Interferon-Gamma Improves Macrophages Function against M. tuberculosis in Multidrug-Resistant Tuberculosis Patients.
Background. Mycobacterium tuberculosis (M. tuberculosis) that causes tuberculosis (TB) kills millions of infected people annually especially multidrug-resistant tuberculosis (MDR-TB). On infection, macrophages recognize the mycobacteria by toll-like receptor (TLR) followed by phagocytosis and control of mycobacteria. In addition, macrophages also secrete IL-12 to induce IFN-γ production by T, which, in turn, increases the phagocytosis and oxidative burst. Individuals with defects in innate or adaptive immunity exhibit increased susceptibility to M. tuberculosis. Understanding these immunologic mechanisms will help in TB control. We aimed to investigate the immunopathologic mechanisms in MDR-TB and role of recombinant human interferon-gamma (rhIFN-γ). Study Design and Methods. Monocyte-derived macrophages (MDMs) were generated from peripheral blood mononuclear cells of MDR-TB patients and healthy subjects and were investigated for immunologic response by ELISA and flow cytometry. Results. Different functional and molecular anomalies were observed in macrophages. In addition, a defective immune response to M. tuberculosis from the patient's MDMs was characterized, which in turn improved by pretreatment with rhIFN-γ. Conclusion. This work highlights the fact that rhIFN-γ improves macrophages function against M. tuberculosis and treatment of patients with poor responsiveness to TB therapy may be needed in future to include IFN-γ as adjuvant therapy after the full characterization of pathological and molecular mechanisms in these and in other more multidrug-resistant TB patients.


Age-related increase of thromboxane B2 and risk of cardiovascular disease in atrial fibrillation.
Aging is strictly associated with an increased incidence of cardiovascular events (CVEs) in the general population. Mechanisms underlying the risk of CVEs are still unclear. Platelet activation contributes to the onset of cardiovascular complications. The incidence of atrial fibrillation (AF) increases with age, and the natural history of AF is often complicated by CVEs. We prospectively investigated the relationship between age, urinary thromboxane (Tx) B2, which reflects platelet activation, and CVEs in 833 AF patients. Median TxB2 level was 120 [66-200] ng/mg of urinary creatinine. At multivariable linear regression analysis, age (B: 0.097, p=0.005) and previous MI/CHD (B: 0.069, p=0.047) were associated with log-TxB2 levels. When we divided our population into age classes (i.e. < 60, 60-69, 70-79, ≥ 80 years), we found a significant difference in TxB2 levels across classes (p=0.005), with a significant elevation at 74.6 years. During a mean follow-up of 40.9 months, 128 CVEs occurred; the rate of CVEs significantly increased with age classes (Log-rank test, p < 0.001). TxB2 levels were higher in patients with, compared to those without, CVEs in patients aged 70-79 (p < 0.001) and ≥ 80 (p = 0.020) years. In conclusion, TxB2 levels enhance by increasing age, suggesting that platelet activation contributes to CVEs in elderly patients with AF.


MiR-1270 Suppresses the Malignant Progression of Breast Cancer via Targeting MMD2.
We aimed to detect the clinical significance of microRNA-1270 (miR-1270) in breast cancer (BCa) development and its potential influence on malignant phenotypes of BCa cells. The miR-1270 level in paired BCa and paracancerous tissues was detected. The Kaplan-Meier method was used for the prognosis analysis of miR-1270 in BCa. The biofunctions of miR-1270 in apoptosis and proliferation of breast cancer cells were evaluated. Downstream target of miR-1270 was predicted and confirmed. The involvement of monocyte to macrophage differentiation associated 2 (MMD2) in BCa development was finally illustrated. miR-1270 was lowly expressed in BCa tissues. Lowly expressed miR-1270 was associated with tumor staging, larger tumor size, and also worse prognostic results in patients with BCa. miR-1270 overexpression suppressed proliferation and increased apoptotic rate of BCa cells. Further exploration showed that MMD2 might be the target of miR-1270. MMD2 was upregulated in BCa tissues and negatively correlated to miR-1270 level. Importantly, MMD2 significantly neutralized the above biofunctions of miR-1270 in malignant phenotypes of BCa. Lowly expressed miR-1270 is a hallmark of poor prognosis in patients with BCa. It inhibits proliferative ability and increases apoptosis in BCa by negatively regulating the MMD2 level.


