Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn's and Other Inflammatory Bowel Diseases.
Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus nerve stimulation, and in particular, the transcutaneous stimulation of the auricular branch of the vagus nerve. Then, we expose the working hypotheses for the modulation of the molecular processes that are responsible for intestinal inflammation in autoimmune diseases and the way we could develop personalized neuroprosthetic therapeutic devices and procedures in favor of the patients.


Using Blueprints to promote interorganizational knowledge transfer in digital health initiatives-a qualitative exploration of a national change program in English hospitals.
The Global Digital Exemplar (GDE) Program is a national attempt to accelerate digital maturity in healthcare providers through promoting knowledge transfer across the English National Health Service (NHS). "Blueprints"-documents capturing implementation experience-were intended to facilitate this knowledge transfer. Here we explore how Blueprints have been conceptualized, produced, and used to promote interorganizational knowledge transfer across the NHS. We undertook an independent national qualitative evaluation of the GDE Program. This involved collecting data using semistructured interviews with implementation staff and clinical leaders in provider organizations, nonparticipant observation of meetings, and key documents. We also attended a range of national meetings and conferences, interviewed national program managers, and analyzed a range of policy documents. Our analysis drew on sociotechnical principles, combining deductive and inductive methods. Data comprised 508 interviews, 163 observed meetings, and analysis of 325 documents. We found little evidence of Blueprints being adopted in the manner originally conceived by national program managers. However, they proved effective in different ways to those planned. As well as providing a helpful initial guide to a topic, we found that Blueprints served as a method of identifying relevant expertise that paved the way for subsequent discussions and richer knowledge transfers amongst provider organizations. The primary value of Blueprinting, therefore, seemed to be its role as a networking tool. Members of different organizations came together in developing, applying, and sustaining Blueprints through bilateral conversations-in some circumstances also fostering informal communities of practice. Blueprints may be effective in facilitating knowledge transfer among healthcare organizations, but need to be accompanied by other evolving methods, such as site visits and other networking activities, to iteratively transfer knowledge and experience.


Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles.
The goal of this review is to summarize our knowledge of the plasticity of striated muscles in terms of contractile proteins. During development or when the working conditions are changed, the intrinsic physiological properties of both cardiac and skeletal muscles are modified. These modifications generally adapt the muscle to the new environmental requirements. One of the best examples is compensatory overload obtained in fast skeletal muscle by synergistic tenotomy and in a fast ventricle, such as in rats, by aortic banding. In both cases, after a few weeks the initial speed of shortening for the unloaded muscle drops, whereas the maximum tension developed remains unchanged. Heat measurements show that efficiency (i.e., g work/mol ATP) is improved at the fiber level. The fast skeletal muscle becomes slow, fatigue resistant, and then more adapted to endurance. For the ventricle as a whole to become slow is beneficial only if one contraction is considered; however, it is detrimental in terms of cardiac output and leads finally to failure. This adaptational process is partly explained by quantitative and qualitative changes in contractile proteins. Protein synthesis is rapidly enhanced and muscles hypertrophy, which in turn multiplies the contractile units and for the cardiac cylinder normalizes the wall stress. In the meantime the structure and, for myosin, the biological activity of several contractile proteins are modified. These modifications are very unlikely to be posttranscriptional and are in fact explained by several isoform shifts. In both tissues, for example, the expression of the gene coding for a fast myosin (MHCf in skeletal muscle, alpha-MHC in ventricles) is repressed and that of the gene coding for a slow myosin (beta-MHC in both tissues) is stimulated. This is accompanied by a coordinated increase in synthesis of other contractile proteins and, in skeletal muscle only, by isoform shifts of myosin light chains and of the TM-TN regulatory system. Other changes are less well understood. During development it has recently been discovered that three different MHCs (MHCemb, MHCneo, and MHCf) appear sequentially in fast skeletal muscle, which explains, for example, several contradictions of immunological cross-reactions. Currently, however, the functional significance of this finding is unknown, and the well-known decrease of shortening velocity observed in cardiac and skeletal muscles during fetal life is unexplained in terms of contractile proteins.(ABSTRACT TRUNCATED AT 400 WORDS)


Androgenetic alopecia, metabolic syndrome, and insulin resistance: Is there any association? A case-control study.
Although several previous studies have investigated the association of metabolic syndrome (MS) and insulin resistance (IR) with androgenetic alopecia (AGA), the results have been inconsistent. We attempted to assess the presence of MS and IR in patients with AGA. This may help to detect if AGA can be considered as a clue for underlying serious systemic diseases. One hundred male patients with stages III-VII AGA, in Hamilton-Norwood classification, and 100 normal, gender- and age-matched control subjects were included. Anthropometric measures, blood pressure, fasting glucose, fasting insulin, high-density lipoprotein cholesterol, and triglycerides were measured for the all participants. The presence of MS and IR was evaluated. There were statistically significant differences regarding mean values of body weight (P < 0.001), height (P = 0.002), waist circumference (P < 0.001), body mass index (P < 0.001), systolic (P < 0.001), and diastolic blood pressure (P < 0.001), fasting glucose (P < 0.001), triglycerides (P < 0.001), high-density lipoprotein cholesterol (P < 0.01), fasting insulin (P = 0.02) and homeostasis model assessment of insulin resistance (P < 0.001) between cases and controls. A statistically significant association was found between AGA and MS (P = 0.002) and between AGA and IR (P < 0.001). Multiple logistic regression analysis revealed that waist circumference (>102 cm) was the most significant risk factor for developing MS. It increased the risk of MS by 1.25-folds (95% CI = 1.10-1.42, P < 0.001). Our results support the recommendation for assessing MS and IR in all young males with stage III or higher AGA. Early intervention is critical to reduce the risk and complications of cardiovascular disease and type 2 diabetes mellitus later in life.


Cell surface marker proteins during mouse spermatogenesis: two-dimensional electrophoretic analysis.
Purified plasma membranes isolated from separated highly homogenous populations of mouse pachytene spermatocytes, round spermatids (step I-8), and residual bodies have been compared using 2-dimensional polyacrylamide gel electrophoresis. Two polypeptides apparently specific to pachytene spermatocytes have been identified. Component Pa has a molecular weight of 90 k daltons (K) and pI of 5.6. Component Pb has a molecular weight of 56.5 K and a pI of 6.0. Four polypeptides detected only in plasma membranes of round spermatids have been identified as follows: RSa, 90-95 K and pI 5.9; RSb, also 90-95 K and pI 5.9; RSc, approximately 88 K and pI 5.5; RSd, 58 K and pI 6.0-6.3. No polypeptides unique to residual body membranes were identified. Short-term culture experiments have established that separated adult mouse spermatogenic cells survive short-term culture in vitro. These cells actively synthesize numerous cellular proteins as determined by the incorporation of [3H]leucine. Investigations concerning the effect of the cell separation procedure on mouse spermatogenic cell membranes indicate that only 7 of 110-120 total plasma membrane constituents are degraded enzymically during cell purification. Only one of these constituents may correspond to the presumptive cell differentiation markers described for pachytene spermatocytes and round spermatids. These results indicate, therefore, that plasma membranes obtained immediately after cell separation are suitable for the detailed biochemical analysis of the most integral surface proteins during spermatogenesis in the mouse.


Genetic evidence for functional redundancy of Platelet/Endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions.
Platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31), a member of the Ig superfamily, is expressed strongly at endothelial cell-cell junctions, on platelets, and on most leukocytes. CD31 has been postulated to play a role in vasculogenesis and angiogenesis, and has been implicated as a key mediator of the transendothelial migration of leukocytes. To further define the physiologic role of CD31, we used targeted gene disruption of the CD31 gene in embryonic stem cells to generate CD31-deficient mice. CD31-deficient mice (CD31KO) are viable and born at the expected Mendelian frequency, remain healthy, and exhibit no obvious vascular developmental defects. In response to inflammatory challenge, polymorphonuclear leukocytes of CD31KO mice are arrested between the vascular endothelium and the basement membrane of inflammatory site mesenteric microvessels, confirming a role for CD31 in the migration of neutrophils through the subendothelial extracellular matrix. Normal numbers of leukocytes are recovered from inflammatory sites in CD31KO mice, however, suggesting that the defect in leukocyte migration across basal lamina observed in the absence of CD31 may be compensated for by the use of other adhesion molecules, or possibly an increased rate of migration. Homing of T lymphocytes in vivo is normal, and CD31KO mice are able to mount a cutaneous hypersensitivity response normally. In addition, CD31-mediated homophilic adhesion does not appear to play a role in platelet aggregation in vitro. This study provides genetic evidence that CD31 is involved in transbasement membrane migration, but does not play an obligatory role in either vascular development or leukocyte migration.


A new sensitive serological assay for detection of lentivirus infections in small ruminants.
Lentivirus infections in small ruminants represent an economic problem affecting several European countries with important sheep-breeding industries. Programs for control and eradication of these infections are being initiated and require reliable screening assays. This communication describes the construction and evaluation of a new serological screening enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to maedi-visna virus (MVV) in sheep and to caprine arthritis encephalitis virus (CAEV) in goats. The solid phase is sensitized with a combination of the major core protein p25 of MVV produced in Escherichia coli and a peptide derived from the immunodominant region of the viral transmembrane protein gp46. The peptide carries an N-terminal biotin residue and is complexed with streptavidin prior to being coated. The new assay was evaluated with 2,336 sheep serum samples from different European countries with large differences in the levels of prevalence of MVV infections, and the results have been compared to those of the standard agar gel immunodiffusion test. Discrepant samples were analyzed by Western blotting with viral lysate, and most sera could be classified unambiguously. The estimated overall sensitivity of the new ELISA was 99.4% (95% confidence interval [CI], 98.4 to 99. 8%) and the specificity was 99.3% (95% CI, 98.7 to 99.6%). A limited set of goat sera (n = 212) was also analyzed, with similar results. These data indicate that the new assay is a reliable tool that can be used in control and eradication programs for small ruminant lentivirus infections.


