Extracellular matrix-associated gene expression in adult sensory neuron populations cultured on a laminin substrate.
In our previous investigations of the role of the extracellular matrix (ECM) in promoting neurite growth we have observed that a permissive laminin (LN) substrate stimulates differential growth responses in subpopulations of mature dorsal root ganglion (DRG) neurons. DRG neurons expressing Trk and p75 receptors grow neurites on a LN substrate in the absence of neurotrophins, while isolectin B4-binding neurons (IB4+) do not display significant growth under the same conditions. We set out to determine whether there was an expression signature of the LN-induced neurite growth phenotype. Using a lectin binding protocol IB4+ neurons were isolated from dissociated DRG neurons, creating two groups - IB4+ and IB4-. A small-scale microarray approach was employed to screen the expression of a panel of ECM-associated genes following dissociation (t=0) and after 24 hr culture on LN (t=24LN). This was followed by qRT-PCR and immunocytochemistry of selected genes. The microarray screen showed that 36 of the 144 genes on the arrays were consistently expressed by the neurons. The array analyses showed that six genes had lower expression in the IB4+ neurons compared to the IB4- cells at t=0 (CTSH, Icam1, Itgβ1, Lamb1, Plat, Spp1), and one gene was expressed at higher levels in the IB4+ cells (Plaur). qRT-PCR was carried out as an independent assessment of the array results. There were discrepancies between the two methods, with qRT-PCR confirming the differences in Lamb1, Plat and Plaur, and showing decreased expression of AdamTs1, FN, and Icam in the IB4+ cells at t=0. After 24 hr culture on LN, there were no significant differences detected by qRT-PCR between the IB4+ and IB4- cells. However, both groups showed upregulation of Itgβ1 and Plaur after 24 hr on LN, the IB4+ group also had increased Plat, and the IB4- cells showed decreased Lamb1, Icam1 and AdamTs1. Further, the array screen also detected a number of genes (not subjected to qRT-PCR) expressed similarly by both populations in relatively high levels but not detectably influenced by time in culture (Bsg, Cst3, Ctsb, Ctsd, Ctsl, Mmp14, Mmp19, Sparc. We carried out immunohistochemistry to confirm expression of proteins encoded by a number of these genes. Our results show that 1B4+ and IB4- neurons differ in the expression of several genes that are associated with responsiveness to the ECM prior to culturing (AdamTs1, FN, Icam1, Lamb1, Plat, Plaur). The data suggest that the genes expressed at higher levels in the IB4- neurons could contribute to the initial growth response of these cells in a permissive environment and could also represent a common injury response that subsequently promotes axon regeneration. The differential expression of several extracellular matrix molecules (FN, Lamb1, Icam) may suggest that the IB4- neurons are capable of maintaining /secreting their local extracellular environment which could aid in the regenerative process. Overall, these data provide new information on potential targets that could be manipulated to enhance axonal regeneration in the mature nervous system.


COVID-19 and cancer: A guide with suggested COVID-19 rule-out criteria to support clinical decision-making.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious zoonotic pathogen that has exacted heavy public health, social and economic tolls. In February 2020, the World Health Organization acronymed the disease caused by SARS-CoV-2 as COVID-19, for coronavirus disease 2019. The number of confirmed COVID-19 infections, which has been detected in at least 103 countries, has reached 1,970,225 worldwide as of April 14, 2020 with 124,544 deaths, according to the U.S. Centers for Disease Control and Prevention (CDC). Many cases of COVID-19 resolve quickly. However, the disease, which, like other respiratory pathogens that cause common cold symptoms is believed to be transmitted through respiratory droplets. Infection with COVID-19 can also lead to significant morbidity and death; this is particularly the case for cancer patients. Moreover, because the signs and symptoms of COVID-19 are easily misattributed to the sequelae of cancer itself, such as pulmonary embolism, or its treatment, such as nausea and diarrhea, diagnosis may be delayed or missed. Potential COVID-19 rule out criteria, based on the Wells' criteria for pulmonary embolism, another protean disease entity, are provided as a decision-making aid. This review summarizes the current understanding of the transmission, clinical presentation, diagnosis and differential diagnosis, pathogenesis, rationale to treat the cancer or not, treatment and prevention of COVID-19 with an emphasis on implications in cancer.


Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.
Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.


Electron beam collimation with focused and curved leaf end MLCs--experimental verification of Monte Carlo optimized designs.
In general, electron beams from conventional accelerators using applicators with lead alloy inserts are not suitable for advanced conformal radiation therapy. However, interesting electron treatments have been demonstrated on a few advanced accelerators. These accelerators have been equipped with helium filled treatment heads and computer controlled MLCs that produce clinically useful energy modulated electron beams or mixed photon electron beams in an automated sequence. This study analyzes the characteristics of different MLC designs, curved and focused leaf ends in helium filled treatment heads, with respect to their effect on electron beams. In addition, this study analyzes the effects that different treatment head designs have on the output factor due to collimator scattering and shielding of secondary sources during treatment. The investigation of the different treatment head designs was performed with the Monte Carlo package BEAM and was verified by experimental methods. The results show that the difference between curved leaf ends and focused ends is negligible in most practical cases. The results also show the importance of scattering foil optimization in the optimization of parameters such as penumbra, virtual source position, and in the reduction of the output variation. In all cases, the experimental data verifies the calculations.


ZnO/Cu2O heterojunction integrated fiber-optic biosensor for remote detection of cysteine.
Indium tin oxide, semiconductor nanomaterial ZnO, and Cu2O were first loaded on the surface of the optical fiber to form an optical fiber probe. Large-volume macroscopic spatial light is replaced by an optical fiber path, and remote light injection is implemented. Based on the optical fiber probe, a photoelectrochemical biosensor was constructed and remote detection of cysteine was realized. In this tiny device, the optical fiber probe not only acts as a working electrode to react with the analyte but also directs the light exactly where it is needed. Simultaneously, the electrochemical behavior of cysteine on the surface of the working electrode is dominated by diffusion-control, which provides strong support for quantitative detection. Then, under the bias potential of 0 V, the linear range of the fiber-optic-based cysteine biosensor was 0.01∼1 μM, the regression coefficient (R2) value was 0.9943. In spiked synthetic urine, the detection of cysteine was also realized by the integrated biosensor. Moreover, benefiting from the low optical fiber loss, the new structure also possesses a unique remote detection function. This work confirms that photoelectrochemical biosensors can be integrated via optical fibers and retain comparable sensing performance. Based on this property, different materials can also be loaded on the surface of the optical fiber for remote detection of other analytes. It is expected to facilitate the research on fiber-optic-based integrated biosensors and show application prospects in diverse fields such as biochemical analysis and disease diagnosis.


[Dopplerographic assessment of the autoregulation of the blood supply to the brain in neurosurgical pathology].
The development of an informative, noninvasive technique for evaluating the reserve of the cerebral circulatory system is a topical task of clinical angioneurology. The authors developed methods of Doppler evaluation of an autoregulatory response from hyperemic changes after short-term regional hypotension caused by digital compression of the cervical carotid. They calculated the indices acceptable in routine clinical practice, defined the range of their values in health and in typical variants of cerebral circulatory insufficiency in patients with disseminated neurosurgical pathology. The carotid compression test by recording linear blood flow velocity in the cerebral arteries is a safe, valid, and reproducible method of semiquantitative assessment of the autoregulation reserve which may be used to determine the tension of resistive vessels in the middle cerebral arterial bed as an important index of the functional status of the cerebral circulatory system.


Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-κB activation in murine macrophages via changes in intracellular calcium.
Prostaglandin D2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ12prostaglandin J2 and 15-deoxy-Δ12,14-prostaglandin J2, act through 2 GPCRs, d-type prostanoid 1 and the chemoattractant receptor homologous molecule expressed on type 2 T-helper cells (Crth2). In addition to its role in allergy and asthma, the role of Crth2 in the resolution of inflammation, to mediate the proresolving functions of endogenous CyPGs, is not well understood. We investigated the regulation of LPS or zymosan-induced inflammatory response by signals from the Crth2 receptor in macrophages that lack Crth2 expression [knockout (KO)]. Increased expression of proinflammatory genes, including Tnf-α, was observed in Crth2 KO cells. Targeting the endogenous biosynthetic pathway of CyPGs with indomethacin or HQL79, which inhibit cyclooxygenases or hematopoietic prostaglandin D synthase, respectively, or use of Crth2 antagonists recapitulated the proinflammatory phenotype as in Crth2 KO cells. Ligand-dependent activation of Crth2 by 13,14-dihydro-15-keto-prostaglandin D2 increased Ca2+ influx through store-operated Ca2+ entry (SOCE) accompanied by the up-regulation of stromal interaction molecule 1 and calcium release-activated calcium modulator 1 expression, suggesting that the proresolution effects of CyPG-dependent activation of SOCE could be mediated by Crth2 during inflammation. Interestingly, Crth2 signaling down-regulated the Ca2+-regulated heat stable protein 1 that stabilizes Tnf-α mRNA via the increased expression of microRNA 155 to dampen inflammatory responses triggered through the TNF-α-NF-κB axis. In summary, these studies present a novel regulatory role for Crth2 during inflammatory response in macrophages.-Diwakar, B. T., Yoast, R., Nettleford, S., Qian, F., Lee, T.-J., Berry, S., Huffnagle, I., Rossi, R. M., Trebak, M., Paulson, R. F., Prabhu, K. S. Crth2 receptor signaling down-regulates lipopolysaccharide-induced NF-κB activation in murine macrophages via changes in intracellular calcium.