In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia.
Classical chemotherapy has an active, but limited, role in acute leukemia with relapse common in adult patients. Recent evidence has implicated signal transduction pathways in leukemic progression and also in resistance to cytotoxic therapy. We have used a short-term, in-vitro incubation assay with cytotoxic analysis by MTT, confirmed by histone-associated DNA fragmentation, to evaluate both classical and nonclassical combinations of drugs. Isobologram median effect analysis, confirmed by curve shift analysis, was used to identify synergy and antagonism. Fluvastatin, a prenylation inhibitor, demonstrates global enhancement of the effects of classical agents in both AML-193 and KG-1 cell lines. Similarly, the m-TOR inhibitors, RAD-001 (everolimus) and rapamycin, also cause time-dependent global enhancement of cytotoxic agents. At clinically achievable combinations, RAD-001 perturbs the AKT pathway in vitro. The unique combination of fluvastatin and an m-TOR inhibitor was synergistic in both cell lines. These effects were independent of whether or not human plasma was used in the assay system. These studies suggest several novel combinations of agents that need to be evaluated in the management of leukemia.


Effect of Early Plasma Exchange on Survival in Patients with Severe Fever with Thrombocytopenia Syndrome: A Multicenter Study.
Despite a high mortality rate, no specific treatment for severe fever with thrombocytopenia syndrome (SFTS) has been established. This study compared the clinical outcomes of SFTS patients treated with plasma exchange (PE group) with those who were not treated (non-PE group) at nine Korean hospitals between May 2013 and August 2015. A total of 53 SFTS patients were included: 24 (45.3%) PE cases and 29 (54.7%) non-PE cases. The overall in-hospital mortality rate was 32.1% (17/53). The in-hospital mortality rate of the PE group did not differ from that of the non-PE group (29.3% vs. 34.5%, p=0.680). Of the 24 PE cases, 16 (66.7%) were treated with PE within 7 days of symptom onset (early PE group). The early PE group survived longer than the non-PE group (mean 28.4 days vs. 22.6 days, p=0.044). Multivariate analysis showed an inverse association between early PE implementation and 30-day mortality (adjusted hazard ratio 0.052, 95% confidence interval 0.004-0.678, p=0.024). The results of this study suggest that early PE implementation may have a beneficial effect on the clinical outcome of SFTS patients.


Nasal septal hematoma.
Nasal septal hematoma is a rare but potentially serious complication of nasal trauma. Proper management consists of early recognition, prompt surgical evacuation of the hematoma, and antimicrobial therapy if a secondary nasal septal abscess is suspected. Clindamycin is recommended as initial therapy until the results of cultures and susceptibility studies are available.


Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.
The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100-300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.-Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.


Diagnosis of anemia and iron deficiency: analytic and biological variations of laboratory tests.
We describe the magnitude of analytic errors and the within-subject biological variations for laboratory tests that are used in the diagnosis of anemia and iron deficiency. For Hb, hematocrit, and red cell indices, coefficients of variation for analytic and biological variations are less than 4%. In general, higher coefficients of variation are characteristic of serum iron, iron-binding capacity, serum ferritin, and erythrocyte protoporphyrin. Particularly high analytic variations between different laboratories have been described for iron-binding capacity and the greatest biological variations have been noted for serum iron. An awareness of these sources of error is helpful in designing studies and in interpreting laboratory results.


E2F and GATA switches turn off WD repeat domain 77 expression in differentiating cells.
WDR77 (WD repeat domain 77) is expressed during earlier lung development when cells are rapidly proliferating, but is absent from adult lung. It is re-activated during lung tumorigenesis and is essential for lung cancer cell proliferation. Signalling pathways/molecules that control WDR77 gene expression are unknown. Promoter mapping, gel shift assay and ChIP revealed that the WDR77 promoter contains bona fide response elements for E2F and GATA transcriptional factors as demonstrated in prostate cancer, lung cancer and erythroid cells, as well as in mouse lung tissues. The WDR77 promoter is transactivated by E2F1, E2F3, GATA1 and GATA6, but suppressed by E2F6, GATA1 and GATA3 in prostate cancer PC3 cells. WDR77 expression is associated with E2F1, E2F3, GATA2 and GATA6 occupancy on the WDR77 gene, whereas, in contrast, E2F6, GATA1 and GATA3 occupancy is associated with the loss of WDR77 expression during erythroid maturation and lung development. More importantly, the loss of WDR77 expression that results from E2F and GATA switches is required for cellular differentiation of erythroid and lung epithelial cells. In contrast, lung cancer cells avoid post-mitotic differentiation by sustaining WDR77 expression. Altogether, the present study provides a novel molecular mechanism by which WDR77 is regulated during erythroid and lung development and lung tumorigenesis.