Spectrally controlled interferometry.
Optical interferometers are typically categorized by their source type into incoherent (white-light) and coherent (laser). Both approaches provide adequate solutions for many measurement applications, offer unique advantages, and suffer distinct limitations. A novel interferometry method, spectrally controlled interferometry, is presented, which successfully merges many advantages from both categories while bypassing some of the limitations. The relationship between measurement accuracy and fringe stability as a function of fundamental control parameters is explored. Surface measurements of common optical components are presented, and method specific noise sources and measurement accuracy are assessed as well.


Deep Learning Based Prediction of Myopia Control Effect in Children Treated With Overnight Orthokeratology.
To develop and validate a deep learning-based model for predicting 12-month axial length (AL) elongation using baseline factors and early corneal topographic changes in children treated with orthokeratology (Ortho-K) and to investigate the association between these factors and myopia control impact. A total of 115 patients with Ortho-K were enrolled. Influential baseline factors that have a statistically significant correlation with 12-month AL from medical records were selected using Pearson correlation coefficients. Simultaneously, the height, area, and volume of the defocus region were directly calculated from the corneal topography. Then, the prediction model was developed by combining multiple linear regression and deep neural network and evaluated in an independent group (83 patients for developing the algorithm and 32 patients for evaluation). Age (r=-0.30, P<0.001), spherical equivalent refractive (SE; r=0.20, P=0.032), and sex (r=0.19, P=0.032) were significantly correlated with the AL elongation while pupil diameter, flat k, steep k, horizontal corneal diameter (white to white), anterior chamber depth, and cell density were not (P>0.1). The prediction model was developed using age, SE, and corneal topographic variation, and the validation of the model demonstrated its effectiveness in predicting AL elongation. The AL elongation was accurately predicted by the deep learning model, which effectively incorporated both baseline factors and corneal topographic variation.


The impact of PRDX4 and the EGFR mutation status on cellular proliferation in lung adenocarcinoma.
Background: Oxidative stress plays key roles in the progression of lung adenocarcinoma. Recently, we reported that peroxiredoxin 4 (PRDX4), an antioxidant enzyme, can be a prognostic marker of lung adenocarcinoma (LUAD). In the present study, we aimed to further investigate the relationship among the PRDX4 expression, epidermal growth factor receptor (EGFR) mutations and cell proliferation in LUAD. Methods: The expression of PRDX4 was immunohistochemically analyzed and the EGFR mutation status was examined in 127 paraffin-embedded human surgical specimens from patients with stage I LUAD. The PRDX4 expression was considered to be high when >40% of the adenocarcinoma cells were positively stained. In vitro, using plasmid transfection methods, PRDX4 plasmid DNAs were transfected into human lung adenocarcinoma cell lines, A549 (EGFR-wild) or PC-9 (EGFR mutant). The viability of these cells was analyzed using a Cell Counting Kit-8 kit. Results: The number of cases with high PRDX4 expression levels among patients with LUAD with EGFR mutations was significantly larger than that in patients with EGFR wild-type. The combination of the PRDX4 expression level with the EGFR mutation status was closely associated with the prognosis of patients with stage I LUAD. Viability assays showed that the proliferation of A549 cells was significantly suppressed after PRDX4 plasmid transfection, while the overexpression of PRDX4 had no effect on the proliferation of EGFR-mutant PC-9 cells. Conclusions: The PRDX4 expression and EGFR mutation status were significantly associated with the prognosis of patients with stage I LUAD, and EGFR mutations affected the role of PRDX4 in the proliferation of LUAD cells.


Effects of cerebellar lesions on saccadic eye movements.
1. Areas of cerebellar cortex related to saccadic eye movements were ablated in three Macaca mulatta monkeys trained to fixate visual targets. There followed a postoperative dysmetria of saccadic eye movements which appeared to be the result of an impairment specifically within the saccadic system. 2. Convergent evidence from two experimental paradigms indicated that the saccadic deficit was a function of the position of the eye in the orbit and did not involve retinal error processing. 3. The pattern of this position-dependent dysmetria suggests that the eye was no longer fully compensating for the elastic restoring forces imposed by the orbital medium and antagonist muscle(s). 4. The similarity of these data to saccadic eye movements of human cerebellar patients and arm movements of rhesus monkeys with cerebellar lesions indicates that the inability to compensate for the differential loads placed on motor systems by the mechanics of those systems may explain several cerebellar symptoms.


Surgical management of colonic diverticulitis and complicated diverticulosis.
The aim of surgery in the management of diverticulitis and complicated diverticulosis is to remove the disease process as quickly as possible. This approach reduces the likelihood of complications and often avoids the necessity of multistage procedures. Indications for resection include failure of a first attack to subside, recurrent attacks, and free perforation with spreading peritonitis. Three-stage procedures should be reserved for extremely serious disease. Other complications requiring surgery are fistula, obstruction, and massive and uncontrolled bleeding. Massive bleeding is caused by diffuse colonic diverticulosis and is rarely associated with diverticulitis. Abdominal mass, obstruction, or recurrent episodes of slight bleeding should suggest the possibility of underlying tumor and are compelling indications for early resection.


Comparison of Kaposi Sarcoma Risk in Human Immunodeficiency Virus-Positive Adults Across 5 Continents: A Multiregional Multicohort Study.
We compared Kaposi sarcoma (KS) risk in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. We included cohort data of human immunodeficiency virus (HIV)-positive adults who started ART after 1995 within the framework of 2 large collaborations of observational HIV cohorts. We present incidence rates and adjusted hazard ratios (aHRs). We included 208140 patients from 57 countries. Over a period of 1066572 person-years, 2046 KS cases were diagnosed. KS incidence rates per 100000 person-years were 52 in the Asia-Pacific and ranged between 180 and 280 in the other regions. KS risk was 5 times higher in South African women (aHR, 4.56; 95% confidence intervals [CI], 2.73-7.62) than in their European counterparts, and 2 times higher in South African men (2.21; 1.34-3.63). In Europe, Latin, and North America KS risk was 6 times higher in men who have sex with men (aHR, 5.95; 95% CI, 5.09-6.96) than in women. Comparing patients with current CD4 cell counts ≥700 cells/µL with those whose counts were <50 cells/µL, the KS risk was halved in South Africa (aHR, 0.53; 95% CI, .17-1.63) but reduced by ≥95% in other regions. Despite important ART-related declines in KS incidence, men and women in South Africa and men who have sex with men remain at increased KS risk, likely due to high human herpesvirus 8 coinfection rates. Early ART initiation and maintenance of high CD4 cell counts are essential to further reducing KS incidence worldwide, but additional measures might be needed, especially in Southern Africa.


Phylogenetic interrelationships of ginglymodian fishes (Actinopterygii: Neopterygii).
The Ginglymodi is one of the most common, though poorly understood groups of neopterygians, which includes gars, macrosemiiforms, and "semionotiforms." In particular, the phylogenetic relationships between the widely distributed "semionotiforms," and between them and other ginglymodians have been enigmatic. Here, the phylogenetic relationships between eight of the 11 "semionotiform" genera, five genera of living and fossil gars and three macrosemiid genera, are analysed through cladistic analysis, based on 90 morphological characters and 37 taxa, including 7 out-group taxa. The results of the analysis show that the Ginglymodi includes two main lineages: Lepisosteiformes and †Semionotiformes. The genera †Pliodetes, †Araripelepidotes, †Lepidotes, †Scheenstia, and †Isanichthys are lepisosteiforms, and not semionotiforms, as previously thought, and these taxa extend the stratigraphic range of the lineage leading to gars back up to the Early Jurassic. A monophyletic †Lepidotes is restricted to the Early Jurassic species, whereas the strongly tritoral species previously referred to †Lepidotes are referred to †Scheenstia. Other species previously referred to †Lepidotes represent other genera or new taxa. The macrosemiids are well nested within semionotiforms, together with †Semionotidae, here restricted to †Semionotus, and a new family including †Callipurbeckia n. gen. minor (previously referred to †Lepidotes), †Macrosemimimus, †Tlayuamichin, †Paralepidotus, and †Semiolepis. Due to the numerous taxonomic changes needed according to the phylogenetic analysis, this article also includes formal taxonomic definitions and diagnoses for all generic and higher taxa, which are new or modified. The study of Mesozoic ginglymodians led to confirm Patterson's observation that these fishes show morphological affinities with both halecomorphs and teleosts. Therefore, the compilation of large data sets including the Mesozoic ginglymodians and the re-evaluation of several hypotheses of homology are essential to test the hypotheses of the Halecostomi vs. the Holostei, which is one of the major topics in the evolution of Mesozoic vertebrates and the origin of modern fish faunas.


Purification and properties of nitroalkane-oxidizing enzyme from Hansenula mrakii.
A nitroalkane-oxidizing enzyme was purified about 1,300-fold from a cell extract of Hansenula mrakii grown in a medium containing nitroethane as the sole nitrogen source by ammonium sulfate fractionation, diethylaminoethyl-cellulose column chromatography, hydroxyapatite column chromatography, and Bio-Gel P-150 column chromatography. The enzyme was shown to be homogeneous upon acrylamide gel electrophoresis and ultracentrifugation. The enzyme exhibits absorption maxima at 274, 370, 415, and 440 nm and a shoulder at 470 nm. Balance studies showed that 2 mol of 2-nitropropane is converted into an equimolar amount of acetone and nitrite with the consumption of 1 mol of oxygen. Hydrogen peroxide is not formed in the enzyme reaction. In addition to 2-nitropropane, 1-nitropropane and nitroethane are oxidatively dentrified by the enzyme, but nitromethane is inert to the enzyme. The nitroalkanes are not oxidized under anaerobic conditions.


