Tumor-Derived Biomarkers in Liquid Biopsy of Glioblastoma.
There is a pressing clinical need for minimally invasive liquid biopsies to supplement imaging in the treatment of glioblastoma. Diagnostic imaging is often difficult to interpret and the medical community is divided on distinguishing among complete response, partial response, stable disease, and progressive disease. A minimally invasive liquid biopsy would supplement imaging and clinical findings and has the capacity to be helpful in several ways: 1) diagnosis, 2) selection of patients for specific treatments, 3) tracking of treatment response, and 4) prognostic value. The liquid biome is the combination of biological fluids including blood, urine, and cerebrospinal fluid that contain small amounts of tumor cells, DNA/RNA coding material, peptides, and metabolites. Within the liquid biome, 2 broad categories of biomarkers can exist: tumor-derived, which can be directly traced to the tumor, and tumor-associated, which can be traced back to the response of the body to disease. Although tumor-associated biomarkers are promising liquid biopsy candidates, recent advances in biomarker enrichment and detection have allowed concentration on a new class of biomarker: tumor-derived biomarkers. This review focuses on making the distinction between the 2 biomarker categories and highlights promising new direction.


MCL1 regulates AML cells metabolism via direct interaction with HK2. Metabolic signature at onset predicts overall survival in AMLs' patients.
We characterize the metabolic background in distinct Acute Myeloid Leukemias (AMLs), by comparing the metabolism of primary AML blasts isolated at diagnosis with that of normal hematopoietic maturing progenitors, using the Seahorse XF Agilent. Leukemic cells feature lower spare respiratory (SRC) and glycolytic capacities as compared to hematopoietic precursors (i.e. day 7, promyelocytes). According with Proton Leak (PL) values, AML blasts can be grouped in two well defined populations. The AML group with blasts presenting high PL or high basal OXPHOS plus high SRC levels had shorter overall survival time and significantly overexpressed myeloid cell leukemia 1 (MCL1) protein. We demonstrate that MCL1 directly binds to Hexokinase 2 (HK2) on the outer mitochondrial membrane (OMM). Overall, these results suggest that high PL and high SRC plus high basal OXPHOS levels at disease onset, arguably with the concourse of MCL1/HK2 action, are significantly linked with shorter overall survival time in AML. Our data describe a new function for MCL1 protein in AMLs' cells: by forming a complex with HK2, MCL1 co-localizes to VDAC on the OMM, thus inducing glycolysis and OXPHOS, ultimately conferring metabolic plasticity and promoting resistance to therapy.


No boundaries: a 2 year experience in a specialized youth mental health care program in the Netherlands.
Young people around the age of 18 receiving mental health care usually face the transition from child and adolescent (CAMHS) to adult mental health services (AMHS) bringing the risk of disruption in continuity of care. Recognizing the importance of early intervention in this vulnerable life-period, this study aims to emphasize the importance of a client-centred approach and continuity of care for this age group. For a deeper understanding of the specific needs of this group, the working method of a Dutch youth mental health (YMH) team working in a secondary mental health care setting is described, including some clinical characteristics and treatment results of patients who accessed this service. Data consist of a detailed description of the working method of the YMH team combined with clinical characteristics of all patients aged 15-25 years accessing the services of the YMH team over a two-year period. The YMH team incorporated suggestions of earlier research into a client centred treatment. Key elements were multidisciplinary meetings, transcending diagnosis, flexibility and collaboration with other care providers. Clinical records showed a complex patient population and significant treatment effect. The group of emerging adults accessing the YMH team can be described as a patient group with a high diversity and complexity of disorders and problems. Continuity of care was met when patients turned 18, allowing treatments to be successfully performed by the same team of professionals using a client-centred approach.


An unusual complication of balloon tamponade in the treatment of esophageal varices: a case report and brief review of the literature.
A Sengstaken-Blakemore tube was unable to be withdrawn 14 h after its initial insertion. Despite a number of recognized maneuvers, both gastric and esophageal balloons remained inflated leading to impaction of the tube. This uncommon complication along with other complications peculiar to the Sengstaken-Blakemore tube are described.


Correlation between serum concentrations of three specific exocrine pancreatic proteins and pancreatic duct morphology at ERCP examinations.
The concentrations of pancreatic amylase, immunoreactive trypsin, and immunoreactive pancreatic specific trypsin inhibitor have been studied in serum drawn from 258 patients before an endoscopic retrograde cholangiopancreatography (ERCP) examination, in which both ducts were successfully filled. The results are correlated to the morphology of the ducts and the diagnosis given at the ERCP examination. One third of the patients with normal morphology of both ducts showed an abnormal concentration of at least one of the measured specific pancreatic proteins. Sixteen out of 38 patients with changes suggestive of chronic pancreatitis and 6 out of 23 patients with changes suggestive of pancreatic cancer showed normal levels of all variables measured. The sensitivity and specificity for pancreatic disease evident by ERCP were around 0.40 and 0.80, respectively, for all three proteins.


Monte Carlo Modeling of Dynamic Tumor Tracking on a Gimbaled Linear Accelerator.
The Vero4DRT (Brainlab AG) linear accelerator is capable of dynamic tumor tracking (DTT) by panning/tilting the radiation beam to follow respiratory-induced tumor motion in real time. In this study, the panning/tilting motion is modeled in Monte Carlo (MC) for quality assurance (QA) of four-dimensional (4D) dose distributions created within the treatment planning system (TPS). Step-and-shoot intensity-modulated radiation therapy plans were optimized for 10 previously treated liver patients. These plans were recalculated on multiple phases of a 4D computed tomography (4DCT) scan using MC while modeling panning/tilting. The dose distributions on each phase were accumulated to create a respiratory-weighted 4D dose distribution. Differences between the TPS and MC modeled doses were examined. On average, 4D dose calculations in MC showed the maximum dose of an organ at risk (OAR) to be 10% greater than the TPS' three-dimensional dose calculation (collapsed cone [CC] convolution algorithm) predicted. MC's 4D dose calculations showed that 6 out of 24 OARs could exceed their specified dose limits, and calculated their maximum dose to be 4% higher on average (up to 13%) than the TPS' 4D dose calculations. Dose differences between MC and the TPS were greatest in the beam penumbra region. Modeling panning/tilting for DTT has been successfully modeled with MC and is a useful tool to QA respiratory-correlated 4D dose distributions. The dose differences between the TPS and MC calculations highlight the importance of using 4D MC to confirm the safety of OAR doses before DTT treatments.


Evaluation of composting parameters, technologies and maturity indexes for aerobic manure composting: A meta-analysis.
Aerobic composting is an efficient method to recover nutrients from animal manure. However, there is considerable variability in the management and maturity criteria used across studies, and a systematic meta-analysis focused on compost maturity is currently lacking. This study investigated the optimal range of startup parameters and practical criteria for manure composting maturity, as well as the effectiveness of in situ technologies in enhancing composting maturity. Most maturity indexes were associated with composting GI, making it an ideal tool for evaluating the maturity of manure composts. GI increased with declined final C/N and (Final C/N)/(Initial C/N) (P < 0.01), and therefore a maturity assessment standard for animal manure composting was proposed: a mature compost has a C/N ratio ≤23 and a GI ≥70, while a highly mature compost has a GI ≥90 and preferably (Final C/N)/(Initial C/N) ≤0.8. Meta-analysis demonstrated that C/N ratio regulation, microbial inoculation and adding biochar and magnesium-phosphate salts are effective strategies for improving compost maturity. Specifically, a greater reduction in the C/N ratio during the composting process is beneficial for improving the maturity of compost product. The optimal startup parameters for composting have been determined, recommending an initial C/N ratio of 20-30 and an initial pH of 6.5-8.5. An initial C/N ratio of 26 was identified as the most suitable for promoting compost degradation and microorganism activity. The present results promoted a composting strategy for producing high-quality compost.


A study of beta-cell function after glucagon stimulation in thalassaemia major treated by high transfusion programme.
An increased incidence of diabetes mellitus and glucose intolerance has been reported in thalassaemia major treated with a high transfusion programme (HTP). To investigate beta-cell function, serum immunoreactive insulin (IRI), C-peptide (CP) and glucose were measured fasting and at 3, 6 and 10 min after i.v. administration of 1 mg glucagon in 20 thalassaemia patients treated by many transfusions and in nine healthy control subjects. Fasting C-peptide concentrations (mean +/- SEM) were higher in the thalassaemic group (2.15 +/- 0.17 ng/ml) than in the controls (1.41 +/- 0.13 ng/ml). After stimulation with glucagon, C-peptide concentrations were consistently higher (P less than 0.01) by approximately 50% in the thalassaemic than in the control group (5.29 +/- 0.31 vs 3.36 +/- 0.21 ng/ml, at 3 min; 5.22 +/- 0.30 vs 3.53 +/- 0.21 ng/ml at 6 min and 4.69 +/- 0.27 vs 3.30 +/- 0.17 ng/ml after 10 min). Plasma IRI concentrations increased in both groups after glucagon stimulation but were not significantly different. The glucose values were approximately 15% higher at each sampling time in the thalassaemic group than those of the normal subjects. It is concluded that disturbances in carbohydrate metabolism in thalassaemia major treated with HTP are the consequence of hepatic cirrhosis which accompanies secondary haemosiderosis, and possibly iron deposition in the beta-cells of the pancreas.


Heart rate variability measure in breast cancer patients and survivors: A systematic review.
In the current study, we aimed to review literature findings showing the clinical importance of cardiac autonomic modulation assessed by heart rate variability analysis in breast cancer (BC) patients and survivors. We conducted a systematic review according to The PRISMA Statement in Medline, Scopus and Web of Science (_-2015) databases. The search was limited to articles in English language, published in peer-reviewed journals, and with adult age samples only (e.g., women, patients, or survivors, diagnosed with BC in any stage). We included observational studies and randomized trials. Detailed heart rate variability analysis (instruments, data collection protocol, and analysis methods) was required. Search terms included autonomic nervous system, heart rate variability, sympathetic and parasympathetic nervous system, autonomic dysfunction, vagal nervous and breast neoplasms, breast cancer and breast tumor. Twelve studies were included in this review. The clinical importance of cardiac autonomic modulation assessed by heart rate variability analysis in BC patients and survivors is demonstrated by association with effects of BC surgery, and treatments, and the adverse effects of surgery and treatments on survivors (e.g., cardiotoxicity, fatigue, and stress). The strength of evidence of included studies is low: small samples size and heterogeneity, presence of confounders, and observational studies design. The heart rate variability analysis could be used as a complementary non-invasive tool for the early diagnosis and better prognosis of autonomic dysfunction, and survival in BC patients. There are many potential clinical applications of heart rate variability analysis in BC patients, and the employment of such approaches could lead to lower impairment of autonomic function in this individuals.