Activating transcription factor 3 inhibits endometrial carcinoma aggressiveness via JunB suppression.
The function of activating transcription factor 3 (ATF3) in cancer is context‑dependent and its role in endometrial carcinoma (EC) is yet to be elucidated. In the present study, ATF3 was indicated to be downregulated, while one of the ATF3‑interacting proteins, JunB, was upregulated in ECs according to western blot analysis. After overexpression in ECs, ATF3 inhibited the proliferation and invasion of EC cells and enhanced apoptosis, as well as suppressed the expression of JunB. The properties of EC cells, including the expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, the cell cycle and apoptosis were all altered by overexpression of ATF3. Furthermore, luciferase activity assay, chromatin precipitation and DNA affinity assay results indicated that ATF3 exerted the aforementioned functions via JunB binding and activator protein‑1 signaling. However, the interaction between ATF3 and JunB did not occur in EC cells under basal conditions, but in ATF3‑overexpressing ECs, which was capable of mitigating EC proliferation, invasion and metastasis. Collectively, the present results suggested that the ATF3/JunB interaction may serve as a potential therapeutic target for ECs.


Visible light-induced difunctionalization of electron-enriched styrenes: synthesis of tetrahydrofurans and tetrahydropyrans.
The difunctionalization of electron-enriched styrenes for the synthesis of substituted tetrahydrofurans and tetrahydropyrans in the presence of photoredox catalysts is described. The procedure is highlighted by its operational simplicity, low catalyst loadings (1 mol%), excellent stereoselectivity and mild reaction conditions.


Anaphylaxis to Oatmeal and Psocid Crisps.
Occasionally, a seemingly straightforward history of food-induced anaphylaxis may prove to be misleading. Both patients and their physicians have a tendency to attribute the cause of an allergic reaction to the most conspicuous ingredient that had been ingested while overlooking less likely causes. Here, we describe a patient whose history pointed to oatmeal allergy, but skin prick tests to oats and serologic testing for oat-specific IgE were negative. Ultimately, we found that the oatmeal had been contaminated with an allergenic insect, Psocid of the order Psocoptera.


Elevated BALF concentrations of alpha- and beta-defensins in patients with pulmonary alveolar proteinosis.
Defensins are endogenous antibiotics and regulators of inflammation, immunity and wound repair. Their concentrations are substantially increased in bronchoalveolar lavage fluid (BALF) of patients with infectious lung diseases. alpha-defensin (HAD) levels are also elevated in patients with idiopathic pulmonary fibrosis (IPF) and correlated with the decline in pulmonary function tests, suggesting the association of defensins with the pathogenesis of interstitial lung diseases. The aim of this study was to determine the profile of defensins in interstitial lung diseases. Serum and BALF levels of HAD and beta-defensin 1 and 2 (HBD-1, and -2) were measured by radioimmunoassay in 63 patients with interstitial lung diseases, including idiopathic pulmonary alveolar proteinosis (PAP), IPF, nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) and pulmonary sarcoidosis, and in 9 healthy volunteers as controls. Levels of HAD in BALF of patients with PAP were significantly higher than those in controls and patients with COP and sarcoidosis. Serum levels of HAD in all groups were significantly higher than those in controls. Levels of HBD-1 and -2 in BALF of patients with PAP were extremely high in all subjects. Serum levels of HBD-1 were higher in all patient groups, with the exception of those with PAP, and those of HBD-2 were also higher in patients with IPF and sarcoidosis, compared with controls. BALF of PAP patients, but not IPF patients and controls, expressed antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. Our findings suggest different kinetics of HAD and HBD-1 and -2 in serum and BALF of interstitial lung diseases and that these antimicrobial peptides in the airway lumen may contribute to prevention of bacterial airway infections in PAP.


