Microorganism identification by matrix-assisted laser/desorption ionization mass spectrometry and model-derived ribosomal protein biomarkers.
An improved data analysis method is described for rapid identification of intact microorganisms from MALDI-TOF-MS data. The method makes no use of mass spectral fingerprints. Instead, a microorganism database is automatically generated that contains biomarker masses derived from ribosomal protein sequences and a model of N-terminal Met loss. We quantitatively validate the method via a blind study that seeks to identify microorganisms with known ribosomal protein sequences. We also include in the database microorganisms with incompletely known sets of ribosomal proteins to test the specificity of the method. With an optimal MALDI protocol, and at the 95% confidence level, microorganisms represented in the database with 20 or more biomarkers (i.e., those with complete or nearly completely sequenced genomes) are correctly identified from their spectra 100% of the time, with no incorrect identifications. Microorganisms with seven or less biomarkers (i.e., incompletely sequenced genomes) are either not identified or misidentified. Robustness with respect to variations in sample preparation protocol and mass analysis protocol is demonstrated by collecting data with two different matrixes and under two different ion-mode configurations. Statistical analysis suggests that, even without further improvement, the method described here would successfully scale up to microorganism databases with roughly 1000 microorganisms. The results demonstrate that microorganism identification based on proteome data and modeling can perform as well as methods based on mass spectral fingerprinting.


Serum uric acid and its correlates in Chinese adult populations, urban and rural, of Beijing. The PRC-USA Collaborative Study in Cardiovascular and Cardiopulmonary Epidemiology.
Reports on serum uric acid (SUA) levels in Chinese populations are sparse, but there is evidence that hyperuricaemia and gout are not uncommon. This paper characterizes SUA levels, their correlates, and their relationship to blood pressure (BP) and prevalent high blood pressure (HBP) for urban and rural adult population samples in north China. In 1987-1988, a cross-sectional study was carried out, using standardized methods, on men and women aged 40.58 in a Beijing area urban steel mill (N = 2013) and on rural farms (1507). Main outcome measures were SUA, systolic and diastolic blood pressure (SBP, DBP), and prevalent HBP (SBP > or = 140 or DBP > or = 90 mmHg or receiving an antihypertensive drug). Mean SUA levels for men were 5.75 mg/dl in urban and 5.58 mg/dl in rural settings; for women, 4.67 and 4.48 mg/dl. Mean values were higher with age in women, but not in men. Age-standardized prevalence rates of HBP were significantly higher in upper SUA strata (men > or = 7.00, women > or = 6.00 mg/dl) than lower SUA strata both with and without inclusion of those on antihypertensive drugs. Mean SUA levels were correspondingly higher in hypertensive than non-hypertensive people. In multiple regression analyses, body mass index and serum triglycerides were strongly associated with SUA. Also SBP, DBP, and HBP were generally associated with SUA for the whole population sample, with smaller coefficients after excluding those on antihypertensive drugs. However, in these multivariate analyses the strength of the association was low order. In addition to its strong association with body mass index, SUA is independently related to serum lipids, particularly triglycerides, and to serum glucose. While some of the univariate relation of SUA to BP is apparently due to the strong relation of body mass to both SUA and BP, a low order significant relation between SUA and BP remains with control for BMI.


Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells.
Hepatocyte growth factor (HGF) plays a plethora of roles in cancer metastasis and tumour growth. The interaction between tumour cells and their surrounding stromal environment is a crucial factor regulating tumour invasion and metastasis. Stromal fibroblasts are the main source of HGF in the body, and release HGF as an inactive precursor (pro-HGF). HGF activator (HGFA), matriptase, urokinase-type plasminogen activator and hepsin are the main factors responsible for converting pro-HGF into active HGF. HAI-1 and HAI-2 are 2 novel Kunitz-type serine protease inhibitors that regulate HGF activity through inhibition of HGFA, matriptase and hepsin action. Recent studies demonstrate that HAI-1 and HAI-2 may also potently inhibit a number of other pro-metastatic serine proteases and therefore have direct bearing on the spread of tumours. Our study examined the potential of these HAI's to suppress the influence of HGF and regulate cancer metastasis. We generated a retroviral expression system that induced HAI expression in a human fibroblast cell line. Forced expression of either HAI-1 or HAI-2 in these fibroblasts resulted in a dramatic decrease in the production of bioactive hepatocyte growth factor (HGF). This reduction in HGF activity subsequently suppressed HGF's metastatic influence on breast cancer cells. To further assess the anti-cancer properties of HAI-1 and HAI-2 we generated recombinant HAI proteins. These recombinant HAI proteins possessed the ability to potently quench HGF activity. We also demonstrate that these recombinant HAI's suppressed fibroblast-mediated breast cancer invasion. An additional ribozyme transgenes study revealed that elimination of HAI-1 and HAI-2 expression, in an MDA-MB-231 breast cancer cell line, significantly enhanced the migratory, proliferative and invasive nature of these breast cancer cells. Overall, our data demonstrates the important roles of HAI-1 and HAI-2 in cancer metastasis, and reveals that these serine protease inhibitors display strong therapeutic potential.


Mitochondrial and nuclear genetic analyses of the tropical black-lip rock oyster (Saccostrea echinata) reveals population subdivision and informs sustainable aquaculture development.
The black-lip rock oyster (Saccostrea echinata) has considerable potential for aquaculture throughout the tropics. Previous attempts to farm S. echinata failed due to an insufficient supply of wild spat; however, the prospect of hatchery-based aquaculture has stimulated renewed interest, and small-scale farming is underway across northern Australia and in New Caledonia. The absence of knowledge surrounding the population genetic structure of this species has raised concerns about the genetic impacts of this emerging aquaculture industry. This study is the first to examine population genetics of S. echinata and employs both mitochondrial cytochrome c oxidase subunit I gene (COI) and single nucleotide polymorphism (SNP) markers. The mitochondrial COI data set included 273 sequences of 594 base pair length, which comprised 74 haplotypes. The SNP data set included 27,887 filtered SNPs for 272 oysters and of these 31 SNPs were identified as candidate adaptive loci. Data from the mitochondrial COI analyses, supports a broad tropical Indo-Pacific distribution of S. echinata, and showed high haplotype and nucleotide diversities (0.887-1.000 and 0.005-0.008, respectively). Mitochondrial COI analyses also revealed a 'star-like' haplotype network, and significant and negative neutrality tests (Tajima's D = - 2.030, Fu's Fs = - 25.638, P < 0.001) support a recent population expansion after a bottleneck. The SNP analyses showed significant levels of population subdivision and four genetic clusters were identified: (1) the Noumea (New Caledonia) sample location; (2) the Bowen (north Queensland, Australia) sample location, and remaining sample locations in the Northern Territory, Australia (n = 8) were differentiated into two genetic clusters. These occurred at either side of the Wessel Islands and were termed (3) 'west' and (4) 'east' clusters, and two migrant individuals were detected between them. The SNP data showed a significant positive correlation between genetic and geographic distance (Mantel test, P < 0.001, R2 = 0.798) and supported isolation by distance. Three candidate adaptive SNPs were identified as occurring within known genes and gene ontology was well described for the sex peptide receptor gene. Data supports the existence of genetically distinct populations of S. echinata, suggesting that management of wild and farmed stocks should be based upon multiple management units. This research has made information on population genetic structure and connectivity available for a new aquaculture species.


Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy Males.
Depression, anxiety, and/or panic disorder are often comorbid and have a complex etiology mediated through the same neuronal network. Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. The CCK-4 challenge model is an accepted method of investigating the pathophysiology of panic and has been shown to mediate neuronal activation via the transient receptor potential canonical (TRPC) ion channels. This study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced anxiety/panic-like symptoms and evaluate circuit engagement. Twenty healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, randomized, two-way cross-over, single dose, placebo-controlled trial. Randomization was to oral BI 1358894 100 mg in the fed state followed by oral placebo in the fed state, or vice versa. Treatments were administered 5 h prior to intravenous CCK-4 50 µg. The primary endpoint was maximum change from baseline of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. Further endpoints included the emotional faces visual analog score (EVAS), the Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 1358894 was assessed based on a number of parameters including occurrence of adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints were analyzed using descriptive statistics. Single oral doses of BI 1358894 were generally well tolerated by the healthy male volunteers included in this study. Adjusted mean maximum change from baseline in PSS sum intensity score was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 1358894 vs placebo). The STAI total score before CCK-4 injection was similar in both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of special interest, AEs leading to discontinuation of trial medication, or deaths. Overall, BI 1358894 reduced psychological and physiological responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and objectively measured stress biomarkers. BI 1358894 had a positive safety profile, and single oral doses were well tolerated by the healthy volunteers. This trial (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.