Mechanical ventilation characteristics and their prediction performance for the risk of moderate and severe bronchopulmonary dysplasia in infants with gestational age <30 weeks and birth weight <1,500 g.
Moderate and severe bronchopulmonary dysplasia (BPD) is a common pulmonary complication in premature infants, which seriously affects their survival rate and quality of life. This study aimed to describe the mechanical ventilation characteristics and evaluate their prediction performance for the risk of moderate and severe BPD in infants with gestational age <30 weeks and birth weight <1,500 g on postnatal Day 14. In this retrospective cohort study, 412 infants with gestational age <30 weeks and birth weight <1,500 g were included in the analysis, including 104 infants with moderate and severe BPD and 308 infants without moderate and severe BPD (as controls). LASSO regression was used to optimize variable selection, and Logistic regression was applied to build a predictive model. Nomograms were developed visually using the selected variables. To validate the model, receiver operating characteristic (ROC) curve, calibration plot, and clinical impact curve were used. From the original 28 variables studied, six predictors, namely birth weight, 5 min apgar score, neonatal respiratory distress syndrome (≥Class II), neonatal pneumonia, duration of invasive mechanical ventilation (IMV) and maximum of FiO2 (fraction of inspiration O2) were identified by LASSO regression analysis. The model constructed using these six predictors and a proven risk factor (gestational age) displayed good prediction performance for moderate and severe BPD, with an area under the ROC of 0.917 (sensitivity = 0.897, specificity = 0.797) in the training set and 0.931 (sensitivity = 0.885, specificity = 0.844) in the validation set, and was well calibrated (P Hosmer-Lemeshow test = 0.727 and 0.809 for the training and validation set, respectively). The model included gestational age, birth weight, 5 min apgar score, neonatal respiratory distress syndrome (≥Class II), neonatal pneumonia, duration of IMV and maximum of FiO2 had good prediction performance for predicting moderate and severe BPD in infants with gestational age <30 weeks and birth weight <1,500 g on postnatal Day 14.


Tumor location influences perioperative and oncologic outcomes in solitary intrahepatic cholangiocarcinoma following curative resection: a multi-center analysis.
To compare perioperative and oncologic outcomes of patients with different locations of intrahepatic cholangiocarcinoma (ICC). A total of 352 ICC patients underwent curative intent hepatectomy were included. Clinical outcomes were compared between ICC patients with tumors located at subcapsular and non-subcapsular, perihepatic vein (pHV) and non-pHV, or periportal vein (pPV) and non-pPV. Kaplan-Meier curves were used to evaluate the influence of tumor location on survival outcomes. Surgical procedures for pPV ICC were associated with longer operative time and elevated intraoperative blood loss compared to non-pPV. Patients with pPV ICC significantly correlated to increased frequency of log odds of positive lymph nodes (LODDS) classification 3-4. In addition, the ICC located at pPV was correlated with both worse overall survival (OS) and disease-free survival (DFS) compared to non-pPV, whereas no significant difference was observed between subcapsular and non-subcapsular or between pHV and non-pHV. A pPV location contributed to poor perioperative outcomes and quick tumor recurrence for patients with solitary ICC undergoing curative resection. A pPV location also contributed to regional lymph node metastases and was a risk factor for intrahepatic recurrence. Subcapsular and pHV locations did not influence clinical outcomes of ICC patients.


A novel resident-as-teacher training program to improve and evaluate obstetrics and gynecology resident teaching skills.
Residents play a significant role in teaching, but formal training, feedback, and evaluation are needed. Our aims were to assess resident teaching skills in the resident-as-teacher program, quantify correlations of faculty evaluations with resident self-evaluations, compare resident-as-teacher evaluations with clinical evaluations, and evaluate the resident-as-teacher program. The resident-as-teacher training program is a simulated, videotaped teaching encounter with a trained medical student and standardized teaching evaluation tool. Evaluations from the resident-as-teacher training program were compared to evaluations of resident teaching done by faculty, residents, and medical students from the clinical setting. Faculty evaluation of resident teaching skills in the resident-as-teacher program showed a mean total score of 4.5 ± 0.5 with statistically significant correlations between faculty assessment and resident self-evaluations (r = 0.47; p < 0.001). However, resident self-evaluation of teaching skill was lower than faculty evaluation (mean difference: 0.4; 95% CI 0.3-0.6). When compared to the clinical setting, resident-as-teacher evaluations were significantly correlated with faculty and resident evaluations, but not medical student evaluations. Evaluations from both the resident-as-teacher program and the clinical setting improved with duration of residency. The resident-as-teacher program provides a method to train, give feedback, and evaluate resident teaching.


Cloning and expression of the gene coding for the transmission blocking target antigen Pfs48/45 of Plasmodium falciparum.
The gene encoding the gametocyte/gamete-specific membrane protein Pfs48/45 of Plasmodium falciparum has been cloned. The Pfs48/45 gene is a non-interrupted, single copy gene that codes for a hydrophobic, non-repetitive protein of 448 amino acid residues containing a putative signal peptide at the N-terminus, a hydrophobic C-terminus and 7 potential N-glycosylation sites. Antibodies directed against a Pfs48/45-glutathione-S-transferase fusion protein reacted with both the 45-kDa and 48-kDa proteins of gametocytes. When Pfs48/45 is expressed in the baculovirus-insect cell system the recombinant Pfs48/45 protein is targeted and exposed to the insect cell surface in such a configuration that it is recognized by transmission-blocking anti-45/48-kDa monoclonal antibodies.


Possible involvement of folate cycle in the pathogenesis of amyotrophic lateral sclerosis.
The folate cycle, which has a close correlation with nucleic acid synthesis as well as with sulfur amino acid metabolism, may have some bearing on the pathogenesis of amyotrophic lateral sclerosis. The folate cycle hypothesis offers a unified explanation of the reduction of RNA and the elevation of taurine in nervous tissue of this disease.


Mitochondrial and chloroplast genomes of maize have a 12-kilobase DNA sequence in common.
A 12-kilobase DNA sequence has been identified in the maize mitochondrial genome which is homologous to part of the inverted repeat of the maize chloroplast genome. In chloroplasts the sequence contains a 16S rRNA gene, and also the coding sequences for tRNAIle and tRNAVal. Mitochondrial DNA from the male-sterile cytoplasms of maize is altered in this region.


Post-mastectomy pain syndrome: incidence and risks.
Post-mastectomy pain syndrome is defined as a chronic pain that persists beyond the normal healing time of 3 months. It is considered a neuropathic condition that arises after surgery for breast cancer. To evaluate the incidence and risk factors of pain syndromes in patients undergoing surgical treatment of breast cancer in the National Cancer Institute. This study is a prospective cohort of women undergoing surgical treatment for breast cancer from September 2008 to June 2009, followed up until 6 months postoperatively. One hundred seventy-four women were examined. The mean age was 58 years. The incidence of pain syndrome was 52%. Younger women (<40 years) and those who were submitted to axillary lymph node dissection (with more than 15 lymph nodes excised) have shown a significantly increased risk of pain syndrome after surgery for breast cancer (relative risk (RR) =5.23 95% confidence interval (CI): 1.11-24.64) and (RR=2.01 95% CI: 1.08-3.75).


Trends in COVID-19-Related Medication Use in US Nursing Homes, 2018-2022.
Little is known about how COVID-19 treatment patterns have evolved over time in nursing homes (NHs) despite the devastating effects of COVID-19 in this setting. The aim was to describe changes in COVID-19-related medication use over time among NH residents in the United States. Retrospective cohort study. This study used electronic health records (EHR) from 11 different US NH corporations between January 1, 2018, and March 31, 2022. The use of medications approved for COVID-19-related conditions or known to be used off-label for COVID-19 during the study period is identified. We described trends in the use of each drug and combined use per 1000 NH residents over calendar time [quarters (Q)]. A total of 59,022 unique residents with the use of an eligible medication were identified. Hydroxychloroquine use sharply increased from 9.8 in 2020Q1 to 30.2 orders per 1000 individuals in 2020Q2. Dexamethasone use increased sharply from 14.8 in 2020Q2 to a peak of 121.9 orders per 1000 individuals in 2020Q4. Azithromycin use increased from 44.1 in 2019Q3 to a peak of 99.9 orders per 1000 individuals in 2020Q4, with a drop in 2020Q3 of 51.3 per 1000 individuals in 2020Q3. Concurrent use of azithromycin and hydroxychloroquine increased sharply from 0.3 in 2020Q1 to 10.6 orders per 1000 residents in 2020Q2 and then drastically decreased to 0.6 per 1000 residents in 2020Q3. Concurrent use of dexamethasone and azithromycin rose considerably from 0.7 in 2020Q2 to 28.2 orders per 1000 residents in 2020Q4. As in other settings, COVID-19-related medication use in NHs appears to have changed in response to the shifting evidence base and availability of medications during the pandemic. Providers should continue to diligently modify their prescribing as new evidence accrues.


Human monoclonal antibodies reactive with colon carcinoma: identification by a novel screening procedure with xenografts.
To identify tumor-associated antigens immunogenic to man, human monoclonal antibodies (MAbs) were generated by fusing regional lymph node lymphocytes (LNLs) of each of three colon adenocarcinoma patients with the M5 mouse myeloma cell line. Heterohybridomas in 19 wells secreted human immunoglobulin (Ig) for at least 60 days. To identify immunoreactive MAbs, we devised an immunohistochemical assay with xenografts of six colon tumors. Binding was visualized with a biotin-conjugated goat antihuman Ig antibody followed by an avidin-biotin-peroxidase complex. This assay detected binding with a sensitivity of 0.5 microgram/ml human Ig. Reactivity against tumor-associated antigens (TAAs) in frozen sections of the colon xenografts was detected in 14 of the 19 supernates. However, only nine (three IgGs, five IgMs and one IgA) were reactive against formalin-fixed sections, showing that formalin-fixation destroyed some but not all antigenicity. Four MAbs were cloned and tested against the entire panel of 19 xenografts. One IgM MAb reacted only against colon carcinomas, while the other three (one each of IgA, IgG and IgM) had broader reactivities. Three of the four human MAbs did not cross-react with melanomas. In summary, human regional lymph nodes contain a high proportion of B lymphocytes sensitized to the autochthonous tumor. Immunostaining of human colon tumor xenografts can readily identify human MAbs reactive with colon carcinomas.