Synthesis of 1,2,3-Triazolo[4,5-h]quinolone Derivatives with Novel Anti-Microbial Properties against Metronidazole Resistant Helicobacter pylori.
Helicobacter pylori infection can lead to gastritis, peptic ulcer, and the development of mucosa associated lymphoid tissue (MALT) lymphoma. Treatment and eradication of H. pylori infection can prevent relapse and accelerate the healing of gastric and duodenal ulcers as well as regression of malignancy. Due to the increasing emergence of antibiotic resistance among clinical isolates of H. pylori, alternative approaches using newly discovered antimicrobial agents in combination with the standard antibiotic regimens for the treatment of H. pylori are of major importance. The purpose of the present study was to investigate the effect of newly synthesized 8-amino 7-substituted fluoroquinolone and their correspondent cyclized triazolo derivatives when either alone or combined with metronidazole against metronidazole-resistant H. pylori. Based on standard antimicrobial susceptibility testing methods and checkerboard titration assay, all of the tested compounds showed interesting antimicrobial activity against 12 clinical strains of H. pylori, with best in vitro effect for compounds 4b and 4c. Fractional inhibitory concentration (FIC) mean values showed synergistic pattern in all compounds of Group 5. In addition, additive activities of some of the tested compounds of Group 4 were observed when combined with metronidazole. In contrast, the tested compounds showed no significant urease inhibition activity. These results support the potential of new fluoroquinolone derivatives to be useful in combination with anti-H. pylori drugs in the management of H. pylori-associated diseases.


Copper-catalyzed TEMPO oxidative cleavage of 1,3-diketones and β-keto esters for the synthesis of 1,2-diketones and α-keto esters.
A copper-catalyzed efficient and practical method has been developed for the synthesis of 1,2-diketones and α-keto esters. TEMPO was used as a radical initiator and scavenger, oxidizing the cleavage of α-methylene of 1,3-diketones and β-keto esters to form 1,2-diketones and α-keto esters. This method provided a general way for the formation of 1,2-dicarbonyl compounds.


Antioxidant Capacities of Fractions of Bamboo Shaving Extract and Their Antioxidant Components.
This research was conducted for evaluation of antioxidant activities of four fractions from bamboo shavings extract (BSE) and their antioxidant components. The antioxidant capacities of BSE and four fractions on ABTS, DPPH, FRAP and total antioxidant capacity assays exhibited the following descending order: DF > n-butanol fraction (BF) > BSE ≈ ethyl acetate fraction (AF) > water fraction (WF). Among the identified phenolic compounds, caffeic acid exhibited the highest antioxidant capacities on DPPH, FRAP and total antioxidant capacity assays. An extremely significant positive correlation between the antioxidant activities with the contents of total flavonoids, total phenolic acids, or total phenolics was observed in this study. The result indicated that the bamboo shaving extract and its solvent fractions could act as natural antioxidants in light of their potent antioxidant activities.


Microspectrophotometric analysis of nuclear DNA in Chara zeylanica.
Microspectrophotometric analysis of the DNA content of nuclei in various parts of Chara zeylanica Willd. revealed that the amount of DNA in the nucleus of an internodal cell equals twice the amount of DNA in the nucleus of a sperm, while the half-anaphase stage of the same nodal cells contains the same amount of DNA as the nuclei of the male gametes. The DNA content of the nuclei of internodal cells may rise as much as 50 times higher than that of the gametes. However, in the oldest (most basal) internodal cells, the DNA content of the minute nuclei falls again to the basic (1 C) amount. Measurements of sister nuclei derived by amitosis indicated that both nuclei have equal amounts of DNA; this was interpreted as further evidence that amitosis is not a disorganized process or manifestation of degeneration. The bearing of these analyses on the question of the site of meiosis in these plants is discussed.


Galactose transport in Saccharomyces cerevisiae. I. Nonmetabolized sugars as substrates and inducers of the galactose transport system.
The inducible galactose transport system in bakers' yeast carries out the facilitated diffusion of the nonmetabolized galactose analogues d-fucose and l-arabinose. This capacity depends on the activity of the Ga 2 gene. In some strains, d-fucose and l-arabinose are also gratuitous inducers. Mutants in which the inducibility of the galactose pathway enzymes is altered show a parallel alteration of the inducibility of the galactose transport system.