The significance of plasma adrenomedullin and calcitonin gene-related peptide concentration in patients with Type 2 diabetes mellitus who are treated for cardiovascular risk factors.
To evaluate the significance of plasma adrenomedullin and calcitonin gene-related peptide (CGRP) concentration in patients with Type 2 diabetes mellitus who are treated for hypertension and dyslipidemia. Plasma adrenomedullin and CGRP concentration, transthoracal echocardiography and ABPM were evaluated in 82 patients with Type 2 diabetes mellitus and 41 control subjects with no previous cardiovascular disease. All the subjects had casual blood pressure ≤140/90 mmHg or received antihypertensive medication, were treated by statin if LDL cholesterol was≥3mmol/L, by fibrates if triacylglyceroles≥2 mmol/L. The mean age was 61±6 in patients with diabetes mellitus and 61±5 years in control subjects (p=0.9). Plasma CGRP was 3.0±1.8 in patients with diabetes mellitus and 2.3±1.0 ng/ml in control subjects (p=0.09). Plasma adrenomedullin was 2.2±0.9 in patients with diabetes mellitus and 2.8±1.1 ng/ml in control subjects (p=0.01). In patients with diabetes mellitus mass index of the left ventricle was significantly higher and the parameters of diastolic function were more deteriorated. Plasma adrenomedullin and CGRP correlated significantly negatively with serum creatinine and positively with mean 24 hours arterial blood pressure in patients with diabetes mellitus but not in control subjects. Plasma adrenomedullin concentration in patients with diabetes mellitus treated for hypertension was significantly reduced. Despite concentration plasma adrenomedullin and CGRP modulation by cardioprotective treatment both neuropeptides remained involved in regulation of hemodynamic and metabolic parameters in patients with Type 2 diabetes mellitus. The low plasma of adrenomedullin in patients with Type 2 diabetic may be marker of the efficient intervention on cardiovascular risk factors.


Cost-effectiveness and cost-utility of an Acceptance and Commitment Therapy intervention vs. a Cognitive Behavioral Therapy intervention for older adults with anxiety symptoms: A randomized controlled trial.
A previous randomized controlled trial in older adults with anxiety symptoms found no differences between a brief blended Acceptance and Commitment Therapy (ACT) intervention and brief face-to-face Cognitive Behavior Therapy (CBT) regarding anxiety symptom severity at posttreatment and 12-month follow-up. A health-economic evaluation comparing these interventions has not yet been conducted. This study examined the one-year cost-effectiveness and cost-utility of blended ACT compared to face-to-face CBT for older adults with anxiety symptoms. The economic evaluation was embedded in a randomized controlled trial comparing blended ACT to CBT in 314 older adults with mild to moderately severe anxiety symptoms. Data were collected at baseline and 3, 6 and 12 months post baseline. For the cost-effectiveness analysis, treatment response was defined as a reliable improvement in anxiety symptom severity (measured with the Generalized Anxiety Disorder-7) between baseline and 12-month follow-up. To assess cost-utility, quality-adjusted life years (QALYs) were computed using EuroQol-5 Dimensions-5 Levels-5 utility scores. Analyses took the societal perspective, including both healthcare costs and productivity costs. Incremental cost-effectiveness ratios were calculated using 2500 bootstraps of seemingly unrelated regression equations of costs and effects. Sensitivity analyses were performed to assess the robustness of the findings. Differences between the blended ACT group and CBT group in treatment response and QALYs were statistically insignificant and clinically irrelevant. The ACT intervention was associated with an average per-participant cost reduction of €466 ($593) compared to CBT, which resulted from lower productivity costs in the blended ACT group. From a healthcare perspective, the ACT intervention was associated with higher costs (by €71 ($90)) than CBT. The results do not indicate that from a health-economic perspective blended ACT should be preferred over CBT in the treatment of older adults with anxiety symptoms. The findings support a model of shared decision making, where clinicians and patients collaboratively decide on the preferred intervention, based on ethical-medical, practical and personal considerations. Netherlands Trial Register: TRIAL NL6131 (NTR6270); https://www.trialregister.nl/trial/6131.


Femoral insertion site in medial patellofemoral ligament reconstruction.
The optimal femoral insertion point in MPFL (medial patellofemoral ligament)-reconstruction still remains ambiguous. Three-dimensional knee simulations based on computerized tomography (CT) images acquired under physiological loading conditions give further insights to predict the optimal femoral insertion site of the MPFL. The hypothesis of the present study is that the optimal insertion point is not as reliable as thought and is dependent on subject-specific anatomical factors. High-resolution 3D images of the knee were acquired in ten weight-bearing knees of healthy subjects in five flexion angles (0 to 120°). The distance between different femoral insertion points and two defined patellar points was computed in each position to quantify length of respective bundles and isometry of the femoral insertion site. The median length of both bundles was maximal in full extension (proximal bundle: 62.2mm and distal bundle: 59.9mm). The shortest ligament length was obtained in the flexion position 90° for bundle I (57.3mm) and 30° for bundle II (85.3mm). The calculated most isometric femoral attachment point showed a non-uniform distribution pattern related to anatomic landmarks. The radiographic landmark showed the worst isometric score value compared to virtually defined spots by surgeons and the computed most isometric point. This study provides results on the MPFL path length under physiological loading conditions using high-resolution bone geometry. The most important finding of this study was that the computed, best isometric femoral insertion point showed a variable anatomical distribution. This suggests that the optimal position for femoral MPFL-graft fixation is patient specific.


Peripheral arterial disease increases the risk of multidrug-resistant bacteria and amputation in diabetic foot infections
The aim of this study was to investigate the microbiological profile and resistance rates of diabetic foot infections (DFIs) and to determine the effect of peripheral arterial disease (PAD) on the microbiology, clinical condition, and treatment outcomes. Characteristics, laboratory and imaging data, and the treatment modalities of patients admitted to our hospital with a diagnosis of DFI (PEDIS classification 3–4) during 2005–2016 were analyzed according to the presence of PAD. Of 112 patients who were included in this study, 86 (76.8%) had PAD. Patients with PAD were older and had higher amputation rates (P < 0.05). A microbiological profile of patients revealed a predominance of gram-positive bacteria (57.1%). Staphylococcus aureus and Streptococcus spp. were the most frequently encountered bacteria. Incidence of Pseudomonas spp. infection was higher in the PAD group (P < 0.05). Of all patients, 24.1% had multidrug-resistant (MDR) microorganisms in their wound cultures. Presence of MDR bacteria in patients with PAD was 4.9-fold higher than that in patients without PAD (P < 0.05). This retrospective study indicates that PAD has a significant role, especially in elderly patients with DFIs. Patients should be promptly evaluated and treated for PAD to prevent infections with resistant microorganisms and limb loss.


Gender differences in signs and symptoms presentation and treatment of Jordanian myocardial infarction patients.
Heart disease is the number one killer in the USA. In Jordan, cardiovascular disease is the leading cause of death, and about 34.5% of women die of cardiovascular disease as compared with 44.25% of men. The differences between men and women in heart disease, such as signs and symptoms presentation, diagnostic and therapeutic interventions, are becoming more apparent in the literature. There is a dearth of research regarding gender differences among Jordanian myocardial infarction (MI) patients. Therefore, the purpose of this study was to explore the differences between Jordanian men and women in signs and symptoms presentation of MI and follow-up care. A convenience sample of 83 patients (26 women and 57 men) who were diagnosed with MI, mentally competent and haemodynamically stable were used to explore the research questions. An interview guide and chart audit were used to elicit information about initial and associated signs and symptoms and treatment plan of MI patients. Chest pain was the most common initial symptom in both men and women. The four most common associated signs and symptoms reported by both men and women were general weakness, sweating, nausea and fatigue. However, women experienced more general weakness and sweating compared with men. Women were less likely to receive intravenous nitroglycerin, heparin and thrombolytic therapy for the treatment of MI. Chest pain was the initial symptom of MI reported by men and women. Although similarities exist in the associated sings and symptoms, women might experience different associated signs and symptoms from men. Despite these similarities, women are still less likely than men to receive the therapeutic regimen used for men.


The exocytosis of lytic granules is impaired in Vti1b- or Vamp8-deficient CTL leading to a reduced cytotoxic activity following antigen-specific activation.
The exocytosis of cytotoxic proteins stored in lytic granules of activated CTL is a key event during killing of target cells. Membrane fusion events that are mediated by soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins are crucial, as demonstrated by patients with familial hemophagocytic lymphohistocytosis type 4 who have mutations in the SNARE protein syntaxin-11 that result in an impaired degranulation of cytotoxic cells. We found an increased mRNA expression of the SNARE protein genes Vti1b and Vamp8 during Ag-specific activation of CTL from TCR-transgenic OT-I mice. Therefore, we investigated the cytolytic activity of CTL from TCR-transgenic Vti1b and Vamp8 knockout mice. At 3 d as well as at 4 d of Ag-specific stimulation, the degranulation of CTL was significantly reduced in Vti1b and Vamp8 knockout mice, as determined by cell surface expression of the degranulation marker CD107a. After 3 d of Ag-specific stimulation, the cytolytic activity of Vti1b- and Vamp8-deficient CTL was reduced to approximately 50% compared with heterozygous controls. However, 4 d after stimulation, the cytotoxic activity of Vti1b- as well as Vamp8-deficient CTL was not impaired anymore. The capacity of Vti1b- and Vamp8-deficient dendritic cells to process Ags and to stimulate the proliferation of CTL was not reduced, arguing against an indirect effect on the activation of CTL. These findings suggest a role of the SNARE proteins vti1b and vesicle-associated membrane protein 8 in the degranulation of CTL. However, a deficiency can apparently be compensated and affects only transiently the cytotoxic activity of CTL during their development to armed effector cells.


A library of aminoglycoside-derived lipopolymer nanoparticles for delivery of small molecules and nucleic acids.
Simultaneous delivery of small molecules and nucleic acids using a single vehicle can lead to novel combination treatments and multifunctional carriers for a variety of diseases. In this study, we report a novel library of aminoglycoside-derived lipopolymers nanoparticles (LPNs) for the simultaneous delivery of different molecular cargoes including nucleic acids and small-molecules. The LPN library was screened for transgene expression efficacy following delivery of plasmid DNA, and lead LPNs that showed high transgene expression efficacies were characterized using hydrodynamic size, zeta potential, 1H NMR and FT-IR spectroscopy, and transmission electron microscopy. LPNs demonstrated significantly higher efficacies for transgene expression than 25 kDa polyethyleneamine (PEI) and lipofectamine, including in presence of serum. Self-assembly of these cationic lipopolymers into nanoparticles also facilitated the delivery of small molecule drugs (e.g. doxorubicin) to cancer cells. LPNs were also employed for the simultaneous delivery of the small-molecule histone deacetylase (HDAC) inhibitor AR-42 together with plasmid DNA to cancer cells as a combination treatment approach for enhancing transgene expression. Taken together, our results indicate that aminoglycoside-derived LPNs are attractive vehicles for simultaneous delivery of imaging agents or chemotherapeutic drugs together with nucleic acids for different applications in medicine and biotechnology.