Animal model for colorectal cancer.
The development of a satisfactory rodent model for cancer of the large intestine began with the discovery by Laqueur and associates in 1962 that the plant product, cycasin (methylazoxymethanol glycoside), is a potent carcinogen for rodents. Soon after that, DMH, AOM, and MAM were found to be even more efficient intestinal carcinogens in rats. These three compounds, plus two direct acting carcinogens (MNNG, MNU) are used almost exclusively in current animal investigations. Although all these chemicals have some degree of activity in all rodents, they are most effective in rats. Various rat strains differ somewhat in susceptibility, Sprague-Dawley being the most sensitive to these carcinogens. Cancers of the large intestine in the animal model resemble adenocarcinomas in humans, and they spread in a similar manner except that metastases to the liver and lung are very uncommon in animals. Animal studies support epidemiological and human experimental observations of dietary factors involved in colorectal cancer formation. Most physicians believe that the majority of colorectal cancers develop from preexisting adenomas. Morson has shown that large adenomas and villous adenomas have a greater risk of developing cancer than small adenomas. Hill has theorized that there are different factors responsible for the formation of small adenomas from normal mucosa, for the growth of small to large adenomas, and for the development of cancer from large adenomas. Animal studies provide some support for this concept. Weak intestinal carcinogens tend to induce more benign adenomas than carcinomas. Very small doses of strong carcinogens also induce some adenomas and a few early polypoid intestinal cancers after a long latent period. Moderate to large amounts of DHM, for example, induce only malignant lesions even when these lesions are as small as 1 mm. These observations suggest a relationship between adenomas and carcinomas. There is also biochemical evidence to support the staged progression of carcinogenesis. An example is the graded increases in ODC activity that occur in tissues undergoing tumorigenesis.


HSP60 Regulates Monosodium Urate Crystal-Induced Inflammation by Activating the TLR4-NF-κB-MyD88 Signaling Pathway and Disrupting Mitochondrial Function.
Acute gout is an inflammatory response induced by monosodium urate (MSU) crystals. HSP60 is a highly conserved stress protein that acts as a cellular "danger" signal for immune reactions. In this study, we aimed to investigate the role and molecular mechanism of HSP60 in gout. HSP60 expression was detected in peripheral blood mononuclear cells (PBMCs) and plasma of gout patients. The effect and molecular mechanism of HSP60 in gout were studied in MSU crystals treatment macrophages and C57BL/6 mice. JC-1 probe and MitoSOX Red were used to measure the mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (mtROS). HSP60 expression was significantly upregulated in the PBMCs and sera of patients with acute gout (AG) compared to those with intercritical gout (IG) or healthy controls (HCs). MSU crystals induced the expression and secretion of HSP60 in the macrophages. HSP60 knockdown or overexpression affects TLR4 and MyD88 expression, IκBα degradation, and the nuclear localization of NF-κB in MSU crystal-stimulated inflammation. Further, HSP60 facilitates MMP collapse and mtROS production and activates the NLRP3 inflammasome in MSU crystal-stimulated macrophages. In MSU crystal-induced arthritis mouse models pretreated with HSP60 vivo-morpholino, paw swelling, myeloperoxidase (MPO) activity, and inflammatory cell infiltration significantly decreased. Our study reveals that MSU crystal stimulates the expression of HSP60, which accelerates the TLR4-MyD88-NF-κB signaling pathway and exacerbates mitochondrial dysfunction.


Baseline, Cross-sectional Survey of Knowledge, Attitudes, and Practices Related to Efficient Use of Government Resources in the Health Sector in Malawi.
Misuse of government resources is a challenge within the health sector that can be addressed by increasing public demand for accountability, reporting suspected misuse of resources, and other client-driven changes. This study was led by the USAID/Health Communication for Life Project to inform the design of social accountability communication messages and interventions. The study also established baseline data on Malawians' knowledge, attitudes, and practices related to efficient use of government resources in the health sector. This baseline, formative research study used a non-experimental, cross sectional survey design. Sampling for the mobile survey was conducted using the random digit dialing technique. Data were collected via mobile phone using interactive voice response technology. Our sample included 1,425 respondents, 67% of whom were male and 33% were female. Respondents were mostly 35 years old or younger, with more than half of female respondents reporting their age as 18-24 years. Our findings indicate that Malawians believe misuse of government resources is pervasive in Malawi. Seventy percent of men and nearly 60% of women reported having noticed, found, or seen drugs believed to be from a government health facility being sold elsewhere. Few respondents who had observed or experienced misuse of government health sector resources reported the incident. When asked the likelihood that they would report a request for a bribe, gift, or favor in exchange for health services in the future, 68% of respondents said they would report it. Social and behavior change communication could serve a key role in motivating those who are aware of misuse of public sector health resources to report the issues they observe and providing them with the information needed to follow through. Further research is needed to understand the best approaches to mitigate underlying factors that drive misuse of resources and underreporting.


The Impact of COVID-19 on Patients With Cancer: A National Study of Patient Experiences.
The coronavirus disease 2019 (COVID-19) pandemic abruptly disrupted cancer care. The impact of these disruptions on patient experiences remain relatively understudied. The objective of this study was to assess patients' perspectives regarding the impact of COVID-19 on their experiences, including their cancer care, emotional and mental health, and social determinants of health, and to evaluate whether these outcomes differed by cancer stage. We conducted a survey among adults with cancer across the United States from April 1, 2020 to August 26, 2020 using virtual snowball sampling strategy in collaboration with professional organizations, cancer care providers, and patient advocacy groups. We analyzed data using descriptive statistics, χ2 and t tests. Three hundred twelve people with cancer participated and represented 38 states. The majority were non-Hispanic White (n=183; 58.7%) and female (n=177; 56.7%) with median age of 57 years. Ninety-one percent spoke English at home, 70.1% had health insurance, and 67% had access to home internet. Breast cancer was the most common diagnosis (n=67; 21.5%). Most had Stage 4 disease (n=80; 25.6%). Forty-six percent (n=145) experienced a change in their care due to COVID-19. Sixty percent (n=187) reported feeling very or extremely concerned that the pandemic would affect their cancer and disproportionately experienced among those with advanced cancer stages compared with earlier stages (P<0.001). Fifty-two percent (n=162) reported impact of COVID-19 on 1 or more aspects of social determinants of health with disproportionate impact among those with advanced cancer stages compared with earlier stages. COVID-19 impacted the care and well-being of patients with cancer and this impact was more pronounced among people with advanced cancer stages. Future work should consider tailored interventions to mitigate the impact of COVID-19 on patients with cancer.


A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma.
The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.


Detecting and defusing cognitive traps: metacognitive intervention in schizophrenia.
Until recently, psychological therapy for schizophrenia was considered harmful or inefficient by many clinicians. The reservation against psychotherapy is partly rooted in the assumption that delusions in particular and schizophrenia in general are not amenable to psychological understanding and represent 'utter madness'. However, meta-analyses suggest that cognitive intervention is effective in ameliorating schizophrenia symptoms. In addition, evidence has accumulated that cognitive biases, such as jumping to conclusions, are involved in the pathogenesis of schizophrenia positive symptoms, particularly delusions. A recently developed group program, called metacognitive training (MCT), is presented targeting these biases. MCT is a hybrid of psychoeducation, cognitive remediation and cognitive-behavioural therapy. This review introduces new evidence on cognitive biases involved in the pathogenesis of schizophrenia and demonstrates how the MCT raises the patients' (metacognitive) awareness to detect and defuse such 'cognitive traps'. At the end, a new individualized variant entitled MCT+ is presented targeting individual delusional ideas. Finally, empirical results are summarized that speak in favour of the feasibility and efficacy of MCT. Recent studies assert marked cognitive biases in schizophrenia. MCT has evolved as a feasible and effective complement of standard psychiatric treatment.


Monocytes can be induced by lipopolysaccharide-triggered T lymphocytes to express functional factor VII/VIIa protease activity.
In the present study we demonstrate that human monocytes can be induced by the model stimulus, lipopolysaccharide (LPS), to produce and assemble on their surface functional Factor VII/VIIa. This protease was not induced in relatively purified monocytes alone following exposure to LPS; but was induced in the presence of Leu-3a positive helper/inducer T cells. The Factor VII/VIIa protease activity represented 35-40% of the potential initiating activity for the extrinsic coagulation pathway and was demonstrated using functional coagulation assays, as well as in amidolytic assays for the activation of Factor X. This activity of cell-bound Factor VII/VIIa appeared to involve a tight adduct of calcium. The identity of the Factor X-activating protease as Factor VII/VIIa was confirmed by the capacity of antibody specific for Factor VII/VIIa to neutralize the cell-bound protease. Further propagation of the extrinsic pathway following generation of Factor Xa required addition of exogenous Factor Va. These results expand the repertoire of proteases that have been identified with appropriately triggered cells of the monocyte/macrophage series, and suggest that initiation and propagation of the extrinsic coagulation protease network on induced monocytes involves not only expression of the initiating cofactor molecule, tissue factor, but also production of Factor VII and its organization into the molecular assembly. Thus, in the absence of exogenous Factor VII/VIIa a directly proteolytic effector cell can be generated. Further molecular assembly of the extrinsic pathway on the monocyte surface sequentially expands the proteolytic capacity of this response. The synthesis and assembly of the extrinsic activation complex by the monocyte and its derived progeny, the macrophage, provides a mechanism by which coagulation is initiated under T cell instruction at sites of immunologic responses.