Clinical characteristics of monomorphic post-transplant lymphoproliferative disorders.
Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoproliferative disorders associated with immunosuppression and Epstein-Barr virus infection. PTLD is classified into three major categories: early lesions, polymorphic PTLD, and monomorphic PTLD. The majority of monomorphic PTLD cases are non-Hodgkin's lymphoma of B-cell origin. This retrospective study was conducted to investigate the incidence, clinical manifestation, treatment, and outcomes of monomorphic PTLD among 5,817 recipients of solid organ or allogeneic hematopoietic stem cell transplantation from five institutions. Fourteen patients with monomorphic PTLD were identified (male:female 11:3; median age 42.6 yr, range 24-60). The overall incidence rate was 0.24%. The most common disease type was diffuse large B cell lymphoma (n=7). The median time between the transplant and diagnosis of PTLD was 85.8 months. However, all cases of PTLD after allogeneic hematopoietic stem cell transplantation occurred within 1 yr after transplantation. Ten of the 14 patients had EBV-positive tumor. Fourteen patients received combination systemic chemotherapy and four patients were treated with radiation therapy. Ten patients achieved a complete response (CR) and two patients a partial response (PR). The median follow-up period for surviving patients was 36.6 months. Nine patients remain alive (eight CR, one PR). Nine of 11 solid organ transplantations preserved graft function. The present study indicates a lower incidence rate and a longer median time before the development of PTLD than those of previous reports. Careful monitoring was needed after allogeneic hematopoietic stem cell transplantation for PTLD.


Chronic basal forebrain activation improves spatial memory, boosts neurotrophin receptor expression, and lowers BACE1 and Aβ42 levels in the cerebral cortex in mice.
The etiology of Alzheimer's dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer's model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2-3-fold increases in frontal cortex immunoblot measures of the neurotrophin receptors for nerve growth factor and brain-derived neurotrophic factor, and a more than 50% decrease in the expression of amyloid cleavage enzyme BACE1. Stimulation also led to lower Aβ42 in 5xFAD mice. These data support a causal relationship between basal forebrain activation and both neurotrophin activation and reduced Aβ42 generation and accumulation. The observation that basal forebrain activation suppresses Aβ42 accumulation, combined with the known high-affinity antagonism of nicotinic receptors by Aβ42, documents bidirectional antagonism between acetylcholine and Aβ42.


Proposing new indicators for glaucoma healthcare service.
Glaucoma is the first leading cause of irreversible blindness worldwide with increasing importance in public health. Indicators of glaucoma care quality as well as efficiency would benefit public health assessments, but are lacking. We propose three such indicators. First, the glaucoma coverage rate (GCR), which is the number of people known to have glaucoma divided by the total number of people with glaucoma as estimated from population-based studies multiplied by 100%. Second, the glaucoma detection rate (GDR), which is number of newly diagnosed glaucoma patients in one year divided by the population in a defined area in millions. Third, the glaucoma follow-up adherence rate (GFAR), calculated as the number of patients with glaucoma who visit eye care provider(s) at least once a year over the total number of patients with glaucoma in given eye care provider(s) in a specific period. Regularly tracking and reporting these three indicators may help to improve the healthcare system performance at national or regional levels.


Infective endocarditis with co-existent acalculous cholecystitis: a rare but important association.
The authors present the case of an otherwise healthy retired male who presented with a history of fevers, rigors and right upper quadrant abdominal pain. Although haematological, biochemical and radiological investigations supported a diagnosis of acalculous cholecystitis, the underlying cause was not obviously apparent and the patient's clinical condition deteriorated rapidly over the course of a few hours despite appropriate medical treatment. Repeat clinical examination was consistent with acute pulmonary oedema in association with a new murmur throughout the whole of the cardiac cycle. Transthoracic echocardiography revealed the presence of severe aortic regurgitation, a presumptive diagnosis of infective endocarditis was made and medical therapy adjusted. Shortly after, the patient suffered a cardiac arrest and an attempt at resuscitation was unsuccessful. Postmortem examination revealed the presence of aortic valve cusp rupture secondary to bacterial endocarditis in addition to gallbladder appearances consistent with acute acalculous cholecystitis.