Melanocytic galectin-3 is associated with tyrosinase-related protein-1 and pigment biosynthesis.
Galectin-3 is a family member of the carbohydrate-binding proteins widely expressed by many cell types and exhibits multiple cellular functions. We demonstrate that melanocytes express galectin-3, which is predominantly localized to the cell body peripherally along the Golgi zone. Downregulation of galectin-3 in human melanocytes using short hairpin RNA technology resulted in the reduction of both melanin synthesis and expression/activity of tyrosinase-related protein-1 (Tyrp-1). In the cell body, galectin-3 colocalizes with melanosome-destined cargo, specifically tyrosinase and Tyrp-1. We studied melanocytes cultured from patients with forms of Hermansky-Pudlak syndrome (HPS) containing defects in trafficking steps governed by biogenesis of lysosome-related organelle complex-2 (BLOC-2) (HPS-5), BLOC-3 (HPS-1), and adaptin-3 (HPS-2). We found that galectin-3 expression mimicked the defective expression of the tyrosinase cargo in dendrites of HPS-5 melanocytes, but it was not altered in HPS-1 or HPS-2 melanocytes. In addition, galectin-3 colocalized predominantly with the HPS-5 component of BLOC-2 in normal human melanocytes. These data indicate that galectin-3 is a regulatory component in melanin synthesis affecting the expression of Tyrp-1.


Designing cost-efficient randomized trials by using flexible recruitment strategies.
Sample size planning for clinical trials is usually based on detecting a target effect size of an intervention or treatment. Explicit incorporation of costs into such planning is considered in this article in the situation where effects of an intervention or treatment may depend on (interact with) baseline severity of the targeted symptom or disease. Because much larger sample sizes are usually required to establish such an interaction effect, investigators frequently conduct studies to establish a marginal effect of the intervention for individuals with a certain level of baseline severity. We conduct a rigorous investigation on how to determine optimum baseline symptom or disease severity inclusion criteria so that the most cost-efficient design can be used. By using a regression model with an interaction term of treatment by symptom severity, power functions were derived for various levels of baseline symptom severity. Computer algorithms and mathematical optimization were used to determine the most cost-efficient research designs assuming either single- or dual-stage screening procedures. In the scenarios we considered, impressive cost savings can be achieved by informed selection of baseline symptom severity via the inclusion criteria. Further cost-savings can be achieved if a two stage screening procedure is used and there are some known, relatively inexpensively collected, pre-screening information. The amount of total cost savings are shown to depend on the ratio of the screening and intervention costs. In our investigation, we assumed that: 1) the cost of approaching available subjects for screening is constant, and 2) all variables are normally distributed. There is a need to carry out further investigations with more relaxed assumptions (e.g., skewed data distribution). As cost becomes a more and more prominent issue in modern clinical trials, cost-saving strategies will become more and more important. Strategies, such as the ones we propose here, can help to minimize costs while maximizing knowledge generation.


The signal peptide anchors apolipoprotein M in plasma lipoproteins and prevents rapid clearance of apolipoprotein M from plasma.
Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic alpha-helixes and beta-sheets. Plasma apolipoprotein (apo) M lacks an external amphipathic motif but, nevertheless, is exclusively associated with lipoproteins (mainly high density lipoprotein). Uniquely, however, apoM is secreted to plasma without cleavage of its hydrophobic NH(2)-terminal signal peptide. To test whether the signal peptide serves as a lipoprotein anchor for apoM in plasma, we generated mice expressing a mutated apoM(Q22A) cDNA in the liver (apoM(Q22A)-Tg mice (transgenic mice)) and compared them with mice expressing wild-type human apoM (apoM-Tg mice). The substitution of the amino acid glutamine 22 with alanine in apoM(Q22A) results in secretion of human apoM without a signal peptide. The human apoM mRNA level in liver and the amount of human apoM protein secretion from hepatocytes were similar in apoM-Tg and apoM(Q22A)-Tg mice. Nevertheless, human apoM was not detectable in plasma of apoM(Q22A)-Tg mice, whereas it was easily measured in the apoM-Tg mice. To examine the plasma metabolism, recombinant apoM lacking the signal peptide was produced in Escherichia coli and injected into wild-type mice. The apoM without signal peptide did not associate with lipoproteins and was rapidly cleared in the kidney. Accordingly, ligation of the kidney arteries in apoM(Q22A)-Tg mice resulted in rapid accumulation of human apoM in plasma. The data suggest that hydrophobic signal peptide sequences, if preserved upon secretion, can anchor plasma proteins in lipoproteins. In the case of apoM, this mechanism prevents rapid loss by filtration in the kidney.


Spanish Version of the Attitude Towards Euthanasia Scale.
Euthanasia is undoubtedly the protagonist of many of the debates around the end of life both among health staff and in the general population. Considering that nurses provide care for terminally ill patients and support families and patients in their final days, it is essential to know their attitudes towards euthanasia. The aims of the study were to adapt and validate the Attitude Towards Euthanasia scale to a Spanish context, to test the dimensionality and to estimate the reliability of the scale. A cross-sectional study was conducted with a non-probabilistic sample of Spanish health-workers of 201 in a University Hospital in Ciudad Real. A self-reported socio-demographic questionnaire and the Euthanasia Attitude Scale were used for data collection. The psychometric properties of the scale were assessed, including reliability and validity using an exploratory and confirmatory factor analysis. Cronbach's alpha of the Attitude Towards Euthanasia scale was α = 0.827 and McDonald's Omega = 0.903. The range of items of homogeneity was from 0.205 to 0.685. For the different exploratory factor analyses carried out, the Bartlett's test of sphericity was p < 0.001 and the sample index value of Kaiser-Meyer-Olkin was over 0.802. in all cases. We present the factorial weights for three models: The first one assumes a unidimensional solution, the second model was composed by three factors and the third model was composed by four factors. In the confirmatory factor analysis, the three models presented an acceptable fit index. The Attitude Towards Euthanasia scale adaptation to a sample of Spanish health workers has shown, with some limitations, appropriate psychometric properties. There have been several differences between the original factorial solution. It would be necessary to replicate the study to reinforce the findings about the number of factors of the scale.


Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature.
To assess whether the polymyalgia rheumatica (PMR)-like syndrome reported as an immune related adverse event (irAE) from checkpoint inhibitor therapy is consistent with the 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) provisional criteria for PMR. The cases were derived from two sources. Group 1 represents reported cases from three contributing centres. Group 2 was derived from a systematic review of the literature searching for all cases reported as PMR or PMR-like illness associated with checkpoint inhibitor therapy. Cases were assessed for the quality of reporting and then analysed to determine whether they fulfilled the 2012 EULAR/ACR provisional criteria for PMR. A total of 49 patients were included for analysis. Among the entire group, 37 (75%) were designated 'complete' indicating that they had sufficient data to reliably apply the 2012 EULAR/ACR criteria. 28 (75%) cases fulfilled complete criteria for PMR. A number of cases also demonstrated some clinical features unusual for idiopathic PMR. This study suggests a high proportion of reported cases of checkpoint inhibitor-related PMR fulfil preliminary criteria for PMR, yet in one quarter clinical details were incomplete making verification problematic. Furthermore, in the absence of a gold standard for the diagnosis of PMR, the relationship of checkpoint inhibitor-related PMR to the idiopathic form remains unclear.


Long term results of glaucoma surgery among participants in an east African population survey.
To evaluate the long term results of glaucoma surgery among people in East Africa. Participants in a population based survey of eye disease prevalence were offered glaucoma surgery using standardised criteria. Either surgical iridectomy or trabeculectomy was carried out as indicated by a medical officer or by one of two ophthalmologists. Trabeculectomy methods included releasable sutures and mitomycin C in the majority of eyes. Subjects were examined during the first week and 2 months after surgery. Nearly 3 years later, re-examination was carried out in those who were still resident in the region. Among 46 people who were offered iridectomy, trabeculectomy, or combined cataract extraction/lens implant/trabeculectomy, 21 people underwent surgery (46%). Of the 21, 19 were re-examined at 3 years (90%), including 16/18 eyes after trabeculectomy. Among these, intraocular pressure (IOP) declined from 29.9 (SD 9.4) mm Hg to 14.7 (5.9) mm Hg, with 16 of 18 eyes (89%) achieving a reduction > 25%. Hypotony maculopathy, late bleb leak, and late endophthalmitis were not detected. Visually significant cataract developed in 5/15 re-examined eyes that underwent trabeculectomy alone (33%), possibly associated with pre-existing cataract and diagnosis of angle closure glaucoma, but not with mitomycin C use. Nearly half of those with glaucoma among residents of rural African villages accepted the offer of surgical therapy. While technical success was achieved at satisfactory levels, the development of cataract must be considered an important issue for application of glaucoma surgical therapy programmes.


[Vegetative pyoderma gangrenosum associated with renal failure].
A case report was presented in which a patient developed vegetative pyoderma gangrenosum that was concomitant with acute renal failure; this led to the critical condition of the patient. He was initially treated with systemic antibiotics because his clinical picture was considered to be pyodermitis, but the response was unsatisfactory. After being treated with levamizol and alfa interferon, an improvement in his general condition and skin lesions was observed. Then surgical exeresis was successfully performed, with skin self-grafting in the face and penis lesions. Pyoderma gangrenosum lesions relapsed but they were treated with prednisone, and then there was a rapid elimination of lesions every time they came up.


Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study.
Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas-dominated group with similar proportions of subjects that were homozygous for F508del.In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects.


Mitochondrial DNA in yeast and some mammalian species.
Yeast DNA, in a cesium chloride density gradient, shows a minor or satellite band with a density lower than that of the main nuclear component. The DNA isolated from purified mitochondria of yeasts corresponds in density to this satellite band. In solution, this DNA more easily undergoes renaturation as compared to DNA from cell nuclei. The ease of this renaturation is presumably due to a homogeneity greater than that of nuclear DNA. Mitochondrial DNA isolated from several mammalian species has the same or higher density than nuclear DNA, but differs in its ready renaturability.