Muscle Transcriptome Sequencing Revealed Thermal Stress-Responsive Regulatory Genes in Farmed Rohu, Labeo rohita (Hamilton, 1822).
Rohu, Labeo rohita, is one of the most important aquaculture species in the Indian subcontinent. Understanding the molecular-level physiological responses to thermal stress or climate change is essential. In the present work, transcriptome sequencing was carried out in the muscle tissue of the rohu in response to heat stress (35 °C) in comparison with the control (28 °C). A total of 125 Gb of sequence data was generated, and the raw-reads were filtered and trimmed, which resulted in 484 million quality reads. Reference-based assembly of reads was performed using L. rohita genome, and a total of 90.17% of reads were successfully mapped. A total of 37,462 contigs were assembled with an N50 value of 1854. The differential expression analysis revealed a total of 107 differentially expressed genes (DEGs) (15 up-, 37 down-, and 55 neutrally regulated) as compared to the control group (Log2FC > 2, P < 0.05). Gene enrichment analysis of DEGs indicates that transcripts were associated with molecular, biological, and cellular activities. The randomly selected differentially expressed transcripts were validated by RT-qPCR and found consistent expression patterns in line with the RNA-seq data. Several transcripts such as SERPINE1(HSP47), HSP70, HSP90alpha, Rano class II histocompatibility A beta, PGC-1 and ERR-induced regulator, proto-oncogene c-Fos, myozenin2, alpha-crystallin B chain-like protein, angiopoietin-like protein 8, and acetyl-CoA carboxylases have been identified in muscle tissue of rohu that are associated with stress/immunity. This study identified the key biomarker SERPINE1 (HSP47), which showed significant upregulation (~ 2- to threefold) in muscle tissue of rohu exposed to high temperature. This study can pave a path for the identification of stress-responsive biomarkers linked with thermal adaptations in the farmed carps.


Futile reperfusion and predicted therapeutic benefits after successful endovascular treatment according to initial stroke severity.
Futile reperfusion (poor functional status despite successful reperfusion) was observed in up to 67% of patients enrolled in recent endovascular treatment (EVT) clinical trials. We investigated the impact of baseline stroke severity on both futile reperfusion and therapeutic benefit of successful EVT. Using a prospective multicenter stroke registry, we identified consecutive ischemic stroke patients with anterior circulation large artery occlusion, who were reperfused successfully by EVT (Thrombolysis in Cerebral Infarction grade 2b-3). The rate of futile reperfusion was assessed across the initial National Institutes of Health Stroke Scale (NIHSS) scores. The frequency of poor outcomes (modified Rankin scale [mRS] 3-6) according to NIHSS scores was compared between patients revascularized successfully by EVT and those who did not receive EVT, after standardizing for age. Among 21,591 patients with ischemic stroke, 972 (4.5%) received EVT within 12 h of onset, including 440 who met study eligibility criteria. Futile reperfusion was observed in 226 of the 440 study-eligible patients (51.4%) and was associated with stroke severity: 20.9% in NIHSS scores ≤5, 34.6% in 6-10, 58.9% in 11-20, and 63.8% in > 20 (p < 0.001). Nonetheless, the therapeutic benefit of EVT also increased with increasing stroke severity (p for interaction < 0.001): 0.1% in NIHSS ≤5, 18.6% in 6-10, 28.7% in 11-20, and 34.3% in > 20. EVT is more beneficial with increasing stroke severity, although futile reperfusion also increases with higher stroke severity.


Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer.
Elevated circulating insulin-like growth factor-1 (IGF-1), a breast epithelial cell mitogen, is associated with breast cancer development. However, its association with breast cancer survival is not established. Circulating concentrations of IGF-1 are controlled via binding proteins, including IGF Binding Protein-3 (IGFBP-3), that may modulate the association of IGF-1 with breast-cancer outcomes. We measured IGF-1 and IGFBP-3 concentrations in serum from 600 women enrolled in the health, eating, activity, and lifestyle (HEAL) study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between IGF-1 and IGFBP-3, and as a ratio, modeled using quintile cut-points, with risk of breast cancer-specific (n = 42 deaths) and all-cause mortality (n = 87 deaths) using Cox proportional hazards models. In models adjusted for body mass index, ethnicity, tamoxifen use at time of blood draw, treatment received at diagnosis and IGFBP-3, women in the highest quintile of IGF-1 level had an increased risk of all-cause mortality (Hazard Ratio (HR) = 3.10, 95% CI 1.21-7.93, p = 0.02), although no dose-response association was evident. The IGF-1/IGFBP-3 ratio, an indicator of free IGF-I levels, was significantly associated with increasing risk of all-cause mortality (HR = 2.83, 95% CI 1.25-6.36 p(trend) = 0.01, upper vs. lower quintile) in a fully adjusted model. In conclusion, high serum levels of IGF-1 and the IGF-1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer. These results need to be confirmed in larger breast cancer survivor cohorts.


Gender differences in the link between depression and cardiovascular disease.
Cardiovascular disease is the leading cause of mortality in women costing more than 500,000 lives each year in the United States alone. Major depression in healthy subjects increases cardiovascular mortality in both men and women. The presence of major depression in patients with recent acute myocardial infarction (AMI) or unstable angina more than doubles the risk of cardiac death in both men and women. In the presence of depression, lack of social integration has an additive effect on cardiac events. Depression is more prevalent in women with coronary heart disease (CHD) than in men. Psychologic counseling as well as cognitive behavioral treatment in women post-AMI seems to adversely affect prognosis, whereas it has neutral effects in men. Pharmacologic treatment of depression with serotonin reuptake inhibitors is safe in men and women post-AMI and is particularly effective in patients with recurrent depression. Whether effective treatment of depression lowers cardiac mortality remains to be proven.


Using knowledge brokering activities to promote allied health clinicians' engagement in research: a qualitative exploration.
Engaging clinicians in research can improve healthcare organisational performance, patient and staff satisfaction. Emerging evidence suggests that knowledge brokering activities potentially support clinicians' research engagement, but it is unclear how best they should be used. This study explores how embedded researchers utilised knowledge brokering activities to engage research interested clinicians in research. A longitudinal qualitative interview based study was co-designed to investigate how experienced research fellows utilise knowledge brokering activities to facilitate allied health clinicians' engagement in research. In one large tertiary level, regional Australian health service, research fellows were matched with research interested clinicians. Qualitative analysis of three longitudinal semi-structured interviews for each research fellow was undertaken. Initial descriptions of their utilisation of knowledge brokering activities were deductively coded. Reflexive thematic analysis was utilised to generate a shared explanation of clinicians' engagement in research. Three research fellows facilitated 21 clinicians' participation in and leadership of clinical research projects over 12 months. They utilised all ten key knowledge brokering activities with each clinician, with differing patterns and examples. Research fellows described using linkage and exchange activities of communicating and collaborating with key stakeholders, and they tailored knowledge management products for individual's engagement. Further, they described a broader learning journey where they clarified and monitored individuals' capabilities, motivation and their contextual support for research engagement. When research fellows chose and tailored knowledge brokering activities to align and extend clinicians' research capabilities and motivation, they created individualised learning curriculums to support clinicians' participation in and leadership of local research projects. Health and academic leaders should consider structuring embedded researcher positions to include knowledge brokering roles and activities, specifically for research interested clinicians who are ready to participate in and lead research projects.


The predictive validity of lay Diagnostic Interview Schedule diagnoses in the general population. A comparison with physician examiners.
A clinical reexamination by psychiatrists is a useful comparison for exploring lay Diagnostic Interview Schedule-derived psychiatric diagnoses in general population surveys, but as a validity standard psychiatric reexamination is less than ideal. There are many potential sources of disagreement that have nothing to do with the validity of either the lay or the psychiatrist examination. Another approach to comparing lay and psychiatrist diagnoses is to examine their relative predictive power. We describe such a comparison using outcome variables derived from the one-year follow-up examination of Epidemiologic Catchment Area respondents done at the St. Louis site. We examine several outcome variables across nine diagnostic categories. Within the limits of the available data, lay and psychiatrist diagnoses appear to be essentially equal in terms of the number of outcomes better predicted and few of the differences in predictive power approach statistical significance. We discuss the implications of these findings for the analysis of lay interviewer Diagnostic Interview Schedule-derived diagnoses.


Vitrification of immature feline oocytes with a commercial kit for bovine embryo vitrification.
The aim of this study was to evaluate the suitability of a commercial kit for bovine embryo vitrification for cryopreserving cat oocytes and to evaluate comparatively the effects of its use with slow freezing procedure on cryotolerance in terms of morphology and oocyte resumption of meiosis. Germinal vesicle stage oocytes isolated from cat ovaries were either vitrified (n = 72) using a vitrification kit for bovine embryo or slow frozen (n = 69) by exposing oocyte to ethylene glycol solution before being transferred to a programmable embryo freezer. After thawing and warming, oocytes were cultured for 48 h and then were examined for meiosis resumption using bisbenzimide fluorescent staining (Hoechst 33342). Fresh immature oocytes (n = 92) were used as the control group. The proportion of oocytes recovered in a morphologically normal state after thawing/warming was significantly higher in frozen oocytes (94.5%) than in the vitrified ones (75%, p < 0.01). Morphological integrity after culture was similar in vitrified (73.6%) and slow frozen oocytes (76.8%); however, only 37.5% of the morphologically normal oocytes resumed meiosis after vitrification compared to 60.9% of those submitted to slow freezing procedure (p < 0.01). Fresh oocytes showed higher morphological integrity (91.3%) and meiosis resumption rates (82.6%, p < 0.002) than cryopreserved oocytes, irrespective of the procedure used. These results suggest that immature cat oocytes vitrified with a kit for bovine embryos retain their capacity to resume meiosis after warming and culture, albeit at lower rates than slow frozen oocytes. Vitrification and slow freezing methods show similar proportions of oocytes with normal morphology after culture, which demonstrate that thawed and warmed oocytes that resist to cryodamage have the same chances to maintain their integrity after 48 h of culture.


