Evaluation of Constant Thickness Cartilage Models vs. Patient Specific Cartilage Models for an Optimized Computer-Assisted Planning of Periacetabular Osteotomy.
Modern computerized planning tools for periacetabular osteotomy (PAO) use either morphology-based or biomechanics-based methods. The latter relies on estimation of peak contact pressures and contact areas using either patient specific or constant thickness cartilage models. We performed a finite element analysis investigating the optimal reorientation of the acetabulum in PAO surgery based on simulated joint contact pressures and contact areas using patient specific cartilage model. Furthermore we investigated the influences of using patient specific cartilage model or constant thickness cartilage model on the biomechanical simulation results. Ten specimens with hip dysplasia were used in this study. Image data were available from CT arthrography studies. Bone models were reconstructed. Mesh models for the patient specific cartilage were defined and subsequently loaded under previously reported boundary and loading conditions. Peak contact pressures and contact areas were estimated in the original position. Afterwards we used a validated preoperative planning software to change the acetabular inclination by an increment of 5° and measured the lateral center edge angle (LCE) at each reorientation position. The position with the largest contact area and the lowest peak contact pressure was defined as the optimal position. In order to investigate the influence of using patient specific cartilage model or constant thickness cartilage model on the biomechanical simulation results, the same procedure was repeated with the same bone models but with a cartilage mesh of constant thickness. Comparison of the peak contact pressures and the contact areas between these two different cartilage models showed that good correlation between these two cartilage models for peak contact pressures (r = 0.634 ∈ [0.6, 0.8], p < 0.001) and contact areas (r = 0.872 > 0.8, p < 0.001). For both cartilage models, the largest contact areas and the lowest peak pressures were found at the same position. Our study is the first study comparing peak contact pressures and contact areas between patient specific and constant thickness cartilage models during PAO planning. Good correlation for these two models was detected. Computer assisted planning with FE modeling using constant thickness cartilage models might be a promising PAO planning tool when a conventional CT is available.


The effect of extend of caval resection in the treatment of inferior vena cava leiomyosarcoma.
A wide and complete surgical resection is the principle modality of therapy in the management of retroperitoneal sarcomas. It is current opinion that, also for inferior vena cava (IVC) leiomyosarcomas, an extended resection of either retroperitoneal tissue and vena cava should be performed. The aim of the study was to investigate the influence of the venous extent of resection on local recurrence and longterm outcome. Up to August 1994, 218 patients were enrolled into The International Registry of Inferior Vena Cava (IVC) Leiomyosarcomas. For the purpose of this study we considered 120 patients who underwent a radical resection of the IVC tumor (i.e. removal of all gross disease with microscopic tumor-free margins and no evidence of distant metastases). Resection included an IVC rim in 53 patients and an IVC segment in 67. There were 3 (2.5%) early postoperative deaths and 7 (5.8%) major complications. Postoperative deep venous thrombosis of the lower limbs was diagnosed in 21 (17.5%) patients and was treated by anticoagulant therapy and/or elastic stocking without long-term sequelae. Overall, tumor recurrence was observed in 67 (57.3%) patients at a mean follow-up of 32 +/- 4 months. Seven, 13 and 4 patients who underwent caval wall resection and 9, 29 and 5 patients submitted to a caval segmental resection had either local recurrences, distant metastases or local and distant metastases (p = NS). Survival rates of the two groups were 55% and 37% at 5-year and 42% and 23% at 10-year, respectively (p = NS). An extended venous resection in IVC leiomyosarcoma does not influence local recurrence rate nor long-term outcome.


Toxicity of epoxy fatty acids and related compounds to cells expressing human soluble epoxide hydrolase.
Soluble epoxide hydrolase (sEH) is suggested to alter the mode of action and increase the toxic potency of fatty acid epoxides. To characterize the structural features necessary for sEH-dependent epoxy fatty acid toxicity, 75 aliphatic compounds were assayed for cytotoxicity in the presence and absence of sEH. Three groups of aliphatic epoxide-diol pairs were described by their observed differential toxicity. Group I compounds were typified by terminal epoxides whose toxicity was reduced in the presence of sEH. Group II compounds were toxic in either their epoxide or diol form, but toxicity was unaffected by sEH. Group III compounds exhibited sEH-dependent toxicity and were therefore used to investigate the structural elements required for cytotoxicity in this study. The optimal structure for group III compounds appeared to be a fatty acid 18-20 atoms long (e.g., a carbon backbone plus a terminal heteroatom) with an epoxide positioned between C-7 and C-12. In the absence of sEH, replacement of epoxides with a vicinal diol was required for toxicity. While diol stereochemistry was unimportant, vicinal diol-induced toxicity exhibited fewer positional constraints to toxicity than sEH-dependent epoxide toxicity. Tested fatty acids and esters with neither an epoxide nor a vicinal diol were not toxic. These data support the hypothesis that long-chain epoxy fatty acid methyl esters are potential pro-toxins metabolized by sEH to more toxic diols. Furthermore, our results suggest that the endogenous compounds, leukotoxin methyl ester, 9,10(Z)-epoxyoctadec-12(Z)-enoic acid methyl ester, and isoleukotoxin methyl ester, 12, 13(Z)-epoxyoctadec-9(Z)-enoic acid methyl ester, are structurally optimized to elicit the observed effect.


An ATP-sensitive potassium channel activator reduces infarct volume in focal cerebral ischemia in rats.
ATP-sensitive potassium channels are activated under hypoxic or ischemic conditions. The effects of ATP-sensitive potassium channel activators on cerebrovasculature and cerebral blood flow (CBF) are not well understood. We examined the effect of the ATP-sensitive potassium channel activator Y-26763 on focal cerebral ischemia in rats. In 24 spontaneously hypertensive rats, either Y-26763 (24 micrograms/kg) or vehicle was given by intracarotid infusion over 60 min, starting 30 min before photochemically induced thrombotic occlusion of the middle cerebral artery. CBF was measured by laser-Doppler flowmetry in the peri-ischemic penumbral cortex. Although Y-26763 lowered systemic blood pressure by 13 mmHg, the infarct volume assessed 3 days after the occlusion was significantly smaller in the Y-26763-treated group (n = 12, 71.2 +/- 22.0 mm3) than in the control group (n = 12, 94.7 +/- 20.4 mm3, P = 0.013). Y-26763 did not affect CBF before or after occlusion compared with CBF values of the control group. The results are consistent with the view that the activation of the ATP-sensitive potassium channel is neuroprotective in focal cerebral ischemia.


[Features of cytochrome P450 evolution].
It is shown that the process of mutation in the CYP2 family of the superfamily of P450 cytochromes is species-specific (man, rat, and mouse). It is also shown that, within one species (rat), different families (CYP2 and CYP11) have different mutation spectra, indicating a high specificity of the mutation process for the families of cytochrome genes. A similar specificity was demonstrated for five families (CYP1, CYP2, CYP6, CYP7, CYP11) as compared with globins and prions. The analysis of the evolutionary mutation pattern, and the pattern of pseudogenes and damaged alleles of the CYP21 family (found in patients with congenital adrenal hyperplasia) does not confirm the widely accepted hypothesis that mutations arising in pseudogenes are transduced to normal alleles of the CYP21 gene through gene conversion.


Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells.
Nitric oxide (NO) inhibits vascular smooth muscle cell (VSMC) proliferation and neointima formation after balloon injury. However, the molecular mechanisms underlying NO-mediated growth arrest are poorly understood. In the present study, we examined the effects of the NO donors sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on cell cycle activity in VSMCs. Stimulation of quiescent rat VSMCs with serum leads to an increase in cyclin-dependent kinase (cdk)2 kinase activity that correlates with a marked induction of cyclin A protein expression. The addition of SNP or SNAP to VSMC cultures at the time of serum stimulation abrogates the induction of cdk2 activity without suppressing protein levels of cdk2 or cyclin E. These NO donors block serum-stimulated upregulation of cyclin A mRNA and protein and repress the serum induction of cyclin A promoter activity in VSMCs. The addition of the nitric oxide donors SNP or SNAP to mitogen-stimulated VSMCs prevents activation of cdk2, a key regulator of the G1 and S phases of the cell cycle. These NO donors do not affect the expression of cdk2 protein but block the mitogen-induced expression of cyclin A, an activating subunit of cdk2. SNP and SNAP also repress the mitogen-stimulated activation of the cyclin A promoter. These data suggest that the antiproliferative effect of NO on VSMCs results, at least in part, from the repression of cyclin A gene transcription.


Beta-blocker dosages and mortality after myocardial infarction: data from a large health maintenance organization.
Although long-term beta-blocker therapy has been found beneficial in patients after an acute myocardial infarction, these drugs are greatly underused by clinicians. Moreover, the dosages of beta-blockers used in randomized controlled trials appear to be much larger than those routinely prescribed. To determine whether an association exists between the dosage of beta-blockers prescribed after a myocardial infarction and cardiac mortality. We performed a retrospective cohort study of 1165 patients who survived an acute myocardial infarction from January 1, 1990, through December 31, 1992. These patients represent a subgroup of the 6851 patients hospitalized at northern California Kaiser Permanente hospitals. Of the 37.7% of patients prescribed beta-blocker therapy, 48.1% were treated with dosages less than 50% of the dosage found to be effective in preventing cardiac death in large randomized clinical trials (lower-dosage therapy). Compared with patients not receiving beta-blockers, those treated with lower-dosage therapy appeared to have a greater reduction in cardiovascular mortality (hazard ratio, 0.33; P=.009) than patients treated with a higher dosage (hazard ratio, 0.82; P=0.51), after adjustment for age, sex, race, disease severity, and comorbidities. The dosages of beta-blockers shown to be effective in randomized trials are not commonly used in clinical practice, and treatment with lower dosages of beta-blockers was associated with at least as great a reduction in mortality as treatment with higher dosages. This suggests that physicians who are reluctant to prescribe beta-blockers because of the relatively large dosages used in the large prospective clinical trials should be encouraged to prescribe smaller dosages.