Demonstration of a new mammalian isoleucine catabolic pathway yielding an Rseries of metabolites.
1. Normal human urine contains small amounts (less than 4 mg/g of creatinine) of 2-ethylhydracrylic acid, formed, we believe, by a previously undisclosed endogenous catabolic pathway for the oxidation of a newly described series of R metabolites of isoleucine. 2. Urinary excretion of 2-ethylhydracrylic acid is variably increased in defects of isoleucine oxidation at distal steps in the catabolic pathway (3-oxoacyl-CoA thiolase deficiency and methylmalonyl-CoA mutase deficiency) and is diminished when proximal steps of the oxidative pathway are blocked as in branched-chain oxo acid decarboxylase deficiency ('maple-syrup-urine' disease). 3. Precursors of R-pathway metabolites [R(-)-2-methylbutyrate and 2-ethylacrylate ] lead to increased 2-ethylhydracrylate excretion in the mammal(rat, rabbit and dog); the corresponding S metabolites [S(+)-2-methylbutyric acid and tiglic acid ], when given in equimolar amounts, have little effect on its excretion, suggesting that little or no interconversion between S and R metabolites occurs in vivo. 4. Studies with 2H-labelled precursors indicate that conversion of R 2-methylbutyrate into 2-ethylhydracrylic acid occurs by a direct pathway (apparently via 2-ethylacrylic acid). 5. The further oxidation of 2-ethylhydracrylic acid to ethylmalonic acid was demonstrated, and may be analogous to S-metabolite oxidation via methyl malonate. 6. Valine metabolites do not interact with the R=isoleucine pathway under the conditions of these experiments in vivo.


Plasmid-mediated complementation of gyrA and gyrB in fluoroquinolone-resistant Bacteroides fragilis.
To identify whether mutations in gyrA and gyrB confer fluoroquinolone resistance in Bacteroides fragilis. Eight fluoroquinolone-resistant (FQR) strains were complemented with plasmid-mediated B. fragilis wild-type gyrA (pMP1) and gyrB (pMP2), and MICs determined. Sequence analysis of the gyrA and gyrB quinolone resistance determining region (QRDR) was performed for all strains. MICs of fluoroquinolones were two- to 32-fold higher than wild-type for all mutants. Five mutants had a substitution in GyrA (Ser-82-->Phe), one mutant had a substitution in GyrA (Asp-81-->Gly), one mutant had a substitution in GyrB (Glu-478-->Lys), and one resistant strain did not contain mutations in the QRDR of gyrA or gyrB. Following complementation with pMP1 or pMP2, the MICs of fluoroquinolones were reduced two- to 32-fold for the mutants. These studies verify that substitutions in GyrA and GyrB confer resistance in B. fragilis. Other mechanisms are also responsible for resistance since not all resistant strains fully complemented to the wild-type phenotype.


Should symptom frequency be factored into scalar measures of alcohol use disorder severity?
To evaluate whether weighting counts of alcohol use disorder (AUD) criteria or symptoms by their frequency of occurrence improves their association with correlates of AUD. Data were collected in personal interviews with a representative sample of US adults interviewed in 1991-92. Analyses were conducted among past-year drinkers (12+ drinks, n = 18 352) and individuals with past-year DSM-IV AUD (n = 2770). Thirty-one symptom item indicators, whose frequency of occurrence was measured in eight categories, were used to create unweighted and frequency-weighted counts of DSM-IV past-year AUD symptoms and criteria. Correlates included density of familial alcoholism and past-year volume of ethanol intake, frequency of intoxication and utilization of alcohol treatment. Although the AUD correlates were associated strongly and positively with the frequency of AUD symptom occurrence, weighting for symptom frequency did not strengthen their association consistently with AUD severity scores. Improved performance of the weighted scores was observed primarily among AUD correlates linked closely with the frequency of heavy drinking and among individuals with AUD. Criterion counts were correlated nearly as strongly as symptom counts with the AUD correlates. Frequency weighting may add somewhat to the validity of AUD severity measures, especially those that are intended for use among individuals with AUD, e.g. in clinical settings. For studying the etiology and course of AUD in the general population, an equally effective and less time-consuming alternative to obtaining symptom frequency may be the use of unweighted criterion counts accompanied by independent measures of frequency of heavy drinking.


Constraints on light interception efficiency due to shoot architecture in broad-leaved Nothofagus species.
Shoot architecture may significantly alter mean quantum flux on foliage and thus, photosynthetic productivity. There is currently only limited information about plastic alterations in shoot structure caused by within-canopy variation in mean integrated irradiance (Q(int)) in broad-leaved trees. We studied leaf and shoot structure, and nitrogen and carbon content in late-successional, widely distributed, temperate, broad-leaved Nothofagus taxa to determine the architectural controls on light harvesting and photosynthetic performance. Nothofagus fusca (Hook. f.) Oersted has larger leaves and less densely leaved shoots than the N. solandri varieties. Nothofagus solandri var. solandri (Hook. f.) Oersted is characterized by rounder leaves that potentially have a larger overlap than the ovate-triangular leaves of N. solandri var. cliffortioides (Hook. f.) Poole. Leaf dry mass (M(A)) and nitrogen content (N(A)) per unit area increased with increasing Q(int) in all species, demonstrating enhanced investment of photosynthetic biomass in high light. Although M(A) differed between species at a common irradiance, there was a uniform relationship between N(A) and Q(int) across species. Leaf carbon content per dry mass and leaf dry mass to fresh mass ratio also scaled positively with irradiance, suggesting greater structural investments in high light. In all species, shoots became more horizontal and flatter at lower Q(int), implying an enhanced use efficiency of direct irradiance in natural leaf positions. In contrast, irradiance effects on leaf aggregation varied among species. Across the data, leaf overlap or leaf area density was often greater at lower irradiances, possibly as a result of limited carbon availability for shoot axis extension growth. In N. fusca, leaves of which were more aggregated in high light, the shoot silhouette to total leaf area ratio (S(S)) declined strongly with increasing irradiance, demonstrating a lower light harvesting efficiency at high Q(int). This effect was only moderate in N. solandri var. cliffortioides and S(S) was independent of Q(int) in N. solandri var. solandri. Although the efficiency of light interception at high irradiances was lowest in N. fusca, this species had the greatest nitrogen content per unit shoot silhouette area (2N(A)/S(S)), indicating superior shoot-level photosynthetic potential. These data collectively demonstrate that shoot architecture significantly affects light interception and photosynthesis in broad-leaved trees, and that structural carbon limitations may constrain leaf light harvesting efficiency at low irradiance.


Neoadjuvant nano-photothermal therapy used before operation effectively assists in surgery for breast cancer.
Nano-photothermal therapy (NPTT) has attracted increasing interest recently due to its high efficiency, excellent selectivity and non-ionizing radiation damage. Despite a tremendous amount of exciting pre-clinical results reported in the past few years, however, the further clinic application of NPTT is still difficult. To combine NPTT with clinical surgery more closely, novel multifunctional optical-magnetic nanosystems have been synthesized and applied for preoperative NPTT to assist in the follow-up surgery, termed "neoadjuvant NPTT". Remarkably, nanoparticles are mainly aggregated in the cytoplasm of tumor cells in vitro and largely accumulated in the tumor in vivo 24 h after injection. Under the guidance of tri-modality imaging, preoperative NPTT could shrink the tumor in a short time and make the boundary between the tumor and surrounding normal tissues clearer, which is conducive to subsequent surgery resection. Furthermore, the 50% survival rate is up to 50 days compared with 35 days for standard surgery, 31 days for PTT alone and 24 days for non-surgery groups. Therefore, NPTT can effectively assist in surgery used before operation. This study provides a new idea for the clinical transformation of NPTT in the future.


Thermal and optical properties of Tm3+ doped tellurite glasses.
Ultraviolet, visible (UV/VIS) and differential thermal analysis (DTA) measurements were carried out in order to investigate the optical and thermal properties of various 0.5 mol.% Tm2O3 containing (1 - x)TeO2 + xLiCl glasses in molar ratio. The samples were prepared by fusing the mixture of their respective reagent grade powders in a platinum cricuble at 750 degrees C for 30 min. DTA curves taken in the 23-600 degrees C temperature range with a heating rate of 10 degrees C/min reveal a change in the value of the glass transition temperature, Tg, while melting was not observed for the glasses containing LiCl content less than 50 mol.%. These glasses were found to be moisture-resistant. However, the glasses with LiCl content higher than 50 mol.%, in which a melting peak was observed at Tc = 401 degrees C, were moisture-sensitive. Absorption measurements in the UV/VIS region of the glasses without Tm2O3 content show that the Urbach cutoff occurs at about 320 nm and, is relatively independent of the LiCl content. Six absorption bands were observed in the Tm2O3 doped glasses corresponding to the absorption of the 1G4, 3F2, 3F3 and 3F4, 3H5 and 3H4 levels from the 3H6 ground level of Tm3+ ions. The spectra also show that the integrated absorption cross-section of each band depends on the glass composition. Judd-Ofelt theory was used to determine the Judd-Ofelt parameters as well as the radiative transition probabilities for the metastable levels of Tm3+ ions in (0.3)LiCl + (0.7) TeO2: 0.01 Tm2O3 glass which is moisture-resistant.


Release of iron from ferritin by xanthine oxidase. Role of the superoxide radical.
Mobilization of iron from ferritin by xanthine oxidase was studied under aerobic and anaerobic conditions. Aerobic iron release amounted to approx. 3.7 nmol/ml in 10 min. This amount was decreased by approx. 30% under anaerobic conditions. Aerobic iron mobilization involved two mechanisms. About 70% was released by O2.- generated by xanthine oxidase. The rest was released by O2(.-)-independent mechanisms, which also accounted for the total iron release when O2 was absent. A possible transfer of reducing equivalents directly from xanthine oxidase to ferritin is discussed. The results imply that, in pathological conditions with increased formation of O2.-, iron may be released from ferritin. Furthermore, in hypoxic tissues xanthine oxidase can release iron from ferritin by an O2(.-)-independent process. Free iron is liable to catalyse the formation of the extremely reactive and damaging OH. radical.