Malignant skin melanoma in Croatia.
Global heating and increased solar ultraviolet irradiance have caused an increase in number of many diseases, particularly skin malignant diseases. Aim of this study was to investigate the influence of climate changes on the health of the population of the Primorsko-goranska and Istria Counties. We gathered and analyzed data about the frequency of skin malignant melanoma in the period of eight years (1998-2005). The data were collected from the Croatian cancer registry. The incidence of malignant skin cancer was estimated overall, by age group and gender. We found that the incidence of the skin melanoma was approximately the same in both counties during the period 1998-2005. However, significant increase has been noted when compared to the situation in the period 1977-1996 (p = 4.95 E-13) The incidence of malignant skin melanoma has risen during the last ten years. It is differently distributed between gender and age groups in Primorsko-goranska and Istria County. It can be related to climate changes, but also to different ways way of life between these two counties.


TRIM37 deficiency induces autophagy through deregulating the MTORC1-TFEB axis.
TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis, patients with TRIM37 mutations have a high risk of developing tumors, suggesting that there may be an alternative pro-survival mechanism for TRIM37-deficient tumor cells. We find that TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. In response to loss of TRIM37 functions, phosphorylation of TFEB is significantly reduced, resulting in its translocation into the nucleus enabling its transcriptional activation of genes involved in lysosome biogenesis and macroautophagy/autophagy. The enhanced autophagy depends on the inhibition of MTORC1 signaling and may serve as an alternative mechanism to survive the loss of TRIM37 functions. Our study unveils a positive role of TRIM37 in regulating the MTORC1-TFEB axis and provides mechanistic insights into the pathogenesis of mulibrey nanism, as well as potential therapeutic treatment. ACTB: actin beta; ATG: autophagy related; CASP3: caspase3; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; CTS: cathepsin proteases; CTSL: cathepsin L; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mulibrey: muscle-liver-brain-eye; NAC: N-acetyl-L-cysteine; PARP1: poly(ADP-ribose) polymerase 1; RAP2A: member of RAS oncogene family; RHEB: Ras homolog enriched in brain; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; RRAGB: Ras related GTP binding B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TRIM37: tripartite motif containing 37.


Pharmacokinetic evaluation of pegaptanib octasodium for the treatment of diabetic edema.
Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy. Pegaptanib octasodium (Macugen) was the first anti-VEGF agent approved for the treatment of neovascular age-related macular degeneration. It is a selective anti-VEGF agent, which only blocks VEGF. It has been shown to be safe and effective in treatment of DME in randomized controlled trials and it may be a safer first-line treatment in patients with diabetes with a predisposition to cardiovascular risk factors. This review covers the pharmacokinetics of pegaptanib octasodium. The authors also evaluate pegaptanib octasodium's clinical efficacy, safety and tolerability in DME. DME is the most common cause of visual loss in patients with diabetes. Pegaptanib has been found to be more effective than laser therapy alone for center-involving DME, its efficacy might be slightly worse than other pan-VEGF blockers, but the number of patients that have significant improvement of vision after treatment are similar to those treated with pan-VEGF blockers. As a selective VEGF blocker, it may have a better ocular and systemic safety profile than pan-VEGF blocking agents. It is reasonable to consider pegaptanib as the first-line treatment for center-involving DME with pan-VEGF blockers reserved for non-responders.


Comparison of local infiltration analgesia with single injection femoral nerve block in total knee arthroplasty.
The purpose of this study was to compare the analgesic and hemostatic effects of Local Infiltration Analgesia (LIA) with single injection femoral nerve block (SFNB). A database of patients undergoing knee arthroplasty between 2008 and 2013 was analyzed. A group of patients who underwent minimally invasive TKA either with SFNB (n = 112) or with LIA (n = 112) were matched. In the early postoperative period, the LIA group had a significantly lower VAS score, a lower drop in Hb and a lower length of hospital stay. Both the SFNB and LIA techniques provide excellent pain relief following TKA. Nevertheless, LIA reduces pain better in the very early postoperative period by a more complete nerve blockade allowing immediate postoperative mobilization and ambulation leading to a shorter hospital stay. Furthermore, LIA decreases perioperative blood loss by its local hemostatic effect.


Recurrent venous thromboembolism in anticoagulated cancer patients: Diagnosis and treatment.
Patients with cancer are at significantly increased risk of venous thromboembolism (VTE), due both to the impact of malignant disease itself and to the impact of certain anticancer drugs on haemostasis. This is true both for first episode venous thromboembolism and recurrence. The diagnosis and management of VTE recurrence in patients with cancer poses particular challenges, and these are reviewed in the present article, based on a systematic review of the relevant scientific literature published over the last decade. Furthermore, it is uncertain whether diagnostic algorithms for venous thromboembolism, validated principally in untreated non-cancer patients, are also valid in anticoagulated cancer patients: the available data suggests that clinical decision rules and D-dimer testing perform less well in this clinical setting. In patients with cancer, computed tomography pulmonary angiography and venography appear to be the most reliable diagnostic tools for diagnosis of pulmonary embolism and deep vein thrombosis respectively. Options for treatment of venous thromboembolism include low molecular weight heparins (at a therapeutic dose or an increased dose), fondaparinux or oral direct factor Xa inhibitors. The choice of treatment should take into account the nature (pulmonary embolism or VTE) and severity of the recurrent event, the associated bleeding risk, the current anticoagulant treatment (type, dose, adherence and possible drug-drug interactions) and cancer progression.


Secondary aorto-esophageal fistula after esophagectomy treated with endovascular treatment: A case report.
Aorto-esophageal fistula (AEF), a postoperative complication of esophagectomy, constitutes a very small percentage of all cases presenting with AEF; however, it is associated with a high mortality rate. Acute massive hemorrhage is the single largest cause of death in patients developing AEF. There is a lack of consensus on the optimal treatment of AEF. We present 3 cases secondary to esophagectomy due to lower thoracic esophageal carcinoma. All 3 patients presented with similar acute symptoms including a critical and life-threatening course with dead feeling, thoracic pain, and projectile hematemesis, and also hypovolemic shock. Digital subtraction angiography identified AEF as the diagnosis of these 3 cases. All patients were treated with emergency thoracic endovascular aortic repair, the aortic fistulas were repaired. All patients successfully survived the perioperative period. Thoracic endovascular aortic repair, a minimally invasive technique, is a better method to achieve faster and safer hemodynamic stability in patients with AEF compared with open thoracic aortic repair.


Flow charts: visualization of vector fields on arbitrary surfaces.
We introduce a novel flow visualization method called Flow Charts, which uses a texture atlas approach for the visualization of flows defined over curved surfaces. In this scheme the surface and its associated flow are segmented into overlapping patches which are then parameterized and packed in the texture domain. This scheme allows accurate particle advection across multiple charts in the texture domain, providing a flexible framework that supports various flow visualization techniques. The use of surface parameterization enables flow visualization techniques requiring the global view of the surface over long time spans, such as Unsteady Flow LIC (UFLIC), particle-based Unsteady Flow Advection-Convolution (UFAC), or dye advection. It also prevents visual artifacts normally associated with view-dependent methods. Represented as textures, Flow Charts can be naturally integrated into GPU flow visualization techniques for interactive performance.


Cautionary tale of using 16S rRNA gene sequence similarity values in identification of human-associated bacterial species.
Modern bacterial taxonomy is based on a polyphasic approach that combines phenotypic and genotypic characteristics, including 16S rRNA sequence similarity. However, the 95 % (for genus) and 98.7 % (for species) sequence similarity thresholds that are currently recommended to classify bacterial isolates were defined by comparison of a limited number of bacterial species, and may not apply to many genera that contain human-associated species. For each of 158 bacterial genera containing human-associated species, we computed pairwise sequence similarities between all species that have names with standing in nomenclature and then analysed the results, considering as abnormal any similarity value lower than 95 % or greater than 98.7 %. Many of the current bacterial species with validly published names do not respect the 95 and 98.7 % thresholds, with 57.1 % of species exhibiting 16S rRNA gene sequence similarity rates ≥98.7 %, and 60.1 % of genera containing species exhibiting a 16S rRNA gene sequence similarity rate <95 %. In only 17 of the 158 genera studied (10.8 %), all species respected the 95 and 98.7 % thresholds. As we need powerful and reliable taxonomical tools, and as potential new tools such as pan-genomics have not yet been fully evaluated for taxonomic purposes, we propose to use as thresholds, genus by genus, the minimum and maximum similarity values observed among species.