Importance of Steric Influences in the Construction of Multicomponent Hybrid Polymetallic Clusters.
The straightforward room temperature synthesis of hybrid polymetallic manganese clusters is investigated, exploiting complementary ligand combinations of p-tert-butylcalix[4]arene and salicylaldoximes. Eight new [MnIII7MnII] clusters have been prepared wherein the simple substitution of alkyl or aryl groups at well-defined positions of the salicylaldoxime scaffold leads to two distinct structure types that, while exhibiting the same general topology, contain the unique MnII ion in different positions. Incorporation of a methyl, ethyl, or isopropyl group at the 3-position of the aromatic skeleton or a phenyl group at the oximic carbon gives structure type A that displays competing weak ferromagnetic and antiferromagnetic interactions. Substitution of a methyl or ethyl group at the oximic carbon atom invokes structure type B, incorporating an additional bulky chloride or nitrate into the metallic core due to the smaller steric imposition and position of the methyl or ethyl group. The distortion of the cluster core is consequently enhanced, switching the magnetic properties and resulting in single-molecule magnet behavior. The presence of tert-butyl groups at the 3- and 5-positions of the salicylaldoxime skeleton leads to a new [MnIV2MnIII2] cluster that is found to be a single-molecule magnet. The bulky tert-butyl group in the 3-position is too large to facilitate Mn8 cluster formation, and thus assembly occurs by an alternative pathway. Characteristic bonding modes of the constituent ligands are retained in every case, and the results presented here give insight into the potential of ligand combinations in future studies, highlighting the importance of steric factors in evaluating their relevant compatibilities.


Paroxysmal eye-head movements in Glut1 deficiency syndrome.
To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS). We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients. A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye-head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement. Paroxysmal eye-head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder.


Is Iron Supplementation Influenced by Sub-Clinical Inflammation?: A Randomized Controlled Trial Among Adolescent Schoolgirls in Myanmar.
Iron absorption was impaired in the presence of sub-clinical inflammation (SCI) and might hamper the effect of iron supplementation. The purpose of the study was to identify the influence of SCI on iron supplementation. A randomized, double-blinded, placebo-controlled experimental study was conducted among anaemic adolescent schoolgirls in Ayeyarwady region, Myanmar. A total of 402 schoolgirls were recruited from six schools screened from 1269 girls who were assigned into one of four groups: Folate group (2.5 mg of folate), Vitamin A group (15,000 IU of vitamin), Iron folate group (60 mg elemental iron and folate) and Iron, and vitamin A and folate group. Supplementation was done once a week for 12 weeks. Iron, vitamin A and inflammation were measured at the baseline, middle and endline. Changes in serum ferritin and body iron were significantly higher in the IFA and IFA + vitA among those without SCI. There was interaction between vitamin A and SCI on Hb changes. Analysis of GLM repeated measure showed interactions between treatment and SCI for hemoglobin and serum transferrin receptor. Those treated with vitamin A had better outcomes when there was SCI. Inflammation accompanied a negative effect on iron supplementation and vitamin A improved efficacy of iron supplementation in the presence of SCI.


High Occurrence of Multiresistant Salmonella Infantis in Retail Meat in Ecuador.
Salmonella enterica is among the most important foodborne pathogens. In Ecuador, there is limited information about non-typhoidal S. enterica occurrence in raw meats, its serotype distribution, and antimicrobial resistance. In this study, we addressed this issue in 1095 retail fresh meats (chicken, pork, veal, lamb, beef, and turkey) in Quito by performing a traditional culture methodology and molecular detection. We found that S. enterica was present in 38.1% of the samples, and Salmonella Infantis was the most common serotype showing a high antibiotic resistance and a wide host range. Some host-adapted serotypes were found in uncommon sources of meat, suggesting cross-contamination and the need to implement good manufacturing practices in meat processing. High levels of multidrug resistance were found in all serotypes. There is an urgent need to identify Salmonella serotypes in food to compare with clinical data and to carry out epidemiological studies to control and prevent outbreaks and infections.


Pancreaticopleural fistula: demonstration by computed tomography and endoscopic retrograde cholangiopancreatography.
Pancreaticopleural fistula is an uncommon complication of chronic pancreatitis or pancreatic trauma. Clinical features include pleural effusion and resulting pulmonary symptoms. Abdominal pain and other clinical manifestations of pancreatitis may be minimal or absent. As in this case, computed tomography and endoscopic retrograde cholangiopancreatography may provide complementary diagnostic information in the evaluation of this condition. A discussion of the pathophysiology, diagnosis, and management of pancreaticopleural fistula is presented.


Chemotherapeutic trial to control enterobiasis in schoolchildren.
To assess several chemotherapeutic schemes for control of enterobiasis, 738 children in five primary schools in Chunchon, Korea, were studied from May 1994 to June 1995. They were divided into 6 groups by the schemes: treatment of once or twice a year; treatment of positive cases or of whole class students; treatment with or without family members. The overall egg positive rate before intervention was 17.5% out of 789 children. Treating all individuals in a class together with family members of positive cases brought better control efficacy than other schemes (p = 0.000). However, when egg positive rate is less than 30%, treating only egg positive cases also can reduce egg positive rate. The confounding factors for the enterobiasis control in primary schoolchildren were new-comer to a class and familial infection.


Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity.
To define practical use and to specify the ideal method for monitoring the liver toxicity of MTX in the management of psoriasis. To systematically review the literature regarding treatment modalities with methotrexate (MTX) in psoriasis, risk of MTX-mediated liver fibrosis and monitoring of hepatic toxicity. A systematic literature search was carried out in Medline, Embase and Cochrane Library databases from 1980 to 2010 searching for randomized controlled trials and observational studies on methods of administering MTX in psoriasis and risk factors and assessment of liver toxicity. We limited the literature search to articles on human subjects over 19 years of age, articles in English or French on psoriasis and articles including psoriatic arthritis and original data. Among 949 references identified, 23 published studies were included. There were no studies focusing directly on the question of MTX treatment modalities. Treatment outcome appears to be dose dependent. A single study in rheumatoid arthritis showed the slightly superior efficacy of subcutaneous administration vs. oral dosing with a similar safety profile. Combination with folic acid may decrease the efficacy of MTX while improving tolerability. The extreme variability of the incidence of hepatic fibrosis in the literature does not allow the risk of hepatic fibrosis to be quantified. Type 2 diabetes and obesity, were associated with a significant increased risk of liver fibrosis. Hepatitis B and C and alcohol consumption were associated with a modest and non-significant increased risk of liver fibrosis. Procollagen III for detection of hepatic fibrosis dosing was the most extensively validated method to monitor liver fibrosis showing a sensitivity of 77.3% and a specificity of 91.5%. The Positive Predictive Value and Negative Predictive Value fluctuated depending on the prevalence of hepatic fibrosis. The sensitivities of the FibroTest and the fibroscan were of 83 and 50%, respectively, with specific features amounting to 61 and 88% respectively. Based on expert experience, the starting dose of MTX is between 5 and 10 mg/week for the first week. Fast dose escalation is recommended in order to obtain a therapeutic target dose of 15-25 mg/week. The maximum recommended dose is 25 mg/week. A folic acid supplement is necessary. The initiation of treatment by oral administration is preferred. In cases where inadequate response is obtained or in the event of poor gastrointestinal tolerance, subcutaneous dosing can be proposed at the same dose. Published data do not confirm the incidence of hepatic fibrosis. Type 2 diabetes and obesity appear to be significant risk factors in fibrosis. A combination of FibroTests and fibroscans together with measurement of the type III serum procollagen aminopeptide seem to be ideal method for monitoring liver toxicity.


Development to blastocysts of one- to two-cell equine embryos after coculture with uterine tubal epithelial cells.
Development of 1- to 2-cell in vivo fertilized equine embryos cultured with or without uterine tubal epithelial cells (UTEC) was studied. One- to 2-cell embryos (n = 26) were collected surgically from the uterine tubes of pony mares 1 day after ovulation. Four- to 8-cell embryos (n = 9) were collected 2 days after ovulation. Presumptive zygotes and 2-cell embryos were cultured with (n = 17) or without (n = 9) UTEC, and all 4- to 8-cell embryos were cocultured with UTEC as positive controls. Uterine tubal epithelial cells were used as cell suspensions within 2 weeks after initiation of cultures. Embryos were cultured to blastocysts or until the embryo had morphologic degeneration. Six presumptive zygotes failed to cleave in vitro. Development to blastocysts of 1-cell (4 of 11) and 2-cell (2 of 6) embryos cocultured with UTEC was similar. Coculture of 1- to 2-cell embryos with UTEC significantly (P = 0.05) improved development to blastocysts, compared with culture in medium alone (35 vs 0%, respectively); however, development to blastocysts of 1- to 2-cell embryos cocultured with UTEC was less (P < 0.025) than that of 4- to 8-cell embryos cocultured with UTEC (35 vs 89%, respectively).


Effects of intermittent high glucose on BeWo choriocarcinoma cells in culture.
The aim of this study was to investigate the cellular effects of intermittent high glucose on the human BeWo placental choriocarcinoma cell line, used as a model of the effects of glucose fluctuation in diabetic pregnancies. BeWo cells were subjected to three different glucose conditions for 48 h: 7 mmol/L (control), 42 mmol/L (high glucose), or 7 and 42 mmol/L glucose (intermittent, alternated every 6 h). Cell viability was assessed using cell counts, a cell proliferation assay, and a cell viability assay. Apoptosis was also studied using a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and by immunocytochemistry of fractin, the N-terminal fragment of actin, which can distinguish apoptotic from necrotic cells. Furthermore, the expression of the well-known survival factors of trophoblast cells, heparin-binding epidermal growth factor-like growth factor and leptin, was evaluated by real-time polymerase chain reaction and Western blot analyses. Intermittent high-glucose conditions significantly decreased cell viability and enhanced apoptosis compared with control or continuous high-glucose conditions. Furthermore, the expression of heparin-binding epidermal growth factor-like growth factor, but not that of leptin, was significantly increased under intermittent high-glucose conditions compared to its expression under either control or continuous high-glucose conditions. These data indicate that intermittent high glucose is more deleterious to BeWo cells than continuous high-glucose conditions. Although further in vitro and in vivo study is necessary, excess fluctuation of glucose levels in the placental circulation might be involved in the impairment of placental development leading to the placental dysfunction.


Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway.
Influenza A viruses are able to adapt to restrictive conditions due to their high mutation rates. Importin-α7 is a component of the nuclear import machinery required for avian-mammalian adaptation and replicative fitness in human cells. Here, we elucidate the mechanisms by which influenza A viruses may escape replicative restriction in the absence of importin-α7. To address this question, we assessed viral evolution in mice lacking the importin-α7 gene. We show that three mutations in particular occur with high frequency in the viral nucleoprotein (NP) protein (G102R, M105K and D375N) in a specific structural area upon in vivo adaptation. Moreover, our findings suggest that the adaptive NP mutations mediate viral escape from importin-α7 requirement likely due to the utilization of alternative interaction sites in NP beyond the classical nuclear localization signal. However, viral escape from importin-α7 by mutations in NP is, at least in part, associated with reduced viral replication highlighting the crucial contribution of importin-α7 to replicative fitness in human cells.


Absence of herpesvirus DNA sequences in the 5T murine model of human multiple myeloma.
Kaposi's sarcoma-associated herpesvirus (KSHV, also known as HHV-8) has been found in patients with multiple myeloma (MM) and postulated to be aetiologically associated with the development of this common plasma cell malignancy. A murine model of MM was previously established in which intravenous transfer of 5T myeloma cells into C57BL/KaLwRij mice resulted in characteristic features of human MM. In the present study, we sought to identify herpesvirus DNA sequences in this murine model of MM through polymerase chain reaction (PCR) analysis using primers specific for KSHV, murine herpesvirus 68 (MHV68) and murine cytomegalovirus (MCMV) as well as consensus primers designed from the highly conserved DNA polymerase genes of the Herpesviridae family. None of the DNA samples from whole bone marrow (n = 6) or dendritic cells enriched by long-term culture (n = 8) of 5T myeloma-bearing mice as well as the 5T myeloma cell lines (n = 3) maintained in long-term culture yielded specific amplification products in any of the PCR assays. Two KSHV-specific serological assays measuring antibodies to KSHV latent and lytic antigens also failed to detect the presence of anti-KSHV antibodies in mice that developed MM. These results suggest that the development of 5T murine MM is unlikely to be involved with KSHV or a KSHV-like murine herpesvirus.


Ultrasound-mediated multifunctional magnetic microbubbles for drug delivery of celastrol in VX2 liver transplant tumors.
Celastrol (CST) has positive pharmacological effects on various cancers, but clinical application is limited because of poor water solubility and systemic toxicity. Ferric oxide (Fe3O4) has a large specific surface area and can be functionalized by inorganic modification to form complex magnetic drug delivery systems. Herein, Fe3O4 was surface-modified with citric acid and polyethylene glycol (PEG) (via) the Mitsunobu reaction and then covalently bound to CST. Finally, magnetic microbubbles (MMBs) containing perfluoropropane (C3F8) and Fe3O4-PEG2K-CST particles were constructed with poly(lactic-co-glycolic acid) (PLGA) as the shell membrane. In vitro studies showed that ultrasound-mediated MMBs exhibited improved inhibition of VX2 cell proliferation compared to inhibition achieved using MMBs without ultrasound mediation, blank MMBs, or free CST. In ultrasound mode, MMBs have favorable imaging properties. After the application of a high mechanical index, MMBs collapse through the cavitation effect, releasing their internal Fe3O4-PEG2K-CST. The CST is then delivered to the tumor microenvironment under acidic conditions. In magnetic resonance imaging T2 mode, a specific hypointense signal was observed in the tumor area compared with that before treatment, whereas no significant change occurred in the signal intensity of the surrounding organs. After treatment, pathological examination of tumor-bearing rabbit tissues showed that iron elements accumulated in several apoptosis cells in the tumor area, with no apparent abnormalities found in other areas. Thus, ultrasound-mediated MMBs could significantly improve the drug uptake of solid tumors and inhibit tumor growth with favorable biological safety.


Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.
Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis. In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events. The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%). Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo. Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.


Norwegian policies to reduce social inequalities in health: Developments from 1987 to 2021.
Reducing social inequalities in health has been an important aim in the development of the Nordic welfare states. This Commentary presents the development of Norwegian policies in this area from 1987 to 2021. Social inequalities entered the political agenda in Norway in the 1980s, but were mostly defined as a problem for selected marginalised groups. The World Health Organization project led by Michael Marmot was an inspiration for Norwegian policy-makers and the concept of the social gradient was introduced. From 2005, levelling the social gradient in health became a central strategy in Norwegian policy-making and culminated in the Public Health Act 2012. This Act focuses on the structural determinants of health and the municipalities have a central role in its implementation. However, the municipalities are mostly responsible for services providing downstream measures and have little control over social determinants such as tax or labour market policies. The Public Health Act is important because it institutionalises social inequalities as a policy field within public health. Not only the municipalities, but all administrative levels have to contribute to meet the aim of reducing the social gradient.


The global war against intestinal parasites--should we use a holistic approach?
Intestinal parasite infections have been known to compromise the quality of human life since prehistoric times. Throughout the ages, human civilizations have fought against parasitism, including intestinal parasites. During the second half of the last century, the focus of disease-combating efforts moved to other imminent public health issues, under the notion that the fight against infectious diseases had been won. However, the disease incidence data indicate that these diseases continue to wreak havoc on human productivity across the globe. Lately, chemotherapeutic intervention has been stressed for the control of intestinal parasitic infections. In this paper we evaluate the need for a holistic approach to address this issue and make recommendations for this cause.


Physiological variations in ovine cerebrovascular calcium sensitivity.
Cerebrovascular reactivity to biogenic amines varies in relation to both arterial diameter and age. The present study examines the hypothesis that these patterns of reactivity are secondary to corresponding variations in the Ca2+ sensitivity of the contractile proteins. To test this hypothesis, we permeabilized segments of common carotid (Com), basilar, main branch middle cerebral, and second-branch middle cerebral (MCA-B) arteries from nonpregnant adult and near-term fetal sheep using beta-escin. Permeabilization methods were carefully validated and adjusted for each artery type. Baseline myofilament Ca2+ sensitivity in both adults and fetuses increased significantly from the Com to the MCA-B and was generally higher in fetuses than in adults. Serotonin dose dependently increased Ca2+ sensitivity via a G protein-dependent mechanism in all arteries. The magnitudes of this effect did not vary among artery types but were significantly greater in fetal than in adult arteries. This effect of serotonin was mimicked by guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable analog of guanosine 5'-triphosphate, and its effects were also much greater in fetal than in adult arteries. We conclude that patterns of cerebrovascular reactivity to biogenic amines were determined, at least in part, by underlying variations in baseline myofilament Ca2+ sensitivity and/or its alteration by G protein-dependent mechanisms.


Heterostructured ZnS/InP nanowires for rigid/flexible ultraviolet photodetectors with enhanced performance.
Heterostructured ZnS/InP nanowires, composed of single-crystalline ZnS nanowires coated with a layer of InP shell, were synthesized via a one-step chemical vapor deposition process. As-grown heterostructured ZnS/InP nanowires exhibited an ultrahigh Ion/Ioff ratio of 4.91 × 103, a high photoconductive gain of 1.10 × 103, a high detectivity of 1.65 × 1013 Jones and high response speed even in the case of very weak ultraviolet light illumination (1.87 μW cm-2). The values are much higher than those of previously reported bare ZnS nanowires owing to the formation of core/shell heterostructures. Flexible ultraviolet photodetectors were also fabricated with the heterostructured ZnS/InP nanowires, which showed excellent mechanical flexibility, electrical stability and folding endurance besides excellent photoresponse properties. The results elucidated that the heterostructured ZnS/InP nanowires could find good applications in next generation flexible optoelectronic devices.


Liver repopulation by c-Met-positive stem/progenitor cells isolated from the developing rat liver.
Self-renewing stem cells responsible for tissue or organ development and regeneration have been recently described. To isolate such cells using flow cytometry, it should be required to find molecules expressing on their cell surfaces. We have previously reported that, on cells fulfilling the criteria for hepatic stem cells, the hepatocyte growth factor receptor c-Met is expressed specifically in the developing mouse liver. In this study, to determine whether c-Met is an essential marker for hepatic stem cells in other animal strains, we examined the potential for in vivo liver-repopulation in sorted fetal rat-derived c-Met+ cells using the retrorsine model. Using flow cytometry and monoclonal antibodies for c-Met and leukocyte common antigen CD45, fetal rat liver cells were fractionated according to the expression of these molecules. Then, cells in each cell subpopulation were sorted and transplanted into the retrorsine-treated adult rats with two-third hepatectomy. At 9 months post transplant, frequency of liver-repopulation was examined by qualitative and quantitative analyses. When we transplanted c-Met+ CD45- sorted cells, many donor-derived cells formed colonies that included mature hepatocytes expressing albumin and containing abundant glycogen in their cytoplasm. In contrast, c-Met- cells and CD45+ cells could not repopulate damaged recipient livers. High enrichment of liver-repopulating cells was conducted by sorting of c-Met+ cells from the developing rat liver. This result suggests that c-Met/HGF interaction plays a crucial role for stem cell growth, differentiation, and self-renewal in rat liver organogenesis. Since the c-Met is also expressed in the fetal mouse-derived hepatic stem cells, this molecule could be expected to be an essential marker for such cell population in the various animal strains, including human.


Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway.
Trans retinoic acid (RA) has proven to be a potent therapeutic agent in the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiproliferative and differentiating effects of RA. In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN; CD437) that not only totally inhibits the proliferation of RA-resistant leukemic cell lines HL-60R and K562 but also induces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21(waf1/cip1) as well as GADD45 mRNA. Manifestations of CD437-mediated programmed cell death are noted within 2 hours, as indicated by both the cleavage and activation of the CPP32 protease and cleavage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not express the retinoid nuclear receptor RAR beta and RAR gamma and express a truncated RAR alpha. Thus, CD437 induction of p21(waf1/cip1) and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving the retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia.


Probing Polarity and pH Sensitivity of Carbon Dots in Escherichia coli through Time-Resolved Fluorescence Analyses.
Intracellular monitoring of pH and polarity is crucial for understanding cellular processes and functions. This study employed pH- and polarity-sensitive nanomaterials such as carbon dots (CDs) for the intracellular sensing of pH, polarity, and viscosity using integrated time-resolved fluorescence anisotropy (FA) imaging (TR-FAIM) and fluorescence lifetime (FLT) imaging microscopy (FLIM), thereby enabling comprehensive characterization. The functional groups on the surface of CDs exhibit sensitivity to changes in the microenvironment, leading to variations in fluorescence intensity (FI) and FLT according to pH and polarity. The FLT of CDs in aqueous solution changed gradually from 6.38 ± 0.05 ns to 8.03 ± 0.21 ns within a pH range of 2-8. Interestingly, a complex relationship of FI and FLT was observed during measurements of CDs with decreasing polarity. However, the FA and rotational correlation time (θ) increased from 0.062 ± 0.019 to 0.112 ± 0.023 and from 0.49 ± 0.03 ns to 2.01 ± 0.27 ns, respectively. This increase in FA and θ was attributed to the higher viscosity accompanying the decrease in polarity. Furthermore, CDs were found to bind to three locations in Escherichia coli: the cell wall, inner membrane, and cytoplasm, enabling intracellular characterization using FI and FA decay imaging. FLT provided insights into cytoplasmic pH (7.67 ± 0.48), which agreed with previous works, as well as the decrease in polarity in the cell wall and inner membrane. The CD aggregation was suspected in certain areas based on FA, and the θ provided information on cytoplasmic heterogeneity due to the aggregation and/or interactions with biomolecules. The combined TR-FAIM/FLIM system allowed for simultaneous monitoring of pH and polarity changes through FLIM and viscosity variations through TR-FAIM.


An explanatory factor analysis of a brief self-report scale to detect neurocognitive impairment among HIV-positive men who have sex with men and transgender women in Peru.
Neurocognitive impairment (NCI) has been associated with poor clinical outcomes in various patient populations. This study used exploratory factor analysis (EFA) to examine the factor structure of the existing 95-item Neuropsychological Impairment Scale (NIS) to create a suitable NCI screening instrument for people living with HIV (PLH). In Lima, Peru, 313 HIV-positive men who have sex with men (MSM) and transgender women (TGW) prescribed antiretroviral therapy (ART) completed the NIS using computer-assisted self-interviews (CASI). The EFA used principal axis factoring and orthogonal varimax rotation, which resulted in 42 items with an 8-factor solution that explained 51.8% of the overall variance. The revised, 8-factor, Brief Inventory of Neurocognitive Impairment for Peru (BINI-P) showed a diverse set of factors with excellent to good reliability (i.e., F1 α = 0.92 to F8 α = 0.78). This EFA supports the use of the BINI-P to screen for NCI among Spanish-speaking, HIV-positive MSM and TGW. Future research should examine the effectiveness of the BINI-P in detecting NCI in clinical care settings and the impact of NCI on HIV health-related outcomes, including linkage and retention in care, ART adherence and HIV risk behaviors.


Dendritic cells can turn CD4+ T lymphocytes into vascular endothelial growth factor-carrying cells by intercellular neuropilin-1 transfer.
Neuropilin-1 (NRP1) is a transmembrane protein expressed on neuronal and endothelial cells where it plays a crucial role in guiding axons and regulating angiogenesis. We have recently shown that NRP1 also is expressed on dendritic cells (DC) in the human immune system and have proposed a role for NRP1 in the first stages of the immune response. In these studies, we show that NRP1 can be transferred with a high efficiency from human DC to T lymphocytes by trogocytosis. The NRP1 transfer can occur independently of T lymphocyte activation; the amount of NRP1 transferred depends on the NRP1 expression level on APC and is enhanced when T cells are activated through the TCR. Moreover, the NRP1 transfer occurs between specific donor and recipient cells, because no NRP1 transfer is observed between endothelial cells and T lymphocytes or between APCs and CD34(+) hemopoietic cells. Finally, we show that a major NRP1 ligand, vascular endothelial growth factor (VEGF)(165), is secreted by mature human DCs and binds to NRP1 captured by T lymphocytes. These results show that NRP1 transfer to T lymphocytes during the immune synapse can convert T lymphocytes into VEGF(165)-carrying cells. Together with the enhanced signaling of VEGF-R2 on endothelial cells in the presence, in trans, of the NRP1-VEGF(165) complex, our results suggest that the intercellular transfer of NRP1 might participate in the Ag-independent remodelling of the endothelial vessels in secondary lymphoid organs during inflammation.


Plasma solute concentrations during gonadotrophin-induced ovulation.
The effects of ovulation induction on some plasma solute concentrations were investigated serially in eleven women, nine of whom conceived in that cycle. Increasing oestrogen output during the follicular phase was associated with decreasing levels of osmolality, urea, total protein and the albumin free protein fraction. Smaller decreases in the concentrations of sodium, potassium, chloride, carbon dioxide combining power (CO2CP) and albumin were not statistically significant. The luteal phase was marked by a rise in osmolality and a fall in CO2CP but no other significant changes. Levels of osmolality, sodium and potassium fell in early pregnancy when oestrogen output was further increased. These results appear consistent with an oestrogen induced expansion of the extracellular fluid compartment by retention of water in excess of solute, which might also account for the similar changes in pregnancy.


Comorbidity effects on shoulder arthroplasty costs analysis of a nationwide private payer insurance data set.
The purpose of this study was to evaluate the effect of common medical comorbidities on the reimbursements of different shoulder arthroplasty procedures. We conducted a retrospective query of a single private payer insurance claims database using PearlDiver (Warsaw, IN, USA) from 2010 to 2014. Our search included the Current Procedural Terminology codes and International Classification of Diseases, Ninth Revision codes for total shoulder arthroplasty (TSA), hemiarthroplasty, and reverse shoulder arthroplasty (RSA). Medical comorbidities were also searched for through International Classification of Diseases codes. The comorbidities selected for analysis were obesity, morbid obesity, hypertension, smoking, diabetes mellitus, hyperlipidemia, atrial fibrillation, chronic obstructive pulmonary disease, cirrhosis, depression, and chronic kidney disease (excluding end-stage renal disease). The reimbursement charges of the day of surgery, 90-day global period, and 90-day period excluding the initial surgical day of each comorbidity were analyzed and compared. Statistical analysis was conducted through analyses of variance or Kruskal-Wallis test. Comorbidities did not have a significant effect on same-day reimbursements but instead caused a significant effect on the subsequent 89-day (interval) and 90-day reimbursements in the TSA and RSA cohorts. For TSA and RSA, the highest reimbursement costs during the 90-day period after surgery were seen with the diagnosis of hepatitis C, followed by atrial fibrillation and later chronic obstructive pulmonary disease. For hemiarthroplasty, the same was true in the following order: hepatitis C, cirrhosis, and atrial fibrillation. Shoulder arthroplasty reimbursements are significantly affected by comorbidities at time intervals following the initial surgical day.


Add-On Complementary Medicine in Cancer Care: Evidence in Literature and Experiences of Integration.
Background: According to the literature an increasing number of cancer patients demand for complementary therapies during their disease. Research has demonstrated that some of these therapies are effective and safe as adjunctive treatments in specific symptoms of these patients. Methods: The aims of the paper are to review the main and recent papers of international literature on the effectiveness of complementary medicine (CM) therapies on side effects of anti-cancer protocols and improvement in the quality of life of oncological patients, and to describe the integration of evidence-based acupuncture, herbal medicine and homeopathy treatments in Public Cancer Network of the region of Tuscany. Results: After the review of literature and the approval of a Regional Resolution, some CM will be introduced in Cancer Departments in Tuscany to additionally treat cancer-related symptoms and side effects of conventional cancer therapy: acupuncture for nausea and post-chemotherapy and post-surgery vomiting, pain, hot flashes of iatrogenic menopause, xerostomia; homeopathy for hot flashes of iatrogenic menopause and the side effects of radiotherapy; herbal medicine for cancer-related fatigue, nausea and vomiting, pain, mucositis, anxiety, and depression. Conclusions: The integration of evidence-based complementary treatments allows for an effective response to the demand coming from cancer patients and combines safety and equity of access in public health systems.


Root-centric β diversity reveals functional homogeneity while phylogenetic heterogeneity in a subtropical forest.
Root-centric studies have revealed fast taxonomic turnover across root neighborhoods, but how such turnover is accompanied by changes in species functions and phylogeny (i.e., β diversity) remains largely unknown. As β diversity can reflect the degree of community-wide biotic homogenization, such information is crucial for better inference of below-ground assembly rules, community structuring, and ecosystem processes. We collected 2480 root segments from 625 0-30 cm soil profiles in a subtropical forest in China. Root segments were identified into 138 species with DNA-barcoding with six root morphological and architectural traits measured per species. By using the mean pairwise (Dpw ) and mean nearest neighbor distance (Dnn ) to quantify species ecological differences, we first tested the non-random functional and phylogenetic turnover of root neighborhoods that would lend more support to deterministic over stochastic community assembly processes. Additionally, we examined the distance-decay pattern of β diversity, and finally partitioned β diversity into geographical and environmental components to infer their potential drivers of environmental filtering, dispersal limitation, and biotic interactions. We found that functional turnover was often lower than expected given the taxonomic turnover, whereas phylogenetic turnover was often higher than expected. Phylogenetic Dpw (e.g., interfamily species) turnover exhibited a distance-decay pattern, likely reflecting limited dispersal or abiotic filtering that leads to the spatial aggregation of specific plant lineages. Conversely, both functional and phylogenetic Dnn (e.g., intrageneric species) exhibited an inverted distance-decay pattern, likely reflecting strong biotic interactions among spatially and phylogenetically close species leading to phylogenetic and functional divergence. While the spatial distance was generally a better predictor of β diversity than environmental distance, the joint effect of environmental and spatial distance usually overrode their respective pure effects. These findings suggest that root neighborhood functional homogeneity may somewhat increase forest resilience after disturbance by exhibiting an insurance effect. Likewise, root neighborhood phylogenetic heterogeneity may enhance plant fitness by hindering the transmission of host-specific pathogens through root networks or by promoting interspecific niche complementarity not captured by species functions. Our study highlights the potential role of root-centric β diversity in mediating community structures and functions largely ignored in previous studies.