Microsatellite Instability (MSI) as an Independent Predictor of Pathologic Complete Response (PCR) in Locally Advanced Rectal Cancer: A National Cancer Database (NCDB) Analysis.
The relationship between microsatellite instability (MSI) and response to neoadjuvant chemoradiation in rectal cancer is not well understood. We utilized the National Cancer Database (NCDB) to investigate the association between MSI and pathologic complete response (pCR) in this patient population. We analyzed 5086 patients between 2010 and 2015 with locally advanced rectal cancer who were tested for MSI and treated definitively with chemoradiation followed by surgery. Primary comparison groups were between 4450 MSI-negative(-) and 636 MSI-positive(+) patients. Multivariable regression analysis was conducted to identify demographic, therapeutic, and clinical characteristics predictive of pCR. Cox proportional-hazard ratios were used for survival. All patients were treated with definitive chemoradiation (median dose 50.4 Gy) followed by resection within 4 months. MSI(+) patients were associated with earlier year of diagnosis and higher-grade tumors (P < 0.05).The overall pCR rate was 8.6%, including 8.9% for MSI(-) and 5.9% for MSI(+) tumors (P = 0.01). Along with lower T stage, MSI(+) cases were significantly associated with a reduced pCR rate (odds ratio 0.65, 95% confidence interval 0.43-0.96) with multivariable analysis. The 5-year survival for patients with pCR was 93% compared with 73% without it (<0.001). Microsatellite instability was independently associated with a reduction in pCR for locally advanced rectal cancer after neoadjuvant chemoradiation in this NCDB-based analysis.


Outside-In Frontal Drill-Out: How I Do It.
The Draf 3 frontal sinusotomy, or modified Lothrop procedure has been used to treat recalcitrant rhinosinusitis, frontal sinus mucocoeles or to provide access for cerebrospinal fluid leaks, frontoethmoid fractures, frontal sinus tumors and skull base tumors. To describe authors approach to the "Outside-In Frontal Drill-Out". Descriptive. The "Outside-In" frontal drill-out is an approach that emphasizes the early identification of the first olfactory neuron, maximization of bone removal, and preservation of the posterior table mucosa. The advantages of this approach are it provides unobstructed view and identifies anatomic limits early, bone removal is fast and efficient; it is safe, and it is a robust technique based upon fixed anatomic landmarks.


Peripheral blood lymphocyte counts in patients with infectious mononucleosis or chronic active Epstein-Barr virus infection and prognostic risk factors of chronic active Epstein-Barr virus infection.
To explore the peripheral blood lymphocyte counts and analyze the prognostic risk factors for the death in patients with chronic active Epstein-Barr virus (CAEBV) infection. Clinical data of 64 patients infected with CAEBV (CAEBV group) and 64 patients with infectious mononucleosis (IM group) in our hospital were retrospectively analyzed. Meanwhile, 64 healthy individuals came for physical examination were enrolled in the control group. The three groups were compared for white blood cell count, lymphocyte count, and levels of peripheral blood NK cells, B cells, CD3+, CD4+, CD8+, CD4+CD28+, CD8+CD28+, CD4+CD25+, DR+CD8+, CD38+CD8+, CD4+ and CD8+ naive T cells and subsets of memory T cells. Patients infected with CAEBV were further divided into a survival subgroup and a death subgroup according to the survival outcome. The data were processed using univariate analysis and multivariate logistic regression analysis. Compared with the control group, the IM group had higher levels of white blood cell count, lymphocyte count, CD3+, CD4+, CD8+, CD4+CD25+, DR+CD8+, CD38+CD8+, effector-memory CD4+CD62L-CD45RO+ and effector-memory CD8+CD62L-CD45RO+, but lower levels of NK cells, B cells, CD4+CD28+, CD8+CD28+, naive CD4+CD62L+CD45RA+ and naive CD8+CD62L+CD45RA+ (all P<0.05). Compared with the control group, the CAEBV group had lower levels of white blood cell count, lymphocyte count, CD3+, CD4+, CD8+, NK cells, B cells, CD4+CD28+, CD8+CD28+, naive CD4+CD62L+CD45RA+ and naive CD8+CD62L+CD45RA+, but higher levels of CD4+CD25+, DR+CD8+, CD38+CD8+, effector-memory CD4+CD62L-CD45RO+ and effector-memory CD8+CD62L-CD45RO+ (all P<0.05). Univariate analysis and multivariate logistic regression analysis showed that EBV DNA>105 copies/mL, platelet count <50×1012/L, albumin <30 g/L and serum ferritin >5000 μg/L were independent risk factors for the death of patients with CAEBV. Patients infected with CAEBV showed imbalance of lymphocyte subsets and immune dysfunction. EBV DNA>105 copies/mL, platelet count <50×1012/L, albumin <30 g/L and serum ferritin >5000 μg/L are risk factors of death in patients with CAEBV.


The contributions of allergic sensitization and respiratory pathogens to asthma inception.
Of the chronic diseases affecting grade-school children, asthma is the most common and accounts for the greatest number of school days missed. Moreover, it can influence family dynamics and function in other ways, and unfortunately, it can also be associated with mortality, particularly in the inner-city environments of the United States. Thus understanding factors that lead to its development in early life is essential in developing strategies aimed at primary prevention. Two risk factors that have been identified by a number of investigators include the development of allergic sensitization and wheezing respiratory tract illnesses caused by viruses and bacteria, either alone or in combination. Both of these factors appear to exert their influences within the first few years of life, such that asthma becomes established before the child enters grade school at age 5 to 6 years. Therefore, because both allergic sensitization and viral and bacterial illnesses can occur in children who do not have asthma, it is paramount to identify genetic and environmental factors that activate, interact with, and/or direct the immune system and components of the respiratory tract along pathways that allow asthma to become established and expressed clinically.


The physical and psychiatric health conditions related to autism genetic scores, across genetic ancestries, sexes and age-groups in electronic health records.
Although polygenic scores (PGS) for autism have been related to various psychiatric and medical conditions, most studies to date have been conducted in research ascertained populations. We aimed to identify the psychiatric and physical conditions associated with autism PGS in a health care setting. We computed PGS for 12,383 unrelated participants of African genetic ancestry (AF) and 65,363 unrelated participants of European genetic ancestry (EU) from Vanderbilt's de-identified biobank. Next, we performed phenome wide association studies of the autism PGS within these two genetic ancestries. Seven associations surpassed the Bonferroni adjusted threshold for statistical significance (p = 0.05/1374 = 3.6 × 10-5) in the EU participants, including mood disorders (OR (95%CI) = 1.08(1.05 to 1.10), p = 1.0 × 10-10), autism (OR (95%CI) = 1.34(1.24 to 1.43), p = 1.2 × 10-9), and breast cancer (OR (95%CI) = 1.09(1.05 to 1.14), 2.6 × 10-5). There was no statistical evidence for PGS-phenotype associations in the AF participants. Conditioning on the diagnosis of autism or on median body mass index (BMI) did not impact the strength of the reported associations. Although we observed some sex differences in the pattern of associations, there was no significant interaction between sex and autism PGS. Finally, the associations between autism PGS and autism diagnosis were stronger in childhood and adolescence, while the associations with mood disorders and breast cancer were stronger in adulthood. Our findings indicate that autism PGS is not only related to autism diagnosis but may also be related to adult-onset conditions, including mood disorders and some cancers. Our study raises the hypothesis that genes associated with autism may also increase the risk for cancers later in life. Future studies are necessary to replicate and extend our findings.


missForest with feature selection using binary particle swarm optimization improves the imputation accuracy of continuous data.
Missing data are a common problem in large-scale datasets and its appropriate handling is crucial for data analyses. Missingness can be categorized as (1) missing completely at random (MCAR), (2) missing at random (MAR), and (3) missing not at random (MNAR). Different missingness mechanisms require different imputation strategies. Multiple imputation, an approach for averaging outcomes across multiple imputed data, is more suitable than single imputation for dealing with various missing mechanisms. missForest, a nonparametric missing value imputation strategy using random forest, is one of the most prevalent multiple imputation methods for missing-data because it can be applied to mixed-type data and does not require distributional assumptions. However, a recent study found that missForest can produce biased results for non-normal data. In addition, missForest is computationally expensive. Therefore, we aimed to further develop the missForest algorithm by combining a binary particle swarm optimization (BPSO)-based feature-selection strategy. The BPSO is an evolutionary algorithm that is well known for global optimization and computational efficiency. By using the BPSO-based feature selection step prior to imputing missing values with missForest, the imputation accuracy for continuous variables could be increased by pruning redundant variables. In this study, missForest with BPSO (BPSOmf) showed better imputation accuracy than missForest alone with respect to continuous variables by feature selection prior to the imputation step. BPSOmf is an appropriate and robust method when the imputation target data consist mainly of continuous variables.


Recovered memory experience in a nonclinical sample is associated with dissociation rather than with aversive experiences.
Different hypotheses exist for the relationship among trauma, dissociation, and recovered memory. According to one view, recovered memory results from dissociation that a survivor adopts as a defense mechanism during a traumatizing event to avoid emotional pain. From this perspective, trauma is a necessary antecedent to relate dissociative symptoms with recovered memory. Another view emphasizes the characteristics of the victim, such as fantasy proneness and atypical cognitive operations. This alternate view holds that trauma is not necessary in relating dissociation to recovered memory. We tested these two hypotheses, measuring recovered memory, dissociative symptoms, childhood interpersonal adversity, and fantasy proneness in a nonclinical sample of college students. Our results showed a significant correlation between recovered memory and dissociative symptoms; the correlation cannot be accounted for by childhood interpersonal adversity, fantasy proneness, or absorption. Recovered events can be negative, neutral, or even positive. Trauma is not necessary in relating recovered memory to dissociative symptoms.


Triamcinolone acetonide-loaded lipid nanocapsules for ophthalmic applications.
Triamcinolone acetonide (TA) is an effective drug widely (off-label) used in the treatment of several ocular diseases involving inflammation and angiogenic processes. However, the use of TA ocular presents some limitations mainly related to its excipient composition, as in the case of benzyl alcohol. Thus, the aim of this work was to obtain an alternative TA formulation based on lipid nanocapsules (LNCs). Triamcinolone acetonide-loaded lipid nanocapsules (TA-LNCs) were obtained by the phase inversion temperature process without the use of irritating excipients, by combining lipids and surfactants generally recognized as safe. Pre-formulation studies were carried out to evaluate the TA solubility in different co-surfactants and to optimize the lipid core composition in order to enhance the drug loading and encapsulation rate in the LNCs. A stable final TA-LNC formulation was obtained with a mean particle size (MPS) of below 50 nm, a narrow size distribution (PDI < 0.2), a negative zeta potential (ZP) and a high encapsulation efficiency (%EE > 98%). In vitro cellular viability assays revealed that blank LNCs and TA-LNCs at 0.1 µg/mL did not affect the viability of the human corneal epithelial (HCE) cells. TA-LNCs showed a high anti-inflammatory activity below the toxicity level, with a reduction of 30% in interleukin (IL)-6 secretion observed in an in vitro model using the same cell line. More importantly, the TA-LNCs revealed a therapeutic efficacy in the endotoxin-induced uveitis (EIU) rabbit model with a significant attenuation of clinical signs of an inflammatory response. These findings make the TA-LNCs a safer and more efficient alternative for the treatment of eye disorders.


