Tuberculosis Associated with HIV Infection.
Tuberculosis (TB) has recently surpassed HIV as the primary infectious disease killer worldwide, but the two diseases continue to display lethal synergy. The burden of TB is disproportionately borne by people living with HIV, particularly where HIV and poverty coexist. The impact of these diseases on one another is bidirectional, with HIV increasing risk of TB infection and disease progression and TB slowing CD4 recovery and increasing progression to AIDS and death among the HIV infected. Both antiretroviral therapy (ART) and latent TB infection (LTBI) treatment mitigate the impact of coinfection, and ART is now recommended for HIV-infected patients independent of CD4 count. LTBI screening should be performed for all HIV-positive people at the time of diagnosis, when their CD4 count rises above 200, and yearly if there is repeated exposure. Tuberculin skin tests (TSTs) may perform better with serial testing than interferon gamma release assays (IGRAs). Any patient with HIV and a TST induration of ≥5 mm should be evaluated for active TB disease and treated for LTBI if active disease is ruled out. Because HIV impairs multiple aspects of immune function, progressive HIV is associated with lower rates of cavitary pulmonary TB and higher rates of disseminated and extrapulmonary disease, so a high index of suspicion is important, and sputum should be obtained for evaluation even if chest radiographs are negative. TB diagnosis is similar in patients with and without TB, relying on smear, culture, and nucleic acid amplification tests, which are the initial tests of choice. TSTs and IGRAs should not be used in the evaluation of active TB disease since these tests are often negative with active disease. Though not always performed in resource-limited settings, drug susceptibility testing should be performed on all TB isolates from HIV-positive patients. Urine lipoarabinomannan testing may also be helpful in HIV-positive patients with disseminated disease. Treatment of TB in HIV-infected patients is similar to that of TB in HIV-negative patients except that daily therapy is required for all coinfected patients, vitamin B6 supplementation should be given to all coinfected patients receiving isoniazid to reduce peripheral neuropathy, and specific attention needs to be paid to drug-drug interactions between rifamycins and many classes of antiretrovirals. In patients requiring ART that contains ritonavir or cobicistat, this can be managed by the use of rifabutin at 150 mg daily in place of rifampin. For newly diagnosed coinfected patients, mortality is lower if treatment is provided in parallel, rather than serially, with treatment initiation within 2 weeks preferred for those with CD4 counts of <50 and within 8 to 12 weeks for those with higher CD4 counts. When TB immune reconstitution inflammatory syndrome occurs, patients can often be treated symptomatically with nonsteroidal anti-inflammatory drugs, but a minority will benefit from steroids. Generally, patients who do not have space-occupying lesions such as occurs in TB meningitis do not require cessation of therapy.


Influence of telopeptides, fibrils and crosslinking on physicochemical properties of type I collagen films.
Type I collagen is widely used in various different forms for research and commercial applications. Different forms of collagen may be classified according to their source, extraction method, crosslinking and resultant ultrastructure. In this study, afibrillar and reconstituted fibrillar films, derived from acid soluble and pepsin digested Type I collagen, were analysed using Lateral Force Microscopy (LFM), Fourier Transform Infra-Red Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and enzymatic stability assays to asses the influence of telopeptides, fibrils and crosslinking. LFM proved to be a useful technique to confirm an afibrillar/fibrillar ultrastructure and to elucidate fibril diameters. FTIR has proved insensitive to ultrastructural differences involving telopeptides and fibrils. DSC results showed a significant increase in T(d) for crosslinked samples (+22-28 degrees C), and demonstrated that the thermal behaviour of hydrated, afibrillar films is more akin to reconstituted fibrillar films than monomeric solutions. The enzymatic stability assay has provided new evidence to show that afibrillar films of Type I collagen can be significantly more resistant to collagenase (by up to 3.5 times), than reconstituted fibrillar films, as a direct consequence of the different spatial arrangement of collagen molecules. A novel mechanism for this phenomenon is proposed and discussed. Additionally, the presence of telopeptide regions in afibrillar tropocollagen samples has been shown to increase resistance to collagenase by greater than 3.5 times compared to counterpart afibrillar atelocollagen samples. One-factor ANOVA analysis, with Fisher's LSD post-hoc test, confirms these key findings to be of statistical significance (P < 0.05). The profound physicochemical effects of collagen ultrastructure demonstrated in this study reiterates the need for comprehensive materials disclosure and classification when using these biomaterials.


Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity.
We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM.


Brain Atrophy Following Deep Brain Stimulation: Management of a Moving Target.
A 51-year-old man with essential tremor (ET) had bilateral ventralis intermedius nucleus deep brain stimulation (VIM-DBS) placed to address refractory tremor. Despite well-placed DBS leads and adequate tremor response, he subsequently experienced worsening. Re-programming of the device and reconfirming the electrical thresholds for benefits and side effects were both performed. Six years following DBS implantation, repeat imaging revealed brain atrophy and a measured lead position change with a coincident change in clinical response. What do we know about brain atrophy affecting lead placement and long-term DBS effectiveness? What are the potential strategies to combat narrowed therapeutic thresholds and to maximize DBS therapeutic benefit? Decreasing the electrical field of stimulation and programming in a bipolar configuration are strategies to provide symptomatic tremor control and to minimize stimulation-induced side effects. Currently, effects of brain atrophy, and factors underpinning emergence of side effects and/or loss of benefit in chronic VIM-DBS remain largely unexplored.


Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function.
Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene.


Comparison of internal and external responsiveness of the generic Medical Outcome Study Short Form-36 (SF-36) with disease-specific measures in rheumatoid arthritis.
To examine the comparative internal and external responsiveness of the generic Medical Outcome Study Short Form-36 Health Survey (SF-36) and disease-specific measures in patients with rheumatoid arthritis (RA). Data were collected from 280 RA patients starting anti-tumor necrosis factor treatment. A total of 168 patients completed a questionnaire including the SF-36, the Arthritis Impact Measurement Scales 2 (AIMS2), the Health Assessment Questionnaire (HAQ), a visual analog scale for general health (VAS-GH), and an 11-point numerical rating scale for pain (NRS pain) at baseline and after 12 months. Internal responsiveness was evaluated with paired samples t-tests and standardized response means (SRM). External responsiveness was investigated with receiver-operating characteristic statistics and Spearman rank-order correlation coefficients. A health transition item was used as the external indicator of change. No significant differences in internal and external responsiveness were found between the SF-36 and disease-specific measures within the domains physical function, pain, and psychological function. In the domain social function, the SF-36 was more responsive than the AIMS2. In the domain general health, the SF-36 was less responsive (only internal) than the AIMS2 and VAS-GH. Our study showed comparable internal and external responsiveness of the SF-36 compared with disease-specific measures (AIMS2, HAQ, NRS pain) in all health domains, except social function and general health domains. The assumption that disease-specific measures are more responsive to detect intervention-related changes over time is not confirmed by our data.


[Factors associated with obesity among adolescents].
Obesity during adolescence is considered a strong predictor of adult obesity. The present study assessed the overweight/obesity prevalence and associated factors in middle class adolescents of a school in the city of Niteroi, Rio de Janeiro, Brazil, and evaluated the correlation between body mass index with anthropometric measures of fatness. The analysis covered 391 students aged from 15 to 17 years. Adolescents had their weight, height, skinfold thickness and upper arm circumference measured at school. A food frequency questionnaire (list of 79 items) and a questionnaire including food habits, parents anthropometric characteristics, physical activity and other factors associated with obesity were filled out by the adolescents at school. The proportion of overweight individuals among boys (Body Mass Index (BMI) greater than the 90th percentile of the Brazilian population) was 23.9%, whereas the prevalence among girls was 7.2%. The fact of being on a slimming diet was a relevant factor for the prediction of BMI and was 7 times more frequent among girls than among boys. Among boys, being on a diet, absence of breakfast, and family body appearance were positively associated with BMI. Among girls these variables were also significantly associated, whereas age at menarche was negatively associated with BMI. Hours of watching TV/video/video-game was associated with BMI only among boys. The correlation coefficient between BMI and measures of fatness varied from 0.7 to 0.9 for boys, and from 0.8 to 0.90 for girls. BMI appears to be a good indicator of obesity among adolescents and showed that girls demonstrated an exaggerated preoccupation with body image and stereotyped slim body patterns.


The likelihood of extinction of iconic and dominant herbivores and detritivores of coral reefs: the parrotfishes and surgeonfishes.
Parrotfishes and surgeonfishes perform important functional roles in the dynamics of coral reef systems. This is a consequence of their varied feeding behaviors ranging from targeted consumption of living plant material (primarily surgeonfishes) to feeding on detrital aggregates that are either scraped from the reef surface or excavated from the deeper reef substratum (primarily parrotfishes). Increased fishing pressure and widespread habitat destruction have led to population declines for several species of these two groups. Species-specific data on global distribution, population status, life history characteristics, and major threats were compiled for each of the 179 known species of parrotfishes and surgeonfishes to determine the likelihood of extinction of each species under the Categories and Criteria of the IUCN Red List of Threatened Species. Due in part to the extensive distributions of most species and the life history traits exhibited in these two families, only three (1.7%) of the species are listed at an elevated risk of global extinction. The majority of the parrotfishes and surgeonfishes (86%) are listed as Least Concern, 10% are listed as Data Deficient and 1% are listed as Near Threatened. The risk of localized extinction, however, is higher in some areas, particularly in the Coral Triangle region. The relatively low proportion of species globally listed in threatened Categories is highly encouraging, and some conservation successes are attributed to concentrated conservation efforts. However, with the growing realization of man's profound impact on the planet, conservation actions such as improved marine reserve networks, more stringent fishing regulations, and continued monitoring of the population status at the species and community levels are imperative for the prevention of species loss in these groups of important and iconic coral reef fishes.