Antecedent Dietary Glutamine Supplementation Benefits Modulation of Liver Pyroptosis in Mice with Polymicrobial Sepsis.
The liver is the main organ responsible for bacterial and endotoxin clearance. Pyroptosis is a form of proinflammatory programmed cell death activated by caspase-1/11 and gasdermin D (GadD). Pyroptosis protects the host against bacterial infection; however, overactive pyroptosis can lead to organ injury. Glutamine (GLN) is a specific amino acid with anti-inflammatory and immunomodulatory properties. This study investigated the effects of GLN pretreatment on liver pyroptosis in a mouse model of polymicrobial sepsis. Mice were assigned to sham, sepsis control (Sepsis-C), and sepsis GLN (Sepsis-G) groups. The sham and Sepsis-C groups were fed the AIN-93G diet. The Sepsis-G group was provided with identical diet components except that part of the casein was replaced by GLN. After feeding the respective diets for 2 weeks, a cecal ligation and puncture (CLP) procedure was performed in the sepsis groups. An antibiotic was administered after CLP. Mice were sacrificed at either 24 or 72 h after CLP. The results showed that sepsis resulted in upregulated liver caspase-1/11 expression. Compared to the Sepsis-C group, the Sepsis-G group had higher liver caspase-11 and NLRP3 gene expressions at 24 h and lower active caspase-1/11 and cleaved GadD protein levels at 72 h after sepsis. Additionally, liver inflammatory cytokine gene expressions had decreased by 72 h post-CLP. The findings suggest that prophylactic administration of GLN initially upregulated liver pyroptosis to eradicate pathogens, yet the process of pyroptosis was suppressed in the late phase of sepsis. This may have beneficially attenuated liver inflammation and injury in an antibiotic-treated septic condition.


New biomarkers for respiratory infections.
Although pneumonia, either community or hospital-acquired, is the most frequent severe respiratory infection, it is an infection difficult to diagnose. At present, the diagnosis of pneumonia relies on a combination of clinical, radiologic, and microbiologic criteria. However, these criteria are far from perfect leading to uncertainty in the diagnosis, risk stratification, and choice of antibiotic therapy. Biomarkers have been used to bring additional information in this setting. The aim of this review is to provide a clear overview of the current evidence for biomarkers to distinguish between patients in several clinical scenarios: to exclude pneumonia in order to withhold antibiotics, to identify the causative pathogen to target antimicrobial treatment, to identify phenotypes of inflammatory response to facilitate adjunctive treatments, to stratify the risk of severe pneumonia and provide the adequate level of care, and to monitor treatment response and de-escalate antibiotic therapy. In recent years the number of new biomarkers increased markedly in different areas like pathogen identification or host response. Although far from the ideal, there are several promising areas that could represent true evolutions in the management of pneumonia, in the near future.


What Dose of Caffeine to Use: Acute Effects of 3 Doses of Caffeine on Muscle Endurance and Strength.
To explore the effects of 3 doses of caffeine on muscle strength and muscle endurance. Twenty-eight resistance-trained men completed the testing sessions under 5 conditions: no-placebo control, placebo control, and with caffeine doses of 2, 4, and 6 mg·kg-1. Muscle strength was assessed using the 1-repetition-maximum test; muscle endurance was assessed by having the participants perform a maximal number of repetitions with 60% 1-repetition maximum. In comparison with both control conditions, only a caffeine dose of 2 mg·kg-1 enhanced lower-body strength (d = 0.13-0.15). In comparison with the no-placebo control condition, caffeine doses of 4 and 6 mg·kg-1 enhanced upper-body strength (d = 0.07-0.09) with a significant linear trend for the effectiveness of different doses of caffeine (P = .020). Compared with both control conditions, all 3 caffeine doses enhanced lower-body muscle endurance (d = 0.46-0.68). For upper-body muscle endurance, this study did not find significant effects of caffeine. This study revealed a linear trend between the dose of caffeine and its effects on upper-body strength. The study found no clear association between the dose of caffeine and the magnitude of its ergogenic effects on lower-body strength and muscle endurance. From a practical standpoint, the magnitude of caffeine's effects on strength is of questionable relevance. A low dose of caffeine (2 mg·kg-1)-for an 80-kg individual, the dose of caffeine in 1-2 cups of coffee-may produce substantial improvements in lower-body muscle endurance with the magnitude of the effect being similar to that attained using higher doses of caffeine.


Delayed reproductive death in X-irradiated Chinese hamster ovary cells.
The cytotoxic effects of X-irradiation may be delayed for many generations of replication in mammalian cells. In addition to a reduced cloning efficiency, progeny of surviving Chinese hamster ovary (CHO) cells isolated after 12-34 population doublings postirradiation showed a variety of abnormalities including lower attachment ability to culture dishes and slower cell cycle progression. When these progeny were seeded as single cells 12-23 generations after irradiation, they formed a higher fraction of abortive colonies and of non-homogeneous colonies containing giant cells. All of these characteristics were evident whether progeny cells were subcultured by trypsinization or by mitotic selection. These results suggest that residual damage may be carried by surviving progeny of irradiated cells over many mitotic cycles; this damage is eventually expressed in terms of pleomorphic changes leading to delayed reproductive failure.


Overexpression of thioredoxins 1 and 2 increases retinal ganglion cell survival after pharmacologically induced oxidative stress, optic nerve transection, and in experimental glaucoma.
Oxidative damage is implicated in retinal ganglion cell (RGC) death after optic nerve transection (ONT) and in glaucoma. We analyzed the expression and protective effects of thioredoxins (TRXs), regulators of the cellular reduction-oxidative (redox) state, in RGCs damaged by pharmacologically induced oxidative stress, ONT, and elevated intraocular pressure (IOP). ONT and glaucoma models in the rat were used. The glaucoma model was generated in albino rats by intracameral injection of india ink followed by ab externo laser applications to the pigmented trabecular band. Retrograde labeling of RGCs was performed with dextran tetramethylrhodamine. RGC isolation from rat retinas was performed with magnetic beads coated with Thy-1 monoclonal antibody. Immunoblot analysis, RGC-5 culture and transfection, and cell viability assays were used. Gene delivery was performed with in vivo electroporation. Endogenous levels of thioredoxin-2 (TRX2) in RGCs after axotomy and in RGC-5 cells after glutamate/buthionine sulfoximine (BSO) treatment were up-regulated. An increased level of TRX-interacting protein (TXNIP) in the retina was observed 2 and 5 weeks after IOP elevation. TRX1 levels were decreased at 2 weeks and more prominently at 5 weeks after IOP elevation. No change in TRX2 levels in response to IOP elevation was detected. Overexpression of TRX1 and TRX2 in RGC-5 treated with glutamate/BSO increased the cell survival by twofold and threefold 24 and 48 hours after treatment, respectively. Overexpression of these proteins in the retina in vivo increased the survival of RGCs by 35% and 135% at 7 and 14 days after ONT, respectively. In hypertensive eyes, RGC loss was approximately 27% after 5 weeks of IOP elevation compared to controls. TRX1 and TRX2 overexpression preserved approximately 45% and 37% of RGCs, respectively, in the glaucoma model compared to controls. Thioredoxin overexpression protects RGCs from death after optic nerve axotomy, in pharmacologically induced oxidative stress in vitro and in an animal model of glaucoma.


Comprehensive care of travelers.
Travel, especially if it is international, often means major changes for the family. Family physicians should assess the epidemiologic risk and psychosocial significance of travel or relocation in light of the family's life-cycle stage and antecedent health. Using core references, which are kept current in partnership with public health agencies, family physicians are able to provide comprehensive immunization, medications, and patient education for all travel risks. Families are given medical record summaries and recommended sources of care at their destination. Eight weeks after their return patients are reassessed for newly acquired illness and helped to integrate the perspectives gained during the travel into the family's future dynamics. Taking advantage of growing travel medicine opportunities, family medicine educators should base the care of travelers and teaching of residents on defined competence priorities. Travelers' health provides a mutually rewarding model of shared care with public health consultants in the community medicine curriculum.


[Cytoplasmic RNA content in the brain and spinal cord neurons of red-cheeked susliks during the hibernation period and on arousal].
By means of scanning cytospectrophotometry of gallocyanin chrome alum stained sections, cytoplasmic RNA content per cell in the neurons of the ground squirrel hippocampus, hypothalamic supraoptic nucleus, and spinal cord anterior horns, was shown to decrease as far as the hibernation went on. Before the arousal the RNA amount increased, the increase being the greatest in the hypothalamic neurons. First days after the arousal, the cytoplasmic RNA content in all the neurons was significantly higher than in the same neurons before the hibernation. Changes of RNA content in the neurons and in the homogenates of corresponding brain areas were compared; important role of the hypothalamus in metabolic reconstruction of the nervous system at various stages of hibernation, was outlined.


