyl chloride octahydrate, assayed gravimetrically by hydroxide precipitation and conversion to the oxide, is used as the zirconium reference standard. Concentration range of zirconium measured was 200-500 mug/100 ml. Recoveries of standard zirconium added to commercial aerosols labeled to contain aluminum and zirconyl hydroxychlorides ranged from 97 to 101% by the fusion procedure. Analysis of these aerosols by direct dilution gave generally slightly lower results than by fusion. It is recommended that the procedures be collaboratively studied after further testing of their general applicability to a variety of drugs and cosmetics.