Anti-neurofascin autoantibody and demyelination.
Demyelination diseases involving the central and peripheral nervous systems are etiologically heterogeneous with both cell-mediated and humoral immunities playing pathogenic roles. Recently, autoantibodies against nodal and paranodal proteins, such as neurofascin186 (NF186), neurofascin155 (NF155), contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1) and gliomedin, have been discovered in not only chronic demyelinating conditions, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy, but also in acute demyelinating conditions, such as Guillain-Barré syndrome. Only a minority of these patients harbor anti-nodal/paranodal protein antibodies; however, these autoantibodies, especially IgG4 subclass autoantibodies to paranodal proteins, are associated with unique features and these conditions are collectively termed nodopathy or paranodopathy. Establishing a concept of IgG4-related nodopathy/paranodopathy contributes to diagnosis and treatment strategy because IgG4 autoantibody-related neurological diseases are often refractory to conventional immunotherapies. IgG4 does not fix complements, or internalize the target antigens, because IgG4 exists in a monovalent bispecific form in vivo. IgG4 autoantibodies can bock protein-protein interaction. Thus, the primary role of IgG4 anti-paranodal protein antibodies may be blockade of interactions between NF155 and CNTN1/CASPR1, leading to conduction failure, which is consistent with the sural nerve pathology presenting paranodal terminal loop detachment from axons with intact internodes in the absence of inflammation. However, it still remains to be elucidated how these autoantibodies belonging to the same IgG4 subclass can cause each IgG4 autoantibody-specific manifestation. Another important issue is to clarify the mechanism by which IgG4 antibodies to nodal/paranodal proteins emerge. IgG4 antibodies develop on chronic antigenic stimulation and can block antibodies that alleviate allergic inflammation by interfering with the binding of allergen-specific IgE to allergens. Thus, environmental antigens cross-reacting with nodal and paranodal proteins may warrant future study.


The effects of phorbol ester, diacylglycerol, phospholipase C and Ca2+ ionophore on protein phosphorylation in human and sheep erythrocytes.
Treatment of human or sheep erythrocytes with PMA (phorbol myristate acetate) enhanced [32P]phosphate labelling of membrane polypeptides of approx. 100, 80 and 46 kDa. The 80 kDa and 46 kDa polypeptides coincided with bands 4.1 and 4.9 respectively on Coomassie-Blue-stained gels. Similar but smaller effects were obtained by treating human cells with 1-oleoyl-2-acetyl-rac-glycerol (OAG), exogenous bacterial phospholipase C or ionophore A23187 + Ca2+, each of which treatments would be expected to raise the concentration of membrane diacylglycerol. In contrast, sheep cells, which do not increase their content of diacylglycerol when treated with phospholipase C or A23187 + Ca2+, only showed enhanced phosphorylation with OAG. Neither human nor sheep cells showed any enhanced [32P]phosphate labelling of phosphoproteins when treated with 1-mono-oleoyl-rac-glycerol. It is concluded that diacylglycerol from a variety of sources can activate erythrocyte protein kinase C, but that the most effective diacylglycerol is that derived from endogenous polyphosphoinositides. In contrast with bacterial phospholipase C and A23187, which stimulate synthesis of phosphatidate by increasing the cell-membrane content of diacylglycerol in human erythrocytes, PMA, OAG or 1-mono-oleoyl-rac-glycerol caused no change in phospholipid metabolism.


Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials.
The randomized clinical trials, RE-LY, ROCKET-AF, and ARISTOTLE, demonstrate that the novel oral anticoagulants (NOACs) are effective options for stroke prevention among non-valvular atrial fibrillation (AF) patients. This study aimed to evaluate the medical cost reductions associated with the use of individual NOACs instead of warfarin from the US payer perspective. Rates for efficacy and safety clinical events for warfarin were estimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE trials, and event rates for NOACs were determined by applying trial hazard ratios or relative risk ratios to such weighted averages. Incremental medical costs to a US health payer of an AF patient experiencing a clinical event during 1 year following the event were obtained from published literature and inflation adjusted to 2010 cost levels. Medical costs, excluding drug costs, were evaluated and compared for each NOAC vs warfarin. Sensitivity analyses were conducted to determine the influence of variations in clinical event rates and incremental costs on the medical cost reduction. In a patient year, the medical cost reduction associated with NOAC usage instead of warfarin was estimated to be -$179, -$89, and -$485 for dabigatran, rivaroxaban, and apixaban, respectively. When clinical event rates and costs were allowed to vary simultaneously, through a Monte Carlo simulation, the 95% confidence interval of annual medical costs differences ranged between -$424 and +$71 for dabigatran, -$301 and +$135 for rivaroxaban, and -$741 and -$252 for apixaban, with a negative number indicating a cost reduction. Of the 10,000 Monte-Carlo iterations 92.6%, 79.8%, and 100.0% were associated with a medical cost reduction >$0 for dabigatran, rivaroxaban, and apixaban, respectively. Usage of the NOACs, dabigatran, rivaroxaban, and apixaban may be associated with lower medical (excluding drug costs) costs relative to warfarin, with apixaban having the most substantial medical cost reduction.


Cross-sectional and longitudinal relations among peer-reported trustworthiness, social relationships, and psychological adjustment in children and early adolescents from the United Kingdom and Canada.
Trustworthiness was examined in children and early adolescents from two countries. In Study 1,505 children in the fifth and sixth school years in the United Kingdom (mean age = 9 years 7 months) were tested across an 8-month period. In Study 2,350 sixth- through eighth-grade Canadian children and early adolescents (mean age = 12 years 11 months) were tested across a 1-year period. Participants completed measures assessing trustworthiness (ratings of promise and secret keeping by peer group and also by best friend in Study 1), assertiveness (Study 1), prosocial behavior (Study 2), social relationships (friendships and peer preference), and psychological adjustment (self-esteem, depressive symptoms, and loneliness). Peer-reported trustworthiness was positively associated with, and predicted changes across time in, the number of friendships. The observed relations were found to be statistically independent of peer preference and peer-reported assertiveness or prosocial behavior. Trustworthiness was found to be positively associated with peer preference (Study 1 and Study 2) and psychological adjustment (Study 1).


Dermabacter jinjuensis sp. nov., a novel species of the genus Dermabacter isolated from a clinical specimen.
A Gram-stain-positive, catalase-positive, facultatively anaerobic, non-motile, coryneform bacterium, designated strain 32T, was isolated from a closed pus sample from a patient having finger necrosis in Korea. Strain 32T was considered as representing a novel species according to its initial identification by matrix-assisted laser desorption/ionization-time-of-flight MS. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 32T belonged to the genus Dermabacter and was closely related to Dermabacter hominis DSM 7083T (=ATCC 49369T) (98.34 % similarity). Optimal growth was observed at 30-40 °C and pH 7. Growth occurred in the presence of 0-6 % (w/v) NaCl. Menaquinones MK-8, MK-7 and MK-9 were the major respiratory quinones. The major polar lipids were phosphatidylethanolamine, phosphatidylcholine, glycolipid and two unknown lipids. The major cellular fatty acids were anteiso-C17 : 0, anteiso-C15 : 0, iso-C16 : 0 and iso-C15 : 0. The DNA G+C content of strain 32T was 62.58 mol%, and the mean level of DNA-DNA relatedness between strain 32T and D. hominis ATCC 49369T was 49±1.6 %. Based on the phenotypic and genotypic characteristics, strain 32T is confirmed to represent a novel species of the genus Dermabacter, for which the name Dermabacter jinjuensis sp. nov. is proposed. The type strain is 32T (=NCCP 16133T=DSM 101003T).


[Automatic analysis of systolic time intervals using polygraphic examinations].
For clinical purpose, poligraphyc signals are analyzed: systolic time intervals (STI) and all other significative magnitudes are measured. A system of modular programs (ATS), in Assembler and Fortran IV languages, digitalizes, filters and analyzes three simultaneous analogical signals: ECG, PCK and CP. ATS, adapted polynomial and gonyometrics leats-squares smoothings to the signals for leaving-out spikes and drifts, employs algorhythms that, by a statistic knowledge of the thresholds of the fist derivative of each signal and of the globality of smoothed signals, converge to the measures of the required significative magnitudes. A statistic investigation (on 100 samples) showed that ATS is better than every manual analysis in terms of efficiency, speed and amount of information. In conclusion ATS program is suitable for clinical purposes.


[Role of the auditory cortex in the formation of complex reflexes to amplitude-modulated stimuli in rats].
Motor alimentary conditioned reflexes to acoustic stimuli were elaborated in 27 laboratory rats. After bilateral ablation of the auditory cortex, differentiation of tonal stimuli from amplitude-modulated (AM) signals with a 5 c/s modulation frequency was completely abolished, without its subsequent restoration in six months after the operation. Differentiation of tonal from AM-stimuli with a 50 and 500 c/s modulation frequency, however, not only persists, but is elaborated in animals with a preliminarily ablated auditory cortex. Results of the investigation permit to draw the conclusion that the auditory cortex is the centre where the coding of stimuli with a low frequency of amplitude modulation is completed. Correspondingly, the structural organization of the sensory part of the arc of conditioned responses to different classes of AM-stimuli is discussed.