Depolymerisation products of hyaluronic acid after exposure to oxygen-derived free radicals.
Preparative chromatographic fractions of human umbilical cord hyaluronic acid (HA) of a molecular weight of 10(6) were subjected to graded oxygen-derived free radical (oxy radical) fluxes produced by: (a) the autoxidation of ferrous ions; (b) the action of xanthine oxidase (XO) on hypoxanthine (HX); and (c) by peripheral blood polymorphonuclear leucocytes that had been stimulated by phorbol myristate acetate (PMA). Analysis by gel chromatography of the products obtained with each of the oxy radical generating systems showed polydispersity in size. The smallest molecules detected had a molecular weight of 10(4). This limiting size was not reduced further by exposure to a second oxy radical flux. The relative proportions of large, medium, and small degradation products were established for various levels of oxy radical flux. Consistently a relatively rapid transition from large to small material was seen on Sepharose 2B chromatography, suggesting an ordered element to the breakdown process. Although the decrease in molecular weight after oxy radical exposure was confirmed by analytical ultracentrifugation, this procedure showed that those samples of lowest viscosity did not have the lowest sedimentation values, possibly reflecting oxy radical-induced repolymerisation. If the size and possibly the conformational characteristics of HA are altered, oxy radical exposure might be expected to alter its biological properties.


Differences in mitochondrial efficiency explain individual variation in growth performance.
The physiological causes of intraspecific differences in fitness components such as growth rate are currently a source of debate. It has been suggested that differences in energy metabolism may drive variation in growth, but it remains unclear whether covariation between growth rates and energy metabolism is: (i) a result of certain individuals acquiring and consequently allocating more resources to growth, and/or is (ii) determined by variation in the efficiency with which those resources are transformed into growth. Studies of individually housed animals under standardized nutritional conditions can help shed light on this debate. Here we quantify individual variation in metabolic efficiency in terms of the amount of adenosine triphosphate (ATP) generated per molecule of oxygen consumed by liver and muscle mitochondria and examine its effects, both on the rate of protein synthesis within these tissues and on the rate of whole-body growth of individually fed juvenile brown trout (Salmo trutta) receiving either a high or low food ration. As expected, fish on the high ration on average gained more in body mass and protein content than those maintained on the low ration. Yet, growth performance varied more than 10-fold among individuals on the same ration, resulting in some fish on low rations growing faster than others on the high ration. This variation in growth for a given ration was related to individual differences in mitochondrial properties: a high whole-body growth performance was associated with high mitochondrial efficiency of ATP production in the liver. Our results show for the first time, to our knowledge, that among-individual variation in the efficiency with which substrates are converted into ATP can help explain marked variation in growth performance, independent of food intake. This study highlights the existence of inter-individual differences in mitochondrial efficiency and its potential importance in explaining intraspecific variation in whole-animal performance.


Craniofacial growth in unoperated craniofacial malformations.
To review current information on craniofacial growth of unoperated patients with craniofacial malformations and stimulate the study of abnormal craniofacial growth through conventional and newer methods. This will lead to improved diagnosis and the understanding of the etiopathogenesis of craniofacial malformations. It is expected that this knowledge will also assist clinicians in planning treatment strategies to better manage these challenging conditions.


Educating medical students about military health: Perspectives from a multidisciplinary lecture initiative.
Medical student education on military health topics is critical in ensuring optimal future care for military service members and their families. Keck School of Medicine of the University of Southern California (Keck SOM) students were invited to participate in an anonymous, voluntary, online survey ("Pre") rating their level of interest, awareness, exposure and comfort with military health issues on a 5-point Likert scale. A student-organized program of four voluntary lectures discussing military health-related topics was then implemented. Students were invited to re-take the survey ("Post") and also indicate which, if any, lectures they had attended. 230 students completed the "Pre" survey. A statistically significant deviation in responses was observed in all four questions, showing high interest (mean: 3.19 ± 1.20, P = 0.002), low awareness (mean: 2.52 ± 1.15, P < 0.001), low comfort (mean: 2.66 ± 1.11, P < 0.001), and low exposure (mean: 1.80 ± 0.95, P < 0.001) to military health issues. 132 students completed the "Post" survey, including 37 lecture attendees and 95 non-attendees. A statistically significant difference in the level of interest (P < 0.05) and exposure (P < 0.05) was observed between these groups. Medical schools that lack military health curricula may underprepare students to care for military-affiliated patients. Student-led programs can help introduce this topic before formalized curricula are instituted.


Does a window of opportunity for rheumatoid arthritis-associated interstitial lung disease exist?
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis, eventually leading to joint destruction. Remarkable advancements in the emergence of molecular targeted therapies and the treatment strategy based on treat-to-target have made it possible for patients to lead their daily lives without disabilities. Specifically, early diagnosis and appropriate treatment without missing a 'window of opportunity' are crucial for improving joint outcomes. On the other hand, interstitial lung disease (ILD) is an extra-articular complication of RA and has an impact on life prognosis. Importantly, it has become evident that achieving remission of arthritis is critical not only for joint outcomes but also to prevent the irreversible progression of pulmonary fibrosis in RA-ILD. Therefore, a 'window of opportunity' may exist not only for joints but also for RA-ILD. However, within RA-ILD, there are cases that progress from an NSIP pattern or airway involvement to a UIP pattern, while there are cases without progression, suggesting that their disease behavior may be diverse. Thus, accumulating evidence is necessary to accurately determine the disease behavior of RA-ILD. This review provides an overview of clinical and radiological features and treatment strategies for RA-ILD, incorporating the latest findings.


Spontaneous diseases in a closed colony of Praomys (Mastomys) natalensis.
In comparison with other rodents, the mastomys is unique as regards the patterns of neoplastic and non-neoplastic diseases that it develops, some of which may constitute suitable animal models for corresponding diseases of man. Among the spontaneous diseases commonly encountered in necropsies of 600 mastomys maintained in a closed colony were: (1) degenerative joint disease of diarthroses and interventricular disks, which develops regularly in the second year of life; (2) renal disease, a type of immune-complex glomerulonephritis, affecting approximately 80% of mastomys in the age bracket 18-36 months; (3) thymomas and thymic hyperplasia affecting 30% of mastomys by the time they are 2 years old or older; (4) a combination of thymoma and polymyositis in a mastomys showing serum-globulin reactivity, presumably auto-antibody against striated muscle; (5) beginning before the age of 1 year, replacement of the normal cell population of the lymphoid tissues by plasma cells, and intense plasma cell infiltration at many other organ and tissue sites; (6) haematopoietic neoplasms, without leukaemic blood, in 10% of mastomys; and (7) histamine-producing argyrophilic carcinoid tumours of the glandular stomach in approximately 60% of old male and 30% of old female mastomys. Additionally, other neoplasms not infrequently encountered in mastomys rarely occur in other rodent species; conversely some neoplasms commonly found in other rodents, including especially tumours of the lung and mammary gland and leukaemia, are rare or absent in mastomys.


The harmony of the cell: the regulatory design of cellular processes.
The living cell is a complex system of interacting processes. The properties of the agents that facilitate these processes, such as enzymes, transporters and receptors, must be tuned to each other if the system is to behave harmoniously. The present chapter describes how the regulatory design of cellular subsystems that makes this harmonious behaviour possible can be visualized on a graph that combines the so-called log-log rate characteristics of these subsystems. The tools that are needed to create and analyse these graphs are metabolic control analysis, supply-demand analysis, enzyme kinetics and computer simulation.


Follow-up Evaluation of Association between Weight Changes, Metabolic, and Hormonal Outcomes in Children - a Single-center Pilot Study.
Fasting blood glucose, insulin level, and lipid profile are the minimal tests according to the Romanian guidelines to evaluate obese children. Cross-sectional studies for pediatric obesity in Romania focused only on epidemiology and management. Our study aimed to evaluate the metabolic and hormonal changes in association with follow-up bodyweight modifications. Medical charts of overweight or obese children presenting at the First Paediatric Hospital, Cluj-Napoca from January 2017 to March 2019 were retrospectively evaluated. Anthropometric measures [e.g., body mass index (BMI), and waist circumference] and blood tests such as inflammatory markers (e.g., white blood cell and neutrophil absolute/relative counts, C-reactive protein), metabolic parameters (e.g., liver enzymes, uric acid, fasting blood glucose, triglycerides, high-density lipoprotein-cholesterol), fasting blood insulin, and cortisol levels were evaluated. Twenty-two overweight or obese children (17 girls, median age of 13 years) monitored on median for 7.5 months were in-cluded in the study. Blood glucose level significantly decreased (p=0.010) and fasting insulin levels increased (p=0.051) at follow-up evaluation, independently of BMI-for-age z-score. Fasting insulin levels were associated with waist circumference (Spearman's rank cor-relation coefficient) ρ=0.58, p=0.030). BMI-for-age z-score proved to be associated with the C-reactive protein level at baseline (ρ=0.70, p=0.036, n=9) and high-density lipoprotein cholesterol at follow-up (ρ=-0.52, p=0.033, n=17). Present analysis found changes in fasting insulin levels in relation to the abdominal circumference and high-density lipoprotein cholesterol and C-reactive protein levels in relation to BMI-for-age z-score in obese children.