Outcomes following restrictive or liberal red blood cell transfusion in patients with lower gastrointestinal bleeding.
Restrictive red blood cell (RBC) transfusion reduces mortality and rebleeding after upper gastrointestinal bleeding (UGIB). However, there is no evidence to guide transfusion strategies in lower gastrointestinal bleeding (LGIB). To assess the association between RBC transfusion strategies and outcomes in patients with LGIB METHODS: This was a post hoc analysis of the UK National Comparative Audit of LGIB and the Use of Blood. The relationships between liberal RBC transfusion and clinical outcomes of rebleeding, mortality and a composite outcome for safe discharge were examined. Transfusion strategy was dichotomised and defined as "liberal" when transfusion was administered for haemoglobin (Hb) ≥80 g/L (or ≥90 g/L in patients with acute coronary syndrome) or major haemorrhage, and "restrictive" otherwise. Multivariable logistic regression models were used to assess the independent association between liberal RBC transfusion and outcomes. Of 2528 consecutive patients enrolled from 143 hospitals in the original study, 666 (26.3%) received RBC transfusion (mean age 73.3 ± 16 years, 49% female, initial mean haemoglobin 90 ± 24 g/L, 2.3% had haemodynamic instability). The rebleeding rate in transfused patients was 42.3%. After adjusting for potential confounders, there was no difference between liberal and restrictive RBC transfusion strategies for the odds of rebleeding (OR 0.89, 95% CI 0.6-1.22), in-hospital mortality (OR 0.54, 95% CI 0.3-1.1) or of achieving the composite outcome (OR 0.72, 95% CI 0.5-1.1). Although these results could be due to residual confounding, they provide an important foundation for the design of randomised trials to evaluate transfusion strategies for LGIB.


Solvent-modulation of the structure and dimensionality in lanthanoid-anilato coordination polymers.
We show the key role that the size and shape of the solvent molecules may play in the dimensionality and structure of a series of lanthanoid-chloranilato coordination polymers. We report the synthesis, structure and magnetic properties of six different coordination polymers prepared with Er(iii) and chloranilato (C6O4Cl22- = 3,6-dichloro-2,5-dihydroxy-1,4-benzoquinone) and six different solvents: [Er2(C6O4Cl2)3(H2O)6]·10H2O (1), [Er2(C6O4Cl2)3(FMA)6]·4FMA·2H2O (2) (FMA = formamide = NH2CHO), [Er2(C6O4Cl2)3(DMSO)4]·2DMSO·2H2O (3) (DMSO = dimethy sulfoxide = Me2SO), [Er2(C6O4Cl2)3(DMF)6] (4) (DMF = dimethylformamide = Me2NCHO), [Er2(C6O4Cl2)3(DMA)4] (5) (DMA = dimethylacetamide = Me2NC(Me)O) and [Er2(C6O4Cl2)3(HMPA)(H2O)3]·H2O (6) (HMPA = hexamethylphosphormamide = (Me2N)3PO). We show how the different solvent molecules modulate and determine important structural parameters such as the coordination number and geometry, the shape and distortions of the cavities, the presence of solvent molecules in these cavities, the interlayer space and even the dimensionality of the structure.


Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review.
Until recently, food allergies to mammalian meats have been considered to be very rare. The observation that patients not previously exposed to the monoclonal chimeric antibody cetuximab suffered from severe anaphylaxis upon first exposure, led to the identification of galactose-alpha-1,3-galactose as a new relevant carbohydrate allergen. These patients later often suffered from anaphylactic reactions to red meat. Epidemiological data indicated that bites by the tick Amblyomma americanum in the USA, later also by Ixodes species in other continents, resulted in sensitisation to alpha-gal. On the other hand, in African patients with parasitic disorders, a high prevalence of anti-alpha-gal IgE, without clinical relevance, has been reported. In our four cases, one patient with a late onset of meat allergy had a history of a tick bite. The other three patients had symptoms from childhood or at a juvenile age. This indicates that in some patients, other ways of sensitisation may also take place. However, in patients without atopy, tick bite-induced IgE to alpha-gal may be more relevant. Diagnosis is based on a history of delayed onset of anaphylaxis. Skin tests with commercially available meat test solutions are often equivocal or negative; skin tests with raw meat and particularly pork kidney are more sensitive. Determination of specific IgE to alpha-gal is commercially available. The highest sensitivity is observed with skin and basophil activation tests with cetuximab which is, however, limited by its high costs.


Combined "hybrid" open and minimally invasive surgical correction of adult thoracolumbar scoliosis: a retrospective cohort study.
Surgery for scoliosis requires extensive exposure, resulting in significant tissue injury and longer recovery times. To minimize morbidity in scoliosis surgery, several studies have shown successful application of a combination of minimally invasive techniques; however, the extent of scoliosis treated has been modest. To achieve some of the benefits of minimally invasive surgery and yet treat curves of greater degree, we have used a combined approach, incorporating both open and minimally invasive techniques. We analyzed a prospectively acquired database in addition to reviewing electronic records of patients undergoing hybrid surgery for thoracolumbar scoliosis. Nine patients were identified. The minimally invasive portion involved the lumbar region in all cases. Pain was assessed by the visual analog scale and disability was measured by the Oswestry Disability Index. Mean preoperative scoliosis was 47.8 degrees, which was corrected to a mean 15.2 degrees. An average of 7.8 spinal levels was treated. Estimated blood loss averaged 1094.4 mL, and length of hospital stay averaged 7.2 days. Acute complications occurred in 2 patients. Longer term complications occurred in 2 patients, consisting of adjacent segment disease. The mean improvement in the visual analog scale score was 3.7 and the mean improvement on the Oswestry Disability Index was 30.5. Average follow-up was 29.2 months. The hybrid approach for the treatment of scoliosis results in acceptable radiographic and clinical outcomes. Complications did not appear increased compared with those expected with scoliosis surgery. Although decreased adjacent tissue injury was achieved with the minimally invasive component of the procedure, a larger comparative study is required to determine magnitude of this benefit.


Estimating the burden of smoking: premature mortality, morbidity, and costs.
Estimation of the burden of disease attributable to smoking has now become standard in documenting the impact of the tobacco epidemic and in motivating tobacco control. This paper addresses the methods used to estimate the attributable burden of mortality and the related estimation of morbidity and economic costs. Estimates of attributable mortality and morbidity for the Americas range widely, reflecting the maturity of the tobacco epidemic. The estimates are highest for the United States, and lower for Mexico and other countries of the Americas.


Symptoms of chest pain and dyspnea and factors associated with chest pain after coronary artery bypass grafting.
Patients in western Sweden who underwent CABG from 1988 to 1991 received prior to coronary angiography and 2 and 5 years after CABG a questionnaire, in which they were asked about symptoms of chest pain and dyspnea. In all, 1,226 patients answered the inquiry prior to CABG, 1,531 patients 2 years and 1,359 patients 5 years after surgery. Both in terms of chest pain and dyspnea there was a marked improvement 2 and 5 years after CABG as compared with prior to surgery. However, between 2 and 5 years after surgery there was a minor deterioration, both regarding chest pain and dyspnea. The most statistically significant preoperative predictors for the occurrence of chest pain more than twice a week 5 years after surgery were concomitant valvular heart disease and obesity.


FT-GPI, a highly sensitive and accurate predictor of GPI-anchored proteins, reveals the composition and evolution of the GPI proteome in Plasmodium species.
Protozoan parasites are known to attach specific and diverse group of proteins to their plasma membrane via a GPI anchor. In malaria parasites, GPI-anchored proteins (GPI-APs) have been shown to play an important role in host-pathogen interactions and a key function in host cell invasion and immune evasion. Because of their immunogenic properties, some of these proteins have been considered as malaria vaccine candidates. However, identification of all possible GPI-APs encoded by these parasites remains challenging due to their sequence diversity and limitations of the tools used for their characterization. The FT-GPI software was developed to detect GPI-APs based on the presence of a hydrophobic helix at both ends of the premature peptide. FT-GPI was implemented in C ++and applied to study the GPI-proteome of 46 isolates of the order Haemosporida. Using the GPI proteome of Plasmodium falciparum strain 3D7 and Plasmodium vivax strain Sal-1, a heuristic method was defined to select the most sensitive and specific FT-GPI software parameters. FT-GPI enabled revision of the GPI-proteome of P. falciparum and P. vivax, including the identification of novel GPI-APs. Orthology- and synteny-based analyses showed that 19 of the 37 GPI-APs found in the order Haemosporida are conserved among Plasmodium species. Our analyses suggest that gene duplication and deletion events may have contributed significantly to the evolution of the GPI proteome, and its composition correlates with speciation. FT-GPI-based prediction is a useful tool for mining GPI-APs and gaining further insights into their evolution and sequence diversity. This resource may also help identify new protein candidates for the development of vaccines for malaria and other parasitic diseases.