Physiological properties of newly formed synapses between sympathetic preganglionic neurons and sympathetic ganglion neurons.
We have examined the physiological properties of transmission at newly formed synapses between sympathetic preganglionic neurons and sympathetic ganglion neurons in vitro. Chick neurons were labeled with fluorescent carbocyanine dyes before they were placed into culture (Honig and Hume, 1986), and were studied by making intracellular recordings during the first 2 weeks of coculture. Evoked monosynaptic excitatory postsynaptic potentials (EPSPs) were not observed until 48 h of coculture. Beyond this time, the frequency with which connected pairs could be found did not vary greatly with time. With repetitive stimulation, the evoked monosynaptic EPSPs fluctuated in amplitude from trial to trial and showed depression at frequencies as low as 1 Hz. To gain further information about the quantitative properties of transmission at newly formed synapses, we analyzed the pattern of fluctuations of delayed release EPSPs. In mature systems, delayed release EPSPs are known to represent responses to single quanta, or to the synchronous release of a small number of quanta. For more than half of the connections we studied, the histograms of delayed release EPSPs were extremely broad. This result suggested that either quantal responses are drawn from a continuous distribution that has a large coefficient of variation or that there are several distinct size classes of quantal responses. The pattern of fluctuations of monosynaptic EPSPs was consistent with both of these possibilities, and was inconsistent with the possibility that monosynaptic EPSPs are composed of quantal subunits with very little intrinsic variation. Although variation in the size of responses to single quanta might arise in a number of ways, one attractive explanation for our results is that the density and type of acetylcholine receptors varies among the different synaptic sites on the surface of developing sympathetic ganglion neurons.


A safety study evaluating non-COVID-19 mortality risk following COVID-19 vaccination.
The safety of COVID-19 vaccines plays an important role in addressing vaccine hesitancy. We conducted a large cohort study to evaluate the risk of non-COVID-19 mortality after COVID-19 vaccination while adjusting for confounders including individual-level demographics, clinical risk factors, health care utilization, and community-level socioeconomic risk factors. The retrospective cohort study consisted of members from seven Vaccine Safety Datalink sites from December 14, 2020 through August 31, 2021. We conducted three separate analyses for each of the three COVID-19 vaccines used in the US. Crude non-COVID-19 mortality rates were reported by vaccine type, age, sex, and race/ethnicity. The counting process model for survival analyses was used to analyze non-COVID-19 mortality where a new observation period began when the vaccination status changed upon receipt of the first dose and the second dose. We used calendar time as the basic time scale in survival analyses to implicitly adjust for season and other temporal trend factors. A propensity score approach was used to adjust for the potential imbalance in confounders between the vaccinated and comparison groups. For each vaccine type and across age, sex, and race/ethnicity groups, crude non-COVID-19 mortality rates among COVID-19 vaccinees were lower than those among comparators. After adjusting for confounders with the propensity score approach, the adjusted hazard ratios (aHRs) were 0.46 (95% confidence interval [CI], 0.44-0.49) after dose 1 and 0.48 (95% CI, 0.46-0.50) after dose 2 of the BNT162b2 vaccine, 0.41 (95% CI, 0.39-0.44) after dose 1 and 0.38 (95% CI, 0.37-0.40) after dose 2 of the mRNA-1273 vaccine, and 0.55 (95% CI, 0.51-0.59) after receipt of Ad26.COV2.S. While residual confounding bias remained after adjusting for several individual-level and community-level risk factors, no increased risk was found for non-COVID-19 mortality among recipients of three COVID-19 vaccines used in the US.


NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus.
Sigma-1 receptors (σ-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of σ-1Rs is their ability to interact and modulate a large number of voltage- and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for σ-1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective σ-1R agonists (+)-SKF 10,047 [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (+)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that σ-1R activation leads to an increased interaction between GluN2 subunits and σ-1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that σ-1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke.


Arthrocentesis and soft tissue aspiration and injection.
Accessing a joint with a needle (arthrocentesis) to extract synovial fluid is a skill intrinsic to the rheumatologist's praxis. Joint aspirations are essential for diagnosing or excluding septic joints, are the gold standard for diagnosing acute crystal arthritis, and can provide valuable information about the nature of other forms of arthritis. In appropriate settings, injecting medications into joints can provide rapid, temporary, or even prolonged relief of pain and swelling and can provide a window of relief until other treatment modalities (anti-inflammatories, immunomodulators, and physical therapy) can enforce durable responses. Soft tissue aspirations (e.g., of bursae) and soft tissue injections (of bursae, tendons, trigger points, and areas of nerve compression) can provide similar relief, earning the practitioner the gratitude of the patient. Here, we provide a primary on joint and soft tissue aspiration and injection, including indications for and against procedures, preparing for procedures, and approaches to specific musculoskeletal structures.


Apolipoprotein B metabolism in hypertriglyceridemic diabetic patients administered either a fish oil- or vegetable oil-enriched diet.
The effect on apolipoprotein B kinetics of a diet enriched in either fish oil or safflower oil was investigated in five hypertriglyceridemic (HTG), non-insulin-dependent diabetic subjects. The fish oil diet decreased plasma triglycerides and VLDL-apoB but increased LDL-apoB and LDL-cholesterol. Total plasma apoB concentration did not change, nor did the increased VLDL-apoB secretion present in these HTG subjects, which, accompanied by impaired lipolysis, accounted for their elevated VLDL. The fish oil-induced fall in VLDL resulted from a decrease in secretion without a change in residence time. The IDL fraction, which also contained small VLDL, was the primary site for the secretion of apoB particles in the HTG subjects. On the fish oil diet there was a further, compensatory increase in the secretion of these lipoproteins such that the transport of apoB in IDL remained the same, as did its mass. In the HTG subjects the major portion of IDL lipoproteins was catabolized, with LDL-apoB production comprising the lesser quantity. On the fish oil diet, a shift in the channeling of the lipoprotein output from IDL resulted in a decrease in the catabolic pathway and an increase in conversion to LDL. As the residence time of LDL did not change, this increased input gave rise to the larger mass of LDL-apoB seen in these hypertriglyceridemic subjects when receiving a fish oil diet.


[Advice from the Health Council of the Netherlands: wish and reality].
On 18 January of this year the Health Council of the Netherlands presented its research agenda for innovative medical products to the Dutch Minister of Health, Welfare and Sports. In its report 'Medical products; new and necessary' the Council describes fifteen health areas in which patients, doctors and nurses believe innovations are necessary. A 'metaprogram' is recommended to stimulate partnership of industry and research. Some comments can be made regarding the way end-users, i.e. patients and health care providers, were consulted concerning the priorities for innovation and the recommended incentives. In addition, these end-users might have assisted in discovering ways to repair 'market failure' of new medical products.


A joint method of coherence factor and nonlinear beamforming for synthetic aperture imaging with a ring array.
Ultrasound computed tomography (USCT) with a ring array is an emerging diagnostic method for breast cancer. In the literature, synthetic aperture (SA) imaging has employed the delay-and-sum (DAS) beamforming technique for ring-array USCT to obtain isotropic resolution reflection images. However, the images obtained by the conventional DAS beamformer suffer from off-axis clutter and low resolution due to inhomogeneity of the medium and phase distortion. To address these issues, researchers have developed adaptive beamforming methods, such as coherence factor (CF) and convolutional beamforming algorithm (COBA), that improve image quality. In this study, we propose a joint method that combines CF with short-lag COBA (SLCOBA). First, we estimate the average sound speed using CF to address tissue inhomogeneity. Based on the corrected sound speed map, SLCOBA effectively suppresses side lobes and enhances image quality. Numerical results show that the proposed method reduces clutter and noise, improving resolution performance. These findings suggest that the proposed method may be a practical option for breast imaging in inhomogeneous mediums in the future.


The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics.
The human intestinal Caco-2 cell line has been extensively used over the last twenty years as a model of the intestinal barrier. The parental cell line, originally obtained from a human colon adenocarcinoma, undergoes in culture a process of spontaneous differentiation that leads to the formation of a monolayer of cells, expressing several morphological and functional characteristics of the mature enterocyte. Culture-related conditions were shown to influence the expression of these characteristics, in part due to the intrinsic heterogeneity of the parental cell line, leading to selection of sub-populations of cells becoming prominent in the culture. In addition, several clonal cell lines have been isolated from the parental line, exhibiting in general a more homogeneous expression of differentiation traits, while not always expressing all characteristics of the parental line. Culture-related conditions, as well as the different Caco-2 cell lines utilized in different laboratories, often make it extremely difficult to compare results in the literature. This review is aimed at summarizing recent, or previously unreviewed, data from the literature on the effects of culture-related factors and the influence of line sub-types (parental vs. different clonal lines) on the expression of differentiation traits important for the use of Caco-2 cells as a model of the absorptive and defensive properties of the intestinal mucosa. Since the use of Caco-2 cells has grown exponentially in recent years, it is particularly important to highlight these methodological aspects in order to promote the standardization and optimisation of this intestinal model.


Experiences of returning to elite alpine skiing after ACL injury and ACL reconstruction.
To explore the experiences of alpine skiing at the elite level after anterior cruciate ligament (ACL) injury and reconstruction. A qualitative approach where semi-structured interviews were conducted, and an analysis of the manifest content was performed. Five ski high school students, two male and three female skiers, who had suffered ACL injuries and undergone ACL reconstructions. Seven categories were identified. The participants described their perceived opportunities with regard to returning to alpine skiing after ACL injury and reconstruction as something positive to do with self-belief, being mentally and physically prepared, regaining confidence in their own ability, being given time and using active strategies. In contrast, perceived barriers to a return to elite alpine skiing gave rise to negative feelings, for example, fear, disheartenment, a total lack of or ambivalent confidence in their own ability and the use of passive strategies. The two male skiers returned to alpine skiing. They reported confidence in their own ability, active strategies and support on all levels, as well as enhanced physical ability. The female skiers did not return to their pre-injury level of competitive alpine skiing. They stated a lack of support on all levels, deterioration in their physical ability and two out of three reported passive strategies and no or ambivalent confidence in their own ability. The most important factors were family support, support on all levels, access to a physiotherapist and time given.