A psychometric assessment of Hare's checklist for psychopathy on an English prison population.
The research scale for psychopathy developed by Hare (1980) represents an important recent advance in the assessment of this disorder in that it emphasizes objectivity and reliability. This study compares the factor structure of the scale derived from an English prison sample with the original Canadian sample in order to assess the cross-cultural generalizability of the checklist and reassess the factorial basis of the scale. Results from the first analysis indicate substantial correspondence between psychopathy factors derived from English and Canadian analyses. Results of a second analysis suggest that four main clusters of traits (emotional detachment, superficial relationships, egocentricity, and impulsivity) are centrally important in the identification of psychopathy. Results of further psychometric analyses suggest increasing the scale's validity by deleting several items having little in common with the main features of psychopathy. It is concluded that Hare's checklist is both applicable to an English population and internally valid, and that future research may usefully investigate correlates of each of the four psychopathy factors.


Personal and job-related factors as determinants of incidence of back injuries among nursing personnel.
The purpose of this multicenter prospective cohort study was to assess personal and job-related factors as determinants of incidence of reported back injuries among nurses. The study population included 5,649 nurses who were surveyed by questionnaire and then observed for a 12-month study period. An annual injury rate of 4.9% was observed. Four factors were found to be significant (P less than .01) predictors of back injury. All four factors--service area, lifting, job category, and previously reported back injury--maintain significance when a forward stepping model of logistic regression is applied. The adjusted odds ratios observed are 4.26 for service areas where lifting occurs most as compared with areas where lifting occurs least; 2.19 for daily lifters v light, occasional, and nonlifters; 1.77 for nursing aides v registered nurses and supervisory personnel; and 1.73 for individuals who have previously reported back injury v those who have not reported previous injury. These findings strongly suggest that job-related rather than personal characteristics are the major predictors of back injury in nurses.


The impact of personal relevance on emotion processing: evidence from event-related potentials and pupillary responses.
Emotional stimuli attract attention and lead to increased activity in the visual cortex. The present study investigated the impact of personal relevance on emotion processing by presenting emotional words within sentences that referred to participants' significant others or to unknown agents. In event-related potentials, personal relevance increased visual cortex activity within 100 ms after stimulus onset and the amplitudes of the Late Positive Complex (LPC). Moreover, personally relevant contexts gave rise to augmented pupillary responses and higher arousal ratings, suggesting a general boost of attention and arousal. Finally, personal relevance increased emotion-related ERP effects starting around 200 ms after word onset; effects for negative words compared to neutral words were prolonged in duration. Source localizations of these interactions revealed activations in prefrontal regions, in the visual cortex and in the fusiform gyrus. Taken together, these results demonstrate the high impact of personal relevance on reading in general and on emotion processing in particular.


Experimental orthotopic tracheal transplantation: The Stanford technique.
The rat heterotopic tracheal transplantation model is widely used as an experimental model to study the development of obliterative airway disease (OAD) and to assess immunosuppressive strategies for chronic rejection. Despite its widespread application, the heterotopic transplantation model does have a number of limitations like the lack of air flow and mucociliary clearance. The present article provides a detailed description of the surgical technique for orthotopic tracheal transplantations, which may share more similarities with lung transplants in humans. The technique is easy to learn, the procedure is well tolerated by the animals, and the grafts develop OAD lesions similar to those of human obliterative bronchiolitis.


Implementing social network analysis to understand the socioecology of wildlife co-occurrence and joint interactions with humans in anthropogenic environments.
Human population expansion into wildlife habitats has increased interest in the behavioural ecology of human-wildlife interactions. To date, however, the socioecological factors that determine whether, when or where wild animals take risks by interacting with humans and anthropogenic factors still remains unclear. We adopt a comparative approach to address this gap, using social network analysis (SNA). SNA, increasingly implemented to determine human impact on wildlife ecology, can be a powerful tool to understand how animal socioecology influences the spatiotemporal distribution of human-wildlife interactions. For 10 groups of rhesus, long-tailed and bonnet macaques (Macaca spp.) living in anthropogenically impacted environments in Asia, we collected data on human-macaque interactions, animal demographics, and macaque-macaque agonistic and affiliative social interactions. We constructed 'human co-interaction networks' based on associations between macaques that interacted with humans within the same time and spatial locations, and social networks based on macaque-macaque allogrooming behaviour, affiliative behaviours of short duration (agonistic support, lip-smacking, silent bare-teeth displays and non-sexual mounting) and proximity. Pre-network permutation tests revealed that, within all macaque groups, specific individuals jointly took risks by repeatedly, consistently co-interacting with humans within and across time and space. GLMMs revealed that macaques' tendencies to co-interact with humans was positively predicted by their tendencies to engage in short-duration affiliative interactions and tolerance of conspecifics, although the latter varied across species (bonnets>rhesus>long-tailed). Male macaques were more likely to co-interact with humans than females. Neither macaques' grooming relationships nor their dominance ranks predicted their tendencies to co-interact with humans. Our findings suggest that, in challenging anthropogenic environments, less (compared to more) time-consuming forms of affiliation, and additionally greater social tolerance in less ecologically flexible species with a shorter history of exposure to humans, may be key to animals' joint propensities to take risks to gain access to resources. For males, greater exploratory tendencies and less energetically demanding long-term life-history strategies (compared to females) may also influence such joint risk-taking. From conservation and public health perspectives, wildlife connectedness within such co-interaction networks may inform interventions to mitigate zoonosis, and move human-wildlife interactions from conflict towards coexistence.


Cadmium at nanomolar concentrations activates Raf-MEK-ERK1/2 MAPKs signaling via EGFR in human cancer cell lines.
Cadmium (Cd) is an environmental contaminant classified as carcinogenic to humans by the International Agency for Research on Cancer, supported by data from occupational exposure. Environmentally relevant dietary exposure to Cd has recently been associated with osteoporosis and cancers of the prostate, endometrium, and breast in the general population. The low exposure effects have been proposed to result from endocrine modulative properties of Cd, which mimic the physiological actions of estrogen and androgen. However, the mechanism of action of Cd is an unanswered question. We have shown previously, using mouse models, that canonical estrogen receptor signaling is not involved in estrogen mimicry effects of Cd. Instead, low-level Cd exposure stimulated the mitogen-activated protein kinases (MAPKs) ERK1/2 in these mice. Here we investigate further the ERK1/2 MAPK signaling activation by Cd in vitro by using nanomolar concentrations of cadmium chloride (CdCl2) in three different human carcinoma cell lines: HepG2, MCF-7, and ECC-1. The findings also were confirmed in previously collected mouse tissue samples. We show that 10(-8)M levels of CdCl2 activate ERK1/2 (Tyr 204) and the p53 specific ubiquitin ligase Mdm2 (Ser 166) via Raf and MEK by acting through the epidermal growth factor receptor (EGFR). Furthermore, our results suggest that the CdCl2-induced activation of ERK1/2 and Mdm2 may interfere with the p53 response to genotoxic compounds in cancer cell lines. Our data collectively suggest that nanomolar levels of CdCl2 activate Raf-MEK-ERK1/2 via EGFR. We hypothesize that this signaling cascade may be involved in observed low exposure effects of Cd in certain human populations.


Binding of transmembrane mucins to galectin-3 limits herpesvirus 1 infection of human corneal keratinocytes.
Epithelial cells lining mucosal surfaces impose multiple barriers to viral infection. At the ocular surface, the carbohydrate-binding protein galectin-3 maintains barrier function by cross-linking transmembrane mucins on the apical glycocalyx. Despite these defense mechanisms, many viruses have evolved to exploit fundamental cellular processes on host cells. Here, we use affinity assays to show that herpes simplex virus type 1 (HSV-1), but not HSV-2, binds human galectin-3. Knockdown of galectin-3 in human corneal keratinocytes by small interfering RNA significantly impaired HSV-1 infection, but not expression of nectin-1, indicating that galectin-3 is a herpesvirus entry mediator. Interestingly, exposure of epithelial cell cultures to transmembrane mucin isolates decreased viral infectivity. Moreover, HSV-1 failed to elute the biological counterreceptor MUC16 from galectin-3 affinity columns, suggesting that association of transmembrane mucins to galectin-3 provides protection against viral infection. Together, these results indicate that HSV-1 exploits galectin-3 to enhance virus attachment to host cells and support a protective role for transmembrane mucins under physiological conditions by masking viral entry mediators on the epithelial glycocalyx.


Quaternary structure dependence of kinetic hole burning and conformational substates interconversion in hemoglobin.
Using a sol-gel encapsulation technique, we have prepared samples of CO saturated human adult hemoglobin locked in the R or T quaternary conformation. We report time-resolved spectra of these samples in the Soret region following flash photolysis, in the time interval ranging from 250 ns to 200 ms and in the temperature interval of 100-170 K. A suitable analysis of the measured difference spectra enables us to obtain the spectral contribution of deoxyHb and HbCO molecules as a function of time and/or of the fraction N(t) of deoxyHb molecules. In our experimental time window geminate CO rebinding to hemoglobin in the T quaternary conformation is about 2 orders of magnitude slower than to hemoglobin in the R conformation: this suggests that the barrier distribution for the CO rebinding, g(H), depends strongly on the protein quaternary structure. In our temperature interval, spectral shifts due to kinetic hole burning (KHB) are present: for HbCO the KHB effect is large in the R conformation and small in the T conformation. For deoxyHb the opposite is true. We attribute the observed behavior to the effect of interconversion between the relevant substates. This effect is stronger for HbCO molecules in the T conformation and for deoxyHb molecules in the R conformation; it confirms the quaternary structure dependence of the hemoglobin energy landscape and suggests enhanced dynamics of ligation intermediate species such as T-state HbCO or R-state deoxyHb.