Large-scale structural analysis of the classical human protein tyrosine phosphatome.
Protein tyrosine phosphatases (PTPs) play a critical role in regulating cellular functions by selectively dephosphorylating their substrates. Here we present 22 human PTP crystal structures that, together with prior structural knowledge, enable a comprehensive analysis of the classical PTP family. Despite their largely conserved fold, surface properties of PTPs are strikingly diverse. A potential secondary substrate-binding pocket is frequently found in phosphatases, and this has implications for both substrate recognition and development of selective inhibitors. Structural comparison identified four diverse catalytic loop (WPD) conformations and suggested a mechanism for loop closure. Enzymatic assays revealed vast differences in PTP catalytic activity and identified PTPD1, PTPD2, and HDPTP as catalytically inert protein phosphatases. We propose a "head-to-toe" dimerization model for RPTPgamma/zeta that is distinct from the "inhibitory wedge" model and that provides a molecular basis for inhibitory regulation. This phosphatome resource gives an expanded insight into intrafamily PTP diversity, catalytic activity, substrate recognition, and autoregulatory self-association.


Site-specific range uncertainties caused by dose calculation algorithms for proton therapy.
The purpose of this study was to assess the possibility of introducing site-specific range margins to replace current generic margins in proton therapy. Further, the goal was to study the potential of reducing margins with current analytical dose calculations methods. For this purpose we investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict the range of proton fields. Dose distributions predicted by an analytical pencil-beam algorithm were compared with those obtained using Monte Carlo (MC) simulations (TOPAS). A total of 508 passively scattered treatment fields were analyzed for seven disease sites (liver, prostate, breast, medulloblastoma-spine, medulloblastoma-whole brain, lung and head and neck). Voxel-by-voxel comparisons were performed on two-dimensional distal dose surfaces calculated by pencil-beam and MC algorithms to obtain the average range differences and root mean square deviation for each field for the distal position of the 90% dose level (R90) and the 50% dose level (R50). The average dose degradation of the distal falloff region, defined as the distance between the distal position of the 80% and 20% dose levels (R80-R20), was also analyzed. All ranges were calculated in water-equivalent distances. Considering total range uncertainties and uncertainties from dose calculation alone, we were able to deduce site-specific estimations. For liver, prostate and whole brain fields our results demonstrate that a reduction of currently used uncertainty margins is feasible even without introducing MC dose calculations. We recommend range margins of 2.8% + 1.2 mm for liver and prostate treatments and 3.1% + 1.2 mm for whole brain treatments, respectively. On the other hand, current margins seem to be insufficient for some breast, lung and head and neck patients, at least if used generically. If no case specific adjustments are applied, a generic margin of 6.3% + 1.2 mm would be needed for breast, lung and head and neck treatments. We conclude that the currently used generic range uncertainty margins in proton therapy should be redefined site specific and that complex geometries may require a field specific adjustment. Routine verifications of treatment plans using MC simulations are recommended for patients with heterogeneous geometries.


Physician-patient communication and patient-reported outcomes in the actinic keratosis treatment adherence initiative (AK-TRAIN): a multicenter, prospective, real-life study of treatment satisfaction, quality of life and adherence to topical field-directed therapy for the treatment of actinic keratosis in Italy.
Patients with multiple actinic keratoses (AKs) should be treated with field-directed therapy. Such treatments challenge patients' adherence due to out-of-pocket costs, length of treatment and severity of local skin reactions (LSRs). Effective physician-patient communication (PPC) may buffer therapy-related distress, thus improving quality of life, treatment satisfaction and adherence. We evaluated the interplay between PPC, LSR intensity (safety) and lesion clearance rates (effectiveness) on treatment satisfaction, quality of life and treatment adherence among patients with multiple AKs receiving topical field-directed therapies. In this observational, multicentre, longitudinal, cohort study, we included 1136 adult patients with discrete, clinically detectable, visible, multiple (three or more lesions in a 25 cm2 area), Grade I/II AKs, for whom the attending dermatologist has prescribed treatment with a topical field-directed therapy. We matched self-reported data and medical information recorded by dermatologists in standard clinical forms. Patients were followed up at two time points (T1: 8 days; T2: 25-30 days) RESULTS: Most patients were elderly, married, men with poor socio-economic status and multiple lesions of the scalp or face. The majority (n = 961) had a prescription of ingenol mebutate (IMB) and 175 received either diclofenac 3% in hyaluronic acid (DHA) or imiquimod 5% (IMQ). Clearance rate at 1 month was 84%. Most patients felt very supported (n = 819, 73%) and rated dermatologist's explanations very clear (n = 608, 54%). Treatment satisfaction (effectiveness and convenience scales) increased along the follow-up, especially for those on IMB (Δpre-post = -4.00; other: Δpre-post = -0.25; interaction P < 0.001). Communication clarity was associated with higher treatment satisfaction scores (β = 0.4-0.6, P < 0.01) and lower risk of non-adherence among IMB patients (risk difference: 16%, P < 0.01). Communication clarity was associated with patient-reported outcomes and adherence beyond AK-related clinical parameters. Our study questions the current episodic approach to AK management and provides the rationale to develop chronic care models fostering patients' engagement and treatment alliance.


Genetic and molecular analysis of the GAL3 gene in the expression of the galactose/melibiose regulon of Saccharomyces cerevisiae.
During the galactose adaptation period of a Saccharomyces cerevisiae strain bearing a naturally occurring gal3 allele, we found a longer induction lag and slower rate of accumulation of GAL10 and MEL1 RNAs compared to wild-type strains. A strain of genotype gal3 gal1 gal7 is noninducible for MEL1 gene expression, but this expression block is bypassed by overexpression of the GAL4 gene or by deletion of the GAL80 gene, either of which causes a constitutive phenotype. An otherwise wild-type strain that bears a chromosomal gal3 gene disruption mutation does not produce wild-type GAL3 RNA and exhibits induction comparable to a strain bearing the naturally occurring gal3. Based on this array of results, we conclude that the GAL3 gene product executes its function at a point before GAL4 mediated transcription of the GAL1-10-7 and MEL1 genes. Thus, the data are consistent with the previously advanced hypothesis that the GAL3 gene product functions to synthesize the inducer or coinducer molecule. In experiments in which the presence of either the plasmid-carried cloned GAL3 gene or the plasmid-carried cloned GAL1-10-7 genes allows MEL1 induction of a gal3 gal1 gal7 cell, we find that loss of the plasmid results in the shutoff of MEL1 expression even when galactose is continuously present. Either GAL3 function or GAL1-10-7 functions are therefore required for both the initiation and the maintenance of the induced state. Since the strains bearing either the naturally occurring gal3 allele or the gal3 disruption (null) allele do induce, the plasmid loss experiments indicate the existence of two completely independent induction initiation-maintenance pathways, one requiring GAL3 function, the other requiring GAL1-10-7 function. Finally, Northern blot analysis reveals two major GAL3 transcripts that differ in size by approximately 500 nucleotides.


Within-plant distribution and binomial sampling of Pentalonia nigronervosa (Hemiptera: Aphididae) on banana.
The banana aphid, Pentalonia nigronervosa Coquerel (Hemiptera: Aphididae), infests banana (Musa spp.) worldwide. Pentalonia nigronervosa is the vector of Banana bunchy top virus (family Nanoviridae, genus Babuvirus) the etiological agent of Banana bunchy top disease (BBTD). BBTD is currently the most serious problem affecting banana in Hawaii. Despite the importance of this vector species, little is known about its biology or ecology. There are also no sampling plans available for P. nigronervosa. We conducted field surveys to develop a sampling plan for this pest. Ten plots were surveyed on seven commercial banana farms on the island of Oahu, HI, for the presence of P. nigronervosa on banana plantlets. We found aphids more frequently near the base of plants, followed by the newest unfurled leaf at the top of the plant. Aphids were least likely to be located on leaves in between the top and bottom of the plant. Aphid infestation on surveyed plots ranged from 8 to 95%. We developed a sequential binomial sampling plan based on our surveys. We also discovered that the within-plant distribution of P. nigronervosa is an important factor to consider when sampling for this pest. Our sampling plan will assist in the development of sustainable management practices for banana production.


Dendritic cell derived exosomes loaded with immunoregulatory cargo reprogram local immune responses and inhibit degenerative bone disease in vivo.
Chronic bone degenerative diseases represent a major threat to the health and well-being of the population, particularly those with advanced age. This study isolated exosomes (EXO), natural nano-particles, from dendritic cells, the "directors" of the immune response, to examine the immunobiology of DC EXO in mice, and their ability to reprogram immune cells responsible for experimental alveolar bone loss in vivo. Distinct DC EXO subtypes including immune-regulatory (regDC EXO), loaded with TGFB1 and IL10 after purification, along with immune stimulatory (stimDC EXO) and immune "null" immature (iDCs EXO) unmodified after purification, were delivered via I.V. route or locally into the soft tissues overlying the alveolar bone. Locally administrated regDC EXO showed high affinity for inflamed sites, and were taken up by both DCs and T cells in situ. RegDC EXO-encapsulated immunoregulatory cargo (TGFB1 and IL10) was protected from proteolytic degradation. Moreover, maturation of recipient DCs and induction of Th17 effectors was suppressed by regDC EXO, while T-regulatory cell recruitment was promoted, resulting in inhibition of bone resorptive cytokines and reduction in osteoclastic bone loss. This work is the first demonstration of DC exosome-based therapy for a degenerative alveolar bone disease and provides the basis for a novel treatment strategy.