The purification and properties of chicken liver RNase: An enzyme which is useful in distinguishing between cytidylic and uridylic acid residues.
A heat-stable endoribonuclease isolated from chicken liver has been purified to homogeneity as evidenced by the presence of a single protein band upon polyacrylamide gel electrophoresis. The enzyme can, in limit digests of 5 S rRNA and 5.8 S rRNA, dinstinguish between cytidylic and uridylic acids bonds at a ratio of 61:1 and, therefore, may be useful in RNA sequence analysis. The means by which the enzyme hydrolyzes substrate is unusual in that kinetic data do not support a simple formation and breakdown of an enzyme . substrate complex. Rather, the existence of a second complex, consisting of 2 mol of substrate and one of enzyme, derived from the initial enzyme . substrate complex, is postulated. In common with the other endonucleases, enzyme activity is inhibited by free poly(A) or tracts of the polypurine present at the 3'-terminus of RNA. Reversal of inhibition and restoration of activity may be achieved by the addition of low concentrations of spermidine to reaction mixtures.


Storage-induced increase in biomarkers of oxidative stress and inflammation in red blood cell components.
Transfusion of blood components may increase the risk of complications in relation to surgery. During storage, red blood cells (RBCs) undergo structural and functional changes that may reduce function and viability after transfusion. The aim of the study was to evaluate the quality of buffy-coat reduced red cells in SAG-M additive solution, by assessing biomarkers of oxidative and inflammatory stress during a storage period of 35 days. Ten units of RBCs were stored for 35 days. Samples were collected from the units at storage days 1, 3, 7, 14, 21, 28 and 35, respectively. The samples were analysed for various biomarkers expressing the oxidative stress and inflammation, including malondialdehyde (MDA), α-tocopherol (AT), dehydroascorbic acid (DHA), ascorbate (ASC), YKL-40 and interleukin-6 (IL-6). The levels ofMDA, ASC, DHA, IL-6 and YKL-40 changed significantly during the storage period (p < 0.001, p < 0.001, p < 0.001, p = 0.004 and p < 0.001 respectively). A significant change in AT levels could not be shown (p = 0.087). RBCs displayed significant changes in all measured indices of oxidative and inflammatory stress during a storage period of 35 days except for AT. The data suggest a possible rationale behind the observation that aging blood products may increase the risk of complications following surgery and blood transfusion.


Investigating the uptake, effectiveness and safety of COVID-19 vaccines: protocol for an observational study using linked UK national data.
The novel coronavirus SARS-CoV-2, which emerged in December 2019, has caused millions of deaths and severe illness worldwide. Numerous vaccines are currently under development of which a few have now been authorised for population-level administration by several countries. As of 20 September 2021, over 48 million people have received their first vaccine dose and over 44 million people have received their second vaccine dose across the UK. We aim to assess the uptake rates, effectiveness, and safety of all currently approved COVID-19 vaccines in the UK. We will use prospective cohort study designs to assess vaccine uptake, effectiveness and safety against clinical outcomes and deaths. Test-negative case-control study design will be used to assess vaccine effectiveness (VE) against laboratory confirmed SARS-CoV-2 infection. Self-controlled case series and retrospective cohort study designs will be carried out to assess vaccine safety against mild-to-moderate and severe adverse events, respectively. Individual-level pseudonymised data from primary care, secondary care, laboratory test and death records will be linked and analysed in secure research environments in each UK nation. Univariate and multivariate logistic regression models will be carried out to estimate vaccine uptake levels in relation to various population characteristics. VE estimates against laboratory confirmed SARS-CoV-2 infection will be generated using a generalised additive logistic model. Time-dependent Cox models will be used to estimate the VE against clinical outcomes and deaths. The safety of the vaccines will be assessed using logistic regression models with an offset for the length of the risk period. Where possible, data will be meta-analysed across the UK nations. We obtained approvals from the National Research Ethics Service Committee, Southeast Scotland 02 (12/SS/0201), the Secure Anonymised Information Linkage independent Information Governance Review Panel project number 0911. Concerning English data, University of Oxford is compliant with the General Data Protection Regulation and the National Health Service (NHS) Digital Data Security and Protection Policy. This is an approved study (Integrated Research Application ID 301740, Health Research Authority (HRA) Research Ethics Committee 21/HRA/2786). The Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub meets NHS Digital's Data Security and Protection Toolkit requirements. In Northern Ireland, the project was approved by the Honest Broker Governance Board, project number 0064. Findings will be made available to national policy-makers, presented at conferences and published in peer-reviewed journals.


High-throughput linkage analysis of Mutator insertion sites in maize.
Insertional mutagenesis is a cornerstone of functional genomics. High-copy transposable element systems such as Mutator (Mu) in maize (Zea mays) afford the advantage of high forward mutation rates but pose a challenge for identifying the particular element responsible for a given mutation. Several large mutant collections have been generated in Mu-active genetic stocks, but current methods limit the ability to rapidly identify the causal Mu insertions. Here we present a method to rapidly assay Mu insertions that are genetically linked to a mutation of interest. The method combines elements of MuTAIL (thermal asymmetrically interlaced) and amplification of insertion mutagenized sites (AIMS) protocols and is applicable to the analysis of single mutants or to high-throughput analyses of mutant collections. Briefly, genomic DNA is digested with a restriction enzyme and adapters are ligated. Polymerase chain reaction is performed with TAIL cycling parameters, using a fluorescently labeled Mu primer, which results in the preferential amplification and labeling of Mu-containing genomic fragments. Products from a segregating line are analyzed on a capillary sequencer. To recover a fragment of interest, PCR products are cloned and sequenced. Sequences with lengths matching the size of a band that co-segregates with the mutant phenotype represent candidate linked insertion sites, which are then confirmed by PCR. We demonstrate the utility of the method by identifying Mu insertion sites linked to seed-lethal mutations with a preliminary success rate of nearly 50%.


3'-Azido-2',3'-dideoxythymidine (zidovudine) uptake mechanisms in T lymphocytes.
The nucleoside reverse transcriptase inhibitors (NRTIs) make up a family of antiretroviral drugs widely used in the treatment of HIV-1 infection. Human concentrative nucleoside transporters and equilibrative nucleoside transporters, encoded by SLC28 and SLC29 gene families, respectively, are known to be involved in the uptake of a variety of nucleoside analogues used in anticancer treatment. We therefore examined whether SLC28- and SLC29-encoded proteins contribute to the entry of these NRTls into the human leukaemic T-cell line Molt-4. Cis-inhibition experiments demonstrated that nucleoside transporters have a negligible role in antiviral drug uptake. Moreover, the previously identified 3'-azido-2',3'-dideoxythymidine (zidovudine; AZT) carriers, organic anion transporters (organic anion transporter [hOATs], members of the SLC22 gene family) have not been detected in T cells, either functionally or at the mRNA level, thus ruling out a role for hOATs in antiviral drug uptake in these cells. Nevertheless, the data provided here argue against the hypothesis of simple diffusion across the plasma membrane as the unique mechanism of AZT uptake. Actually, this pyrimidine derivative seems to have a temperature-sensitive route of entrance, a finding that, along with the evidence that, AZT inhibits its own uptake and its transport into phytohaemagglutinin-stimulated peripheral blood mononuclear cells is upregulated, strongly support the idea that AZT uptake into T-cells is associated with a mediated and regulated, transport mechanism.


Adaptation of the proximal humerus to physical activity: A within-subject controlled study in baseball players.
The proximal humerus is a common, yet understudied site for osteoporotic fracture. The current study explored the impact of prolonged physical activity on proximal humerus bone health by comparing bone properties between the throwing and nonthrowing arms within professional baseball players. The proximal humerus in throwing arms had 28.1% (95% CI, 17.8 to 38.3%) greater bone mass compared to nonthrowing arms, as assessed using dual-energy x-ray absorptiometry. At the level of the surgical neck, computed tomography revealed 12.0% (95% CI, 8.2 to 15.8%) greater total cross-sectional area and 31.0% (95% CI, 17.8 to 44.2%) greater cortical thickness within throwing arms, which contributed to 56.8% (95% CI, 44.9 to 68.8%) greater polar moment of inertia (i.e., estimated ability to resist torsional forces) compared to nonthrowing arms. Within the humeral head and greater tubercle regions, throwing arms had 3.1% (95% CI, 1.1 to 5.1%) more trabecular bone, as assessed using high-resolution magnetic resonance imaging. Three-dimensional mapping of voxel- and vertex-wise differences between arms using statistical parametric mapping techniques revealed throwing arms had adaptation within much of the proximal diaphysis, especially the posterolateral cortex. The pattern of proximal diaphysis adaptation approximated the pattern of strain energy distribution within the proximal humerus during a fastball pitch derived from a musculoskeletal and finite element model in a representative player. These data demonstrate the adaptive ability of the proximal humerus to physical activity-related mechanical loads. It remains to be established how they translate to exercise prescription to improve bone health within the proximal humerus; however, they provide unique insight into the relationship between prolonged loading and skeletal adaptation at a clinically relevant osteoporotic site.


Hospital autopsy: Endangered or extinct?
To determine the hospital autopsy rate for the UK in 2013. A study of data from a 'Freedom of Information' request to all (n=186) acute NHS Trusts within England (n=160), NHS Boards in Scotland (n=14) and Wales (n=7) and Social Care Trusts in Northern Ireland (n=5). Hospital autopsy rates were calculated from the number of hospital autopsies performed in 2013 as a percentage of total inpatient deaths in the Trust that year. The UK response rate was 99% (n=184), yielding a mean autopsy rate of 0.69%. The mean rates were 0.51% (England), 2.13% (Scotland), 0.65% (Wales) and 0.46% (Northern Ireland). 23% (n=38) of all included respondents had a rate of 0% and 86% (n=143) a rate less than 1%. The decline in hospital autopsy has continued relentlessly and, for better or for worse, the practice is on the verge of extinction in the UK. The study highlights to health professionals and policy makers the magnitude of this decline. Further research should investigate the impact of this on patient safety, clinical audit, public health and medical education.


Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis.
Autophagy and microRNA (miRNA) are important regulators during cancer cell tumorigenesis. Impaired autophagy and high expression of the oncogenic microRNA MIR224 are prevalent in hepatocellular carcinoma (HCC); however, the relationship between the 2 phenomena remains elusive. In this study, we are the first to reveal that autophagy selectively regulates MIR224 expression through an autophagosome-mediated degradation system. Based on this finding, we further demonstrated that in hepatitis B virus (HBV)-related HCC, aberrant autophagy (low autophagic activity) results in accumulation of MIR224 and decreased expression of the target gene Smad4, which leads to increased cell migration and tumor formation. Preferential recruitment of MIR224 into the autophagosome was clearly demonstrated by a) miRNA in situ hybridization under confocal microscopy, and b) immunogold labeling of MIR224 under electron microscopy compared with a ubiquitously expressed microRNA MIRlet7e/let-7. Furthermore, we found that off-label use of amiodarone, an antiarrhythmic agent, effectively suppressed HCC tumorigenesis through autophagy-mediated MIR224 degradation both in vitro and in vivo. In summary, we identified amiodarone as a new autophagy inducer, which may provide an alternative approach in HCC therapy through a novel tumor suppression mechanism.


Single-molecule fluorescence studies on cotranscriptional G-quadruplex formation coupled with R-loop formation.
G-quadruplex (GQ) is formed at various regions of DNA, including telomeres of chromosomes and regulatory regions of oncogenes. Since GQ is important in both gene regulation and genome instability, the biological and medical implications of this abnormal DNA structure have been intensively studied. Its formation mechanisms, however, are not clearly understood yet. We report single-molecule fluorescence experiments to monitor the cotranscriptional GQ formation coupled with R-loop formation using T7 RNA polymerase. The GQ is formed very rarely per single-round transcription. R-loop formation precedes and facilitates GQ formation. Once formed, some GQs are extremely stable, resistant even to RNase H treatment, and accumulate in multiple-round transcription conditions. On the other hand, GQ existing in the non-template strand promotes the R-loop formation in the next rounds of transcription. Our study clearly shows the existence of a positive feedback mechanism of GQ and R-loop formations, which may possibly contribute to gene regulation and genome instability.


Global, regional, and national burdens of intraocular foreign bodies in children and adolescents from 1990 to 2019: a trend analysis.
This study aimed to evaluate trends in global, regional, and national burdens of intraocular foreign bodies among children and adolescents (aged 0 - 19 years) between 1990 and 2019 according to age, sex, and socio-demographic index. This study obtained data from the Global Burden of Disease Study 2019 and evaluated the number of cases, rates per 100,000 persons, and average annual percentage changes among children and adolescents. The annual percentage changes in the incidence and years lived with disability rates across various age groups were investigated using joinpoint software. For intraocular foreign bodies in children and adolescents, the incidence and year lived with disability rates decreased in all age groups between 1990 and 2019. However, the number of incident cases and years lived with disability increased from 1091.94 [95% uncertainty interval (UI), 610.91-1839.52] and 89,245 (95% UI, 6.65-18.67) in 1990 to 1134.85 (95% UI, 665.01-1867.50) and 92,108 (95% UI, 32,052-192,153) in 2019, respectively. Age was positively correlated with the number of cases, incidence, and years lived with disability rates. However, there were significant decreases in both the incidence and years lived with disability rates among children and adolescents, especially in the 15-18 years age group, males, and most high-income regions. Notably, the incidence and years lived with disability rates were significantly decreased in middle and high-middle socio-demographic index regions but were increased in low and low-middle socio-demographic index regions. Despite the remarkable progress between 1990 and 2019 in reducing the global burden of intraocular foreign bodies, there has been an increase in the number of cases, with substantial disparity across age groups, sexes, regions, and countries. Our results could inform more effective strategies for reducing the burden among children and adolescents.


Prevention of hyperglycemic signal pathways in metabolic syndrome carotid artery of rats.
Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor /insulin receptor substrate 1(IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Zucker fatty rats (8 weeks) were treated with vehicle (0.5 % methyl cellulose in physiological saline, p.o.), amlodipine (3 mg/kg/day, p.o.), atorvastatin (10 mg/kg/day, p.o.), or the combination of amlodipine plus atorvastatin (3 + 10 mg/kg/day, p.o.) for 28 days, and anti-insulin-like growth factor 1 (IGF-1)/IRS-1/PI3K/Akt pathways were evaluated. Our present immunohistochemical study first demonstrated that a combination of amlodipine plus atorvastatin treatment prevented an arteriosclerotic process compared to the single treatment with amlodipine or atorvastatin with strong recoveries of pTyr IRS-1, pPI3K, and pAkt expressions and with remarkable restraints of IGF-1 and pSer IRS-1. As a result, combination therapy with amlodipine plus atorvastatin showed a strong synergistic effect to prevent atherosclerotic processes. The present study newly suggests a synergistic benefit of combination therapy with amlodipine plus atorvastatin for strong prevention of atherosclerotic processes, which could reduce the clinical risk of cerebrovascular events for obesity patients.


CholecystokininB receptor from human Jurkat lymphoblastic T cells is involved in activator protein-1-responsive gene activation.
The aim of this study was to analyze the role of cholecystokinin (CCK(B)) receptor in human lymphoblastic Jurkat T cells. We investigated the trophic effect resulting from activation of such a receptor by using the reporter gene strategy. For this purpose, we transiently transfected Jurkat T cells with the reporter plasmid p[(TRE)3-tk-Luc] and found that CCK-8 was able to dose-dependently induce luciferase expression related to activator protein-1 (AP-1) activation with a maximal response identical to that obtained with compounds known to activate AP-1 complex (quantitatively, the same level of induction was obtained with 1 nM 12-O-tetradecanoylphorbol-13-acetate, 100 microM diacylglycerol, or 4 nM epidermal growth factor). The involvement of the CCK(B) receptor in such a stimulation was demonstrated by the inhibiting effect of the selective CCK(B) receptor antagonist PD-135,158. This effect was confirmed in COS-7 cells transfected with the cDNA of CCK(B) receptor cloned from Jurkat T cells. To better understand the AP-1-dependent luciferase expression in Jurkat T cells, we tested two specific inhibitors of serine/threonine phosphatases-1 and -2A: okadaic acid and calyculin A. These compounds strongly increased the phorbol-12-myristate-13-acetate response, whereas we have not observed a contribution of phosphatase inhibitors on a CCK-8-induced luciferase activity. To confirm that CCK(B) receptors are involved in AP-1 response, we investigated the CCK-8 effect on interleukin-2 expression, a natural endogenous gene regulated by several factors, including AP-1. In Jurkat T cells activated by phorbol-12-myristate-13-acetate and phytohemagglutinin, CCK-8 induced IL-2 expression. This induction was abolished by PD-135,158. Our results indicate that CCK-8 exerts a trophic effect in Jurkat T cells through stimulation of CCK(B) receptors by modulation of expression of AP-1-regulated genes.


The out-of-network benefit: problems and policy solutions.
Health insurance plans that include coverage for out-of-network providers are common and have the potential to reduce health care costs and even improve quality. Yet, consumers may be exposed to significant unexpected and unreasonable out-of-pocket costs due to lack of accurate information on network participation, nontransparent out-of-pocket costs, inadequate provider networks, involuntary use of out-of-network emergency care, and use of out-of-network providers at in-network hospitals. Although the Affordable Care Act and some states provide some consumer protections, these may not be adequate.


An endoglucanase, EglA, from the hyperthermophilic archaeon Pyrococcus furiosus hydrolyzes beta-1,4 bonds in mixed-linkage (1-->3),(1-->4)-beta-D-glucans and cellulose.
The eglA gene, encoding a thermostable endoglucanase from the hyperthermophilic archaeon Pyrococcus furiosus, was cloned and expressed in Escherichia coli. The nucleotide sequence of the gene predicts a 319-amino-acid protein with a calculated molecular mass of 35.9 kDa. The endoglucanase has a 19-amino-acid signal peptide but not cellulose-binding domain. The P. furiosus endoglucanase has significant amino acid sequence similarities, including the conserved catalytic nucleophile and proton donor, with endoglucanases from glucosyl hydrolase family 12. The purified recombinant enzyme hydrolyzed beta-1,4 but not beta-1,3 glucosidic linkages and had the highest specific activity on cellopentaose (degree of polymerization [DP] = 5) and cellohexaose (DP = 6) oligosaccharides. To a lesser extent, EglA also hydrolyzed shorter cellodextrins (DP < 5) as well as the amorphous portions of polysaccharides which contain only beta-1,4 bonds such as carboxymethyl cellulose, microcrystalline cellulose, Whatman paper, and cotton linter. The highest specific activity toward polysaccharides occurred with mixed-linkage beta-glucans such as barley beta-glucan and lichenan. Kinetics studies with cellooliogsaccharides and p-nitrophenyl-cellooligosaccharides indicated that the enzyme had three glucose binding subsites (-I, -II, and -III) for the nonreducing end and two glucose binding subsites (+I and +II) for the reducing end from the scissile glycosidic linkage. The enzyme had temperature and pH optima of 100 degreesC and 6.0, respectively; a half-life of 40 h at 95 degreesC; and a denaturing temperature of 112 degreesC as determined by differential scanning calorimetry. The discovery of a thermostable enzyme with this substrate specificity has implications for both the evolution of enzymes involved in polysaccharide hydrolysis and the occurrence of growth substrates in hydrothermal vent environments.


Advanced Respiratory Models for Hazard Assessment of Nanomaterials-Performance of Mono-, Co- and Tricultures.
Advanced in vitro models are needed to support next-generation risk assessment (NGRA), moving from hazard assessment based mainly on animal studies to the application of new alternative methods (NAMs). Advanced models must be tested for hazard assessment of nanomaterials (NMs). The aim of this study was to perform an interlaboratory trial across two laboratories to test the robustness of and optimize a 3D lung model of human epithelial A549 cells cultivated at the air-liquid interface (ALI). Potential change in sensitivity in hazard identification when adding complexity, going from monocultures to co- and tricultures, was tested by including human endothelial cells EA.hy926 and differentiated monocytes dTHP-1. All models were exposed to NM-300K in an aerosol exposure system (VITROCELL® cloud-chamber). Cyto- and genotoxicity were measured by AlamarBlue and comet assay. Cellular uptake was investigated with transmission electron microscopy. The models were characterized by confocal microscopy and barrier function tested. We demonstrated that this advanced lung model is applicable for hazard assessment of NMs. The results point to a change in sensitivity of the model by adding complexity and to the importance of detailed protocols for robustness and reproducibility of advanced in vitro models.