[Chemiluminescence suppression in roots of Pisum sativum L. by various metal ions].
The effect of rare metal ions on the activity of the peroxidase system in Pisum sativum L. roots was studied by luminol-dependent chemiluminescence. Trivalent ions of scandium, gallium, indium, and lanthanum, to different extents, inhibit the chemiluminescence of damaged P. sativum roots. A decreased generation of superoxide due to the formation of the complex between metal ions and NADP can underlie the inhibited activity of peroxidase system. The possible mechanism of inhibition of the peroxidase system activity by metal ions is discussed.


Adjudicating paravalvular leaks of transcatheter aortic valves: a critical appraisal.
Paravalvular leakage (PVL) is an important complication of transcatheter aortic valve implantation (TAVI). It contributed to the erosion of the clinical benefits of TAVI and confidence of its adoption as a default therapy in low surgical-risk patients. Newer TAVI technologies are provided with effective paravalvular sealing as well as retrieval/reposition mechanisms that are believed to considerably lower the risk of PVL. Meanwhile, developments in timely detection and accurate quantitation of PVL remain lagging behind those technological advances. The Valve Academic Research Consortium-standardized criteria of PVL assessment are based on echocardiography and are, according to experts' opinion, not adequately validated. Peri-procedural diagnosis, based on angiographic, haemodynamic, and/or echocardiographic methods, is so far without standardization of acquisition or interpretation. The aim of this report is to review the strengths and limitations of the current technologies used for PVL adjudication. Understanding this strengths/limitations ratio is important to define an appropriate scheme for detection and quantitation of PVLs both in clinical trials and in routine clinical practice.


Phosphate/hexose 6-phosphate antiport in Streptococcus lactis.
After growth in appropriate media, resting cells of Streptococcus lactis 7962 showed a rapid exchange between external and internal pools of inorganic phosphate. This exchange was not found in other strains of S. lactis (ML3, 133, or K1) or in Streptococcus faecalis. Phosphate exchange in S. lactis 7962 did not require other anions or cations in the assay medium, nor was phosphate influx affected by the membrane potential and pH gradient formed during glycolysis. Thus, the exchange reaction was independent of known ionic drivers (H+, Na+, OH-, etc.). Experiments testing inhibitions of phosphate entry suggested that alternative substrates for exchange included arsenate, as well as the 6-phosphates of glucose, 2-deoxyglucose, fructose, mannose, or glucosamine, and direct studies with 2-deoxyglucose 6-phosphate verified that resting cells could accumulate this sugar phosphate to levels expected for exchange with internal phosphate. Two other observations supported the idea of an exchange between phosphate and sugar phosphate. First, early addition of the heterologous substrate blocked entry of the test compound, whereas later addition caused efflux of preaccumulated material. Second, expression of phosphate exchange and 2-deoxyglucose 6-phosphate transport varied in parallel. Both activities were found at high levels after growth in medium supplemented with rhamnose or arabinose, at intermediate levels with addition of galactose, and at low levels after growth with glucose, fructose, or mannose. We conclude that these findings describe a novel anion antiporter that mediates the exchange of phosphate (arsenate) and sugar 6-phosphates.


Myonecrosis: A Rare Complication of Cryoneurolysis.
Considered a safe and effective procedure, cryoneurolysis has been used to provide pain relief for chronic joint pain for decades. The procedure is similar to common ultrasound-guided percutaneous procedures. Although the literature is limited on the efficacy and safety of cryoneurolysis, there is a consensus that the use of cryoneurolysis is effective, with a risk profile similar to that of other percutaneous procedures. We are reporting the case of a 74-year-old male who underwent cryoneurolysis for chronic right knee pain. Initially, the patient had complete symptomatic improvement, but subsequently developed rigors and right knee swelling, prompting him to seek emergency medical care. Computed tomography angiography was significant for myonecrosis and phlegmon with early abscess formation. The patient continued to improve symptomatically with i.v. antibiotics. He was discharged home on hospital day 8 with a peripherally inserted central catheter. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Cryoneurolysis will likely continue to gain popularity as an option for pain management in osteoarthritis and other degenerative joint diseases. It is essential for physicians to be alert to the possibility of severe, albeit rare, complications of a seemingly safe procedure, given the potential to impact a patient's morbidity and quality of life drastically.


Comparative effectiveness of botulinum toxin versus non-surgical treatments for treating lateral epicondylitis: a systematic review and meta-analysis.
To explore the effectiveness of botulinum toxin compared with non-surgical treatments in patients with lateral epicondylitis. Data sources including PubMed, Scopus, Embase and Airity Library from the earliest record to February 2017 were searched. Study design, patients' characteristics, dosage/brand of botulinum toxin, injection techniques, and measurements of pain and hand grip strength were retrieved. The standardized mean differences (SMDs) in pain relief and grip strength reduction were calculated at the following time points: 2-4, 8-12, and 16 weeks or more after injection. Six randomized controlled trials (321 participants) comparing botulinum toxin with placebo or corticosteroid injections were included. Compared with placebo, botulinum toxin injection significantly reduced pain at all three time points (SMD, -0.729, 95% confidence interval [CI], -1.286 to -0.171; SMD, -0.446, 95% CI, -0.740 to -0.152; SMD, -0.543, 95% CI, -0.978 to -0.107, respectively). Botulinum toxin was less effective than corticosteroid at 2-4 weeks (SMD, 1.153; 95% CI, 0.568-1.737) and both treatments appeared similar in efficacy after 8 weeks. Different injection sites and dosage/brand did not affect effectiveness. Botulinum toxin decreased grip strength 2-4 weeks after injection, and high equivalent dose could extend its paralytic effects to 8-12 weeks. When treating lateral epicondylitis, botulinum toxin was superior to placebo and could last for 16 weeks. Corticosteroid and botulinum toxin injections were largely equivalent, except the corticosteroid injections were better at pain relief in the early stages and were associated with less weakness in grip in the first 12 weeks.


Steroidogenic capacity of residual ovarian tissue in 4-vinylcyclohexene diepoxide-treated mice.
Menopause is an important public health issue because of its association with a number of disorders. Androgens produced by residual ovarian tissue after menopause could impact the development of these disorders. It has been unclear, however, whether the postmenopausal ovary retains steroidogenic capacity. Thus, an ovary-intact mouse model for menopause that uses the occupational chemical 4-vinylcyclohexene diepoxide (VCD) was used to characterize the expression of steroidogenic genes in residual ovarian tissue of follicle-depleted mice. Female B6C3F1 mice (age, 28 days) were dosed daily for 20 days with either vehicle or VCD (160 mg kg(-1) day(-1)) to induce ovarian failure. Ovaries were collected on Day 181 and analyzed for mRNA and protein. Acyclic aged mice were used as controls for natural ovarian senescence. Relative to cycling controls, expression of mRNA encoding steroidogenic acute regulatory protein (Star); cholesterol side-chain cleavage (Cyp11a1); 3beta-hydroxysteroid dehydrogenase (Hsd3b); 17alpha-hydroxylase (Cyp17a1); scavenger receptor class B, type 1 (Scarb1); low-density lipoprotein receptor (Ldlr); and luteinizing hormone receptor (Lhcgr) was enriched in VCD-treated ovaries. In acyclic aged ovaries, mRNA expression for only Cyp17a1 and Lhcgr was greater than that in controls. Compared to cycling controls, ovaries from VCD-treated and aged mice had similar levels of HSD3B, CYP17A1, and LHCGR protein. The pattern of protein immunofluorescence staining for HSD3B in follicle-depleted (VCD-treated) ovaries was homogeneous, whereas that for CYP17A1 was only seen in residual interstitial cells. Circulating levels of FSH and LH were increased, and androstenedione levels were detectable following follicle depletion in VCD-treated mice. These findings support the idea that residual ovarian tissue in VCD-treated mice retains androgenic capacity.


Lentiviral vectors for cancer immunotherapy and clinical applications.
The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.


An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants.
The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.


A case-control study of gallbladder cancer in hungary.
Our previous study indicated an association of chili pepper consumption with gallbladder cancer (GBC) in the presence of gallstones (GS) in Chile. We investigated whether or not a similar association was present in Hungary, where mortality from GBC is high and chili peppers are frequently consumed. In a case-control study, we compared 41 female GBC patients with GS and 30 gender and GS-matched hospital controls. Trained staff interviewed all subjects to determine socioeconomic status, family history, past history and life style habits (smoking, alcohol intake, dietary habits and elimination habits). Because mean ages differed significantly between the case and control groups, age-adjusted odds ratios (ORs) were calculated. A shorter education period (< 10 years / > or = 16 years) was indicated to be a risk factor (age-adjusted OR (95%CI): 3.2 (1.2-8.7)). In addition, the intake of Hungarian hot pepper (yes / no) was found to be significantly higher in the GBC cases than in controls (age-adjusted OR (95%CI): 8.4 (2.3-30.4)). There were no differences between the case and control groups for other variables. Multivariate logistic regression analysis retained only Hungarian hot pepper consumption as a significant independent risk factor for GBC. Its age-adjusted OR was 16.2 (95%CI: 2.1-126.2), while there were no differences associated with low education, frequent consumption of fresh fruit and vegetables, low socioeconomic status or smoking. Hungarian hot pepper consumption was identified as a risk factor for GBC by multivariate logistic regression analysis.