Ortholog alleles at Xa3/Xa26 locus confer conserved race-specific resistance against Xanthomonas oryzae in rice.
The rice disease resistance (R) gene Xa3/Xa26 (having also been named Xa3 and Xa26) against Xanthomonas oryzae pv. oryzae (Xoo), which causes bacterial blight disease, belongs to a multiple gene family clustered in chromosome 11 and is from an AA genome rice cultivar (Oryza sativa L.). This family encodes leucine-rich repeat (LRR) receptor kinase-type proteins. Here, we show that the orthologs (alleles) of Xa3/Xa26, Xa3/Xa26-2, and Xa3/Xa26-3, from wild Oryza species O. officinalis (CC genome) and O. minuta (BBCC genome), respectively, were also R genes against Xoo. Xa3/Xa26-2 and Xa3/Xa26-3 conferred resistance to 16 of the 18 Xoo strains examined. Comparative sequence analysis of the Xa3/Xa26 families in the two wild Oryza species showed that Xa3/Xa26-3 appeared to have originated from the CC genome of O. minuta. The predicted proteins encoded by Xa3/Xa26, Xa3/Xa26-2, and Xa3/Xa26-3 share 91-99% sequence identity and 94-99% sequence similarity. Transgenic plants carrying a single copy of Xa3/Xa26, Xa3/Xa26-2, or Xa3/Xa26-3, in the same genetic background, showed a similar resistance spectrum to a set of Xoo strains, although plants carrying Xa3/Xa26-2 or Xa3/Xa26-3 showed lower resistance levels than the plants carrying Xa3/Xa26. These results suggest that the Xa3/Xa26 locus predates the speciation of A and C genome, which is approximately 7.5 million years ago. Thus, the resistance specificity of this locus has been conserved for a long time.


A Random Forest-Cellular Automata modelling approach to explore future land use/cover change in Attica (Greece), under different socio-economic realities and scales.
This paper explores potential future land use/cover (LUC) dynamics in the Attica region, Greece, under three distinct economic performance scenarios. During the last decades, Attica underwent a significant and predominantly unregulated process of urban growth, due to a substantial increase in housing demand coupled with limited land use planning controls. However, the recent financial crisis affected urban growth trends considerably. This paper uses the observed LUC trends between 1991 and 2016 to sketch three divergent future scenarios of economic development. The observed LUC trends are then analysed using 27 dynamic, biophysical, socio-economic, terrain and proximity-based factors, to generate transition potential maps, implementing a Random Forests (RF) regression modelling approach. Scenarios are projected to 2040 by implementing a spatially explicit Cellular Automata (CA) model. The resulting maps are subjected to a multiple resolution sensitivity analysis to assess the effect of spatial resolution of the input data to the model outputs. Findings show that, under the current setting of an underdeveloped land use planning apparatus, a long-term scenario of high economic growth will increase built-up surfaces in the region by almost 24%, accompanied by a notable decrease in natural areas and cropland. Interestingly, in the case that the currently negative economic growth rates persist, artificial surfaces in the region are still expected to increase by approximately 7.5% by 2040.


Theoretical analysis of a rotating-disk partially confocal scanning microscope.
Confocal scanning microscopy is widely used for three-dimensional (3-D) visualization of fixed specimens but has found only a limited 3-D reconstruction application for living specimens because the high intensity of the excitation often damages the specimen or causes the fluorescent dye to bleach. Computational optical-sectioning microscopy also suffers from drawbacks because nonconfocal 3-D imaging is fundamentally constrained by an artifactual elongation in the optical axis imposed by the so-called missing cone. We investigate the imaging properties of a new rotating-disk partially confocal scanning microscope (PCSM) that greatly reduces collection time by using multiple apertures for both excitation and detection, effectively working as many confocal microscopes in parallel. We show that this PCSM behaves as a hybrid microscope; near the in-focus plane it behaves near the theoretical optimum for confocal microscopy, and away from this plane its behavior approaches that of a nonconfocal microscope. We also show that the rotating-disk PCSM does not suffer from a missing cone. In fact, the optical transfer function of the theoretically optimal confocal microscope and the rotating-disk PCSM have practically the same bandpass in the spatial-frequency domain.


Carbon disulfide removal by zero valent iron.
The use of zero valent iron (Fe0) for the remediation of water contaminated with carbon disulfide (CS2), a common groundwater contaminant, has been evaluated in this study. Mineralogical analysis of Fe0 filings and polished Fe0 cross-sections indicates that iron sulfide is formed due to the removal of carbon disulfide from solution by Fe0. The kinetics of CS2 removal by Fe0 was examined through both batch and column testing, and it is demonstrated that CS2 is removed rapidly from solution. A linear relationship was observed, through batch testing, between the pseudo-first-order rate constant (k(obs)) and the surface area concentration of Fe0 (rho(a)). Data obtained from kinetic batch tests performed at four temperature levels conformed to the Arrhenius equation, and the calculated apparent activation energy (E(a)) was 37 +/- 2.3 kJ mol(-1), indicating that the kinetics of CS2 removal by Fe0 is controlled by a chemical surface reaction. The temperature correction factors for CS2 from a reference of 25 degrees C were x 1.4 for 18 degrees C, x 1.7 for 15 degrees C, x 2.0 for 12 degrees C, and x 2.3 for 9 degrees C. Surface area normalization of k(obs) obtained through batch and column testing gives specific reaction rate constants (k(SA)) within 1 order of magnitude, indicating that k(SA) values are useful as a general descriptor of CS2-Fe0 reaction kinetics and that these values provide a clear starting point for design calculations prior to commencing site-specific treatability studies for permeable reactive barrier design.


Incident hypertension and its predictors: the Isfahan Cohort Study.
The present study aimed to investigate the incidence and predictors of hypertension in an Iranian adult population. Isfahan Cohort Study was a longitudinal population-based study that was conducted on adults aged 35 years or older, living in urban and rural areas of three districts in central Iran. After 7 years of follow-up, 3283 participants were re-evaluated using a standard protocol similar to the baseline. At both measurements, participants underwent medical interview, physical examination, and fasting blood measurements. Participants (n = 833) with prevalent hypertension were excluded from the analysis, resulting in a sample size of 2450. The participants' age was 47.3 ± 9.4 years (mean ± SD) and 50.7% were men. During the follow-up period, 542 (22.1%) individuals developed hypertension, 49.6% of whom were aware of their disease, 42.4% were treated, but only 24.9% were controlled. Incidence rates have shown no sex-specific difference across age and blood pressure (BP) categories. Multivariate-adjusted model controlled for all study covariates showed that age, male sex, general and central obesity, hypertriglyceridemia, impaired fasting glucose, diabetes mellitus, baseline BP at least 120/80 mmHg (nonoptimal BP), and parental history of hypertension independently contributed to the development of hypertension. Higher education level and more than 10% decrease in waist circumference over 7-year follow-up represented protective effects. In men, weight loss decreased and weight gain increased the risk of developing hypertension. Nonoptimal BP along with central obesity and hypertriglyceridemia together were responsible for 71% of the burden of hypertension. Our findings imply that there are other factors in addition to nonoptimal BP that deserve integrating into the risk assessment criteria for developing hypertension.


Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases.
The status of cholinergic receptors in dementia is related to the question of potential cholinergic therapy. Whilst muscarinic receptor binding is generally reported to be normal or near normal, findings are reported which indicate substantial reductions of hippocampal nicotinic (high affinity nicotine) binding (occurring in conjunction with decreased choline acetyltransferase) in both Alzheimer's and Parkinson's but not Huntington's disease. A further indication that nicotinic receptor function may be abnormal in Alzheimer's disease is the extensive loss of an endogenous compound, detected for the first time in human brain, which inhibits normal nicotinic binding. Both receptor binding and the inhibitor are also substantially decreased with increasing age in the normal hippocampus.


BLR: a flexible pipeline for haplotype analysis of multiple linked-read technologies.
Linked-read sequencing promises a one-method approach for genome-wide insights including single nucleotide variants (SNVs), structural variants, and haplotyping. We introduce Barcode Linked Reads (BLR), an open-source haplotyping pipeline capable of handling millions of barcodes and data from multiple linked-read technologies including DBS, 10× Genomics, TELL-seq and stLFR. Running BLR on DBS linked-reads yielded megabase-scale phasing with low (<0.2%) switch error rates. Of 13616 protein-coding genes phased in the GIAB benchmark set (v4.2.1), 98.6% matched the BLR phasing. In addition, large structural variants showed concordance with HPRC-HG002 reference assembly calls. Compared to diploid assembly with PacBio HiFi reads, BLR phasing was more continuous when considering switch errors. We further show that integrating long reads at low coverage (∼10×) can improve phasing contiguity and reduce switch errors in tandem repeats. When compared to Long Ranger on 10× Genomics data, BLR showed an increase in phase block N50 with low switch-error rates. For TELL-Seq and stLFR linked reads, BLR generated longer or similar phase block lengths and low switch error rates compared to results presented in the original publications. In conclusion, BLR provides a flexible workflow for comprehensive haplotype analysis of linked reads from multiple platforms.


Combining modelling tools to evaluate a goose management scheme.
Many goose species feed on agricultural land, and with growing goose numbers, conflicts with agriculture are increasing. One possible solution is to designate refuge areas where farmers are paid to leave geese undisturbed. Here, we present a generic modelling tool that can be used to designate the best locations for refuges and to gauge the area needed to accommodate the geese. With a species distribution model, locations are ranked according to goose suitability. The size of the area to be designated as refuge can be chosen by including more or less suitable locations. A resource depletion model is then used to estimate whether enough resources are available within the designated refuge to accommodate all geese, taking into account the dynamics of food resources, including depletion by geese. We illustrate this with the management scheme for pink-footed goose Anser brachyrhynchus implemented in Norway. Here, all geese can be accommodated, but damage levels appear to depend on weather, land use and refuge size.