Changes in positive and negative peer influences and depressive symptoms from adolescence to young adulthood.
Peers are believed to continue as prominent sources of influence for young adults. However, having peers who use alcohol and drugs is associated with depressive symptoms in young adults and research on the effects of having peers who model positive activities beyond adolescence is scarce. In this 10-year study of 644 Canadian youth (52% female), we used multilevel modeling to examine the effects of within-person and between-person differences in the interplay of peer behaviours and changes in depressive symptoms between ages 14 and 25. Data were collected via face-to-face interviews and surveys for private topics. Youth with close friends who used drugs and alcohol consistently reported more depressive symptoms at each age, whereas having friends who engaged in positive activities was associated with fewer depressive symptoms, especially during adolescence. Moreover, at times when youth had more substance-using peers than usual (within person variation), they also reported more symptoms. Substance-using peer contexts convey both short- and long-term risks for depressive symptoms. However, the protective effects of having peers who are engaged in positive activities, while generally protective, may be reduced in young adulthood. It is possible that older youth withdraw from peers and activities as their depression worsens, and prosocial activities become less supervised by parents, more optional, and more expensive.


Increased expression in erythrocytic Ii antigens in sickle cell disease and sickle cell trait.
The reactivity of human erythrocytes with anti-I and anti-i sera was estimated in 36 normal adults, 18 individuals with sickle cell anemia and 27 individuals with sickle cell trait, by quantitative hemagglutination with a sensitive autoanalyzer system. SS erythrocytes showed significantly increased I and i reactivity when compared to normal erythrocytes. AS erythrocytes also demonstrated some increase in Ii reactivity. No correlation was found between erythrocytic HbF content and i reactivity.


Survivorship and Etiologies of Failure in Single-stage Revision Arthroplasty for Periprosthetic Joint Infection: A Meta-analysis.
Single-stage revision arthroplasty for periprosthetic joint infection (PJI) may yield comparable infection-free survivorship with two-stage revision arthroplasty. It is unclear if the most common mode of failure of single-stage revision arthroplasty is infection or aseptic loosening. In this meta-analysis, we sought to (1) determine survivorship and (2) compare rates of different etiologies of failure of single-stage revision total hip arthroplasty (THA) and total knee arthroplasty (TKA). Preferred Reporting Items for Systematic Review and Meta-analyses guidelines search was done using search terms for "single stage revision," "exchange arthroplasty," "periprosthetic infection," "PJI," and "single stage." Patient demographics such as age, body mass index, and mean follow-up time were recorded. Overall survivorship and rates of revision surgery were aggregated using a random-effects model. Comparison of septic and aseptic loosening rates was done by risk difference and associated 95% confidence interval (CI) calculation. Twenty-four studies were identified with 2,062 and 147 single-stage revision THA and TKA procedures performed between 1984 and 2019, respectively. The weighted mean follow-up and age were 69.8 months and 66.3 years, respectively, with 55% men overall. The all-cause revision surgery rate was 11.1% and 11.8% for THA and TKA, respectively. The revision surgery rate secondary to infection and aseptic loosening and associated 95% CI for the risk difference for THA and TKA was 5.5% and 3.3% (-1.7% to 5.0%), and 3% and 8.8% (-11.4% to 2.3%), respectively. Revision surgeries due to instability and fracture combined and mortality rate were both less than 3%. Single-stage revision THA and TKA for PJI demonstrated overall high rates of survivorship, low mortality, and revision surgeries secondary to infection and aseptic loosening to be equivalent. Aseptic loosening after single-stage revision TKA might be higher than in primary TKA. As implant survivorship from infection improves in PJI, surgeons should be aware of aseptic loosening as an equally common mode of failure.


A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma.
The CS1 antigen provides a unique target for the development of an immunotherapeutic strategy to treat patients with multiple myeloma (MM). This study aimed to identify HLA-A2(+) immunogenic peptides from the CS1 antigen, which induce peptide-specific cytotoxic T lymphocytes (CTL) against HLA-A2(+) MM cells. We identified a novel immunogenic HLA-A2-specific CS1(239-247) (SLFVLGLFL) peptide, which induced CS1-specific CTL (CS1-CTL) to MM cells. The CS1-CTL showed a distinct phenotype, with an increased percentage of effector memory and activated CTL and a decreased percentage of naïve CTL. CS1(239-247) peptide-specific CD8(+) T cells were detected by DimerX analyses and demonstrated functional activities specific to the peptide. The CTL displayed HLA-A2-restricted and antigen-specific cytotoxicity, proliferation, degranulation and γ-interferon (IFN-γ) production against both primary MM cells and MM cell lines. In addition, the effector memory cells subset (CD45RO(+) CCR7(-) /CD3(+) CD8(+) ) within CS1-CTL showed a higher level of CD107a degranulation and IFN-γ production as compared to effector cells (CD45RO(-) CCR7(-) /CD3(+) CD8(+) ) against HLA-A2(+) primary MM cells or MM cell lines. In conclusion, this study introduced a novel immunogenic HLA-A2-specific CS1(239-247) peptide capable of inducing antigen-specific CTL against MM cells that will provide a framework for its application as a novel MM immunotherapy.


Birth Weight Gradient in Parent-Reported Special Healthcare Needs among Children Born Preterm.
To characterize the association of birth weight with parent-reported special healthcare needs (SHCN) and unmet healthcare needs among children born prematurely. We analyzed data from the 2016-2017 National Survey of Children's Health. Prematurity, birth weight, SHCN, and unmet healthcare needs were reported for one child per participating household. We analyzed children age 0-5 years, and classified birthweight among children born preterm as very low birth weight (VLBW, <1500 g), low birth weight (LBW, 1500-2500 g), and normal weight (NBW, >2500 g). Term-born NBW children were included as a reference group. The analysis included 190 VLBW preterm, 688 LBW preterm, 884 NBW preterm, and 15 629 NBW term-born children. Weighted SHCN prevalence was 10%, and 1% had unmet healthcare needs. On multivariable analysis, children born preterm and VLBW had significantly higher odds of SHCN compared with NBW term-born children (OR, 9.8; 95% CI, 4.9-19.6). Preterm LBW and NBW preterm groups had smaller increases in SHCN odds (OR, 2.5 and OR, 1.6, respectively). The odds of unmet healthcare needs did not differ among the 4 study groups. Among children under 5 years of age, preterm birth and VLBW are associated with very high likelihood of SHCN, compared with LBW/NBW preterm or NBW term-born children. However, requirements for additional health services in this group were adequately met, according to caregiver report.


Truncated titin proteins in dilated cardiomyopathy.
Truncating variants in TTN (TTNtvs) are the most common known cause of nonischemic dilated cardiomyopathy (DCM), but how TTNtvs cause disease has remained controversial. Efforts to detect truncated titin proteins in affected human DCM hearts have failed, suggesting that disease is caused by haploinsufficiency, but reduced amounts of titin protein have not yet been demonstrated. Here, we leveraged a collection of 184 explanted posttransplant DCM hearts to show, using specialized electrophoretic gels, Western blotting, allelic phasing, and unbiased proteomics, that truncated titin proteins can quantitatively be detected in human DCM hearts. The sizes of truncated proteins corresponded to that predicted by their respective TTNtvs; the truncated proteins were encoded by the TTNtv-bearing allele; and no degradation fragments from protein encoded by either allele were detectable. In parallel, full-length titin was less abundant in TTNtv+ than in TTNtv− DCM hearts. Disease severity or need for transplantation did not correlate with TTNtv location. Transcriptomic profiling revealed few differences in splicing or allelic imbalance of the TTN transcript between TTNtv+ and TTNtv− DCM hearts. Studies with isolated human adult cardiomyocytes revealed no defects in contractility in cells from TTNtv+ compared to TTNtv− DCM hearts. Together, these data demonstrate the presence of truncated titin protein in human TTNtv+ DCM, show reduced amounts of full-length titin protein in TTNtv+ DCM hearts, and support combined dominant-negative and haploinsufficiency contributions to disease.


Early local tetanus: does tetanus toxin change the stimulus evoked discharge in afferents from the injected muscle?
1. Tetanus toxin was injected into gastrocnemius muscles of cats and for 24 h its action on nerve condution of muscle afferents was investigated. 2. During this period stimulus threshold and latency remained constant. No signs of fatigue were observed.


13C Natural Abundance of Serum Retinol Is a Novel Biomarker for Evaluating Provitamin A Carotenoid-Biofortified Maize Consumption in Male Mongolian Gerbils.
Crops such as maize, sorghum, and millet are being biofortified with provitamin A carotenoids to ensure adequate vitamin A (VA) intakes. VA assessment can be challenging because serum retinol concentrations are homeostatically controlled and more sensitive techniques are resource-intensive. We investigated changes in serum retinol relative differences of isotope amount ratios of (13)C/(12)C (δ(13)C) caused by natural (13)C fractionation in C3 compared with C4 plants as a biomarker to detect provitamin A efficacy from biofortified (orange) maize and high-carotene carrots. The design was a 2 × 2 × 2 maize (orange compared with white) by carrot (orange compared with white) by a VA fortificant (VA+ compared with VA-) in weanling male Mongolian gerbils (n = 55), which included a 14-d VA depletion period and a 62-d treatment period (1 baseline and 8 treatment groups; n = 5-7/group). Liver VA and serum retinol were quantified, purified by HPLC, and analyzed by GC combustion isotope ratio mass spectrometry for (13)C. Treatments affected liver VA concentrations (0.048 ± 0.039 to 0.79 ± 0.24 μmol/g; P < 0.0001) but not overall serum retinol concentrations (1.38 ± 0.22 μmol/L). Serum retinol and liver VA δ(13)C were significantly correlated (R(2) = 0.92; P < 0.0001). Serum retinol δ(13)C differentiated control groups that consumed white maize and white carrots (-27.1 ± 1.2 δ(13)C‰) from treated groups that consumed orange maize and white carrots (-21.6 ± 1.4 δ(13)C‰ P < 0.0001) and white maize and orange carrots (-30.6 ± 0.7 δ(13)C‰ P < 0.0001). A prediction model demonstrated the relative contribution of orange maize to total dietary VA for groups that consumed VA from mixed sources. Provitamin A efficacy and quantitative estimation of the relative contribution to dietary VA were demonstrated with the use of serum retinol δ(13)C. This method could be used for maize efficacy or effectiveness studies and with other C4 crops biofortified with provitamin A carotenoids (e.g., millet, sorghum). Advantages include no extrinsic tracer dose, 1 blood sample, and higher sensitivity than serum retinol concentrations alone.