Combination oxycodone 5 mg/ibuprofen 400 mg for the treatment of pain after abdominal or pelvic surgery in women: a randomized, double-blind, placebo- and active-controlled parallel-group study.
The sensation of pain arises from both central and peripheral sites, and inflammation may be one of its underlying causes. Combination therapy with analgesic agents having multimodal mechanisms of action and complementary pharmacokinetic properties enhances pain relief by addressing the different pathways of pain while limiting individual drug doses and, therefore, the potential for adverse effects caused by any single agent. Oxycodone and ibuprofen each have been used effectively as monotherapy and in other combinations for the treatment of acute pain; a fixed combination of these analgesics may improve pain relief in the setting of abdominal or pelvic surgery, where trauma and any resultant inflammation may be present at the same time. This study evaluated and compared the analgesic efficacy and tolerability of a single-dose combination tablet containing oxycodone 5 mg/ibuprofen 400 mg with either agent alone and with placebo in women who had undergone abdominal or pelvic surgery. In this multicenter, randomized, double-blind,placebo- and active-controlled, parallel-group trial, women experiencing moderate to severe pain between 14 and 48 hours after surgery were randomized per protocol to receive a single dose of study medication in a 3:3:1:1 ratio (combination oxycodone/ibuprofen, ibuprofen, oxycodone, and placebo, in that order). Over a 6-hour study period, patients recorded their assessments of pain intensity (100-mm visual analog scale and 4-point scale), relief from starting pain, and overall evaluation of study drug based on prespecified definitions and rating scales. Based on these data, the following primary efficacy end points were determined: total pain relief 6 hours after dosing (TOTPAR6) and sum of pain intensity differences 6 hours after dosing (SPID6). Other end points included the time to onset of pain relief, time to use of rescue medication, and patient's global rating of analgesic effectiveness. Tolerability was evaluated on the basis of observed and patient-reported adverse events and findings on physical examination. Four hundred fifty-six women participated in the study. They were primarily white and had a mean age of 41.6 years and a mean body weight of 171.5 pounds. Combination treatment was associated with significantly better TOTPAR6 and SPID6 scores compared with ibuprofen alone (P < 0.02 and P < 0.015, respectively), oxycodone alone (P < 0.009 and P < 0.001), or placebo (both, P < 0.001). Fewer patients receiving combination treatment required rescue medication, and the time to use of rescue medication was significantly longer in the combination-treatment group compared with the other groups (P < 0.05). Patients' global ratings of analgesic efficacy were significantly higher in the combination-treatment group compared with all other groups (P < 0.044 vs ibuprofen alone; P < 0.001 vs oxycodone alone and placebo). The onset of pain relief occurred within 15 minutes of dosing with all 4 regimens. Nausea was the most frequently reported treatment-emergent adverse event in all 4 groups. The incidence of treatment-emergent adverse events was highest with placebo (55.0%), followed by oxycodone alone (44.2%), ibuprofen alone (42.3%), and combination treatment (40.8%). In this population of women who had undergone abdominal or pelvic surgery, the combination of oxycodone 5 mg/ibuprofen 400 mg was significantly more effective than either agent alone or placebo in the treatment of moderate to severe postoperative pain.


Sixth grade students who use alcohol: do we need primary prevention programs for "tweens"?
Young adolescent alcohol users drink at higher rates than their peers throughout adolescence and appear to be less amenable to intervention. This study compares those who reported alcohol use in the past year to those who reported no use in a multiethnic, urban sample of sixth graders in 61 schools in Chicago in 2002 (N = 4,150). Demographic, behavioral, intrapersonal, and socioenvironmental factors were identified based on behavioral theories and potential mediators of the Project Northland Chicago intervention. Single and multiple regression models were created for users and nonusers to determine associations between these factors and alcohol use behavior and intentions. The multiple regression models explained 35% and 56% of the variance in alcohol use behavior and intentions between students for nonusers and users, respectively. Results suggest that primary prevention programs for alcohol use should occur prior to sixth grade, particularly for the substantial group at high risk for early use.


Patterns of DNA methylation and gene expression in human tumor cell lines.
Restriction endonuclease analysis was used to determine the methylation status of collagen, c-Ha-ras, and thymidine kinase genes in human fibroblasts and tumor cell lines. When digested with the methylation sensitive enzymes HpaII or HhaI, the DNA of each cell line generated a unique banding pattern for each gene examined. No generalized trend of gene hypomethylation or decreases in overall cytosine methylation were observed in tumor cell lines when compared to fibroblasts. Collagen biosynthetic profiles were also determined, and no correlations could be made between patterns of type I and type III collagen gene methylation and expression. Our findings support those of a previous report in which methylation and expression of the chick alpha 2(I) collagen gene were examined, and this represents the first such analysis of the pro-alpha 1 (III) collagen gene. MspI restriction fragment length polymorphisms were detected within c-Ha-ras, pro-alpha 2(I) collagen, pro-alpha 1(III) collagen, and thymidine kinase genes. The ras gene polymorphisms can be attributed to variation in the number of tandem repeats within a MspI fragment at the 3' end of the gene. The other gene polymorphisms may be due to base pair mutations at methylated cytosine residues within CCGG sequences.


Distinct roles of the Adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation.
Adenovirus early proteins E4 ORF3 and E4 ORF6 have complementary functions during viral infection. Both proteins facilitate efficient viral DNA replication, late protein expression, and prevention of concatenation of viral genomes. Additionally, E4 ORF6 is involved in the shutoff of the host cell protein synthesis through its interaction with the E1B 55K protein. This complex also leads to the degradation of p53. A unique function of E4 ORF3 is the reorganization of nuclear structures known as PML oncogenic domains (PODs). The function of these domains is unclear, but PODs have been implicated in a number of important cellular processes, including transcriptional regulation, apoptosis, transformation, and response to interferon. The goal of this study was to determine the functional significance of the reorganization of PODs by E4 ORF3. Point mutations were made in the E4 ORF3 gene. These mutants were recombined into a virus lacking E4 ORF6 and expressed under the control of the natural virus E4 promoter. The panel of mutant viruses was used to investigate the role of E4 ORF3 during the course of the viral infection program. One of the mutant viruses exhibited aberrant reorganization of PODs and had a severe defect in viral DNA replication, thus leading to a dramatic decrease in virus production. A number of mutants accumulated viral DNA and infectious virus particles to wild-type levels but showed significant viral genome concatenation. These data show that E4 ORF3 is a multifunctional protein and that a specific rearrangement of nuclear PML domains is coupled to efficient viral DNA replication. This function is distinct from the role of E4 ORF3 in the regulation of virus genome concatenation via inhibition of cellular double-strand break repair.


A flagellum-specific chaperone facilitates assembly of the core type III export apparatus of the bacterial flagellum.
Many bacteria move using a complex, self-assembling nanomachine, the bacterial flagellum. Biosynthesis of the flagellum depends on a flagellar-specific type III secretion system (T3SS), a protein export machine homologous to the export machinery of the virulence-associated injectisome. Six cytoplasmic (FliH/I/J/G/M/N) and seven integral-membrane proteins (FlhA/B FliF/O/P/Q/R) form the flagellar basal body and are involved in the transport of flagellar building blocks across the inner membrane in a proton motive force-dependent manner. However, how the large, multi-component transmembrane export gate complex assembles in a coordinated manner remains enigmatic. Specific for most flagellar T3SSs is the presence of FliO, a small bitopic membrane protein with a large cytoplasmic domain. The function of FliO is unknown, but homologs of FliO are found in >80% of all flagellated bacteria. Here, we demonstrate that FliO protects FliP from proteolytic degradation and promotes the formation of a stable FliP-FliR complex required for the assembly of a functional core export apparatus. We further reveal the subcellular localization of FliO by super-resolution microscopy and show that FliO is not part of the assembled flagellar basal body. In summary, our results suggest that FliO functions as a novel, flagellar T3SS-specific chaperone, which facilitates quality control and productive assembly of the core T3SS export machinery.


Efficacy and safety of abciximab versus tirofiban in addition to ticagrelor in STEMI patients undergoing primary percutaneous intervention.
Platelet glycoprotein IIb/IIIa inhibitors (GPIs) have been part of the adjuvant treatment of acute coronary syndrome for years. However, real-life data regarding the efficacy and safety of GPIs under the current indications are lacking in the setting of potent platelet inhibition. The objectives were to assess the efficacy and safety of abciximab versus tirofiban in patients with ST-elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) and pretreated with ticagrelor, and to identify independent predictor factors of efficacy, bleeding and platelet drop. Three hundred sixty-two patients were divided by GPI administered. Clinical, laboratory, angiographic and outcome characteristics were compared. The primary objective was a composite efficacy endpoint (death from any cause, nonfatal myocardial infarction and nonfatal stroke) at 30 days. The secondary objectives were its individual components, safety (bleeding) and the impact on platelet count during hospital stay. The composite efficacy endpoint was similar in the abciximab and tirofiban groups (6.1% vs 7.3%; p = .632). There were also no differences in cardiovascular death (2.5% vs 2.4%; p = .958), nonfatal myocardial infarction (3% vs 4.3%; p = .521) and nonfatal stroke (0.5% vs 1.8%; p = .332). Tirofiban administration was associated with a higher incidence of bleeding (11.6% vs 22%; p = .008) with no differences in BARC ≥ 3b bleeding (3.6 vs 2.5%; p = .760). In STEMI patients undergoing PPCI with ticagrelor, abciximab and tirofiban had similar rates in the composite efficacy endpoint at 30 days. The 30-day bleeding rate was significantly higher in the tirofiban group. Tirofiban administration was an independent predictor of both bleeding and platelet count drop.


Feasibility and acceptability of TRANSFoRm to improve clinical trial recruitment in primary care.
Recruitment of study participants is a challenging process for health professionals and patients. The Translational Medicine and Patient Safety in Europe (TRANSFoRm) clinical trial tools enable automated identification, recruitment and follow-up in clinical trials, potentially saving time, effort and costs for all parties involved. This study evaluates the acceptability and feasibility of TRANSFoRm to improve clinical trial recruitment in primary care. A feasibility study was conducted in three general practices in Poland. Participants were physicians and patients with gastro-oesophageal reflux disease. Semi-structured interviews were held to obtain feedback about the usefulness, ease of use and overall experience with the TRANSFoRm tools and to identify potential usability issues. Data were analysed thematically. A total of 5 physicians and 10 patients participated in the study. Physicians were satisfied with the usefulness of the system, as it enabled easier and faster identification, recruitment and follow-up of patients compared with existing methods. Patients found the TRANSFoRm apps easy to use to report patient outcomes. However, they also felt that the apps may not be useful for patients with limited exposure to smartphone and web technologies. Two main usability issues were identified: physicians could not access the result of the randomization at the end of each visit, and participants could not locate the follow-up reminder email. This study provides new evidence on the acceptability and feasibility of TRANSFoRm to enable automated identification, recruitment and follow-up of study participants in primary care trials. It also helps to better understand and address users' requirements in eHealth-supported clinical research.