DFT simulation of the X-ray diffraction pattern of aluminum-ion-intercalated graphite used as the cathode material of the aluminum-ion battery.
Many breakthroughs have been achieved in rechargeable aluminum-ion battery technologies in recent years. Most recently, operando X-ray diffraction (XRD) combined with density functional theory (DFT) calculations was reported to study the chloroaluminate anion (AlCl4-)-intercalated graphite cathode of the battery. However, there are quite a few discrepancies between the measured and simulated XRD patterns. This work is focused on the simulation of XRD patterns of graphite intercalation compounds (GICs) with DFT calculations. Our results reveal that both the geometry of AlCl4- in graphite and the gallery height of GICs are dependent on the intercalant density. At low intercalant density, the gallery height keeps constant, but at high intercalant densities, the gallery height is linearly related to the intercalant density. Our simulated XRD patterns are highly consistent with the measured operando XRD patterns. Not only do the angles of the peaks match very well, but also the relative intensities and the corresponding electrode capacities show reasonable agreement with the experimental results. The DFT simulation of the XRD pattern provides significant information on the stage index and the charge capacity of the GIC electrode.


Nucleation of microtubules in vitro by isolated spindle pole bodies of the yeast Saccharomyces cerevisiae.
Spindle pole bodies (SPBs) were isolated from the yeast Saccharomyces cerevisiae by an adaptation of the Kleinschmidt monolayer technique. Spheroplasts prepared from the cells were lysed on an air-water interface. Spread preparations were picked up on grids, transferred to experimental test solutions, and prepared for whole-mount electron microscopy. Using purified exogenous tubulin from porcine brain tissue, the isolated SPBs were shown to nucleate the assembly of microtubules in vitro. Microtubule growth was directional and primarily onto the intranuclear face of the SPB. Neither the morphology nor the microtubule-initiating capacity of the SPB was affected by treatment with the enzymes DNase, RNase, or phospholipase although both properties were sensitive to trypsin. Analysis of SPBs at various stages of the cell cycle showed that newly replicated SPBs had the capacity to nucleate microtubules. SPBs isolated from exponentially growing cells initiated a subset of the yeast spindle microtubules equivalent to the number of pole-to-pole microtubules seen in vivo. However, SPBs isolated from cells in stationary phase and therefore arrested in G1 nucleated a number of microtubules equal to the total chromosomal and pole-to-pole tubules in the yeast spindle. This may mean that in G1-arrested cells, the SPB is associated with microtubule attachment sites of the yeast chromatin.


Basic Blue Skies Research in the UK: Are we losing out?
The term blue skies research implies a freedom to carry out flexible, curiosity-driven research that leads to outcomes not envisaged at the outset. This research often challenges accepted thinking and introduces new fields of study. Science policy in the UK has given growing support for short-term goal-oriented scientific research projects, with pressure being applied on researchers to demonstrate the future application of their work. These policies carry the risk of restricting freedom, curbing research direction, and stifling rather than stimulating the creativity needed for scientific discovery. This study tracks the tortuous routes that led to three major discoveries in cardiology. It then investigates the constraints in current research, and opportunities that may be lost with existing funding processes, by interviewing selected scientists and fund providers for their views on curiosity-driven research and the freedom needed to allow science to flourish. The transcripts were analysed using a grounded theory approach to gather recurrent themes from the interviews. The results from these interviews suggest that scientists often cannot predict the future applications of research. Constraints such as lack of scientific freedom, and a narrow focus on relevance and accountability were believed to stifle the discovery process. Although it was acknowledged that some research projects do need a clear and measurable framework, the interviewees saw a need for inquisitive, blue skies research to be managed in a different way. They provided examples of situations where money allocated to 'safe' funding was used for more innovative research. This sample of key UK scientists and grant providers acknowledge the importance of basic blue skies research. Yet the current evaluation process often requires that scientists predict their likely findings and estimate short-term impact, which does not permit freedom of research direction. There is a vital need for prominent scientists and for universities to help the media, the public, and policy makers to understand the importance of innovative thought along with the need for scientists to have the freedom to challenge accepted thinking. Encouraging an avenue for blue skies research could have immense influence over future scientific discoveries.


New tools can propel research in lysosomal storage diseases.
Historically, the clinical manifestations of lysosomal storage diseases offered an early glimpse into the essential digestive functions of the lysosome. However, it was only recently that the more subtle role of this organelle in the dynamic regulation of multiple cellular processes was appreciated. With the need for precise interrogation of lysosomal interplay in health and disease comes the demand for more sophisticated functional tools. This demand has recently been met with 1) induced pluripotent stem cell-derived models that recapitulate the disease phenotype in vitro, 2) methods for lysosome affinity purification coupled with downstream omics analysis that provide a high-resolution snapshot of lysosomal alterations, and 3) gene editing and CRISPR/Cas9-based functional genomic strategies that enable screening for genetic modifiers of the disease phenotype. These emerging methods have garnered much interest in the field of neurodegeneration, and their use in the field of metabolic disorders is now also steadily gaining momentum. Looking forward, these robust tools should accelerate basic science efforts to understand lysosomal dysfunction distal to substrate accumulation and provide translational opportunities to identify disease-modifying therapies.


Relationship between People's Interest in Medication Adherence, Health Literacy, and Self-Care: An Infodemiological Analysis in the Pre- and Post-COVID-19 Era.
The prevalence of non-communicable diseases has risen sharply in recent years, particularly among older individuals who require complex drug regimens. Patients are increasingly required to manage their health through medication adherence and self-care, but about 50% of patients struggle to adhere to prescribed treatments. This study explored the relationship between interest in medication adherence, health literacy, and self-care and how it changed during the COVID-19 pandemic. We used Google Trends to measure relative search volumes (RSVs) for these three topics from 2012 to 2022. We found that interest in self-care increased the most over time, followed by health literacy and medication adherence. Direct correlations emerged between RSVs for medication adherence and health literacy (r = 0.674, p < 0.0001), medication adherence and self-care (r = 0.466, p < 0.0001), and health literacy and self-care (r = 0.545, p < 0.0001). After the COVID-19 pandemic outbreak, interest in self-care significantly increased, and Latin countries showed a greater interest in self-care than other geographical areas. This study suggests that people are increasingly interested in managing their health, especially in the context of the recent pandemic, and that infodemiology may provide interesting information about the attitudes of the population toward chronic disease management.


Bascom II combined with VSD treatment involving the preservation of tissue bridges for recurrent complex pilonidal sinuses with a literature review.
For patients with large and deep-seated recurrent complex pilonidal sinuses, the use of traditional open excision or flap reconstruction surgery may lead to high surgical difficulty, significant local damage, numerous complications, slow healing, and a high risk of recurrence. This article reports a case of recurrent complex pilonidal sinus and discusses the advantages of Bascom II combined with VSD treatment involving the preservation of tissue bridges. The patient, a 31-year-old male, presented with recurrent swelling, pain, and purulent discharge from the sacrococcygeal region for over a year. Upon physical examination, extensive lumps and sinus tracts were observed in the lumbosacral tail area, with the lesion extending from L4 to the tip of the coccyx. Under general anesthesia, a segmental resection was performed, and the lumbosacral mass lesion was excised, preserving normal tissue bridges. The mature sinus tract at the upper part of the coccyx was removed, and Bascom II reconstruction surgery was performed. In the late stage at the site of lumbar sacral lesion excision, VSD was applied to promote wound healing. The combination of Bascom II with lesion tunnel-like removal can reduce the damage, elevate gluteal cleft, and lower the recurrence rate. Subsequently, with the addition of VSD, it can accelerate the elimination of necrotic tissue, reduce infection risk, and expedite wound healing. This case explores the advantages and characteristics of combining various techniques in the treatment of recurrent complex pilonidal sinuses, emphasizes the utility of VSD as an adjunctive therapy for large lesions.


Estimating heritability explained by local ancestry and evaluating stratification bias in admixture mapping from summary statistics.
The heritability explained by local ancestry markers in an admixed population (hγ2) provides crucial insight into the genetic architecture of a complex disease or trait. Estimation of hγ2 can be susceptible to biases due to population structure in ancestral populations. Here, we present heritability estimation from admixture mapping summary statistics (HAMSTA), an approach that uses summary statistics from admixture mapping to infer heritability explained by local ancestry while adjusting for biases due to ancestral stratification. Through extensive simulations, we demonstrate that HAMSTA hγ2 estimates are approximately unbiased and are robust to ancestral stratification compared to existing approaches. In the presence of ancestral stratification, we show a HAMSTA-derived sampling scheme provides a calibrated family-wise error rate (FWER) of ∼5% for admixture mapping, unlike existing FWER estimation approaches. We apply HAMSTA to 20 quantitative phenotypes of up to 15,988 self-reported African American individuals in the Population Architecture using Genomics and Epidemiology (PAGE) study. We observe hˆγ2 in the 20 phenotypes range from 0.0025 to 0.033 (mean hˆγ2 = 0.012 ± 9.2 × 10-4), which translates to hˆ2 ranging from 0.062 to 0.85 (mean hˆ2 = 0.30 ± 0.023). Across these phenotypes we find little evidence of inflation due to ancestral population stratification in current admixture mapping studies (mean inflation factor of 0.99 ± 0.001). Overall, HAMSTA provides a fast and powerful approach to estimate genome-wide heritability and evaluate biases in test statistics of admixture mapping studies.