Migraine and allergy: a review and clinical update.
Migraine and allergy are both common diseases. Many patients suffer from both, and the vast majority of patients with "sinus headache" complaints are found to have migraine, making migraine identification important to allergists. This review addresses the possibility that allergy and migraine are comorbid conditions, focusing on epidemiology, shared biochemical pathways, and underlying mechanisms. Therapeutic implications of this possible relationship have been the subject of several recent studies, making a review of this association timely and prudent.


Electrophoretic analyses of myofibrillar proteins from the body wall muscles of Ascaris suum.
A myofibrillar protein extract has been isolated from the muscle of Ascaris suum. Two-dimensional electrophoresis of this extract revealed that the myosin light chain 1 (ALC1) migrates as 3 components with approximate isoelectric points in the range of 5.3-5.6. The most acidic component of ALC1 appeared to be phosphorylated when the myofibrillar extract was incubated for 10 s with catalytic subunit of cAMP dependent protein kinase and [gamma-32P] ATP. The myosin light chain 2 (ALC2) migrated as a single component in isoelectric focusing with an approximate isoelectric point of 5.5 Actin was resolved into 2 components with identical molecular weight but isoelectric points differing by approximatley 0.2 pH units. A protein was tentatively identified in the myofibrillar extract as tropomyosin. It migrated as a single band with an approximate isoelectric point of 5.0 and a molecular weight of 39 000. None of the troponin components could be identified in the myofibrillar extract. It is postulated that muscle contraction in A. suum muscle could be controlled by phosphorylation of myosin.


Analysis of the main risk factors for gestational diabetes diagnosed with International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria in multiple pregnancies.
The aim is to investigate the proportion of multiple pregnancies with gestational diabetes mellitus (GDM) diagnosed using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria and to identify the impact of age, body mass index (BMI), and mode of conception on incidence of GDM. This is a single center, retrospective cohort study on 656 multiple pregnancies screened for GDM with 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation, between January 2010 and January 2016. The diagnosis of gestational diabetes mellitus (GDM) was reached through the IADPSG. The incidence of GDM in our population was 15.1%. When patients who conceived through heterologous assisted reproduction technology were compared with those who conceived spontaneously, there was a significant difference for GDM (31.1 vs 13.6%, p < 0.001, OR 2.86). A similar finding was also observed comparing egg donation IVF/ICSI patients with homologous IVF/ICSI patients (31.1 vs 14.8%, p = 0.006, OR 2.59). Incidence of GDM was significantly higher in obese than in non-obese patients (42.5 vs 14.8%, p < 0.001, OR 4.88) and in women over 35 compared to younger patients (18.4 vs 11.1%, p = 0.01, OR 1.81). Logistic regression comparing the diabetes onset with conception mode gave a p = 0.07. The calculation of the Chi-square and odds ratio for single mode of conception showed that homologous vs conceived spontaneously p = 0.90, OR 0.97, heterologous vs homologous p = 0.01 with OR 2.46, and heterologous vs conceived spontaneously p = 0.01 with OR 2.39. Logistic regression showed that age and BMI are risk factors for developing GDM, respectively, p = 0.03 with OR 1.4 and p < 0.01 and OR 1.09. The contribution our study can make is improved counseling about GDM risks for couples with multiple pregnancies. Our data support the role of age, BMI, and mode of conception as risk factors for GDM in multiple pregnancies.


Two-species mixture of quantum degenerate Bose and Fermi gases.
We have produced a macroscopic quantum system in which a 6Li Fermi sea coexists with a large and stable 23Na Bose-Einstein condensate. This was accomplished using interspecies sympathetic cooling of fermionic 6Li in a thermal bath of bosonic 23Na. The system features rapid thermalization and long lifetimes.


Hemispheric asymmetry emerges at distinct parts of the occipitotemporal cortex for objects, logograms and phonograms: a functional MRI study.
Behavioral and neuropsychological studies have suggested that the right hemisphere has a special advantage in the visual recognition of logograms. While this long-standing 'right hemisphere hypothesis' has never been investigated systematically by previous neuroimaging studies, a candidate neural substrate of such asymmetry might be found within the occipitotemporal cortex that is known to exhibit lateralized response to a certain class of stimuli, such as letters and faces. The present study examined the hemispheric specialization of brain activation during naming of objects, logograms and phonograms using functional magnetic resonance imaging. The three types of stimuli overall produced left-predominant activation of the perisylvian and inferior parietal regions relative to the resting baseline. This inter-hemispheric difference was significant irrespective of the stimuli type. In the occipitotemporal cortex, six subregions showing lateralized response were identified. That is, the three stimuli commonly produced left-lateralized response in the posterior fusiform and superior temporal gyri and right-lateralized response in the extrastriate cortex. Only logograms and objects produced a distinct cluster showing right-lateralized activation in the medial anterior fusiform gyrus associated with semantic knowledge, whereas only phonograms produced a left-lateralized activation in the posterior middle temporal cortex close to the site associated with visual perception of alphabetical letters. These findings suggest that while these stimuli similarly recruit the left perisylvian language area as a common neural component for naming, processing of objects and logograms becomes left-lateralized only in the downstream of the occipitotemporal cortex. By contrast, visual processing of phonograms is specialized to the left hemisphere in earlier stages of the area. The present data provide further evidence suggesting that both the left-right and anterior-posterior axes of the occipitotemporal cortex are differentially tuned according to the specific features of visual stimuli.


The role of qualification and quality management in the prescription of antipsychotics and potentially inappropriate medication (PIM) in nursing home residents in Germany: results of the HIOPP-3-iTBX study.
Nursing home residents (NHR) show high rates of polypharmacy. The HIOPP-3-iTBX study is the first cRCT on medication optimization in nursing homes (NH) in Germany. The intervention did not result in a reduction of PIM and/or antipsychotics. This analysis looks at structure quality in the HIOPP-3-iTBX study participants. Evaluation of structure quality as part of a cluster-randomized controlled intervention study. Structure quality in multiprofessional teams from n = 44 NH (n = 44 NH directors, n = 91 family doctors (FD), and n = 52 pharmacies with n = 62 pharmacists) was assessed using self-designed questionnaires at baseline. Main aspects of the questionnaires related to the qualification of participants, quality management, the medication process and size of the facilities. All completed questionnaires were included. number of PIM/antipsychotics was drawn from the baseline medication analysis in 692 NHR. Data were analyzed by descriptive statistics and mixed model logistic regression. The presence of a nurse with one of the additional qualifications pain nurse or Zertifiziertes Curriculum (Zercur) Geriatrie in the participating NH was associated with a lower risk for the prescription of PIM/antipsychotics. No association between any characteristic in the other participants at baseline was observed. The results support the known role of nursing qualification in the quality and safety of care. Further studies need to look more closely at how use is made of the additional qualifications within the multiprofessional teams. Perspectively, the results can contribute to the development of quality standards in NH in Germany.


Determination of lamivudine-resistant variants of hepatitis B virus by denaturing gradient gel electrophoresis: a novel approach to monitoring drug resistance.
A DGGE-based assay for hepatitis B virus (HBV) drug-resistance monitoring was designed and checked for feasibility. It detects mutations within the YMDD motif related to lamivudine resistance. The YMDD motif of HBV polymerase was amplified by the set of primers designed in this study. DGGE analysis of the amplicons was performed on 9% polyacrylamide gels containing a 20-40% gradient of urea plus formamide and electrophoresis was performed. DNA sequencing was performed using a standard protocol. Based on the DGGE pattern of previously sequenced HBV variants, a reference ladder consisting of bands was constructed within and near the YMDD motif of HBV with excellent resolution. The genotypes of all the fragments included in the ladder were confirmed by sequencing after DGGE analysis. The flexibility of DGGE was demonstrated by the ability to add more bands to the migration ladder when new variants were discovered during the analysis of patient specimens. Clinical samples from HBV-infected patients were also used to demonstrate the performance of this approach. This preliminary feasibility study of HBV drug-resistance monitoring by means of DGGE shows the potential advantage of this approach for low-cost screening for viral drug resistance in clinical settings. The presented example can be extended to detect other mutations related to drug resistance in the HBV genome as well as other viruses.


Glycine immunoreactivity localized in the cochlear nucleus and superior olivary complex.
Polyclonal antibodies were made in rabbits against glycine conjugated to bovine serum albumin with glutaraldehyde and were used for immunocytochemical studies in the cochlear nucleus and superior olivary nucleus of the guinea-pig. Antibodies selective for glycine were prepared by affinity chromatography. By dot-blot analysis this preparation showed a strong recognition of glycine conjugates and relatively little recognition of conjugates of most other amino acids tested. However, there was a significant reaction with conjugates of alanine and beta-alanine, and this cross-reaction could not be removed by affinity chromatography without eliminating the preparation's recognition of glycine. The affinity-purified preparation showed only a weak recognition of conjugates of gamma-aminobutyrate (GABA) which was detectable at high concentrations of primary antibody. Immunocytochemical studies showed several intensely staining cell bodies in the cochlear nucleus and superior olivary complex. Most immunoreactive cell bodies in the cochlear nucleus were in the dorsal cochlear nucleus, being present in both the superficial and deep layers. Scattered immunoreactive cells were present in the ventral cochlear nucleus. Intense staining of cell bodies was seen in the medial nucleus of the trapezoid body, and these cells appear to correspond to the principal cells of that nucleus. Punctate labelling, suggestive of immunoreactive presynaptic terminals, was also apparent, particularly in the ventral cochlear nucleus and lateral superior olive. In the ventral cochlear nucleus, immunoreactive puncta were found around unlabeled cell bodies, at times nearly covering the perimeter of the cell. A population of glycine-immunoreactive cell bodies in the superficial dorsal cochlear nucleus also labeled with anti-GABA antibodies as determined through double-labeling studies. However, glycine-positive cells in the deep dorsal cochlear nucleus were not labeled with anti-GABA antibodies, and some populations of GABA-positive cells in the superficial layers were not labeled with anti-glycine antibodies. In the hippocampus intense staining of cell bodies and puncta was seen with anti-GABA antibodies while essentially no staining was seen with anti-glycine antibodies. These results suggest that anti-glycine antibodies can be useful for immunocytochemical identification of glycinergic neurons. From this study several populations of putative glycinergic neurons are identified in the auditory nuclei of the brain stem using these antibodies. Some populations of GABA-containing neurons also contain high levels of glycine or a related molecule.