The spindle assembly checkpoint: progress and persistent puzzles.
The spindle assembly checkpoint is a conserved mitotic signalling pathway that ensures the equal segregation of chromosomes to daughter cells. Despite intensive work in many model organisms, key features of this safety mechanism remain unexplained. In the present review, I briefly summarize advances made in the last few years, and then focus on unexplored corners of this signalling pathway.


Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials.
The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency. We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups. We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2-<4%, 32% for those with counts of 4-<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV1) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count. Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies. GlaxoSmithKline (study ID 201595).


Identification of a novel nutrient-sensing histidine kinase/response regulator network in Escherichia coli.
When carbon sources become limiting for growth, bacteria must choose which of the remaining nutrients should be used first. We have identified a nutrient-sensing signaling network in Escherichia coli that is activated at the transition to stationary phase. The network is composed of the two histidine kinase/response regulator systems YehU/YehT and YpdA/YpdB and their target proteins, YjiY and YhjX (both of which are membrane-integrated transporters). The peptide/amino acid-responsive YehU/YehT system was found to have a negative effect on expression of the target gene, yhjX, of the pyruvate-responsive YpdA/YpdB system, while the YpdA/YpdB system stimulated expression of yjiY, the target of the YehU/YehT system. These effects were confirmed in mutants lacking any of the genes for the three primary components of either system. Furthermore, an in vivo interaction assay based on bacterial adenylate cyclase detected heteromeric interactions between the membrane-bound components of the two systems, specifically, between the two histidine kinases and the two transporters, which is compatible with the formation of a larger signaling unit. Finally, the carbon storage regulator A (CsrA) was shown to be involved in posttranscriptional regulation of both yjiY and yhjX.


Depletion-mode carrier-plasma optical modulator in zero-change advanced CMOS.
We demonstrate the first (to the best of our knowledge) depletion-mode carrier-plasma optical modulator fabricated in a standard advanced complementary metal-oxide-semiconductor (CMOS) logic process (45 nm node SOI CMOS) with no process modifications. The zero-change CMOS photonics approach enables this device to be monolithically integrated into state-of-the-art microprocessors and advanced electronics. Because these processes support lateral p-n junctions but not efficient ridge waveguides, we accommodate these constraints with a new type of resonant modulator. It is based on a hybrid microring/disk cavity formed entirely in the sub-90 nm thick monocrystalline silicon transistor body layer. Electrical contact of both polarities is made along the inner radius of the multimode ring cavity via an array of silicon spokes. The spokes connect to p and n regions formed using transistor well implants, which form radially extending lateral junctions that provide index modulation. We show 5 Gbps data modulation at 1265 nm wavelength with 5.2 dB extinction ratio and an estimated 40 fJ/bit energy consumption. Broad thermal tuning is demonstrated across 3.2 THz (18 nm) with an efficiency of 291 GHz/mW. A single postprocessing step to remove the silicon handle wafer was necessary to support low-loss optical confinement in the device layer. This modulator is an important step toward monolithically integrated CMOS photonic interconnects.


A Higher Rate of Pulmonary Fungal Infection in Chronic Obstructive Pulmonary Disease Patients with Influenza in a Large Tertiary Hospital.
Influenza is considered a self-limiting disease. However, in patients with chronic obstructive pulmonary disease (COPD), it may result in serious outcomes during the flu season. The aims of this retrospective study were to explore the characteristics of hospitalized patients with COPD complicated by influenza and determine the factors affecting the prognosis of these patients. Demographic and clinical data were collected for 278 patients totally from the West China Hospital between January 1, 2016 and February 28, 2018. Among the patients with influenza, the positive fungal culture rate, and the rates of antifungal drug and systemic corticosteroids use were higher for those with COPD than for those without COPD. Respiratory failure was more common in patients with influenza and COPD than in patients with influenza only, while the proportion of severe cases was higher among the former than among the latter. Among the patients with COPD, the positive fungal culture rate, particularly for Aspergillus, and the rate of systemic corticosteroids use were higher for those with influenza than for those without influenza. Multivariate analysis revealed that a COPD history of >20 years and smoking for >20 pack-years were independent factors for susceptibility of COPD patients to influenza. Aspergillus infection seems to be more common in patients with influenza and COPD. In addition, COPD complicated by influenza during the seasonal outbreak can easily progress to a severe disease state. Heavy smokers and patients with a prolonged COPD history are more likely to be infected by influenza.


Seroprevalence of Trypanosoma cruzi Infection in Schoolchildren and in Pregnant Women from an Amazonian Region in Orellana Province, Ecuador.
Chagas disease is a parasitic disease caused by the protozoan parasite Trypanosoma cruzi and about 230,000 persons are estimated to be infected in Ecuador. However, limited studies have been performed in the Amazon region, on the eastern side of the country. We evaluated here the seroprevalence of Trypanosoma cruzi infection in 12 rural villages of the Loreto canton, Orellana Province in schoolchildren aged 5-15 years and in pregnant women. A total of 1,649 blood samples were tested for Trypanosoma cruzi antibodies by enzyme-linked immunosorbent assay and indirect hemaglutination, and discordant samples were tested by indirect immunofluorescence assay. We detected a seroprevalence of anti-Trypanosoma cruzi antibodies of 1.3% in schoolchildren aged 5-15 years, indicating the persistence of a constant and active vectorial transmission in the Loreto County and confirming the need of the implementation of nonconventional vector control. We also observed a seroprevalence of 3.8% in pregnant women, indicating a clear risk of congenital transmission. Further studies should help define this risk more precisely and implement current international guidelines for the diagnosis, treatment, and care of these cases.


Progressive Representation Adaptation for Weakly Supervised Object Localization.
We address the problem of weakly supervised object localization where only image-level annotations are available for training object detectors. Numerous methods have been proposed to tackle this problem through mining object proposals. However, a substantial amount of noise in object proposals causes ambiguities for learning discriminative object models. Such approaches are sensitive to model initialization and often converge to undesirable local minimum solutions. In this paper, we propose to overcome these drawbacks by progressive representation adaptation with two main steps: 1) classification adaptation and 2) detection adaptation. In classification adaptation, we transfer a pre-trained network to a multi-label classification task for recognizing the presence of a certain object in an image. Through the classification adaptation step, the network learns discriminative representations that are specific to object categories of interest. In detection adaptation, we mine class-specific object proposals by exploiting two scoring strategies based on the adapted classification network. Class-specific proposal mining helps remove substantial noise from the background clutter and potential confusion from similar objects. We further refine these proposals using multiple instance learning and segmentation cues. Using these refined object bounding boxes, we fine-tune all the layer of the classification network and obtain a fully adapted detection network. We present detailed experimental validation on the PASCAL VOC and ILSVRC datasets. Experimental results demonstrate that our progressive representation adaptation algorithm performs favorably against the state-of-the-art methods.


Enhanced stability and performance of few-layer black phosphorus transistors by electron beam irradiation.
Few layer black phosphorus (BP) has recently emerged as a potential graphene analogue due to its high mobility and direct, appreciable, band gap. The fabrication and characterization of field effect transistors (FETs) involves exposure of the channel material to an electron beam (e-beam) in imaging techniques such as transmission electron microscopy (TEM) and scanning electron microscopy (SEM), and fabrication techniques like electron beam lithography (EBL). Despite this, the effect of e-beam irradiation on BP-FET performance has not been studied experimentally. In this work, we report the first experimental study on the impact of e-beam irradiation on BP-FETs. An electron beam is known to induce defects and structural changes in 2D materials like graphene, MoS2etc. resulting in the deterioration of the device quality. However, for BP-FETs, we observe an improvement in the on-current and carrier mobility (μ) along with a decrease in threshold voltage (Vth) on exposure to an e-beam with 15 keV energy for 80 seconds. These changes can be attributed to the capture of electrons by traps near the SiO2-BP interface and reduced BP surface roughness due to e-beam exposure. Hysteresis measurements and physical characterization (i.e. atomic force microscopy (AFM), X-ray photoelectron (XPS) and Raman spectroscopies) validate these mechanisms. Reduced hysteresis indicates occupation of the traps, AFM surface scans indicate reduced surface roughness and XPS data show a reduced phosphorus oxide (POx) peak immediately after exposure. Raman measurements indicate a probable structural change due to the interaction between e-beam and BP which could result in better stability.


Progression of hair loss in men with androgenetic alopecia (male pattern hair loss): long-term (5-year) controlled observational data in placebo-treated patients.
Relatively little is known about the progression of androgenetic alopecia (AGA; male pattern hair loss) in untreated men. We evaluated the long-term (5-year) progression of AGA in men treated with placebo in a controlled clinical trial setting. We analyzed pooled data over 5 years from two replicate studies with finasteride 1 mg/day in men with predominantly vertex-pattern AGA. Each study consisted of an initial 1-year, randomized, double-blind, placebo-controlled base study and four consecutive, 1-year, double-blind, placebo-controlled extension studies. Change over time in scalp hair growth was evaluated by four predefined endpoints: scalp hair counts; assessment of standardized clinical photographs by an expert panel; investigator clinical assessment; and patient self-assessment. All four predefined endpoints demonstrated progressive scalp hair loss in men receiving placebo over the 5-year study period, with a loss of 239 hairs from baseline (26.3% decline in hair density) measured in the target area at 5 years (p < 0.001 vs. baseline). Similarly, visible progression of scalp hair loss was demonstrated by global photographic assessment, with 75% of placebo patients rated as worsened from baseline at 5 years. We found that scalp hair loss continued in a progressive manner over a 5-year period in placebo-treated men with AGA.