Assessing the psychometric and ecometric properties of neighborhood scales using adolescent survey data from urban and rural Scotland.
Despite the well-established need for specific measurement instruments to examine the relationship between neighborhood conditions and adolescent well-being outcomes, few studies have developed scales to measure features of the neighborhoods in which adolescents reside. Moreover, measures of neighborhood features may be operationalised differently by adolescents living in different levels of urban/rurality. This has not been addressed in previous studies. The objectives of this study were to: 1) establish instruments to measure adolescent neighborhood features at both the individual and neighborhood level, 2) assess their psychometric and ecometric properties, 3) test for invariance by urban/rurality, and 4) generate neighborhood level scores for use in further analysis. Data were from the Scottish 2010 Health Behaviour in School-aged Children Survey, which included an over-sample of rural adolescents. The survey responses of interest came from questions designed to capture different facets of the local area in which each respondent resided. Intermediate data zones were used as proxies for neighborhoods. Internal consistency was evaluated by Cronbach's alpha. Invariance was examined using confirmatory factor analysis. Multilevel models were used to estimate ecometric properties and generate neighborhood scores. Two constructs labeled neighborhood social cohesion and neighborhood disorder were identified. Adjustment was made to the originally specified model to improve model fit and measures of invariance. At the individual level, reliability was .760 for social cohesion and .765 for disorder, and between .524 and .571 for both constructs at the neighborhood level. Individuals in rural areas experienced greater neighborhood social cohesion and lower levels of neighborhood disorder compared with those in urban areas. The scales are appropriate for measuring neighborhood characteristics experienced by adolescents across urban and rural Scotland, and can be used in future studies of neighborhoods and health. However, trade-offs between neighborhood sample size and reliability must be considered.


Cutaneous toxicities of new targeted cancer therapies: must know for diagnosis, management, and patient-proxy empowerment.
The world of oncology treatment is rapidly changing, and with the investigation into and utilization of molecular signaling pathways for cancer treatment, many new targeted small-molecule oral agents have been introduced as therapies, with more new drugs appearing every year. These agents, while generally considered less toxic overall than traditional chemotherapy, are not without adverse effects. The authors undertook an extensive literature search to determine the incidence, severity, and management strategies for small-molecule oral targeted agents approved by the FDA between 2013 and 2018. Dermatologic adverse effects are among the most frequently seen with many of these targeted therapies, and may include rashes, palmar-plantar dysesthesia, alopecia, secondary skin malignancies, and hair and nail changes. Rarely, more severe cutaneous toxicities are seen, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis. In many cases, there is no specific management strategy suggested in the literature for these toxicities, but frequent monitoring of the skin, prophylactic management of palmar-plantar dysesthesia, use of corticosteroids and/or antihistamines, and intervention with dose interruption are suggested depending on circumstance and severity. Patient education and timely intervention is warranted in order to ensure that patient treatment is optimized.


Child deaths due to firearm-related İnjuries in Adana, Turkey.
Death by firearm is unacceptable for children who need to be under the protection of the state and the family, wherever and however. Firearm-related fatality is common among all ages. One of the causes of this high rate is likely the easy access to firearms. This study aims to discuss the characteristics of deaths attributable to childhood firearm injuries in Adana, Turkey and to compare them with similar studies. In this study, the records of 448 (1.97%) cases under 18 years of age who died due to firearm-related injuries among a total of 22,668 cases whose autopsies were performed by the Morgue Department, Council of Forensic Medicine Adana Group Administration between January 1, 2004 and December 12, 2017 were retrospectively evaluated. Age ranged from 45 days to 18 years; 285 cases were male and 163 cases were female, and male/female ratio was 1.7. The majority of cases were between 13 and 18 years of age (n: 340, 76.0%). According to the manner of death, the leading cause was homicide (n: 212, 47.4%) and the most frequently used type of firearm were shotguns (n: 226). Single firearm wound was present in 82.8% of the cases. The location of entrance wounds revealed that 185 wounds were located in the head-neck. Although homicide was the leading manner of death among the overall cases, it was determined that suicide was the leading cause among the 13-18 age group (n: 149). Firearm-related injuries and deaths in children should bring child neglect to the agenda. Presence of firearms at home and easy access are the causes of increased firearm injuries and death in children. Easily accessible weapons in homes are often involved in suicides and homicides, as well as accidents, which are more common in young children and adolescents. We believe that the use of firearms outside of the security forces should be prohibited and that strict laws should be enforced on the handling and use of firearms.


Stereoselective separation of psychoactive substances: Multivariate optimization and validation of a capillary electrophoresis method using carboxymethyl-β-CD/deep eutectic solvent dual system.
A comprehensive study was performed to determine an optimum enantioseparation method for fluorine-substituted amphetamine and cathinone derivatives (fluor-amphetamine and fluor-cathinone derivatives), using a binary system consisting of carboxymethyl-β-CD (CM-β-CD) and a deep eutectic solvent (DES), namely choline chloride-ethylene glycol (ChCl-EG). Under this framework, the optimization and modeling of the separation conditions in a binary system were performed with the objective of maximizing resolution and minimizing analysis time. This was achieved through the application of response surface methodology. In particular, the effect of chiral selector concentration and percentage of DES on resolution and analysis time were investigated and optimized using a complete experimental design. The optimum enantioseparation conditions were determined to be 13.84 mM CM-β-CD and 0.15% v/v ChCl-EG for fluorine-substituted amphetamine derivatives and 14.36 mM and 0.75% v/v ChCl-EG for fluorine-substituted cathinone derivatives, respectively. This combination resulted in a baseline separation for eight out of the nine analytes studied. Overall, the results demonstrated the synergistic effect of the CM-β-CD/DES dual system and highlighted the significance of DESs as additives in capillary electrophoresis.


Prognostic correlation of plasma cell acid phosphatase and beta-glucuronidase in multiple myeloma: a Southwest Oncology Group study.
In 1982 a randomized trial of either alternating or syncopated VMCP/VBAP regimens for the treatment of active multiple myeloma was begun (Southwest Oncology Group Study 8229/30). A concurrent investigation was undertaken to evaluate the clinical importance and significance of cytochemically stainable plasma cell acid phosphatase (AP) and beta-glucuronidase enzymes (BG). Pretreatment bone marrow aspirates were available for analysis from 399 patients for AP and 398 patients for BG. The AP scores ranged between 42 and 395, and the BG scores ranged between 1 and 346. There was a significant increase of AP (P = .001) and BG (P = .002) in multiple myeloma as compared with a set of patients with benign plasmacytosis. The enzyme scores did not significantly relate to Ig idiotype of myeloma or other prognostic variables except that the BG scores varied significantly with the level of albumin (P = .03) and hemoglobin (P = .01). Analysis of patient groups with different levels of enzyme scores showed that 61 of 398 patients with an AP score of less than 130 had a poorer median survival of 1.7 versus 2.8 years for patients with higher scores (P = .001). In the multivariate analysis of survival, low AP score was an important prognostic factor (P = .006), but BG did not contribute significantly. It is suggested that the subset of patients presenting with low AP should be considered for specialized or more aggressive therapy.


[Activity of carbohydrate metabolism enzyme activity in normal and pathologic parodontal tissues].
The activity of hexokinase, glucose-6-phosphate dehydrogenase, pyruvate dehydrogenase, isocytrate dehydrogenase, alpha-ketoglutarate dehydrogenase and the ATR content in the alveolar process and gingiva of dogs are established to decrease considerably in experimental cholestasis, induced by ligation of the common bile duct. Incorporation of tissue proteins into the Krebs cycle through the reverse NAD-dependent malate dehydrogenase reaction is a compensatory reaction favouring an increase of the ATP amount in the alveolar process.


Metastatic heterogeneity of breast cancer cells is associated with expression of a heterogeneous TGFβ-activating miR424-503 gene cluster.
TGFβ signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGFβ activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGFβ signaling can be overactivated and sustained. To better understand how the TGFβ inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424-503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGFβ signaling, leading to enhanced TGFβ signaling and metastatic capability of breast cancer cells. Moreover, antagonizing miR424-503 in breast cancer cells suppressed metastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424-503 cluster contributed to the heterogeneity of TGFβ activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novel mechanism, mediated by elevated expression of the miR424-503 cluster, underlying TGFβ activation and metastasis of human breast cancer.


Site of reactivity models predict molecular reactivity of diverse chemicals with glutathione.
Drug toxicity is often caused by electrophilic reactive metabolites that covalently bind to proteins. Consequently, the quantitative strength of a molecule's reactivity with glutathione (GSH) is a frequently used indicator of its toxicity. Through cysteine, GSH (and proteins) scavenges reactive molecules to form conjugates in the body. GSH conjugates to specific atoms in reactive molecules: their sites of reactivity. The value of knowing a molecule's sites of reactivity is unexplored in the literature. This study tests the value of site of reactivity data that identifies the atoms within 1213 reactive molecules that conjugate to GSH and builds models to predict molecular reactivity with glutathione. An algorithm originally written to model sites of cytochrome P450 metabolism (called XenoSite) finds clear patterns in molecular structure that identify sites of reactivity within reactive molecules with 90.8% accuracy and separate reactive and unreactive molecules with 80.6% accuracy. Furthermore, the model output strongly correlates with quantitative GSH reactivity data in chemically diverse, external data sets. Site of reactivity data is nearly unstudied in the literature prior to our efforts, yet it contains a strong signal for reactivity that can be utilized to more accurately predict molecule reactivity and, eventually, toxicity.