Areola-nipple perception threshold to faradic electricity: a new measure of sensibility of the breasts.
We describe a new method to study the sensibility of the nipple-areola complex of the breast with faradic electricity delivered through an electromyographic device used to monitor peripheral nerve conduction. The objective results of faradic pulses (2-50 mA per pulse) delivered to the nipple-areola complex of the breast through a Nihon-Kohden II machine (Evoked potential/Electromyographs, Nihon-Kohden Co., Japan) were evaluated in normal volunteers to get a basal measure that was defined by the patient as "a soft electric discharge." The measures were recorded and their output discharges averaged (at least 5 to each complex). Twenty-eight volunteers with normal breasts, 28 patients with breast hypertrophy before and after breast reduction, and 28 patients before and after breast augmentation were studied. The faradic pulses were perceived from 1.5 to 3.5 mA in the areola and from 3 to 5.5 mA in the nipple in the control group and from 4.5 to 7.0 mA in the areola and from 6.5 to 9.5 mA in the nipple in the breast hypertrophy group with no significant changes before and after surgery. In the breast augmentation group the faradic pulses were very similar to the volunteers that had normal breasts, but 13 months after breast augmentation with silicone gel prosthesis, a difference was found because all the patients had a higher threshold and three cases had lost sensibility of the nipple-areola complex. In normal breasts the areola had a lower threshold for faradic pulses compared to the nipple. Hypertrophic breasts had a higher threshold to the faradic stimulation than normal subjects in the pre- and postoperative period. Hypoplastic breasts before breast augmentation had a perception threshold similar to that of the normal volunteers but after breast augmentation this perception was much higher.


Growth and refuge location in continuous, modular organisms: experimental and computer simulation studies.
Guilds of crustose bryozoans exhibited a range of growth outlines, varying from circular to elongate, and the stones on which they grew contained a range of refuge types, varying in size from a few mm2 to a few hundred cm2. These refuges, if encountered by the growing colonies of competitively subordinate species such as Electra pilosa L., enabled the latter to avoid competitive exclusion due to overgrowth mortality. Computer simulations suggested that, although modular organisms which are elongate are, in general, more likely to encounter spatial refuges than those with a different shape through vegetative growth, shape is less important than the size of the organisms themselves or the size and density of the spatial refuges. Moreover significant interactions between these 4 variables showed that they should be considered together and not in isolation from one another. Examples are given of variable growth forms in continuous, modular organisms from different taxa, including plants, and the importance of these predictive studies to refuge location by modular organisms is discussed.


Peripheral injection of ghrelin induces Fos expression in the dorsomedial hypothalamic nucleus in rats.
Peripheral ghrelin has been shown to act as a gut-brain peptide exerting a potent orexigenic effect on food intake. The dorsomedial nucleus of the hypothalamus (DMH) is innervated by projections from other brain areas being part of the network of nuclei controlling energy homeostasis, among others NPY/AgRP-positive fibers arising from the arcuate nucleus (ARC). The aim of the study was to determine if peripherally administered ghrelin affects neuronal activity in the DMH, as assessed by Fos expression. The number of Fos positive neurons was determined in the DMH, paraventricular nucleus of the hypothalamus (PVN), ARC, ventromedial hypothalamic nucleus (VMH), nucleus of the solitary tract (NTS) and in the area postrema (AP) in non-fasted Sprague-Dawley rats in response to intraperitoneally (ip) injected ghrelin (3 nmol/rat) or vehicle (0.15 M NaCl). Peripheral ghrelin induced a significant increase in the number of Fos-ir positive neurons/section compared with vehicle in the ARC (mean+/-SEM: 49+/-2 vs. 23+/-2 neurons/section, p=0.001), PVN (69+/-5 vs. 34+/-3, p=0.001), and DMH (142+/-5 vs. 83+/-5, p<0.001). Fos-ir positive neurons were mainly localized within the ventral part of the DMH. No change in Fos expression was observed in the VMH (53+/-8 vs. 48+/-6, p=0.581), NTS (42+/-2 vs. 40+/-3, p=0.603), and in the AP (7+/-1 vs. 5+/-1, p=0.096). Additional double-labelling with anti-Fos and anti-AgRP revealed that Fos positive neurons in the DMH were encircled by a network of AgRP-ir positive fibers. These data indicate that peripheral ghrelin activates DMH neurons and that NPY-/AgRP-positive fibers may be involved in the response.


Modeling of highway stormwater runoff.
Highways are stormwater intensive landuses since they are impervious and have high pollutant mass emissions from vehicular activity. Vehicle emissions include different pollutants such as heavy metals, oil and grease, particulates from sources such as fuels, brake pad wear and tire wear, and litter. To understand the magnitude and nature of the stormwater emissions, a 3-year study was conducted to quantify stormwater pollutant concentrations, mass emission rates, and the first flush of pollutants. Eight highway sites were monitored over 3 years for a large suite of pollutants. The monitoring protocol emphasized detecting the first flush and quantifying the event mean concentration. Grab and flow-weighted composite samples, rainfall, and runoff data were collected. A new runoff model with four parameters was developed that to describe the first flush of pollutants for a variety of rainfall and runoff conditions. The model was applied to more than 40 events for 8 pollutants, and the parameters were correlated to storm and site conditions, such as total runoff, antecedent dry days, and runoff coefficient. Improved definitions of first flush criteria are also presented.


Mechanical Circulatory Support Therapy in the Cardiac Intensive Care Unit.
Mechanical circulatory support (MCS) includes temporary and durable mechanical devices used for two sets of indications: 1. acute heart failure (HF) secondary sepsis, a myocardial infarction, or pulmonary emboli, and 2. for chronic end-stage HF secondary to worsening cardiomyopathy despite guideline driven medical treatment. This article is to aide cardiac intensive care unit (ICU) nurses in understanding the history of MCS therapy, the care of the MCS patient in the cardiac ICU, the critical and collaborative role of transplant teams with MCS therapy, educational needs for a successful discharge, and implications for education and shared decision-making when placing these devices.


Peritoneal dialysis as therapeutic option in heart failure patients.
Each episode of acute decompensated heart failure (HF) incrementally adds to mortality. Peritoneal dialysis (PD) offers an alternative therapeutic option in refractory HF and reduces the incidence of decompensation episodes. The objective of this study was to determine the efficacy of PD, in terms of functional status, surrogate endpoints, rate of hospitalizations, and mortality. This study is based on the registry of the German Society of Nephrology, involving 159 patients receiving PD treatment due to refractory HF between January 2010 and December 2014. Body weight was reduced by PD (82.2 ± 14.9 to 78.4 ± 14.8 kg, P < 0.001), and significant improvements in New York Heart Association functional class (3.38 ± 0.55 to 2.85 ± 0.49, P < 0.001) were found already after 3 months. Left ventricular ejection fraction did not change (31.5 ± 13.8 to 34.0 ± 15.7%, P = 0.175). C-reactive protein improved with PD treatment (33.7 ± 52.6 to 17.1 ± 26.3 mg/L, P = 0.004). Blood urea nitrogen/creatinine ratio decreased significantly (148.7 ± 68.3 to 106.7 ± 44.8 mg/dL, P < 0.001). Hospitalization rates decreased significantly (total number 2.86 ± 1.88 to 1.90 ± 1.78, P = 0.001, and 39.2 ± 30.7 to 27.1 ± 25.2 days, P = 0.004). One year mortality was 39.6% in end-stage HF patients treated with PD. Peritoneal dialysis offers an additional therapeutic option in end-stage HF and is associated with improved New York Heart Association classification and reduced hospitalization. Although PD treatment was associated with various benefits, further studies are necessary to identify which patients benefit the most from PD.


Amitriptyline: sex-dependent effect on sympathetic response and anxiety in rats submitted to early maternal separation and variable chronic stress in adulthood.
The aim of the present study was to determine the effects of chronic treatment with the antidepressant amitriptyline on sympathetic nervous system activity and anxiety in male and female rats submitted to maternal separation (MS) and variable chronic stress (VCS). We observed that the treatment with amitriptyline produced a significant increase in norepinephrine (NE) plasma levels in non-maternally separated (NMS), non-stressed (NVCS) males in relation to vehicle-treated males, whereas in females the antidepressant produced a significant decrease in epinephrine (E) and NE when compared to the vehicle-treated group. In NMS/VCS males, amitriptyline produced a significant increase in the time spent on the open arms (TIME) in relation to the vehicle-treated group. In NMS/VCS females, amitriptyline produced a significant increase in TIME when compared to males. MS/VCS females showed a significant increase in the number of entries into the open arms (ENTRIES) in relation to males with the same treatment. This result suggests that there is a dimorphic response in coping with physical or emotional stressful situations and that amitriptyline acts in a differential way, being more effective in females.


Imaging findings in pediatric patients with persistent airway symptoms after surgery for double aortic arch.
The purpose of this study was to review the imaging findings of children referred for cross-sectional imaging to evaluate persistent airway symptoms after surgical therapy for double aortic arch. Airway narrowing is clearly shown on cross-sectional imaging in patients with persistent airway symptoms after surgical therapy for double aortic arch. Two patterns of airway compression are typically seen: narrowing of the trachea at the level of the postsurgical arch and narrowing of the left main bronchus as a result of compression from a midline descending aorta. Both patterns may be seen in patients regardless of whether the left or the right arch has been ligated.


Acute and chronic effects of diazepam on the polychaete Hediste diversicolor: Antioxidant, metabolic, pharmacologic, neurotoxic and behavioural mechanistic traits.
Pharmaceutical drugs are widespread environmental contaminants, but data about their adverse effects are still limited to a few compounds. This study analyzed the acute (96 h) and chronic (28 days) impacts of environmentally realistic levels of diazepam (acute exposure: 0.001, 0.01, 0.1, 1, 10 μg/L; chronic exposure: 0.1, 1, 10, 100, 1000 ng/L), in the polychaete Hediste diversicolor, by measuring behavioral and biochemical (catalase [CAT], glutathione-S-transferases [GSTs], cholinesterases [ChEs], glutathione peroxidase [GPx], lipid peroxidation [TBARS]) parameters. Acute exposure to diazepam altered behavioral traits, decreasing burrowing times and causing hyperactivity, whilst burrowing time increased and hypoactivity resulted after chronic exposure. All biomarkers were affected after the chronic exposure, with the exception of lipid peroxidation. Our data demonstrate that realistic levels of diazepam may impair behavioral and biochemical traits in polychaetes, suggesting that diazepam exposure presents a significant challenge to the environment that supports these organisms.