Invasive Esophageal Candidiasis with Chronic Mediastinal Abscess and Fatal Pneumomediastinum.
BACKGROUND Invasive candidiasis is a potential problem for patients receiving long-term immunosuppressive treatment. Psoriatic arthritis is one of many chronic diseases that can be successfully treated with immunosuppressive drugs, in spite of a documented and accepted risk for infectious complications. Critical awareness of possible infection must be part of the surveillance of such patients. CASE REPORT This is the case of a 68-year-old Norwegian male, treated with long-term immunosuppression for psoriatic arthritis, hospitalized with acute subcutaneous and mediastinal emphysema of unknown cause. He died of acute respiratory failure with circulatory collapse shortly after admission. The autopsy revealed mediastinal and subcutaneous emphysema and a mediastinal abscess containing Candida with probable entrance from the esophagus. CONCLUSIONS We consider invasive candidiasis of the esophagus to be the cause of both the chronic abscess and the acute mediastinal emphysema. This case illustrates the importance of awareness of invasive candidiasis as a possible complication in a patient with long-term immunosuppression.


Family history of atrial fibrillation as a predictor of atrial substrate and arrhythmia recurrence in patients undergoing atrial fibrillation catheter ablation.
A commonly held notion is that patients with a family history of atrial fibrillation (AF) have worse atrial substrate and higher rates of arrhythmia recurrence following ablation. We sought to examine differences in atrial substrate and catheter ablation outcomes in patients with a 1st degree family member with paroxysmal or persistent AF (PeAF) compared to those without. A total of 256 consecutive patients undergoing their 1st ablation for AF (123 paroxysmal, 133 persistent) with >1 year follow up were included. The presence of one 1st-degree family relative was defined as a 'positive family history'. Clinical characteristics, electroanatomic map findings, ablation characteristics and outcomes were compared in patients with and without a positive family history of AF. Patients with paroxysmal fibrillation with a positive family history (n = 57; 46%) had similar clinical characteristics and arrhythmia recurrence after catheter ablation as those without. Of those that recurred, patients with a positive family history were more likely to have progressed to PeAF (P = 0.05). Patients with PeAF with a positive family history (n = 75; 56%) had similar clinical characteristics, electroanatomic mapping findings and ablation characteristics, but worse long term arrhythmia free survival (P = 0.04). The presence of a 1st-degree family member with AF does not impact the clinical outcomes of catheter ablation for paroxysmal AF. However, a positive family history is associated with worse arrhythmia free survival in patients with PeAF. This finding is not explained by differences in clinical characteristics, atrial substrate assessed by voltage maps or ablation characteristics.


Pretreatment Mean Apparent Diffusion Coefficient Is Significantly Correlated With Event-Free Survival in Patients With International Federation of Gynecology and Obstetrics Stage Ib to IIIb Cervical Cancer.
To assess the prognostic impact of the pretreatment mean apparent diffusion coefficient (ADCmean) values of tumors obtained by diffusion-weighted magnetic resonance imaging. We evaluated the prognostic value of the ADCmean for event-free survival (EFS) and overall survival (OS) among patients with uterine cervical cancer. We included 171 patients diagnosed as having International Federation of Gynecology and Obstetrics stage Ib to IIIb cervical cancer by pretreatment magnetic resonance imaging scans, regardless of therapeutic methods. In all patients and in patients with squamous cell carcinoma (SCC; n = 123), the optimal cutoff values of the tumor ADCmean for EFS and for OS were determined, respectively. The prognostic significance of the ADCmean was evaluated using univariate and multivariate Cox regression analyses. In the univariate analyses, the ADCmean values were significantly associated with negative effects on EFS both in all patients and in patients with SCC, while not being significantly associated with OS in both groups. In the multivariate analysis, ADCmean was an independent biomarker for EFS (P < 0.05) in patients with SCC along with lymph node metastasis and definitive surgery, whereas ADCmean was not independently significant in EFS in all patients. The pretreatment ADCmean value of the tumor was an independent prognostic factor for EFS in International Federation of Gynecology and Obstetrics stage Ib to III SCC of the uterine cervix.


Campylobacter fetus subsp. jejuni in a turkey processing plant.
Cecal cultures taken over a 1-year period from 600 turkeys at a poultry processing plant were all positive for Campylobacter fetus subsp. jejuni. Swabs of the cloaca and fresh feces were likewise all positive. Of 33 freshly dressed turkey carcases, 94% were positive before chilling in tanks of chlorinated ice and water; 34% of 83 carcasses were still positive after overnight soaking in the tanks. Increasing the chlorine content from 50 to 340 ppm (50 to 340 micrograms/ml) did not cause a decrease in the number of positive carcasses. C. fetus subsp. jejuni was isolated from wastewater gutters as well as from chutes and conveyor belts in the packaging room. Water samples from the five water treatment lagoons for the plant were all positive for C. fetus subsp. jejuni while the plant was in operation, but 4 days after the plant closed for the winter, all water samples were negative.


Draft genome assembly of the Bengalese finch, Lonchura striata domestica, a model for motor skill variability and learning.
Vocal learning in songbirds has emerged as a powerful model for sensorimotor learning. Neurobehavioral studies of Bengalese finch (Lonchura striata domestica) song, naturally more variable and plastic than songs of other finch species, have demonstrated the importance of behavioral variability for initial learning, maintenance, and plasticity of vocalizations. However, the molecular and genetic underpinnings of this variability and the learning it supports are poorly understood. To establish a platform for the molecular analysis of behavioral variability and plasticity, we generated an initial draft assembly of the Bengalese finch genome from a single male animal to 151× coverage and an N50 of 3.0 MB. Furthermore, we developed an initial set of gene models using RNA-seq data from 8 samples that comprise liver, muscle, cerebellum, brainstem/midbrain, and forebrain tissue from juvenile and adult Bengalese finches of both sexes. We provide a draft Bengalese finch genome and gene annotation to facilitate the study of the molecular-genetic influences on behavioral variability and the process of vocal learning. These data will directly support many avenues for the identification of genes involved in learning, including differential expression analysis, comparative genomic analysis (through comparison to existing avian genome assemblies), and derivation of genetic maps for linkage analysis. Bengalese finch gene models and sequences will be essential for subsequent manipulation (molecular or genetic) of genes and gene products, enabling novel mechanistic investigations into the role of variability in learned behavior.


Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection.
Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 x 10(-6)), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.


Genomic signatures predict poor outcome in undifferentiated pleomorphic sarcomas and leiomyosarcomas.
Undifferentiated high-grade pleomorphic sarcomas (UPSs) display aggressive clinical behavior and frequently develop local recurrence and distant metastasis. Because these sarcomas often share similar morphological patterns with other tumors, particularly leiomyosarcomas (LMSs), classification by exclusion is frequently used. In this study, array-based comparative genomic hybridization (array CGH) was used to analyze 20 UPS and 17 LMS samples from untreated patients. The LMS samples presented a lower frequency of genomic alterations compared with the UPS samples. The most frequently altered UPS regions involved gains at 20q13.33 and 7q22.1 and losses at 3p26.3. Gains at 8q24.3 and 19q13.12 and losses at 9p21.3 were frequently detected in the LMS samples. Of these regions, gains at 1q21.3, 11q12.2-q12.3, 16p11.2, and 19q13.12 were significantly associated with reduced overall survival times in LMS patients. A multivariate analysis revealed that gains at 1q21.3 were an independent prognostic marker of shorter survival times in LMS patients (HR = 13.76; P = 0.019). Although the copy number profiles of the UPS and LMS samples could not be distinguished using unsupervised hierarchical clustering analysis, one of the three clusters presented cases associated with poor prognostic outcome (P = 0.022). A relative copy number analysis for the ARNT, SLC27A3, and PBXIP1 genes was performed using quantitative real-time PCR in 11 LMS and 16 UPS samples. Gains at 1q21-q22 were observed in both tumor types, particularly in the UPS samples. These findings provide strong evidence for the existence of a genomic signature to predict poor outcome in a subset of UPS and LMS patients.


Phylogenomics using Target-Restricted Assembly Resolves Intrageneric Relationships of Parasitic Lice (Phthiraptera: Columbicola).
Parasitic "wing lice" (Phthiraptera: Columbicola) and their dove and pigeon hosts are a well-recognized model system for coevolutionary studies at the intersection of micro- and macroevolution. Selection on lice in microevolutionary time occurs as pigeons and doves defend themselves against lice by preening. In turn, behavioral and morphological adaptations of the lice improve their ability to evade host defense. Over macroevolutionary time wing lice tend to cospeciate with their hosts; yet, some species of Columbicola have switched to new host species. Understanding the ecological and evolutionary factors that influence coadaptation and codiversification in this system will substantially improve our understanding of coevolution in general. However, further work is hampered by the lack of a robust phylogenetic framework for Columbicola spp. and their hosts. Previous attempts to resolve the phylogeny of Columbicola based on sequences from a few genes provided limited support. Here, we apply a new approach, target restricted assembly, to assemble 977 orthologous gene sequences from whole-genome sequence data generated from very small, ethanol-preserved specimens, representing up to 61 species of wing lice. Both concatenation and coalescent methods were used to estimate the species tree. These two approaches yielded consistent and well-supported trees with 90% of all relationships receiving 100% support, which is a substantial improvement over previous studies. We used this new phylogeny to show that biogeographic ranges are generally conserved within clades of Columbicola wing lice. Limited inconsistencies are probably attributable to intercontinental dispersal of hosts, and host switching by some of the lice. [aTRAM; coalescent; coevolution; concatenation; species tree.].


Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial.
Concerns regarding the risk of estrogen replacement have resulted in a significant increase in the use of soy products by menopausal women who, despite the lack of evidence of the efficacy of such products, seek alternatives to menopausal hormone therapy. Our goal was to determine the efficacy of soy isoflavone tablets in preventing bone loss and menopausal symptoms. The study design was a single-center, randomized, placebo-controlled, double-blind clinical trial conducted from July 1, 2004, through March 31, 2009. Women aged 45 to 60 years within 5 years of menopause and with a bone mineral density T score of -2.0 or higher in the lumbar spine or total hip were randomly assigned, in equal proportions, to receive daily soy isoflavone tablets, 200 mg, or placebo. The primary outcome was changes in bone mineral density in the lumbar spine, total hip, and femoral neck at the 2-year follow-up. Secondary outcomes included changes in menopausal symptoms, vaginal cytologic characteristics, N -telopeptide of type I bone collagen, lipids, and thyroid function. After 2 years, no significant differences were found between the participants receiving soy tablets (n = 122) and those receiving placebo (n = 126) regarding changes in bone mineral density in the spine (-2.0% and -2.3%, respectively), the total hip (-1.2% and -1.4%, respectively), or the femoral neck (-2.2% and -2.1%, respectively). A significantly larger proportion of participants in the soy group experienced hot flashes and constipation compared with the control group. No significant differences were found between groups in other outcomes. In this population, the daily administration of tablets containing 200 mg of soy isoflavones for 2 years did not prevent bone loss or menopausal symptoms. clinicaltrials.gov Identifier: NCT00076050.


Temporal organization of the cell cycle.
The coordination of growth, DNA replication and division in proliferating cells can be adequately explained by a 'clock + checkpoint' model. The clock is an underlying cyclical sequence of states; the checkpoints ensure that the cycle proceeds without mistakes. From the molecular complexities of the control system in modern eukaryotes, we isolate a simple network of positive and negative feedbacks that embodies a 'clock + checkpoints'. The model accounts for the fundamental physiological properties of mitotic cell divisions, evokes a new view of the meiotic program, and suggests how the control system may have evolved in the first place.


Evaluation of pneumonia in children: comparison of MRI with fast imaging sequences at 1.5T with chest radiographs.
Although there has been a study aimed at magnetic resonance imaging (MRI) evaluation of pneumonia in children at a low magnetic field (0.2T), there is no study which assessed the efficacy of MRI, particularly with fast imaging sequences at 1.5T, for evaluating pneumonia in children. To investigate the efficacy of chest MRI with fast imaging sequences at 1.5T for evaluating pneumonia in children by comparing MRI findings with those of chest radiographs. This was an Institutional Review Board-approved, HIPPA-compliant prospective study of 40 consecutive pediatric patients (24 boys, 16 girls; mean age 7.3 years ± 6.6 years) with pneumonia, who underwent PA and lateral chest radiographs followed by MRI within 24 h. All MRI studies were obtained in axial and coronal planes with two different fast imaging sequences: T1-weighted FFE (Fast Field Echo) (TR/TE: 83/4.6) and T2-weigthed B-FFE M2D (Balanced Fast Field Echo Multiple 2D Dimensional) (TR/TE: 3.2/1.6). Two experienced pediatric radiologists reviewed each chest radiograph and MRI for the presence of consolidation, necrosis/abscess, bronchiectasis, and pleural effusion. Chest radiograph and MRI findings were compared with Kappa statistics. All consolidation, lung necrosis/abscess, bronchiectasis, and pleural effusion detected with chest radiographs were also detected with MRI. There was statistically substantial agreement between chest radiographs and MRI in detecting consolidation (k = 0.78) and bronchiectasis (k = 0.72) in children with pneumonia. The agreement between chest radiographs and MRI was moderate for detecting necrosis/abscess (k = 0.49) and fair for detecting pleural effusion (k = 0.30). MRI with fast imaging sequences is comparable to chest radiographs for evaluating underlying pulmonary consolidation, bronchiectasis, necrosis/abscess, and pleural effusion often associated with pneumonia in children.


INTERFERENCE IN VISUAL RECOGNITION.
Pictures of common objects, coming slowly into focus, were viewed by adult observers. Recognition was delayed when subjects first viewed the pictures out of focus. The greater or more prolonged the initial blur, the slower the eventual recognition. Interference may be accounted for partly by the difficulty of rejecting incorrect hypotheses based on substandard cues.


Vitamin D3 and K2 and their potential contribution to reducing the COVID-19 mortality rate.
The world is desperately seeking for a sustainable solution to combat the coronavirus strain SARS-CoV-2 (COVID-19). Recent research indicated that optimizing Vitamin D blood levels could offer a solution approach that promises a heavily reduced fatality rate as well as solving the public health problem of counteracting the general vitamin D deficiency. This paper dived into the immunoregulatory effects of supplementing Vitamin D3 by elaborating a causal loop diagram. Together with D3, vitamin K2 and magnesium should be supplemented to prevent long-term health risks. Follow up clinical randomized trials are required to verify the current circumstantial evidence.


Anion exchanger 1b in stereocilia is required for the functioning of mechanotransducer channels in lateral-line hair cells of zebrafish.
The anion exchanger (AE) plays critical roles in physiological processes including CO2 transport and volume regulation in erythrocytes and acid-base regulation in renal tubules. Although expression of the AE in inner-ear hair cells was reported, its specific localization and function are still unclear. Using in situ hybridization, we found that the AE1b transcript is expressed in lateral-line hair cells of zebrafish larvae. An immunohistochemical analysis with a zebrafish-specific antibody localized AE1b to stereocilia of hair cells, and the expression was eliminated by morpholino knockdown of AE1b. A non-invasive, scanning ion-selective electrode technique was applied to analyze mechanotransducer (MET) channel-mediated Ca2+ influx at stereocilia of hair cells of intact fish. Ca2+ influx was effectively suppressed by AE1b morpholino knockdown and inhibitor (DIDS) treatment. Elevating external Ca2+ (0.2 to 2 mM) neutralized the inhibition of DIDS. Taken together, this study provides solid evidence to show that AE1b in stereocilia is required for the proper functioning of MET channels.


Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice.
Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1(+/+) and trpa1(-/-) mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1(-/-) mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.


Reproducibility of Volumetric Computed Tomography of Stable Small Pulmonary Nodules with Implications on Estimated Growth Rate and Optimal Scan Interval.
To use clinically measured reproducibility of volumetric CT (vCT) of lung nodules to estimate error in nodule growth rate in order to determine optimal scan interval for patient follow-up. We performed quantitative vCT on 89 stable non-calcified nodules and 49 calcified nodules measuring 3-13 mm diameter in 71 patients who underwent 3-9 repeat vCT studies for clinical evaluation of pulmonary nodules. Calculated volume standard deviation as a function of mean nodule volume was used to compute error in estimated growth rate. This error was then used to determine the optimal patient follow-up scan interval while fixing the false positive rate at 5%. Linear regression of nodule volume standard deviation versus the mean nodule volume for stable non-calcified nodules yielded a slope of 0.057 ± 0.002 (r2 = 0.79, p<0.001). For calcified stable nodules, the regression slope was 0.052 ± 0.005 (r2 = 0.65, p = 0.03). Using this with the error propagation formula, the optimal patient follow-up scan interval was calculated to be 81 days, independent of initial nodule volume. Reproducibility of vCT is excellent, and the standard error is proportional to the mean calculated nodule volume for the range of nodules examined. This relationship constrains statistical certainty of vCT calculated doubling times and results in an optimal scan interval that is independent of the initial nodule volume.


Homologues of the Cf-9 disease resistance gene (Hcr9s) are present at multiple loci on the short arm of tomato chromosome 1.
The tomato Cf-4 and Cf-9 genes map at a genetically complex locus on the short arm of chromosome 1 and confer resistance against Cladosporium fulvum through recognition of different pathogen-encoded avirulence determinants. Cf-4 and Cf-9 are members of a large gene family (Hcr9s, Homologues of Cladosporium fulvum resistance gene Cf-9), some of which encode additional distinct recognition specificities. A genetic analysis of the majority of Hcr9s suggests that their distribution is spatially restricted to the short arm of chromosome 1. Two loci of clustered Hcr9 genes have been analyzed physically that mapped distal (Northern Lights) and proximal (Southern Cross) to the Cf-4/9 locus (Milky Way). Sequence homologies between intergenic regions at Southern Cross and Milky Way indicate local Hcr9 duplication preceded cluster multiplication. The multiplication of clusters involved DNA flanking Hcr9 sequences as indicated by conserved lipoxygenase sequences at Southern Cross and Milky Way. The similar spatial distribution of Hcr9 clusters in different Lycopersicon spp. suggests Hcr9 cluster multiplication preceded speciation.