A pragmatic dialogue amongst stakeholders on the impact of COVID-19 on Irish cancer patients and healthcare services and lessons learned.
COVID-19 disrupted cancer care services in Ireland, from screening and diagnostics to treatments, possibly impacting physical health outcomes owing to delayed diagnosis and treatment changes. This study explores how cancer care and patients in Ireland were affected by COVID-19 from the perspective of Irish policy, clinical and patient stakeholders using a qualitative approach. The findings could inform future strategic and implementation plans for the current challenges faced and lessons learned will be identified. A thematic analysis of a multi-stakeholder online workshop representing policy and clinical and patient stakeholders was completed. The pandemic exasperated prior challenges including under-resourced services, access barriers, staff shortages and lack of interoperability in information technology (IT) systems. Overall, the measures implemented protected cancer patients from COVID-19; however, some groups were more vulnerable, with apparent demographic and socio-economic inequalities. Many hard-fought gains from the previous decade, in terms of cancer screening, diagnosis and survivorship, were eroded. As we transition to the peri-COVID-19 period, staff burnout, poor IT infrastructure and lack of good quality data must be addressed to minimise further disruptions and restore and enhance cancer services. Overall, innovations and measures adopted during the pandemic protected cancer patients; however, some groups were particularly vulnerable, and inequalities may have widened further. Only proven effective and efficient innovations introduced during the pandemic should be retained and enhanced. Good quality data is needed to inform such decisions when choosing amongst them.


Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials.
Lopinavir/ritonavir (LPV/r) is the first ritonavir-boosted protease-inhibitor used in second-line anti-retroviral treatment (ART) in resource-limited regions. To evaluate the efficacy and safety outcomes of LPV/r in treatment-naïve and -experienced HIV-infected adults and pregnant women, we performed a meta-analysis of randomized controlled trials. Ten cohorts from 8 articles involving 2,584 ART-naïve patients, 5 cohorts from 4 articles involving 1,124 ART-experienced patients, and 8 cohorts from 7 articles involving 2,191 pregnant women were selected for the meta-analyses. For ART-naïve patients, the virologic response rate (72.3%) of LPV/r combined with tenofovir (TDF) plus lamivudine/emtricitabine (3TC/FTC) arms was significantly greater than that of LPV/r plus non-TDF-FTC arms (65.5%, p = 0.047). For ART-experienced patients, the use of LPV/r revealed a 55.7% probability of virologic success. The incidence of abnormal total cholesterol (6.9%) for ART-experienced patients was significantly lower than that for ART-naïve patients (13.1%, p < 0.001). The use of LPV/r in pregnant women revealed a mother-to-child transmission (MTCT) rate of 1.1%, preterm birth rate of 13.2%, and low birth weight rate of 16.2%. Our meta-analysis indicated that LPV/r was an efficacious regimen for ART-naïve patients and was more tolerable for ART-experienced patients. LPV/r also displayed a significant effect in preventing MTCT.


Feasibility of EMG-based neural network controller for an upper extremity neuroprosthesis.
The overarching goal of this project is to provide shoulder and elbow function to individuals with C5/C6 spinal cord injury (SCI) using functional electrical stimulation (FES), increasing the functional outcomes currently provided by a hand neuroprosthesis. The specific goal of this study was to design a controller based on an artificial neural network (ANN) that extracts information from the activity of muscles that remain under voluntary control sufficient to predict appropriate stimulation levels for several paralyzed muscles in the upper extremity. The ANN was trained with activation data obtained from simulations using a musculoskeletal model of the arm that was modified to reflect C5 SCI and FES capabilities. Several arm movements were recorded from able-bodied subjects and these kinematics served as the inputs to inverse dynamic simulations that predicted muscle activation patterns corresponding to the movements recorded. A system identification procedure was used to identify an optimal reduced set of voluntary input muscles from the larger set that are typically under voluntary control in C5 SCI. These voluntary activations were used as the inputs to the ANN and muscles that are typically paralyzed in C5 SCI were the outputs to be predicted. The neural network controller was able to predict the needed FES paralyzed muscle activations from "voluntary" activations with less than a 3.6% RMS prediction error.


The PP2C-type phosphatase AP2C1, which negatively regulates MPK4 and MPK6, modulates innate immunity, jasmonic acid, and ethylene levels in Arabidopsis.
Wound signaling pathways in plants are mediated by mitogen-activated protein kinases (MAPKs) and stress hormones, such as ethylene and jasmonates. In Arabidopsis thaliana, the transmission of wound signals by MAPKs has been the subject of detailed investigations; however, the involvement of specific phosphatases in wound signaling is not known. Here, we show that AP2C1, an Arabidopsis Ser/Thr phosphatase of type 2C, is a novel stress signal regulator that inactivates the stress-responsive MAPKs MPK4 and MPK6. Mutant ap2c1 plants produce significantly higher amounts of jasmonate upon wounding and are more resistant to phytophagous mites (Tetranychus urticae). Plants with increased AP2C1 levels display lower wound activation of MAPKs, reduced ethylene production, and compromised innate immunity against the necrotrophic pathogen Botrytis cinerea. Our results demonstrate a key role for the AP2C1 phosphatase in regulating stress hormone levels, defense responses, and MAPK activities in Arabidopsis and provide evidence that the activity of AP2C1 might control the plant's response to B. cinerea.


The Role of Polarity in Nonplanar Semiconductor Nanostructures.
The lack of mirror symmetry in binary semiconductor compounds turns them into polar materials, where two opposite orientations of the same crystallographic direction are possible. Interestingly, their physical properties (e.g., electronic or photonic) and morphological features (e.g., shape, growth direction, and so forth) also strongly depend on the polarity. It has been observed that nanoscale materials tend to grow with a specific polarity, which can eventually be reversed for very specific growth conditions. In addition, polar-directed growth affects the defect density and topology and might induce eventually the formation of undesirable polarity inversion domains in the nanostructure, which in turn will affect the photonic and electronic final device performance. Here, we present a review on the polarity-driven growth mechanism at the nanoscale, combining our latest investigation with an overview of the available literature highlighting suitable future possibilities of polarity engineering of semiconductor nanostructures. The present study has been extended over a wide range of semiconductor compounds, covering the most commonly synthesized III-V (GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb) and II-VI (ZnO, ZnTe, CdS, CdSe, CdTe) nanowires and other free-standing nanostructures (tripods, tetrapods, belts, and membranes). This systematic study allowed us to explore the parameters that may induce polarity-dependent and polarity-driven growth mechanisms, as well as the polarity-related consequences on the physical properties of the nanostructures.


BRAC's experience in scaling-up MNP in Bangladesh.
Despite progress in health status and achievements in Millennium Development Indicators, Bangladesh presents a gloomy scenario for nutrition. In 2009, BRAC (formerly known as Bangladesh Rural Advancement Committee) has begun to implement a community-based approach of Alive & Thrive with Family Health International 360, aiming to reduce undernutrition among children under two by promoting exclusive breastfeeding and appropriate complementary feeding practices. To address anemia and other micronutrient deficiencies, home-fortification with micronutrient powders (MNP) has been promoted among under-fives across Bangladesh along with the Global Alliance for Improved Nutrition (GAIN). BRAC's frontline community health workers play a critical role in promoting micronutrient powders with better feeding practices. Over the years, improvements have been observed in the intervention areas: exclusive breastfeeding rose from 49% to 83% of children (0-6 months), 86% of children received complementary feeding at 6-8 months with about two/thirds being fed the recommended number of times; and 70% of children (6-59 months) adhered to MNP use, ie consumption of 1 sachet per day in the past 60 days. However, many challenges are still observed in traditional feeding practices, along with limited skills of community health workers and households' poor access to quality food, necessitating constant interactions between caregivers, mothers-in-law and fathers with the frontline workers. Maintaining the supply chain of micronutrient powders and a visible and convincing change in nutritional status of children are key success factors. The partnerships between BRAC, GAIN and Renata, the producer of MNP in Bangladesh, have given birth to a home-fortification model that can deliver impact at scale.


Inflammatory Measures in Depressed Patients With and Without a History of Adverse Childhood Experiences.
Background: Major depressive disorder (MDD) is a complex psychiatric condition with different subtypes and etiologies. Exposure to adverse childhood experiences (ACE) is an important risk factor for the development of MDD later in life. Evidence suggests that pro-inflammatory processes may convey this risk as both MDD and ACE have been related to increased levels of inflammation. In the present study, we aimed to disentangle the effects of MDD and ACE on inflammation levels. Methods: Markers of inflammation (plasma interleukin(IL)-6 and high sensitive C-reactive protein (hsCRP) concentrations, white blood cell (WBC) count and a composite inflammation score (CIS) combining all three) were assessed in 23 MDD patients with ACE, 23 MDD patients without ACE, 21 healthy participants with ACE, and 21 healthy participants without ACE (mean age: 35 ± 11 (SD) years). None of the patients and participants was taking psychotropic medication. ACE was assessed with the Early Trauma Inventory (ETI) and was defined as moderate to severe exposure to sexual or physical abuse. Results: Group differences in the different inflammatory measures were observed. MDD patients with ACE showed significantly higher IL-6 concentrations (p = 0.018), higher WBC counts (p = 0.003) and increased general inflammation levels as indicated by the CIS (p = 0.003) compared to healthy controls. In contrast, MDD patients without ACE displayed similar inflammation levels to the control group (p = 0.93). Conclusion: We observed elevated inflammation in MDD patients with a history of ACE, which could indicate a subtype of "inflammatory depression". Accordingly, MDD patients with ACE might potentially benefit from anti-inflammatory therapies.