The Antibiotic Cement Bead Rouleaux: A Technical Trick to Maximize the Surface Area to Volume Ratio of Cement Beads to Improve the Elution of Antibiotics.
The use of antibiotic-impregnated cement as a local antibiotic delivery system is well-established as an adjunctive treatment for chronic osteomyelitis. Because the elution of antibiotics is a surface area phenomenon, the geometry of the cement is an important consideration. The antibiotic cement bead rouleaux technique is a simple and efficient method of bead fabrication that requires only 10 minutes of preparation time and readily available operating room supplies. The discoid structure of the beads provides 3 times the surface-area-to-volume ratio of a spherical bead, which facilitates antibiotic elution. Given the speed and ease of fabrication, along with optimized geometry, the antibiotic cement bead rouleaux is a useful addition to the surgeon's repertoire.


Effect of short-term low molecular weight heparin on patency following successful salvage of arteriovenous access with recurrent thrombosis.
This study aims to investigate the effect of low molecular weight heparin (LMWH) in maintaining the patency of arteriovenous (AV) access with recurrent thrombosis. Following successful thrombectomy, 66 patients with recurrent thrombosis were included in the study. The primary, assisted primary and secondary patency rates of patients who received LMWH (n = 24) were compared with those who did not receive anticoagulant (n = 42) using Kaplan-Meier analysis. Cox-regression analysis was performed to investigate potential predictors of patency rates. The mean dose of enoxaparin used was 40 ± 13.1 mg or 0.74 ± 0.2 mg/kg daily for a median duration of 14 (IQR 7,28) days. The mean trough anti-Xa concentrations measured after two doses of LMWH was 0.17 ± 0.13 IU/mL. Kaplan-Meier analyses for mean primary, assisted primary and secondary patency rates of LMWH vs no anticoagulation groups were 149 (95% CI: 91 - 207) vs 87 (95% CI: 42-132) days (P < .006), 230 (95% CI: 142-320) vs 107 (95% CI: 62-150) days (P = .01) and 438 (299-579) vs 294 (95% CI: 197-392) days (P = .08) respectively. LMWH remained a significant protective predictor of primary (HR: 0.49; 95% CI: 0.25-0.86; P = .02) and assisted primary patency rates (HR: 0.51; 95% CI: 0.27-0.98; P = .04) after adjusting for patient age, access age, type of AV access, presence of peripheral vascular disease and haemoglobin levels. LMWH may improve short and mid-term patency rates for AV accesses with recurrent thrombosis.


Characterisation of Leishmania isolates from Laikipia District, Kenya.
Using cloned kDNA sequences from the reference strain of Leishmania tropica IC-067, we have screened leishmanial isolates from Laikipia District of Kenya and identified these isolates as L. tropica. One isolate, IC-331, from a rat (Rattus rattus) was typed as L. tropica. This is the first time that L. tropica has been isolated from a wild rodent in Kenya and thus the first indication that the disease caused by L. tropica might be a zoonosis. The leishmanial isolates, especially those of sandflies, display extensive heterogeneity, prompting a need for selecting local and/or regional reference strains to generate species-specific DNA probes for use in identifying field isolates.


A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia.
The cilium is a microtubule-based organelle that contains a unique complement of proteins for cell motility and signalling functions. Entry into the ciliary compartment is proposed to be regulated at the base of the cilium. Recent work demonstrated that components of the nuclear import machinery, including the Ran GTPase and importins, regulate ciliary entry. We hypothesized that the ciliary base contains a ciliary pore complex whose molecular nature and selective mechanism are similar to those of the nuclear pore complex. By microinjecting fluorescently labelled dextrans and recombinant proteins of various sizes, we characterize a size-dependent diffusion barrier for the entry of cytoplasmic molecules into primary cilia in mammalian cells. We demonstrate that nucleoporins localize to the base of primary and motile cilia and that microinjection of nucleoporin-function-blocking reagents blocks the ciliary entry of kinesin-2 KIF17 motors. Together, this work demonstrates that the physical and molecular nature of the ciliary pore complex is similar to that of the nuclear pore complex, and further extends functional parallels between nuclear and ciliary import.


Ethylene induced cotton leaf abscission is associated with higher expression of cellulase (GhCel1) and increased activities of ethylene biosynthesis enzymes in abscission zone.
Ethylene induced cotton (Gossypium hirsutum var RST-39) leaf abscission has been characterized by measuring the activities of ACC synthase (ACS, E.C. 220.127.116.11), ACC oxidase (ACO, E.C. 126.96.36.199) and cellulase (E.C. 188.8.131.52). In addition, a leaf abscission specific cDNA (GhCel1) has been cloned from cotton, which belongs to the alpha(2) subgroup of cellulases that possess a C-terminus carbohydrate-binding domain. Measurement of enzyme activity in the abscission zones of cotton leaf explants exposed to ethylene for 48h compared to non-treated controls indicated a more than 5-fold increase in the activity of ACS, 1.2-fold increase in the activity of ACO and about 2.7-fold increase in the activity of cellulase in the ethylene treated explants. This increase was accompanied by a substantial decrease in the force required to separate the petiole from the stem (break strength) and an increased accumulation of cellulase transcript in the abscission zone. Treatment of explants with 1-Methylcyclopropene (1-MCP) prior to ethylene resulted in significant inhibition of enzyme activities and transcript accumulation. It is concluded that ethylene response of cotton leaf abscission leads to higher cellulase expression and increased activities of ethylene biosynthesis enzymes in the abscission zone.


Food intake control and RNA content of hypothalamic neurons in infant rats.
The influence of glycerol, glucose and lysine administration on the total RNA content in individual neurons of the ventromedial hypothalamus (VMH) and lateral hypothalamus area (LHA) in infant male rats was studied. Sixty minutes after administration, the total RNA content of the VMH neurons significantly decreased--from 13th day after glycerol and from 17th day after the glucose and lysine administration. The total RNA content of LHA neurons significantly increased from 17th day after glycerol and glucose and on 25th day after lysine administration. The noted changes of the RNA content, and especially the changes of the RNA proportion in these hypothalamic regions are well corresponding with the onset of the hypophagic effect of glycerol, glucose and amino acids in infant rats. The oppositional changes of the RNA content of VMH and LHA neurons are in conformity with the different role of these hypothalamic centers in food intake control.


The Relationship Between Central Drusen Volume and Low-Luminance Deficit in Age-Related Macular Degeneration.
To determine the relationship between central drusen volume and low-luminance deficit (LLD) in visual acuity (VA) in patients with intermediate age-related macular degeneration (AMD). In this cross-sectional study, 42 patients with intermediate AMD underwent testing for VA and low-luminance VA (LLVA), as well as spectral-domain optical coherence tomography. LLD was calculated as the difference between VA and LLVA. Central drusen volume was measured in the central 3 mm of the macula, defined as the volume between the inner border of the retinal pigment epithelium and Bruch's membrane. Mean ± standard deviation (SD) LLD was 0.32 ± 0.12 logMAR and mean ± SD drusen volume was 0.18 ± 0.09 mm3. No linear relationship was identified between central 3 mm drusen volume and LLD (P = 0.215). R2 for the bivariate linear model was 0.038 (95% confidence interval 0-0.222). Limitation of the analysis to drusen volumes measured in the central 1 mm of the macula did not impact results (R2 = 0.075), nor did incorporation of lens status into the model (R2 = 0.067) or censoring of patients with nonfoveal subretinal drusenoid deposits (R2 = 0.071). The amount of drusen within the central 3 mm of the macula does not appear to be related to LLD in intermediate AMD. These measures may be manifestations of different underlying pathophysiological mechanisms. Understanding relationships between markers for AMD progression may help guide development of improved clinical grading scales for AMD.


Noxa1 as a moderate activator of Nox2-based NADPH oxidase.
Noxa1 was discovered as an activating factor for Nox1, an O(2)(-)-generating enzyme. Subsequent studies have shown that Noxa1 is colocalized with Nox2 in several cell types, including vascular cells. Nox2 activation by Noxa1 has been examined in reconstituted model cells. However, little is known about the kinetic properties of Noxa1 in Nox2 activation. In the present study, we used purified cyt.b(558) (Nox2 plus p22(phox)), Rac(Q61L), and Noxo1 to examine the ability of Noxa1 to activate Nox2. In the pure reconstitution system, Noxa1 activated Nox2 with lower efficiency than p67(phox), a canonical activator of Nox2. The EC(50) value of Noxa1 was considerably higher than that of p67(phox). The V(max) value with Noxa1 and Noxo1 was one-third of that with p67(phox) and p47(phox). The EC(50) value of Noxo1 or Rac(Q61L) was also higher when Noxa1 was used. The affinity of FAD for the oxidase and the stability of the active complex were remarkably low when Noxa1 and Noxo1 were used compared with p67(phox) and p47(phox). The stability was not improved by fusion of Noxa1 with Rac(Q61L). These findings show that Noxa1 has quite different kinetic properties from p67(phox) and suggest that Noxa1 may function as a moderate activator of Nox2.


Correlated insulator of excitons in WSe2/WS2 moiré superlattices.
A panoply of unconventional electronic states has been observed in moiré superlattices. Engineering similar bosonic phases remains, however, largely unexplored. We report the observation of a bosonic correlated insulator in tungsten diselenide/tungsten disulfide (WSe2/WS2) moiré superlattices composed of excitons, that is, tightly bound electron-hole pairs. We develop a pump probe spectroscopy method that we use to observe an exciton incompressible state at exciton filling νex = 1 and charge neutrality, indicating a correlated insulator of excitons. With varying charge density, the bosonic correlated insulator continuously transitions into an electron correlated insulator at charge filling νe = 1, suggesting a mixed correlated insulating state between the two limits. Our studies establish semiconducting moiré superlattices as an intriguing platform for engineering bosonic phases.


Comparison of anatomic and functional results after retinotomy for retinal detachment in pediatric and adult patients.
We investigated characteristics and treatment outcomes of pediatric vs adult retinal detachment managed by retinotomy and retinectomy. This was a retrospective, nonrandomized, interventional study involving 20 pediatric patients and 25 adult patients operated with vitrectomy and retinectomy due to retinal detachment. Outcome measures included preoperative and postoperative visual acuity at 6 months and at final visit, postoperative proliferative vitreoretinopathy, silicone oil removal, final intraocular pressure (IOP), and final anatomic success, defined as complete retinal reattachment. Reattachment was observed in 60% (12/20) of pediatric patients and 88% (22/25) of adults at final visit (p=0.041). Statistically significant improvement in visual acuity was observed in adults (p<0.001) but not in children (p=0.360) due to large proportion of anatomic failure. Children required a higher number of further reoperations (p=0.008). Postoperative proliferative vitreoretinopathy was significantly more frequent in pediatric eyes (p=0.003). The clinical features and prognosis for pediatric retinotomies and retinectomies are different from those for adults. When a decision to perform retinotomy in children is made, we can anticipate significantly lower anatomic success than in adults. Even though the overall visual acuity was worse in children than in adults, 25% of pediatric eyes achieved 5/50 or better vision.