Stressors, resources, and stress responses in pregnant African American women: a mixed-methods pilot study.
This research aimed to develop an initial understanding of the stressors, stress responses, and personal resources that impact African American women during pregnancy, potentially leading to preterm birth. Guided by the ecological model, a prospective, mixed-methods, complementarity design was used with 11 pregnant women and 8 of their significant others. Our integrated analysis of quantitative and qualitative data revealed 2 types of stress responses: high stress responses (7 women) and low stress responses (4 women). Patterns of stress responses were seen in psychological stress and cervical remodeling (attenuation or cervical length). All women in the high stress responses group had high depression and/or low psychological well-being and abnormal cervical remodeling at one or both data collection times. All but 1 woman had at least 3 sources of stress (racial, neighborhood, financial, or network). In contrast, 3 of the 4 women in the low stress responses group had only 2 sources of stress (racial, neighborhood, financial, or network) and 1 had none; these women also reported higher perceived support. The findings demonstrate the importance of periodically assessing stress in African American women during pregnancy, particularly related to their support network as well as the positive supports they receive.


Human-resources strategies for managing HIV/AIDS: the case of the South African forestry industry.
Previous work has focused on HIV prevalence among forestry workers and the impact of HIV/AIDS on the sustainability of forest resources. Following a review of work examining the impacts of HIV/AIDS on the South African economy, this article presents original qualitative research examining the responses of company management to the HIV epidemic across a range of enterprises in the South African forestry industry, including large companies, contractors and cooperatives. At the level of the enterprise, management occupies a critical nexus, at which the intersecting requirements of complex government legislation, the wellbeing of workers and the demands of the business must be met. The research demonstrates that large forestry companies tend to provide only a small fraction of their workforces with HIV/AIDS education, prevention or treatment services, as they have essentially outsourced the requirement through the use of labour-supply contractors who, by and large, provide workers with scant HIV/AIDS-related programmes or benefits. Moreover, the extent to which the different types of forestry enterprises incorporate the management of HIV/AIDS in the workforce with the management of the business is highly variable, and in most instances falls short of legislative requirements that have been in place for over a decade. The implications of this for the forestry industry in South Africa are acute.


EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023.
On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.


Hearing and facial function outcomes for neurofibromatosis 2 clinical trials.
Vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2), occurring in >95% of patients. These tumors develop on the vestibulocochlear nerve and are associated with significant morbidity due to hearing loss, tinnitus, imbalance, facial weakness, and risk of early mortality from brainstem compression. Although hearing loss and facial weakness have been identified as important functional outcomes for patients with NF2, there is a lack of consensus regarding appropriate endpoints in clinical trials. The functional outcomes group reviewed existing endpoints for hearing and facial function and developed consensus recommendations for response evaluation in NF2 clinical trials. For hearing endpoints, the functional group endorsed the use of maximum word recognition score as a primary endpoint, with the 95% critical difference as primary hearing outcomes. The group recommended use of the scaled measurement of improvement in lip excursion (SMILE) system for studies of facial function. These recommendations are intended to provide researchers with a common set of endpoints for use in clinical trials of patients with NF2. The use of common endpoints should improve the quality of clinical trials and foster comparison among studies for hearing loss and facial weakness.


Experimental and finite element analysis of strains induced by axial tibial compression in young-adult and old female C57Bl/6 mice.
Axial compression of the mouse tibia is used to study strain-adaptive bone (re)modeling. In some studies, comparisons between mice of different ages are of interest. We characterized the tibial deformation and force-strain relationships in female C57Bl/6 mice at 5-, 12- and 22-months age. A three-gauge experimental method was used to determine the strain distribution at the mid-diaphysis, while specimen-specific finite element analysis was used to examine strain distribution along the tibial length. The peak strains in the tibial mid-diaphyseal cross-section are compressive and occur at the postero-lateral apex. The magnitudes of these peak compressive strains are 1.5 to 2 times those on the opposite, antero-medial face (a site often used for strain gauge placement). For example, -10 N force applied to a 5-months old mouse engenders a peak compressive strain of -2800 µε and a tensile strain on the antero-medial face of +1450 µε. The orientation of the neutral axis at the mid-diaphysis did not differ with age (p=0.46), indicating a similar deformation mode in young and old tibiae. On the other hand, from 5- to 22-months there is a 25% reduction in cortical thickness and moment of inertia (p<0.05), resulting in significantly greater tibial strain magnitudes in older mice for equivalent applied force (p<0.05). We conclude that comparisons of tibial loading responses in young-adult and old C57Bl/6 tibiae are facilitated by similar deformation pattern across ages, but that modest adjustment of force levels is required to engender matching peak strains.


Longitudinal Relationships Between Decline in Speech-in-Noise Recognition Ability and Cognitive Functioning: The Longitudinal Aging Study Amsterdam.
Purpose Various directional hypotheses for the observed links between aging, hearing, and cognition have been proposed: (a) cognitive load on perception hypothesis, (b) information degradation hypothesis, (c) sensory deprivation hypothesis, and (d) common cause hypothesis. Supporting evidence for all 4 hypotheses has been reported. No studies have modeled the corresponding 4 causal pathways into 1 single model, which would be required to evidence that multiple directional hypotheses apply. The aim of the current study was to tease out which pathways apply for 5 different cognitive measures. Method Data from 1,029 respondents of the Longitudinal Aging Study Amsterdam were used spanning a maximum follow-up of 7 years (3 measurements). Speech-in-noise recognition ability (digit triplet speech-in-noise test) was included as a measure of auditory function. Cognitive measures included global cognitive functioning, fluid intelligence, information processing speed, and verbal memory (immediate recall and retention). Bivariate dual change score modeling was used to model the causal pathways between hearing, cognition, and baseline age. Results For information processing speed, global cognitive functioning, fluid intelligence, and memory-immediate recall, all pathways except for the sensory deprivation pathway were supported. For memory-retention, only the common cause and the sensory deprivation pathways were supported. Conclusions Causal pathways corresponding to all 4 hypotheses were supported. Support for the common cause hypothesis, the information degradation hypothesis, and the cognitive load on perception hypotheses was found for 4 of 5 cognitive measures. This was unexpected in some cases (e.g., support for the information degradation pathway for cognitive measures that do not rely on auditory stimuli). The sensory deprivation pathway that emerged for memory-retention might point toward processes related to early stages of dementia. In summary, the results show that the links between decline in auditory function, cognition, and aging are complex and most likely are captured by pathways belonging to various directional hypotheses.


Ocular disorders in patients infected with the human immunodeficiency virus at the University of Benin Teaching Hospital, Benin City, Nigeria.
Ocular diseases occur at all stages of HIV infection. Reports have documented that the prevalence of these diseases vary from region to region. Thus the objective of this study is to determine the prevalence of these ocular disorders among people infected with HIV at the University of Benin Teaching Hospital, Benin City, Nigeria The study was prospective in design and all patients who tested positive for HIV antibodies over a 5-year period from September 1997 to August 2002 in Dermatology and Ophthalmology Units at the University of Benin Teaching Hospital (UBTH), Benin City, Nigeria, were examined for the presence of ocular disease. Twenty-one of the 526 HIV-positive patients had ocular disease, giving a prevalence rate of 4.0%. Their mean age was 39.5 +/- 10.5 years. Fourteen patients (2.7%) had Herpes zoster ophthalmicus, four (0.8%) had Squamuos cell carcinoma, two (0.4%) had Kaposi's sarcoma while one (0.2%) had Cytomegalovirus retinitis. The signs seen on ocular examination were vesicular rash (66.7%) diminished vision (57.1%) corneal ulcers (38.0%), conjunctival injection (38.0%), and eyelid nodules (28.6%), preauricular lymphadenopathy (28.6%), purulent eye discharge (19.0), conjunctival nodules (9.5%), papilledema (9.5%), ptosis (9.5%), sudden visual loss in both eyes (9.5%), pupillary dilatation (4.8%), chemosis (4.8%), uveitis (4.8%), and retinal hemorrhage (4.8%). In this study the prevalence of ocular disorders was 4.0% in the 526 HIV-positive patients studied. Herpes zoster ophthalmicus was the commonest ocular disease encountered, occurring in 2.7% of the study population. This is in keeping with reports from other parts of the world. We recommend that young patients presenting with Herpes zoster ophthalmicus, conjunctival Squamuos cell carcinoma and sudden onset bilateral blindness should be screened for HIV infection.


A framework for integrating heterogeneous clinical data for a disease area into a central data warehouse.
Structured collection of clinical facts is a common approach in clinical research. Especially in the analysis of rare diseases it is often necessary to aggregate study data from several sites in order to achieve a statistically significant cohort size. In this paper we describe a framework how to approach an integration of heterogeneous clinical data into a central register. This enables site-spanning queries for the occurrence of specific clinical facts and thus supports clinical research. The framework consists of three sequential steps, starting from a formal data harmonization process, to the data transformation methods and finally the integration into a proper data warehouse. We implemented reusable software templates that are based on our best practices in several projects in integrating heterogeneous clinical data. Our methods potentially increase the efficiency and quality for future data integration projects by reducing the implementation effort as well as the project management effort by usage of our approaches as a guideline.