Assessment of the accuracy of serial electrocardiograms in the diagnosis of myocardial infarction.
The diagnostic accuracy of the 12-lead scalar electrocardiogram (ECG) for the presence or absence of acute transmural myocardium infarction (MI) was studied in 25 patients who died while in hospital for treatment of ischemic chest pain. Detailed autopsy studies revealed myocardial necrosis in 17 patients, with the ECG accurate in 11 (44%) of the 25 patients. None of the five patients with autopsy-proven subendocardial infarction had abnormal Q waves. The admission ECG was diagnostic in only 4 of the 17 patients (24%) with infarction. The creatine kinase (CK) and CK-MB results agreed with the pathologic findings in 22 of the 25 patients (88%), were falsely negative in one patient, and falsely positive in two of the patients. In this selected population the most reliable diagnostic tests were CK or CK-MB isoenzymes. The ECG was frequently unhelpful (7 of 25 patients) because of left bundle branch block or paced rhythm, but when unaffected by these depolarization abnormalities it was useful in establishing the correct diagnosis.


Internalizing Symptoms and Externalizing Behaviors in Latinx Adolescents with Same Sex Behaviors in Miami.
Sexual minorities report poorer mental health relative to heterosexual counterparts, but this is underexplored in Latinx youth. This study compares internalizing symptoms and externalizing behaviors in Latinx adolescents with Same Sex Behaviors (LASSB) to their Latinx adolescent peers who did not report same sex behaviors (non-LASSB). It also explores the moderating role of biculturalism on the relationship between internalizing symptoms and externalizing behaviors, and same-sex behaviors. Individual-level baseline data (Total N=1,634; LASSB n=195) from five trials of a preventive intervention for Latinx adolescents were synthesized. Normal and clinical levels of internalizing symptoms and externalizing behaviors were determined, and logistic regression models were conducted to determine the odds of LASSB reporting these behaviors relative to non-LASSB. Additional adjusted models tested for the moderating effect of biculturalism. LASSB reported significantly higher odds of normal levels of all externalizing behaviors and clinical levels of anxious/depressed compared to non-LASSB. Biculturalism significantly moderated the association between same-sex behavior and clinical levels of internalizing behaviors; however, in subgroup analyses among LASSB, biculturalism did not significantly predict any of these behaviors. Latinx adolescents exhibited mental health disparities by same-sex behavior. Biculturalism may be an important indicator for describing these disparities in LASSB and should be further explored.


Impaired decision-making under risk in individuals with alcohol dependence.
Alcohol dependence is associated with poor decision-making under ambiguity, that is, when decisions are to be made in the absence of known probabilities of reward and loss. However, little is known regarding decisions made by individuals with alcohol dependence in the context of known probabilities (decision under risk). In this study, we investigated the relative contribution of these distinct aspects of decision-making to alcohol dependence. Thirty recently detoxified and sober asymptomatic alcohol-dependent individuals and 30 healthy control participants were tested for decision-making under ambiguity (using the Iowa Gambling Task[IGT]) and decision-making under risk (using the Cups Task and Coin Flipping Task). We also tested their capacities for working memory storage (digit span forward) and dual tasking (operation span task). Compared to healthy control participants, alcohol-dependent individuals made disadvantageous decisions on the IGT, reflecting poor decisions under ambiguity. They also made more risky choices on the Cups and Coin Flipping Tasks reflecting poor decision-making under risk. In addition, alcohol-dependent participants showed some working memory impairments, as measured by the dual tasking, and the degree of this impairment correlated with high-risk decision-making, thus suggesting a relationship between processes subserving working memory and risky decisions. These results suggest that alcohol-dependent individuals are impaired in their ability to decide optimally in multiple facets of uncertainty (i.e., both risk and ambiguity) and that at least some aspects of these deficits are linked to poor working memory processes.


Discrimination of mammalian GPI-anchored proteins by hydropathy and amino acid propensities.
The glycosylphosphatidylinositol (GPI) attachment is a most important post-translational modification of proteins that plays essential roles in promoting the biochemical activities of eukaryotic cells. Described here is an analysis of the amino acid properties of mammalian GPI-anchored proteins (GPI-APs) and the development of an innovative method of detecting them. GPI-APs are characterized by two high-hydropathy regions: the signal peptide, located inside the Endoplasmic Reticulum (ER), and the GPI attachment signal, a sequence adjacent to the GPI-anchoring site (the ω-site). Especially in sequence analysis of known GPI-APs, there were some distinct aspects of the amino acid propensities around the ω-sites. Therefore, a method of detecting GPI-APs was developed based on hydropathy profiles and a position-specific scoring matrix (PSSM) calculated by position-specific amino acid propensities. First, sequences of GPI-APs and negative controls, determined by screening based on hydropathy and residue volume profiles, were aligned based on residue volume profiles in the C-terminal region, and the position-specific amino acid propensities of each group were calculated according to their alignment positions. Then, a PSSM was devised using the amino acid propensities of GPI-APs and negative controls, and discrimination scores were estimated for each dataset. Based on these scores at a threshold was fixed for each dataset. GPI-APs were detected with 81.1% sensitivity and a 0.818 success rate in an optimized calculation region determined by adjusting the window size of this region using a 5-fold dataset. The results indicate that a PSSM around the ω-site can effectively discriminate GPI-APs.


Apolipoprotein B Is Related to Metabolic Syndrome Independently of Low Density Lipoprotein Cholesterol in Patients with Type 2 Diabetes.
Increased low density lipoprotein cholesterol (LDL-C) level and the presence of metabolic syndrome (MetS) are important risk factors for cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). Recent studies demonstrated apolipoprotein B (apoB), a protein mainly located in LDL-C, was an independent predictor of the development of CVD especially in patients with T2DM. The aim of this study was to investigate the relationship between apoB and MetS in T2DM patients. We analyzed 912 patients with T2DM. Fasting blood samples were taken for glycated hemoglobin, high-sensitivity C-reactive protein, total cholesterol, triglyceride (TG), high density lipoprotein cholesterol, LDL-C, and apoB. MetS was defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria. We performed a hierarchical regression analysis with apoB as the dependent variable. Age, sex, the number of components of MetS and LDL-C were entered at model 1, the use of lipid-lowering medications at model 2, and the individual components of MetS were added at model 3. Seventy percent of total subjects had MetS. ApoB level was higher in subjects with than those without MetS (104.5±53.3 mg/dL vs. 87.7±33.7 mg/dL, P<0.01) even after adjusting for LDL-C. ApoB and LDL-C were positively correlated to the number of MetS components. The hierarchical regression analysis showed that the increasing number of MetS components was associated with higher level of apoB at step 1 and step 2 (β=0.120, P<0.001 and β=0.110, P<0.001, respectively). At step 3, TG (β=0.116, P<0.001) and systolic blood pressure (β=0.099, P<0.05) were found to significantly contribute to apoB. In patients with T2DM, apoB is significantly related to MetS independently of LDL-C level. Of the components of MetS, TG, and systolic blood pressure appeared to be determinants of apoB.


The noncalcemic vitamin D analogs EB1089 and 22-oxacalcitriol suppress serum-induced parathyroid hormone-related peptide gene expression in a lung cancer cell line.
PTH-related peptide (PTHrP) mediates the syndrome of humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung. This study was undertaken to determine whether 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and two nonhypercalcemic analogs, EB1089 and 22-oxa-1,25-(OH)2D3 (22-oxacalcitriol), suppress serum- and epidermal growth factor (EGF)-induced PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. PTHrP expression was up-regulated by serum and EGF in a concentration- and time-dependent manner. Nuclear run-on analysis showed that this induction was mediated via a transcriptional mechanism, and that sequences within promoter 1 were responsible. All three vitamin D3 compounds decreased both basal and serum- and EGF-induced steady state PTHrP messenger RNA and secreted peptide levels. These effects were again mediated via a transcriptional mechanism through sequences within promoter 1. All three vitamin D3 compounds also decreased the proliferation of NCI H520 cells in a concentration- and time-dependent manner. 1,25-(OH)2D3 is hypercalcemic in vivo. However, the noncalcemic analogs EB1089 and 22-oxa-1,25-(OH)2D3 have therapeutic potential, as they suppress not only the basal but also the growth factor-stimulated levels of PTHrP in a cancer cell line associated with hypercalcemia.


Black tea increases hypertonic stress resistance in C. elegans.
Here we identified that BTE (black tea extract), within the studied concentration range, is more effective than GTE (green tea extract) in protecting C. elegans against hypertonic stress, by enhancing survival after exposure to various salts, and alleviating suffered motility loss and body shrinkage. The mechanism of such protection may be due to the ability of black tea to induce the conserved WNK/GCK signaling pathway and down-regulation of the expression levels of nlp-29. Intriguingly, black tea does not relieve hypertonicity-induced protein damage. The findings implicate the potential health benefits of black tea consumed worldwide.


Relationship of Choroidal Vasculature and Choriocapillaris Flow With Alterations of Salivary α-Amylase Patterns in Central Serous Chorioretinopathy.
An abnormality in choroidal vasculature is a known factor in the pathogenesis of central serous chorioretinopathy (CSC), a chorioretinal disease affecting mostly middle-aged males. The purpose of the present study was to investigate the role of the autonomic nervous system (ANS) in the pathophysiology of CSC. This was a cross-sectional observational study in which characteristic choroidal vasculature metrics were assessed by measuring the subfoveal choroidal thickness (FCT) and the choroidal vascularity index (CVI) using the imaging technique of enhanced-depth imaging spectral-domain optical coherence tomography (EDI-SD-OCT). Furthermore, flow signal void area features were also evaluated in the study population using OCT angiography (OCTA). Diurnal patterns of salivary α-amylase (a-AMY) production, proposed as a marker of autonomic activity, were assessed in an adult male study population affected by acute naïve CSC in comparison with matched healthy controls. Results include an overall higher diurnal output of salivary a-AMY production, which is in line with the phenomenon of a sympathetic "drive" playing a role in the pathophysiology of CSC, and a flattened diurnal percentage variation in α-AMY in CSC-affected subjects. Furthermore, Pearson's coefficient test revealed statistically significant correlations between salivary α-AMY diurnal percentage variation and selected choroidal imaging biomarkers (FCT, CVI, and flow signal void area). Finally, multiple linear regression analysis identified salivary α-AMY diurnal percentage production as the sole predictor of the CVI and flow signal void area in the study population. Autonomic nervous system dysregulation was highlighted in CSC patients.