Resilience in Times of Economic Boom and Bust: A Narrative Study of a Rural Population Dependent upon the Oil and Gas Industry.
How do residents of small towns that depend on oil and gas extraction or processing industries withstand economic boom and bust cycles? To answer this question, this article reports on a narrative analysis of residents' life stories gathered from 37 adults of a small town on the Canadian prairies dependent on the oil and gas industry, employing the theories of narrative inquiry and narrative identity. Participants aged 30 to 76 were interviewed and their experiences of living in an unstable economy that is dependent mostly on a single resource extraction industry were explored. Specifically, we asked participants about the effect of economic change on factors related to resilience like family interactions, work choices, educational pathways, and the quality of their social lives. Our analysis of adult narratives looked for patterns in the relationship between risk exposure, promotive and protective factors at multiple systemic levels (individual, relational, cultural), and functional outcomes such as individual coping, community cohesion, and social and economic sustainability. Results show that a strong identity, in particular expressions of personal agency, communion, and engagement in meaning making are contributing factors to adult resilience in a context of economic change. Our results also highlight how positive attitudes towards a better future may inadvertently undermine the need for residents of oil and gas-dependent towns to commit to economic diversification and other potential resilience-promoting strategies.


Brisk walking can be a maximal effort in heart failure patients: a comparison of cardiopulmonary exercise and 6 min walking test cardiorespiratory data.
Cardiopulmonary exercise test (CPET) and 6 min walking test (6MWT) are frequently used in heart failure (HF). CPET is a maximal exercise, whereas 6MWT is a self-selected constant load test usually considered a submaximal, and therefore safer, exercise, but this has not been tested previously. The aim of this study was to compare the cardiorespiratory parameters collected during CPET and 6MWT in a large group of healthy subjects and patients with HF of different severity. Subjects performed a standard maximal CPET and a 6MWT wearing a portable device allowing breath-by-breath measurement of cardiorespiratory parameters. HF patients were grouped according to their CPET peak oxygen uptake (peakV̇O2 ). One hundred and fifty-five subjects were enrolled, of whom 40 were healthy (59 ± 8 years; male 67%) and 115 were HF patients (69 ± 10 years; male 80%; left ventricular ejection fraction 34.6 ± 12.0%). CPET peakV̇O2 was 13.5 ± 3.5 mL/kg/min in HF patients and 28.1 ± 7.4 mL/kg/min in healthy subjects (P < 0.001). 6MWT-V̇O2 was 98 ± 20% of the CPET peakV̇O2 values in HF patients, while 72 ± 20% in healthy subjects (P < 0.001). 6MWT-V̇O2 was >110% of CPET peakV̇O2 in 42% of more severe HF patients (peakV̇O2 < 12 mL/kg/min). Similar results have been found for ventilation and heart rate. Of note, the slope of the relationship between V̇O2 at 6MWT, reported as a percentage of CPET peakV̇O2 vs. 6MWT V̇O2 reported as the absolute value, progressively increased as exercise limitation did. In conclusion, the last minute of 6MWT must be perceived as a maximal or even supramaximal exercise activity in patients with more severe HF. Our findings should influence the safety procedures needed for the 6MWT in HF.


Plasma 1,25 hydroxycholecalciferol concentrations and net intestinal calcium, phosphate and magnesium absorption in man.
We evaluated the relationship between plasma concentrations of the renal hormone (I,25(OH)2 vitamin D and net intestinal CA,PO4 and Mg absorption in healthy volunteers eating similar diets. Net intestinal CA absorption was positively correlated to plasma I,25(OH)2D concentrations. By contrast, there was no significant correlation between PO4 and Mg absorption and plasma I,25(OH)2D concentrations. We conclude that net intestinal Ca absorption is critically dependent upon the availability of renal homone, while other factors must play a dominant role in regulating net intestinal PO4 and MG absorption.


Epigenetic regulation of soluble guanylate cyclase (sGC) β1 in breast cancer cells.
Soluble guanylate cyclase (sGC) is a heterodimer composed of α and β subunits. The loss of sGCβ1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGCβ1 in breast cancer tissues are correlated with greater survival probability than lower sGCβ1 levels. However, there is no information on sGC regulation by epigenetic mechanisms. We examined the role of histone deacetylase (HDAC) inhibitors in regulating sGCα1 and -β1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines. The class I HDAC inhibitors increased the expression of sGCβ1 more than sGCα1. Transient overexpression of HDAC3, but not HDAC1 or HDAC2, significantly reduced sGCβ1 mRNA. Chromatin immunoprecipitation assay confirmed an enhanced binding of HDAC3 to the sGCβ1 proximal promoter, which could be reversed by panobinostat (LBH-589) treatment. Mutations at the CCAAT binding sequence, a major element regulating sGCβ1 expression, markedly reduced the efficacy of LBH-589 in augmenting sGCβ1 promoter activity. LBH-589 markedly enhanced the binding of nuclear transcription factor Y, subunit α, to the sGCβ1 promoter (CCAAT binding sequence). In summary, HDAC3 is an endogenous antagonist of sGCβ1 expression. Inhibition of HDAC3 with targeted therapy could benefit treatment of the diseases associated with sGCβ1 down-regulation and/or deficiency such as cancer and several vascular-related diseases.-Sotolongo, A., Mónica, F. Z., Kots, A., Xiao, H., Liu, J., Seto, E., Bian, K., Murad, F. Epigenetic regulation of soluble guanylate cyclase (sGC) β1 in breast cancer cells.


Photobiomodulation increases uprighting tooth movement and modulates IL-1β expression during orthodontically bone remodeling.
This study investigated the effects of photobiomodulation (PBM) in acceleration of orthodontic movement of inferior molar uprighting movement. Thirty-four individuals, with indication of molar uprighting movement for oral rehabilitation, were randomly divided in two groups: verticalization + PBM (808 nm, 100 mW, 1 J per point, 10 points and 25 J/cm2 ) or verticalization + PBM simulation. Elastomeric chain ligatures were changed every 30 days for 3 months. FBM was performed immediately, 24 h, 72 h, 1 and 2 months after activation. The primary outcome was the amount of uprighting movement. Secondary outcomes were pain, amount of medication, OHIP-14 questionnaire, and cytokine IL-1β. PBM group increase uprighting movement when compared to control after 3 months and modulate IL-1β expression. For pain control, the amount of medication and OHIP-14 no difference were found. This study suggests that PBM accelerates tooth movement during molar uprighting, due to modulation of IL-1β during bone remodeling.


Variation in the genetic structure of Peromyscus populations. I. Genetic heterozygosity--its relationship to adaptive divergence.
The genetic structure of nine Peromyscus maniculatus nebrascensis demes from southeastern Wyoming was determined by analyzing allozymes encoded by 23 genetic loci with polyacrylamide gel electrophoresis. Genetic variability is extremely high for two genetic parameters; the proportion of loci polymorphic per deme averaged 0.41. Previous estimates of genetic heterozygosity for species within the genus Peromyscus have a mean of 0.06. The results of the present study suggest that genetic heterozygosity is considerably higher within P. maniculatus demes than within demes of other species in the genus. Geographic range is correlated with heterozygosity among Peromyscus species, as is adaptive divergence into broad-niched species. These correlates suggest that high heterozygosity may reflect an adaptation to a variable environment.


Sacubitril-valsartan improves conduit vessel function and functional capacity and reduces inflammation in heart failure with reduced ejection fraction.
The Prospective comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan (trade name Entresto), but the physiological processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF (n = 11, 10 M/1 F, left ventricular ejection fraction = 27 ± 8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function [brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)], functional capacity [six-minute walk test (6MWT) distance], and the proinflammatory biomarkers tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and at 1, 2, and 3 mo of treatment. %FMD improved after 1 mo of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25 ± 1.75%; 1 mo: 5.23 ± 2.36%; 2 mo: 5.81 ± 1.79%; 3 mo: 6.35 ± 2.77%), whereas RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420 ± 92 m; 1 mo: 436 ± 98 m; 2 mo: 465 ± 115 m; 3 mo: 460 ± 110 m), and there was a sustained reduction in TNF-α (baseline: 2.38 ± 1.35 pg/mL; 1 mo: 2.06 ± 1.52 pg/mL; 2 mo: 1.95 ± 1.34 pg/mL; 3 mo: 1.92 ± 1.37 pg/mL) and a reduction in IL-18 at month 3 (baseline: 654 ± 150 pg/mL; 1 mo: 595 ± 140 pg/mL; 2 mo: 601 ± 176 pg/mL; 3 mo: 571 ± 127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF.NEW & NOTEWORTHY We observed an approximately twofold improvement in conduit vessel function (brachial artery FMD), increased functional capacity (6MWT distance), and a reduction in inflammation (TNF-α and IL-18) following 3 mo of sacubitril-valsartan therapy. These findings provide important new information concerning the physiological mechanisms by which this new drug class provokes favorable changes in HFrEF pathophysiology.


Economic Impact Analysis of Incorporation of Elecsys sFlt-1/PlGF Ratio Into Routine Practice for the Diagnosis and Follow-Up of Pregnant Women With Suspected Preeclampsia in Argentina.
Preeclampsia (PE) is a hypertensive disorder of pregnancy that can cause severe complications and adverse fetal/maternal outcomes. We aimed to estimate the annual economic impact of incorporating Elecsys® sFlt-1/PlGF PE ratio, which measures soluble fms-like tyrosine kinase-1 and placental growth factor, into routine clinical practice in Argentina to aid diagnosis of PE and hemolysis, elevated liver enzymes, and low platelets syndrome from second trimester onward in pregnancies with clinical suspicion of PE. A decision tree was used to estimate annual economic impact on the Argentine health system as a whole, including relevant costs associated with diagnosis, follow-up, and treatment from initial presentation of clinically suspected PE to delivery. Annual costs of a standard-of-care scenario and a scenario including PE ratio (reference year 2021) were analyzed. The economic model estimated that using the sFlt-1/PlGF ratio would enable the overall health system to save ∼$6987 million Argentine pesos annually (95% confidence interval $12 045-$2952 million), a 39.1% reduction in costs versus standard of care, mainly due to reduced hospitalizations of women with suspected PE. The economic impact calculation estimated net annual savings of approximately $80 504 Argentine pesos per patient with suspected PE. Based on the assumed uncertainty of the parameters, the likelihood the intervention would be cost saving was 100% for the considered scenarios. Our analysis suggests that the implementation of the sFlt-1/PlGF ratio in women with suspected PE in Argentina will enable the health system to achieve significant savings, contributing to more efficient clinical management through the likely reduction of unnecessary hospitalizations, depending on assumptions. Results rest on the payers' ability to recover savings generated by the intervention.