[The mechanisms of action of ketamine].
The review systematizes the latest data on the main mechanisms of realization of some pharmacological properties of ketamine which are particularly valuable in the treatment of many diseases and conditions. The authors present the main aspects of the ketamine effect on the central mechanisms of anesthesia and hemodynamics and give the characteristics of its neuroprotective action. It is shown that these effects are realized also at the cost of the non-competitive blockade of the NMDA receptors in the central nervous system.


The RihA, RihB, and RihC ribonucleoside hydrolases of Escherichia coli. Substrate specificity, gene expression, and regulation.
Pyrimidine-requiring cdd mutants of Escherichia coli deficient in cytidine deaminase utilize cytidine as a pyrimidine source by an alternative pathway. This has been presumed to involve phosphorylation of cytidine to CMP by cytidine/uridine kinase and subsequent hydrolysis of CMP to cytosine and ribose 5-phosphate by a putative CMP hydrolase. Here we show that cytidine, in cdd strains, is converted directly to cytosine and ribose by a ribonucleoside hydrolase encoded by the previously uncharacterized gene ybeK, which we have renamed rihA. The RihA enzyme is homologous to the products of two unlinked genes, yeiK and yaaF, which have been renamed rihB and rihC, respectively. The RihB enzyme was shown to be a pyrimidine-specific ribonucleoside hydrolase like RihA, whereas RihC hydrolyzed both pyrimidine and purine ribonucleosides. The physiological function of the ribonucleoside hydrolases in wild-type E. coli strains is enigmatic, as their activities are paralleled by the phosphorolytic activities of the nucleoside phosphorylases, and a triple mutant lacking all three hydrolytic activities grew normally. Furthermore, enzyme assays and lacZ gene fusion analysis indicated that rihB was essentially silent unless activated by mutation, whereas rihA and rihC were poorly expressed in glucose medium due to catabolite repression.


Phase I study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel chemotherapy for locally advanced cervical carcinoma in Japanese women.
The purpose of this study was to evaluate the use of concurrent chemoradiotherapy involving weekly administration of cisplatin and paclitaxel for the treatment of locally advanced cervical carcinoma in Japanese women. Twenty Japanese patients were registered for this phase I study. Radiation therapy was performed using external irradiation and high-dose rate intracavitary irradiation of the pelvis. Chemotherapy was performed once a week until termination of the radiation therapy. The dose of cisplatin was decided as 30 mg/m2, and the initial dose of paclitaxel was set as 30 mg/m2, with a planned incremental increase of 10 mg/m2 up to 70 mg/m2. When 3 to 6 patients were registered at each dose level and dose-limiting toxicity (DLT) was noted in more than 3 patients, the dose level was assumed to be the maximum tolerated dose. Among the 20 patients, 1 patient experienced DLT during 2 courses because of dehydration and arrhythmia. In another patient, chemotherapy was discontinued after 4 courses because of a hypersensitivity reaction to paclitaxel at dose level 3. No patient experienced DLT resulting from hematologic toxicities. All patients underwent radiation therapy according to schedule without any discontinuations. A complete response was obtained in 16 patients. Based on the results obtained from this study, weekly administration of 30 mg/m2 cisplatin and 50 mg/m2 paclitaxel with concurrent chemoradiotherapy can be considered a tolerable and safe dose for the treatment of locally advanced cervical carcinoma in Japanese women.


Developing and regenerating a sense of taste.
Taste is one of the fundamental senses, and it is essential for our ability to ingest nutritious substances and to detect and avoid potentially toxic ones. Taste buds, which are clusters of neuroepithelial receptor cells, are housed in highly organized structures called taste papillae in the oral cavity. Whereas the overall structure of the taste periphery is conserved in almost all vertebrates examined to date, the anatomical, histological, and cell biological, as well as potentially the molecular details of taste buds in the oral cavity are diverse across species and even among individuals. In mammals, several types of gustatory papillae reside on the tongue in highly ordered arrangements, and the patterning and distribution of the mature papillae depend on coordinated molecular events in embryogenesis. In this review, we highlight new findings in the field of taste development, including how taste buds are patterned and how taste cell fate is regulated. We discuss whether a specialized taste bud stem cell population exists and how extrinsic signals can define which cell lineages are generated. We also address the question of whether molecular regulation of taste cell renewal is analogous to that of taste bud development. Finally, we conclude with suggestions for future directions, including the potential influence of the maternal diet and maternal health on the sense of taste in utero.


Mechanisms of bacterial antibiotic resistance.
Infectious complications are major contributing factors to morbidity and mortality in the ICU setting. Organisms frequently encountered in the ICU include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae (particularly in trauma victims), enterococci, Klebsiella pneumoniae, Enterobacter spp., Acinetobacter baumanii, Escherichia coli, and Stenotrophomonas (Xanthomonas) maltophilia. Antibiotics have played a major role in the treatment of infections caused by such bacterial pathogens. Organisms have responded to the antibiotic challenge, however, evolving and developing resistance to all available antimicrobial agents to a greater or lesser degree. Specific mechanisms of resistance include reductions in cell-wall membrane permeability, alterations of antimicrobial agent target sites, enzymatic inactivation of antibiotics, and development of bypass pathways around antimicrobial targets. This article describes, pathogen by pathogen, antimicrobial agents that are useful for the treatment of infection in the ICU setting and the mechanisms whereby bacteria have short-circuited our antimicrobial armamentarium.


A computational study on how structure influences the optical properties in model crystal structures of amyloid fibrils.
Amyloid fibrils have been shown to have peculiar optical properties since they can exhibit fluorescence in the absence of aromatic residues. In a recent study, we have shown that proton transfer (PT) events along hydrogen bonds (HBs) are coupled to absorption in the near UV range. Here, we gain more insights into the different types of hydrogen bonding interactions that occur in our model systems and the molecular factors that control the susceptibility of the protons to undergo PT and how this couples to the optical properties. In the case of the strong N-C termini interactions, a nearby methionine residue stabilizes the non-zwitterionic NH2-COOH pair, while zwitterionic NH3+-COO- is stabilized by the proximity of nearby crystallographic water molecules. Proton motion along the hydrogen bonds in the fibril is intimately coupled to the compression of the heavier atoms, similar to what is observed in bulk water. Small changes in the compression of the hydrogen bonds in the protein can lead to significant changes in both the ground and excited state potential energy surfaces associated with PT. Finally, we also reinforce the importance of nuclear quantum fluctuations of protons in the HBs of the amyloid proteins.


Monetary rewards modulate inhibitory control.
The ability to override a dominant response, often referred to as behavioral inhibition, is considered a key element of executive cognition. Poor behavioral inhibition is a defining characteristic of several neurological and psychiatric populations. Recently, there has been increasing interest in the motivational dimension of behavioral inhibition, with some experiments incorporating emotional contingencies in classical inhibitory paradigms such as the Go/NoGo and Stop Signal Tasks (SSTs). Several studies have reported a positive modulatory effect of reward on performance in pathological conditions such as substance abuse, pathological gambling, and Attention Deficit Hyperactive Disorder (ADHD). However, experiments that directly investigate the modulatory effects of reward magnitudes on the performance of inhibitory tasks are scarce and little is known about the finer grained relationship between motivation and inhibitory control. Here we probed the effect of reward magnitude and context on behavioral inhibition with three modified versions of the widely used SST. The pilot study compared inhibition performance during six blocks alternating neutral feedback, low, medium, and high monetary rewards. Study One compared increasing vs. decreasing rewards, with low, high rewards, and neutral feedback; whilst Study Two compared low and high reward magnitudes alone also in an increasing and decreasing reward design. The reward magnitude effect was not demonstrated in the pilot study, probably due to a learning effect induced by practice in this lengthy task. The reward effect per se was weak but the context (order of reward) was clearly suggested in Study One, and was particularly strongly confirmed in study two. In addition, these findings revealed a "kick start effect" over global performance measures. Specifically, there was a long lasting improvement in performance throughout the task when participants received the highest reward magnitudes at the beginning of the protocol. These results demonstrate a dynamical behavioral inhibition capacity in humans, as illustrated by the reward magnitude modulation and initial reward history effects.


"I was so worried about every drop of milk" - feeding problems at home are a significant concern for parents after major heart surgery in infancy.
Increasing numbers of operations in small infants with complex congenital heart disease are being carried out in the UK year on year, with more surviving the initial operation. However, even after successful surgery some of these infants remain fragile when they are discharged home. The aim of the study was to elicit parents' experiences of caring for a child with complex needs after major congenital heart surgery. We conducted a qualitative study involving semi-structured interviews with parents of 20 children (aged <1-5 months at hospital discharge), who had undergone open heart surgery and subsequently died or been readmitted unexpectedly to intensive care following their initial discharge home. Feeding difficulties following discharge from the specialist surgical centre emerged as one of the most significant parental concerns spontaneously raised in interviews. For some parents the impact of feeding difficulties overshadowed any other cardiac concerns. Key themes centred around feeding management (particularly the practical challenges of feeding their baby), the emotional impact of feeding for parents and the support parents received or needed after discharge with respect to feeding. Caring for a child with congenital heart disease following surgery is demanding, with feeding difficulties being one of the most significant parent stressors. Local health professionals can be a good source of support for parents provided that they are well informed about the needs of a cardiac baby and have realistic expectations of weight gain. Specialist surgical centres should consider addressing issues of parental stress around feeding and weight gain prior to hospital discharge. © 2016 Blackwell Publishing Ltd.