A ratio estimation method for determining the prevalence of cocaine use.
This paper presents an approach to estimating the prevalence of cocaine use, based upon a new ratio estimation technique. This method can be applied to random samples of overlapping populations for which no sampling frames exist. When the ratio estimation method is applied to the two study samples (drawn from populations of people using cocaine and people using heroin) the ratio of cocaine users to heroin users (C/H) was 1.55, with a 95% confidence interval of +/- 0.48. Such estimates should be applied with caution. However, if used with reference to national estimates of about 75,000 heroin users, application of the present estimate suggests that there may be about 116,000 cocaine users in the UK.


Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.
Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T(991) tonically inhibits KCC3; however, cell swelling triggers Thr(991) dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr(991) phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3(T991A/T991A) mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase-regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration.


Rare adverse events due to house dust mite sublingual immunotherapy in pediatric practice: two case reports.
Sublingual route, a noninjective way of allergen administration appears to be associated with a lower incidence of severe systemic reactions compared with the subcutaneous route. Local adverse reactions are reported which resolve spontaneously within a few days without need for discontinuation of treatment. Hereby, we report two pediatric cases, one with persistent asthma and the other one with persistent allergic rhinitis. Both were treated by house dust mite sublingual immunotherapy, one of whom developed severe wheezing (grade 2 systemic reaction based on World Allergy Organization subcutaneous systemic reaction grading system) and the other intractable vomiting (grade 3 local reaction based on World Allergy Organization sublingual immunotherapy local adverse events grading system) at the end of the build-up phase which repeated on re-administration of the same dose. Both of those two cases completed their 3-year immunotherapy successfully by patient-based adjustment of the highest tolerated dose of the maintenance.


Methyl-beta-cyclodextrin prevents Ca2+-induced Ca2+ release in smooth muscle cells of mouse urinary bladder.
We examined the effects of methyl-beta-cyclodextrin (MbetaCD) on Ca(2+)-induced Ca(2+) release (CICR) in smooth muscle cells (SMCs) of mouse urinary bladder (UB). Short depolarization of UBSMCs under voltage-clamp elicited several local Ca(2+) transients (Ca(2+) hot spots) via CICR within 20 ms in discrete sub-sarcolemmal areas. Then, the Ca(2+) wave spread to whole areas. The pretreatment with 10 mM MbetaCD significantly attenuated Ca(2+) hot spots in UBSMCs and reduced contraction by single direct electrical pulse stimulation in UBSM strips. MbetaCD may prevent CICR by attenuating the coupling between voltage-dependent Ca(2+) channels and ryanodine receptors in Ca(2+) hot spot areas.


Anisotropic flexibility and rigidification in a TPE-based Zr-MOFs with scu topology.
Tetraphenylethylene (TPE)-based ligands are appealing for constructing metal-organic frameworks (MOFs) with new functions and responsiveness. Here, we report a non-interpenetrated TPE-based scu Zr-MOF with anisotropic flexibility, that is, Zr-TCPE (H4TCPE = 1,1,2,2-tetra(4-carboxylphenyl)ethylene), remaining two anisotropic pockets. The framework flexibility is further anisotropically rigidified by installing linkers individually at specific pockets. By individually installing dicarboxylic acid L1 or L2 at pocket A or B, the framework flexibility along the b-axis or c-axis is rigidified, and the intermolecular or intramolecular motions of organic ligands are restricted, respectively. Synergistically, with dual linker installation, the flexibility is completely rigidified with the restriction of ligand motion, resulting in MOFs with enhanced stability and improved separation ability. Furthermore, in situ observation of the flipping of the phenyl ring and its rigidification process is made by 2H solid-state NMR. The anisotropic rigidification of flexibility in scu Zr-MOFs guides the directional control of ligand motion for designing stimuli-responsive emitting or efficient separation materials.


Diffuse large B-cell lymphoma recurring with zosteriform cutaneous lesions.
A 75-year-old woman presented with edema of the left leg in December 2012. On examination, there was a palpable 5-cm tumor in the left lower abdomen, and PET/CT showed lymphadenopathy of the tracheal, para-aortic, left iliac and inguinal regions with increased FDG uptake. We performed histopathological examination of the iliac lymph node and diagnosed diffuse large B-cell lymphoma (DLBCL), stage IIIA. The patient received 8 courses of R-CHOP chemotherapy and achieved a complete response. In April 2014, she noticed seven new painful erythematous vesicles <1 cm in size on the skin of the left lower abdominal region. Herpes zoster was suspected and valacyclovir was administered. However, this medication had no effect, and the vesicles enlarged and became nodular. Histopathological examination of one of the skin lesions revealed the infiltration of DLBCL and the diagnosis of zosteriform cutaneous recurrence of DLBCL was thus made. Skin lesions mimicking herpes zoster have been reported in certain types of hematological malignancies, and histopathological diagnosis should be performed in such cases.