Polyneuropathy in critically ill patients.
Five patients developed a severe motor and sensory polyneuropathy at the peak of critical illness (sepsis and multiorgan dysfunction complicating a variety of primary illnesses). Difficulties in weaning from the ventilator as the critical illness subsided and the development of flaccid and areflexic limbs were early clinical signs. However, electrophysiological studies, especially needle electrode examination of skeletal muscle, provided the definite evidence of polyneuropathy. The cause is uncertain, but the electrophysiological and morphological features indicate a primary axonal polyneuropathy with sparing of the central nervous system. Nutritional factors may have played a role, since the polyneuropathy improved in all five patients after total parenteral nutrition had been started, including the three patients who later died of unrelated causes. The features allow diagnosis during life, and encourage continued intensive management since recovery from the polyneuropathy may occur.


Effects of anti-insulin receptor antibodies on in vivo insulin metabolism.
The effects of anti-insulin receptor antibodies (AIRA) on receptor binding and insulin metabolism were studied in two patients with the type B, severe insulin resistance syndrome. Insulin binding was determined using rat hepatocytes in primary culture and the patient's own red blood cells. Plasma and urinary insulin concentrations and metabolic clearance rates (MCR) were determined in the two patients and in four normal controls in response to infusions of insulin for 60-120 min at rates ranging from 1 to 925 mU/kg/min. In patient 1, basal insulin concentration was 1400 microU/ml. After infusion of 1, 10, and 925 mU/kg/min of insulin it rose to 3800, 5500, and 225,000 microU/ml, respectively. Respective MCRs were 19, 110, and 186 ml/min. In patient 2, basal insulin concentration was 440 microU/ml. After infusion of 1, 10, and 100 mU/kg/min of insulin it rose to 720, 2500, and 18,800 microU/ml, respectively. Respective MCRs were 193, 262, and 294 ml/min. In controls, basal insulin concentration was 4 +/- 0.3 microU/ml. After infusion of 1 and 10 mU/kg/min of insulin, it rose to 82 +/- 17 and 1288 +/- 50 microU/ml. Respective MCRs were 950 and 630 ml/min. These data showed that, in patients with AIRA: (1) insulin metabolism took place at the same rate but at higher insulin concentrations than in normal controls, and (2) MCR increased with rising insulin concentration but remained subnormal even at the highest insulin concentrations. In contrast, MCR in normal controls decreased with increasing insulin concentrations. The data suggest that prevention of insulin binding prevents insulin metabolism at physiologic insulin concentrations and that supraphysiologically elevated insulin concentrations are needed to activate nonreceptor mechanisms.


Mutational and structural analysis of an ancestral fungal dye-decolorizing peroxidase.
Dye-decolorizing peroxidases (DyPs) constitute a superfamily of heme-containing peroxidases that are related neither to animal nor to plant peroxidase families. These are divided into four classes (types A, B, C, and D) based on sequence features. The active site of DyPs contains two highly conserved distal ligands, an aspartate and an arginine, the roles of which are still controversial. These ligands have mainly been studied in class A-C bacterial DyPs, largely because no effective recombinant expression systems have been developed for the fungal (D-type) DyPs. In this work, we employ ancestral sequence reconstruction (ASR) to resurrect a D-type DyP ancestor, AncDyPD-b1. Expression of AncDyPD-b1 in Escherichia coli results in large amounts of a heme-containing soluble protein and allows for the first mutagenesis study on the two distal ligands of a fungal DyP. UV-Vis and resonance Raman (RR) spectroscopic analyses, in combination with steady-state kinetics and the crystal structure, reveal fine pH-dependent details about the heme active site structure and show that both the aspartate (D222) and the arginine (R390) are crucial for hydrogen peroxide reduction. Moreover, the data indicate that these two residues play important but mechanistically different roles on the intraprotein long-range electron transfer process. DATABASE: Structural data are available in the PDB database under the accession number 7ANV.


Tinnitus and suicide: An unresolved relation.
Tinnitus is an auditory phantom sensation which can be a devastating condition for the affected person causing annoyance and discomfort. It may be associated with psychiatric conditions. Patients with highly annoying tinnitus and different comorbidities may have a higher risk of expressing suicidal behaviour and ideation. We aimed to review available reports on the prevalence of suicide and suicidal behaviour with tinnitus patients in order to collate current concepts and to identify possible alarming signs and risk factors. A comprehensive search for appropriate studies listed in PubMed, Ovid and Cochrane databases was conducted using appropriate keyword combinations. We identified 22 publications including original articles, case reports and reviews of which 10 fit our stringent search criteria. Most importantly, from the present studies it appears not feasible to univocally conclude on the co-incidence of tinnitus and suicide. This is due to methodological differences in these approaches, complex interrelations between tinnitus and other psychiatric comorbidities and confounding factors such as the inclusion of patients suffering from post-traumatic stress disorder. More concerted actions involving different medical disciplines are needed to reflect the ethiological heterogeneity of tinnitus and suicide or suicidal behaviour to test for a relationship.


["To Milena" (A essay of narrative medicine)].
Narrative medicine is becoming an increasingly popular way of communicating medical problems. This a letter that the author sends to a recently deceased patient. He describes his apprehensions on the use of invasive forms of diagnosis or treatments and the use of repeated hospital admissions in the context of a chronic and progressive disease. He also discusses the use of methods to "accelerate" death in suffering patients. He finally describes the dignity of his patient to face a chronic and debilitating condition.


Ketamine improves nasogastric tube insertion.
Nasogastric (NG) intubation is one of the most common procedures performed in the emergency department (ED) and other hospital settings. The aim of this study was to compare the level of pain during NG tube insertion in groups receiving local ketamine plus water-soluble lubricating gel and water-soluble lubricating gel alone (the latter is the common practice in our hospital). It was hypothesised that ketamine has local anaesthetic effects in reducing the pain of NG tube insertion in the ED. This prospective double-blind randomised clinical trial was performed on alert haemodynamically stable subjects aged >18 years who required NG tube placement for diagnostic or therapeutic purposes in the ED of a teaching hospital during January and June 2008. The subjects were divided into two groups using randomised allocation software. The ketamine group received intranasal ketamine, while an equivalent volume of sterile water was instilled into the nasal cavity in the control group. The same amount of lubricating gel was used in both groups. The pain of NG tube placement was measured using a standard 100 mm visual analogue scale (VAS). The physician was asked to evaluate the difficulty of the procedure using a 5-point Likert scale. Seventy-two subjects were enrolled in the study (36 subjects in each group). There was a significant difference between the pain score of the ketamine and control groups (19.03+/-3.56 vs 33.33+/-5.31), while the difficulty score was not statistically different between the two groups (2.39+/-1.25 vs 2.78+/-1.56). Intranasal ketamine is an effective agent in reducing pain during NG tube insertion among patients without serious underlying illness.


Pain quality descriptors and sex-related differences in patients with shoulder pain.
Pain quality assessment is applicable to pain evaluation and treatment. However, shoulder pain quality descriptors mostly remain unknown. Furthermore, sex-related differences considerably affect clinical pain experience. The aim of this study was to investigate pain quality descriptors and to compare sex-related differences in using pain descriptors among patients with shoulder pain. A sample of 120 patients (41 males and 79 females) with shoulder pain was recruited from Department of Physical Medicine and Rehabilitation. Shoulder pain quality descriptors were investigated using a 36-item pain quality list. Sex-related differences in the number and frequency of pain quality descriptors were compared using independent t-test and X2 test, respectively. Fifteen commonly used shoulder pain quality descriptors were identified. Among them, "sore" was the most frequently used, followed by "pulled". Deep pain sensations (eg, sore, pulled, torsion, and taut) were relatively more predominant than superficial pain sensations (eg, pricking and lacerating). In terms of sex-related differences, female patients used more pain quality descriptors than the male patients (5.5 vs 3.7, P<0.001). The frequency of paroxysmal, dullness, and constriction-related pain quality descriptors, such as "shooting", "faint", "clicking", and "squeezing", were higher in females than in males (all P<0.05). The results provide commonly used shoulder pain quality descriptors that are useful for assessing shoulder pain and for developing a new shoulder pain assessment tool. Because the shoulder pain quality profiles differed between male and female participants, clinicians and researchers should consider sex-related differences in assessing and treating shoulder pain.


Protective effect of ascorbic acid and Ginkgo biloba against learning and memory deficits caused by fluoride.
Fluoride is present in the ground water, World Health Organization permitted level of fluoride in the ground water is 0.5 ppm. Tooth pastes, mouth washes, tea and sea fish are the sources of fluoride. Exposure to these multiple sources results in several adverse effects in addition to the fluorosis. The present study aimed to test the effect of vitamin C and Ginkgo biloba against the behavioural deficits caused by fluoride. Rats were divided into five groups with six animals in each group (n = 6). Control group received ordinary tap water with 0.5 ppm of fluoride, the remaining groups received 100 ppm of fluoride for 30 days prior to fluoride exposure. Two groups of animals received 100 mg/kg body weight of vitamin C and G. biloba for 15 days prior to fluoride exposure. After 45 days, behavioural studies (T-Maze, passive avoidance) were conducted on the experimental animals. The results of the present study showed no behavioural deficits in the control group of animals however, the rats that received fluoride water exhibited impairment in their spatial learning and memory deficits. The deficits are not marked in the vitamin C and G. biloba groups. To conclude chronic exposure to high levels of fluoride causes severe impairment in the spatial learning and memory, these deficits can be ameliorated with the vitamin C and G. biloba.