Genetic and in vivo determinants of glucocorticoid sensitivity in relation to clinical outcome of childhood nephrotic syndrome.
Following initial glucocorticoid treatment, the clinical course in children with nephrotic syndrome is highly variable. Intrinsic sensitivity to glucocorticoids might be a determinant of this variability. Functional polymorphisms of the glucocorticoid receptor gene NR3C1 have been associated with either relatively impaired (GR-9β) or increased (BclI) glucocorticoid sensitivity. Here, in a prospective, well-defined cohort of children with nephrotic syndrome, we evaluated both carriage of GR-9β+TthIII-1 and BclI haplotypes in 113 children and a dexamethasone suppression test in 90 children in relation to their clinical outcome over a median follow-up of 4.4 years. Carriers of GR-9β+TthIII-1 had a significantly higher incidence of steroid dependence 13/25 (52%) compared with noncarriers 19/75 (25%) with a hazard ratio adjusted for gender, age, and descent of 3.04 with 95% confidence interval 1.37-6.74. Both first and frequent relapses happened significantly more often in GR-9β+TthIII-1 carriers than in noncarriers. There were no significant differences in therapeutic outcomes between carriers and noncarriers of the BclI haplotype. Results of the dexamethasone test showed no associations with clinical outcome. Thus, the GR-9β+TthIII-1 haplotype of the glucocorticoid receptor gene offers new insights into the clinical course of children with nephrotic syndrome.


Increased iron levels correlate with the selective nigral dopaminergic neuron degeneration in Parkinson's disease.
The staging of Lewy-related pathology in sporadic Parkinson's disease (PD) reveals that many brain nuclei are affected in PD during different stages, except the ventral tegmental area (VTA), which is close related to the substantia nigra (SN) and enriched in dopamine (DA) neurons. Why DA neurons are selectively degenerated in the SN of PD is far from known. In the present study, we observed that the number of tyrosine hydroxylase immunoreactive neurons decreased and iron-staining positive cells increased in the SN, but not in the VTA, in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated PD mice. Increased expression of divalent metal transporter 1 and decreased expression of ferroportin 1 might associate with this increased nigral iron levels. Lipofuscin granular aggregations and upregulation of alpha-synuclein (α-synuclein) were also observed only in the SN. These results suggest that increased iron levels associate with the selective degeneration of DA neurons in the SN. The intracellular regulation mechanisms for the iron transporters may be different in the SN and VTA under the same conditions. Moreover, the lipofuscin granular aggregations and upregulation of α-synuclein were also involved in the selective degeneration of dopaminergic neurons in the SN.


Effect of cinnamon essential oil dietary supplementation on the growth, fatty acid composition, and meat quality of tilapia.
This study was conducted to investigate the effects of dietary supplementation of 0%, 0.2%, 0.35%, and 0.5% cinnamon essential oil on growth performance, fatty acid, and fillet quality of tilapia (Oreochromis niloticus). The results of growth experiments showed that the weight gain rate linearly and quadratically increased with increasing cinnamon essential oil doses (p < 0.05). The results of fatty acids experiments showed that the addition of essential oil significantly decreased the saturated fatty acids levels from 36.67% to 30.82% and increased the polyunsaturated fatty acids (PUFA) levels from 24.55% to 46.89%; especially, the n - 3 PUFA of 0.5% essential oil treatment showed the highest levels. Moreover, the n - 6 PUFA of 0.2% essential oil treatment were increased from 22.17% to 32.99%. The results of fillet quality experiments showed that the hardness and cohesiveness were linearly and quadratically increased with the increasing essential oil doses on days 4 and 7, respectively. The b* values linearly and quadratically decreased as the doses increased on day 7 (p < 0.05). The total volatile basic nitrogen levels were quadratically decreased with increasing cinnamon essential oil doses on day 7 (p < 0.05). In general, it can be concluded that cinnamon essential oil presented positive effects on the growth, nutritive values, and meat quality in tilapia.


A second opsin gene expressed in the ultraviolet-sensitive R7 photoreceptor cells of Drosophila melanogaster.
We have identified a second Drosophila opsin gene, Rh4, which is expressed specifically in the ultraviolet-sensitive R7 photoreceptor cells. The two R7 opsins, Rh3 and Rh4, are expressed in nonoverlapping subsets of R7 cells. The Rh4 opsin shares 72% amino acid identity with Rh3, but is only about 35% homologous with the other 2 Drosophila opsins, ninaE and Rh2. Twenty-eight amino acids are conserved among all 4 invertebrate and 5 vertebrate opsin genes thus far sequenced, suggesting that these residues play an important role in rhodopsin function.


Generalization Error of a Regression Model for Non-Invasive Blood Pressure Monitoring using a Single Photoplethysmography (PPG) Signal.
Photoplethysmography (PPG) sensors integrated in wearable devices offer the potential to monitor arterial blood pressure (ABP) in patients. Such cuffless, non-invasive, and continuous solution is suitable for remote and ambulatory monitoring. A machine learning model based on PPG signal can be used to detect hypertension, estimate beat-by-beat ABP values, and even reconstruct the shape of the ABP. Overall, models presented in literature have shown good performance, but there is a gap between research and potential real-world use cases. Usually, models are trained and tested on data from the same dataset and same subjects, which may lead to overestimating their accuracy. In this paper: we compare cross-validation, where the test data are from the same dataset as training data, and external validation, where the model is tested on samples from a new dataset, on a regression model which predicts diastolic blood pressure from PPG features. The results show that, in the cross-validation, the predicted and the real values are linearly dependent, while in the external validation, the predicted values are not related to the real ones, but probably just through an average value.


Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.
Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Relationship between graft failure following anterior cruciate ligament reconstruction and hamstring autograft diameter.
With the increase in the number of individuals participating in sports, anterior cruciate ligament (ACL) injuries are also increasing gradually and the number of patients requiring surgical treatment is increasing in parallel. The primary aim of this study was to investigate the relationship between the need for revision surgery and graft diameter following primary ACL reconstruction (ACLR) using hamstring autografts. The secondary aim of the study was to clarify relationships between anthropometric characteristics and graft diameter. Patients who underwent ACLR with hamstring autografts were included in this retrospective study. The age, body mass index, height, and weight of all patients were recorded preoperatively and the diameters of the grafts were recorded during surgery. The relationship between revision rate and graft diameter and the relationships between anthropometric measurements and graft diameter were investigated for these patients at least one year after surgery. This study included 58 people with graft diameters of ≤7 mm and 261 people with graft diameters of >7 mm. A statistically significant difference was found between the graft diameters of the group that needed revision surgery and the group that did not (p<0.001). A positive relationship was also found between the patient's height and graft diameter (r=0.168). In this study, it was found that the risk of ACL revision surgery increased by 5.5 times among patients with graft diameters of ≤7 mm. The positive relationship between the patient's height and graft diameter can make a significant difference in terms of the need for revision surgery.


Enhancement of Conventional and Photodynamic Therapy for Treatment of Cervical Cancer with Cannabidiol.
Cervical cancer (CC) is the fourth most diagnosed cancer in women worldwide. Conventional treatments include surgery, chemo- and radiotherapy, however these are invasive and may cause severe side effects. Furthermore, approximately 70% of late-stage CC patients experience metastasis, due to treatment resistance and limitations. Thus, there is a dire need to investigate alternative therapeutic combination therapies. Photodynamic therapy (PDT) is an alternative CC treatment modality that has been clinically proven to treat primary CC, as well as to limit secondary metastasis. Since PDT is a non-invasive localized treatment, with fewer side effects and lessened resistance to dose repeats, it is considered far more advantageous. However, more clinical trials are required to refine its delivery and dosing, as well as improve its ability to activate specific immune responses to eradicate secondary CC spread. Cannabidiol (CBD) isolates have been shown to exert in vitro CC anticancer effects, causing apoptosis post treatment, as well as inducing specific immune responses, which obstruct tumor invasion and angiogenesis, and so hinder CC metastatic spread. This review paper discusses the current conventional and alternative PDT treatment modalities for CC, as well as their limitations over the last 10 years. It has a particular focus on the combinative administration of CBD with these treatments in order to prevent CC secondary migration and so possibly encourage future research studies to focus on this synergistic effect to eradicate CC.


Microbial destruction of cyanide wastes in gold mining: process review.
Microbial destruction of cyanide and its related compounds is one of the most important biotechnologies to emerge in the last two decades for treating process and tailings solutions at precious metals mining operations. Hundreds of plant and microbial species (bacteria, fungi and algae) can detoxify cyanide quickly to environmentally acceptable levels and into less harmful by-products. Full-scale bacterial processes have been used effectively for many years in commercial applications in North America. Several species of bacteria can convert cyanide under both aerobic and anaerobic conditions using it as a primary source of nitrogen and carbon. Other organisms are capable of oxidizing the cyanide related compounds of thiocyanate and ammonia under varying conditions of pH, temperature, nutrient levels, oxygen, and metal concentrations. This paper presents an overview of the destruction of cyanide in mining related solutions by microbial processes.