Poly[aqua-bis-(μ-formato-κO:O')(μ-pyrazine-κN:N')nickel(II)].
In the title compound, [Ni(CHO(2))(2)(C(4)H(4)N(2))(H(2)O)], the nickel(II) cations are coordinated by three O-bonded-formato anions, two N-bonded-pyrazine ligands and one water mol-ecule in an octa-hedral coordination mode. The nickel(II) cations are connected by μ-1,3-bridging formato anions and N,N'-bridging pyrazine ligands into a three dimensional coordination network. The asymmetric unit consists of one nickel(II) cation, one water mol-ecule and two crystallograph-ically independent formato anions in general positions as well as two crystallographically independent pyrazine ligands, which are located on centers of inversion.


Preparation and synthetic application of a novel ketene silyl acetal of methyl trifluoropyruvate.
[reaction: see text] A novel trifluoromethyl ketene silyl acetal (4) of methyl trifluoropyruvate (1) was prepared in 82% yield by metal Mg reduction in a (TMS)Cl/THF system. Subsequent carbon-carbon bond formation such as Mukaiyama aldol, Michael addition, and other nucleophilic reactions of 4 at the trifluoromethylated carbon with various electrophiles gave various coupling products in high yields.


Inhalation of particulate matter containing free radicals leads to decreased vascular responsiveness associated with an altered pulmonary function.
Airborne particulate matter (PM) is associated with an increased risk for cardiovascular diseases. Although the goal of thermal remediation is to eliminate organic wastes through combustion, when incomplete combustion occurs, organics chemisorb to transition metals to generate PM-containing environmentally persistent free radicals (EPFRs). Similar EPFR species have been detected in PM found in diesel and gasoline exhaust, woodsmoke, and urban air. Prior in vivo studies demonstrated that EPFRs reduce cardiac function secondary to elevations in pulmonary arterial pressures. In vitro studies showed that EPFRs increase ROS and cytokines in pulmonary epithelial cells. We thus hypothesized that EPFR inhalation would promote lung inflammation and oxidative stress, leading to systemic inflammation, vascular endothelial injury, and a decline in vascular function. Mice were exposed to EPFRs for either 4 h or for 4 h/day for 10 days and lung and vascular function were assessed. After a 4-h exposure, plasma nitric oxide (NO) was reduced while endothelin-1 (ET-1) was increased, however lung function was not altered. After 10 day, plasma NO and ET-1 levels were again altered and lung tidal volume was reduced. These time course studies suggested the vasculature may be an early target of injury. To test this hypothesis, an intermediate time point of 3 days was selected. Though the mice exhibited no marked inflammation in either the lung or the blood, we did note significantly reduced endothelial function concurrent with a reduction in lung tidal volume and an elevation in annexin V protein levels in the lung. Although vascular dysfunction was not dependent upon inflammation, it may be associated with an injury at the air-blood interface. Gene expression analysis suggested roles for oxidative stress and aryl hydrocarbon receptor (Ahr) signaling. Studies probing the relationship between pulmonary oxidative stress and AhR signaling at the air-blood interface with vascular dysfunction seem warranted.NEW & NOTEWORTHY Particulate matter (PM) resulting from the combustion of organic matter is known to contribute to cardiopulmonary disease. Despite hypotheses that cardiovascular dysfunction occurring after PM exposures is secondary to lung or systemic inflammation, these studies investigating exposures to PM-containing environmentally persistent free radicals (EPFRs) demonstrate that cardiovascular dysfunction precedes pulmonary inflammation. The cardiopulmonary health consequences of EPFRs have yet to be thoroughly evaluated, especially in healthy, adult mice. Our data suggest the vasculature as a direct target of PM exposure, and our studies aimed to elucidate the mechanisms contributing to EPFR-induced vascular dysfunction.