Trends in the Incidence and Mortality of Diabetes in China from 1990 to 2017: A Joinpoint and Age-Period-Cohort Analysis.
Background: The prevalence of diabetes mellitus is rapidly increasing in China, but the secular trends in incidence and mortality remain unknown. This study aims to examine time trends from 1990 to 2017 and the net age, period, and cohort effects on diabetes incidence and mortality. Methods: Incidence and mortality rates of diabetes (1990⁻2017) were collected for each 5-year age group (from 5⁻9 to 80⁻84 age group) stratified by gender from the Global Burden of Disease 2017 Study. The average annual percentage changes in incidence and mortality were analyzed by joinpoint regression analysis; the net age, period, and cohort effects on the incidence and mortality were estimated by age-period-cohort analysis. Results: The joinpoint regression analysis showed that age-standardized incidence significantly rose by 0.92% (95% CI: 0.6%, 1.3%) in men and 0.69% in women (95% CI: 0.3%, 1.0%) from 1990 to 2017; age-standardized mortality rates rose by 0.78% (95% CI: 0.6%, 1.0%) in men and decreased by 0.12% (95% CI: -0.4%, 0.1%) in women. For age-specific rates, incidence increased in most age groups, with exception of 30⁻34, 60⁻64, 65⁻69 and 70⁻74 age groups in men and 25⁻29, 30⁻34, 35⁻39 and 70⁻74 age groups in women; mortality in men decreased in the younger age groups (from 20⁻24 to 45⁻49 age group) while increased in the older age groups (from 50⁻54 to 80⁻84 age group), and mortality in women decreased for all age groups with exception of the age group 75⁻79 and 80⁻84. The age effect on incidence showed no obvious changes with advancing age while mortality significantly increased with advancing age; period effect showed that both incidence and mortality increased with advancing time period while the period trend on incidence began to decrease since 2007; cohort effect on incidence and mortality decreased from earlier birth cohorts to more recent birth cohorts while incidence showed no material changes from 1982⁻1986 to 2012⁻2016 birth cohort. Conclusions: Mortality decreased in younger age groups but increased in older age groups. Incidence increased in most age groups. The net age or period effect showed an unfavorable trend while the net cohort effect presented a favorable trend. Aging likely drives a continued increase in the mortality of diabetes. Timely population-level interventions aiming for obesity prevention, healthy diet and regular physical activity should be conducted, especially for men and earlier birth cohorts at high risk of diabetes.


Commentary: navigating the labyrinth of long-term care: shoring up informal caregiving in a home- and community-based world.
Informal caregivers face difficulties navigating the services and funding sources that constitute long-term care. Indeed, barriers to identifying and accessing even the most basic resources compound the sense of isolation felt by millions of unpaid individuals who provide the bulk of long-term care. Though expansion of home- and community-based options is welcomed, it may also shift additional caregiving burden onto an already overburdened informal care system, especially when the intention is to delay or substitute for institutional care. This essay argues that growing government emphasis on rebalancing long-term care away from nursing homes will founder unless public officials recognize increased burdens on the informal care system.


Electrocortical amplification for emotionally arousing natural scenes: the contribution of luminance and chromatic visual channels.
Emotionally arousing scenes readily capture visual attention, prompting amplified neural activity in sensory regions of the brain. The physical stimulus features and related information channels in the human visual system that contribute to this modulation, however, are not known. Here, we manipulated low-level physical parameters of complex scenes varying in hedonic valence and emotional arousal in order to target the relative contributions of luminance based versus chromatic visual channels to emotional perception. Stimulus-evoked brain electrical activity was measured during picture viewing and used to quantify neural responses sensitive to lower-tier visual cortical involvement (steady-state visual evoked potentials) as well as the late positive potential, reflecting a more distributed cortical event. Results showed that the enhancement for emotional content was stimulus-selective when examining the steady-state segments of the evoked visual potentials. Response amplification was present only for low spatial frequency, grayscale stimuli, and not for high spatial frequency, red/green stimuli. In contrast, the late positive potential was modulated by emotion regardless of the scene's physical properties. Our findings are discussed in relation to neurophysiologically plausible constraints operating at distinct stages of the cortical processing stream.


Individual Prediction of Optimal Treatment Allocation Between Electroconvulsive Therapy or Ketamine using the Personalized Advantage Index.
Introduction: Electroconvulsive therapy (ECT) and ketamine are two effective treatments for depression with similar efficacy; however, individual patient outcomes may be improved by models that predict optimal treatment assignment. Here, we adapt the Personalized Advantage Index (PAI) algorithm using machine learning to predict optimal treatment assignment between ECT and ketamine using medical record data from a large, naturalistic patient cohort. We hypothesized that patients who received a treatment predicted to be optimal would have significantly better outcomes following treatment compared to those who received a non-optimal treatment. Methods: Data on 2526 ECT and 235 mixed IV ketamine and esketamine patients from McLean Hospital was aggregated. Depressive symptoms were measured using the Quick Inventory of Depressive Symptomatology (QIDS) before and during acute treatment. Patients were matched between treatments on pretreatment QIDS, age, inpatient status, and psychotic symptoms using a 1:1 ratio yielding a sample of 470 patients (n=235 per treatment). Random forest models were trained and predicted differential patientwise minimum QIDS scores achieved during acute treatment (min-QIDS) scores for ECT and ketamine using pretreatment patient measures. Analysis of Shapley Additive exPlanations (SHAP) values identified predictors of differential outcomes between treatments. Results: Twenty-seven percent of patients with the largest PAI scores who received a treatment predicted optimal had significantly lower min-QIDS scores compared to those who received a non-optimal treatment (mean difference=1.6, t=2.38, q<0.05, Cohen's D=0.36). Analysis of SHAP values identified prescriptive pretreatment measures. Conclusions: Patients assigned to a treatment predicted to be optimal had significantly better treatment outcomes. Our model identified pretreatment patient factors captured in medical records that can provide interpretable and actionable guidelines treatment selection.


Silicon Nitride Background in Nanophotonic Waveguide Enhanced Raman Spectroscopy.
Recent studies have shown that evanescent Raman spectroscopy using a silicon nitride (SiN) nanophotonic waveguide platform has higher signal enhancement when compared to free-space systems. However, signal-to-noise ratio from the waveguide at a low analyte concentration is constrained by the shot-noise from the background light originating from the waveguide itself. Hence, understanding the origin and properties of this waveguide background luminescence (WGBL) is essential to developing mitigation strategies. Here, we identify the dominating component of the WGBL spectrum composed of a broad Raman scattering due to momentum selection-rule breaking in amorphous materials, and several peaks specific to molecules embedded in the core. We determine the maximum of the Raman scattering efficiency of the WGBL at room temperature for 785 nm excitation to be 4.5 ± 1 × 10-9 cm-1·sr-1, at a Stokes shift of 200 cm-1. This efficiency decreases monotonically for higher Stokes shifts. Additionally, we also demonstrate the use of slotted waveguides and quasi-transverse magnetic polarization as some mitigation strategies.


Preferential activation of iron regulatory protein-2 in cell lines as a result of higher sensitivity to iron.
Iron regulatory proteins (IRP)-1 and 2 are cytoplasmic mRNA-binding proteins that control intracellular iron homeostasis by regulating the translation of ferritin mRNA and stability of transferrin receptor mRNA in an iron-dependent fashion. Although structurally and functionally similar, the two IRP are different in their mode of regulation, pattern of tissue expression and modulation by multiple factors, such as bioradicals. In the present study RNA bandshift assays demonstrated that IRP-2, but not IRP-1, activity was higher in cultured cells than in tissues. Increased expression of IRP-2 in cell lines was not related to immortalization and differentiation but seemed associated to cell proliferation, although not closely dependent on cell growth rate. As a growing cell consumes more iron than its quiescent counterpart, we assessed the iron status of cell lines and found that ferritin content was lower than in tissues. Analysis of IRP activity in cell lines supplemented with heme or non-heme iron and in livers of iron-loaded and iron-deficient rats indicated that IRP-2 responds more promptly than IRP-1 to modulations of iron content. We propose that enhanced IRP-2 activity in cultured cells could be due to a proliferation-dependent, relative iron deficiency that is sensed first by IRP-2.


Crossmodal associations between visual textures and temperature concepts.
Visual textures are critical in how individuals form sensory expectations about objects, which include somatosensory properties such as temperature. This study aimed to uncover crossmodal associations between visual textures and temperature concepts. In Experiment 1 (N = 193), we evaluated crossmodal associations between 43 visual texture categories and different temperature concepts (via temperature words such as cold and hot) using an explicit forced-choice test. The results revealed associations between striped, cracked, matted, and waffled visual textures and high temperatures and between crystalline and flecked visual textures and low temperatures. In Experiment 2 (N = 247), we conducted six implicit association tests (IATs) pairing the two visual textures most strongly associated with low (crystalline and flecked) and high (striped and cracked) temperatures with the words cold and hot as per the results of Experiment 1. When pairing the crystalline and striped visual textures, the results revealed that crystalline was matched to the word cold, and striped was matched to the word hot. However, some associations found in the explicit test were not found in the IATs. In Experiment 3 (N = 124), we investigated how mappings between visual textures and concrete entities may influence crossmodal associations with temperature and these visual textures. Altogether, we found a range of association strengths and automaticity levels. Importantly, we found evidence of relative effects. Furthermore, some of these crossmodal associations are partly influenced by indirect mappings to concrete entities.