Trends in clinical features and severity of Plasmodium vivax malaria among children at tertiary care center in North India.
Malaria is a significant cause of morbidity and mortality in adults and children. Plasmodium falciparum is the primary cause of severe malaria, but recently Plasmodium vivax is also recognized to cause severe malaria-associated morbidity and mortality. The study focuses on determining the mortality related to severity parameters in individuals under 12 years and their critical presentation in P.vivax malaria-infected children. A prospective cross-sectional hospital-based study was conducted at Safdarjung Hospital, New Delhi, and ICMR-NIMR, New Delhi. All clinically suspected cases were admitted for screening. Exclusion criteria (rapid malaria antigen test, microscopy and medication history) were applied to all the admitted patients (n = 221) to obtain P.vivax patients only. Patients aged ≤ 12 years were included in the study. DNA was extracted from dried blood spots and amplified by nested PCR, followed by visualization on gel electrophoresis. A total of 221 clinically suspected cases of malaria were screened for P.vivax. After implementing various exclusion criteria, 45/221 cases were enrolled for the study, among which 44.4% (20/45) of children had the symptoms of severe malaria in terms of cerebral malaria, thrombocytopenia, anemia, pancytopenia, acute respiratory distress syndrome and hemophagocytic lymphohistiocytosis. Plasmodium vivax mono-infection can cause severe manifestation and must be treated as P.falciparum without any delay because it may lead to increased morbidity and mortality. A changing trend in clinical symptoms has shown in P.vivax which was an earlier phenomenon of P.falciparum.


Anterior cervical discectomy (ACD) versus anterior cervical fusion (ACF), clinical and radiological outcome study.
This study was conducted on 90 patients with symptomatic cervical disc disease with one or two-level disc pathology. Clinical and radiological outcome was compared to determine which technique was advantageous for patients with disc disease. Problems related to donor site as well as those related to fusion bed and grafts have stimulated investigators to avoid fusion. Patients were allocated at random for either the ACF (n=50) or the ACD (n=40) procedures. The standard Smith-Robinson technique was performed on all patients in this study. Patients were followed-up clinically and radiologically according to the study protocol. The clinical long-term outcome was comparable in both groups, though those who had ACF were more satisfied. There was significant incidence of kyphosis in the ACD group (P=0.02). Osseous union was slow and less satisfactory with ACD (64%) than with ACF (94%). Pain at the donor site was not a significant problem in the long-term. Hospital stay and operative time was shortened in ACD patients though not significantly. Spondylotic patients were less satisfied with ACD though not significantly. Conclusions. The issue of whether to fuse or not to fuse has not come to an end yet. The technique is still in need of more refinement of disc excision and graft harvesting and shaping, as well as more adequately controlled studies. Until that, ACD has to be limited to those patients with a soft single disc without spondylosis.


In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma.
Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) are in early clinical development for multiple myeloma (MM) therapy. Despite all encouraging pre-clinical data, clinical activity of HDACi and DNMTi is mostly lacking. To optimize the trials, characterization of the in vivo response towards HDACi and DNMTi will be crucial. Therefore, we investigated the transcriptional response after in vivo treatment with the HDACi quisinostat or DNMTi decitabine using the murine 5T33MM model. We identified 504 and 154 genes deregulated by quisinostat and decitabine, respectively. Of interest, MM patients' gene expression levels of 62 quisinostat- and 25 decitabine-deregulated genes were predictive for overall survival of patients. This prognostic information was implemented in a DNA methylation and histone acetylation score. A high score was related to a high proliferative and immature phenotype of MM cells. Furthermore, highly scored MM patients had an adverse overall survival. Interestingly, bio-informatic prediction tools revealed an association of quisinostat-deregulated genes with lymphocyte activation, proliferation, immune-effector mechanisms and T-helper-1 development. Overall, treatment of 5T33MM mice with epigenetic modulating agents led to the translation of gene signatures to predict overall survival of MM patients. HDACi mainly deregulated tumoral immunomodulatory pathways, supporting the rationale to combine HDACi with immunomodulatory therapies.


Thromboxane does not mediate pulmonary vascular response to monocrotaline pyrrole.
The possible involvement of thromboxane (Tx) in the pulmonary hypertension caused by monocrotaline pyrrole (MCTP) administration to rats was investigated by pharmacological intervention of Tx synthesis and action. The cyclooxygenase inhibitor, ibuprofen, at doses that inhibited platelet function and suppressed plasma Tx levels, did not attenuate MCTP-induced right ventricular hypertrophy or increased lung weight. Dazmegrel, an inhibitor of Tx synthetase, did not affect the MCTP-induced increase in lung weight or the elevation of lactate dehydrogenase activity or protein concentration in bronchopulmonary lavage fluid, despite significant reduction of the plasma concentration of Tx. Dazmegrel also did not alter the vascular leak or right ventricular hypertrophy due to administration of MCTP to rats. Finally, the Tx receptor antagonist L-640,035 was tested using a dosing regimen that reduced the increase in right ventricular pressure caused by a stable endoperoxide analogue in MCTP-treated rats. Cotreatment with L-640,035 did not attenuate the increase in lung weight, lavage fluid lactate dehydrogenase activity or protein concentration, or the pulmonary hypertension caused by MCTP. These results indicate that interference with Tx synthesis or action does not attenuate the toxic effects of MCTP and suggest that Tx is not necessary for the cardiopulmonary response to MCTP.


Gastric atrophy, metaplasia, and dysplasia: a clinical perspective.
Gastric carcinoma of the intestinal type originates in dysplastic epithelium, which in turn develops in the milieu of atrophic gastritis and intestinal metaplasia. Cancers also may develop less often from gastric adenomatous polyps, which represent dysplastic epithelium arising in a raised lesion. The main causes of chronic atrophic gastritis and gastric atrophy are autoimmune due to pernicious anemia or chronic Helicobacter pylori infection. In the former condition, there is severe atrophy of the corpus (oxyntic mucosa), with the antrum being speared. In contrast, chronic atrophic gastritis consequent to H. pylori infection is a multifocal pangastritis, involving independent foci in the corpus and antrum of the stomach. For the most part, these clinical conditions are silent; the only manifestation of both these forms of chronic atrophic gastritis is cobalamin (vitamin B(12)) deficiency. In the case of the autoimmune gastritis of pernicious anemia, cobalamin deficiency results form the absence of intrinsic factor. When cobalamin deficiency occurs in patients with H. pylori-related gastritis, for the most part, it is because these patients have hypochlorhydria and are therefore unable to release cobalamin from its bound form in food. Patients may have advanced neuropsychiatric manifestations of cobalamin deficiency and yet not be anemic, have a normal blood smear, and even have serum cobalamin levels in the normal range. The condition may be identified by demonstrating elevated levels of homocysteine and methylmalonic acid. Intestinal metaplasia may be of the enteric (grade I), enterocolic (grade II), or colonic (grade III) type. Grade III intestinal metaplasia has traditionally been thought of as the most sinister variety, although the extent of atrophy and metaplasia may be a better marker for premalignancy than the mere identification of small areas of grade III intestinal metaplasia. Over the years, there has been much disagreement and a high degree of interrater variability, especially between Western and Japanese pathologists, as to the different grades of dysplasia and early gastric cancer. Recent consensus conferences at Vienna and Padova have resulted in better understanding of what constitutes these lesions, and it is hoped that in the near future agreement between pathologists will improve as a consequence. For the present, it is imperative that clinicians obtain second opinions from two or more expert pathologists on biopsy specimens before arriving at a diagnosis of either low- or high-grade dysplasia. The former histologic diagnosis is tantamount to subjecting the patient to endoscopic surveillance and the latter is tantamount to a decision regarding the resection of the lesion, both decisions being psychologically disturbing for patients. At this time, population screening for H. pylori is not recommended in Western countries, but most experts would agree that H. pylori should be eradicated if detected as part of the appropriate investigation of a clinical disorder such as dyspepsia. Certain other specific conditions may also be considered to be precancerous, such as the gastric remnant after a partial gastrectomy and the gastric mucosa in familial adenomatous polyposis syndrome and in familial Peutz-Jeghers syndrome and perhaps Ménétrier disease.


Adenoid cystic carcinoma of the breast: A case report and literature review.
Adenoid cystic carcinoma (ACC) is a rare malignant tumor of the breast that occurs in <0.1% of all patients diagnosed with breast cancer. The mean patient age at the time of diagnosis is 50-60 years. Typically, the tumor presents as a subareolar mass or as pain in the breast. While the radiological appearances of ACC are generally non-specific, the diagnosis can be made on fine-needle aspiration cytology. In the present study, a 58-year-old female patient was admitted to the Department of Radiation Oncology (Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey) with complaints of pain in the upper outer quadrant of the right breast. An excision biopsy of a lump in the upper outer quadrant revealed ACC, and perineural invasion was present. Subsequently, the patient underwent breast conservation surgery and sentinel lymph node dissection. Pathology from the second surgery depicted ACC in the form of microscopic foci around the initial surgical cavity, with two reactive sentinel lymph nodes and the closest negative margin at 2 mm. The patient was treated with radiotherapy following the surgery. No recurrence and metastasis were found after 20 months of follow-up. In conclusion, mammary ACC is a rare malignant neoplasm of the breast. Although surgery is the main treatment, the optimal adjuvant treatment of ACC of the breast has not yet been determined due to its low incidence.