School holidays: examining childhood, gender norms, and kinship in children's shorter-term residential mobility in urban Zambia.
This article discusses a practice of child residential mobility in Zambia that is frequently overlooked in migration studies and difficult to capture through standard survey methods: the practice of 'going on holiday' to the homes of relatives during breaks in the school term. Drawing on child-centered and quantitative research, this article examines the multiple dimensions of 'going on holiday' for children living in a low-income urban settlement in Lusaka. Findings suggest that the practice was gendered and may map onto changing norms in schooling in Zambia. Within a context where resources are severely constrained, going on holiday may serve as one means for cultivating reciprocity, sharing the burden of care and household labor, and strengthening kin ties. This work further demonstrates the importance of using locally meaningful terms and practices in survey research where general questions about children's mobility may fail to capture the nature and extent of children's movements.


Epidemiology of obstetric critical illness.
Obstetric intensive care unit (ICU) admissions comprise only a small part of severe maternal morbidity. The incidence rate of both remains relatively unclear due to inconsistent definitions across publications, although this has begun to be addressed. There is a relative paucity of information regarding disease-specific survival following obstetric ICU admission, but outcomes are clearly related to the cause of admission and the quality of care. The ratio between maternal near-miss cases (many of whom are admitted to ICUs) and maternal death may provide insight into the preventability of death. Hemorrhage and pre-eclampsia constitute the leading causes of ICU admission and have relatively low mortality rates, perhaps demonstrating the impact of informed care in managing obstetric critical illness. Obstetric sepsis, heart disease and anesthesia complications should be the focus of future research. The incidence of obstetric sepsis has been increasing in the last decade, with mortality rates remaining relatively high. The incidence of obstetric heart disease is increasing and maternal complications have been attributed to fractionated care of mothers within this category. Anesthesia complications remain a predominant cause of maternal death and likely intensive care admission. Data are lacking regarding the relative proportion of cases per disease that remain treated outside the ICU; and the outcomes of various management strategies. The only study of the health status of survivors of obstetric ICU admission revealed that six months after hospital discharge, one in five women still had a poorer health-related quality of life than those of a reference age- and sex-matched cohort.


[Falling Short of Minimum Volume Standards, Exemptions and Their Consequences from 2018 Onwards. Complex Procedures on Oesophagus and Pancreas in German Hospitals from 2006 to 2014].
The minimum volume standards for hospitals in Germany, in force since 2004, provide four exemptions for non-complying hospitals. This study investigates the extent and importance of these exemptions for complex procedures on the oesophagus and pancreas for all non-complying hospitals and for the revised minimum volume regulations in force since the beginning of 2018. Longitudinal, descriptive analyses of data on minimum volume standards and their exemptions for complex procedures on the oesophagus and pancreas, as presented by the hospital quality report cards of the reporting years from 2006 to 2014. For each year and both procedures, about 120 hospitals with some 500 cases report non-compliance with the minimum volume standards. Of these a third report no exemptions (with 180 procedures), a third state emergencies (110), and another third report exemptions due to internal hospital restructuring (210). Ensuring geographical access to care as an exemption is of no importance. After the three year exemption period for installation of a new service line, 20% of the hospitals with procedures on the oesophagus and 30% on the pancreas complied with the minimum volume standards. After the two-year period for staff realignment, the figures were 40 and 50%, respectively. Exemptions do not entirely explain all procedures performed by hospitals not complying with the minimum volume standards. The revised minimum volume regulations' restructuring of exemptions to "emergencies" and "new or renewed service lines" with a two year exemption period, are concordant with the empirical findings of this study.


Early preweaning methamphetamine and postweaning rearing conditions interfere with the development of peripheral stress parameters and neural growth factors in gerbils.
Adrenal steroid hormones and neuronal growth factors are two interacting systemic factors that mediate the environment's influence on the brain's structure and function. In order to further elucidate their role and relationship in the effects of early stressful experience and isolated rearing (IR), this study measured blood corticosterone titres and relative adrenal weights and assessed nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) concentrations in brain regions of both hemispheres of young adult Mongolian gerbils injected on postnatal day 14 with a single high dose of methamphetamine (MA) or saline and raised after weaning either in an enriched or an impoverished environment. Irrespective of MA challenge, IR decreased corticosterone titres to about half, but increased relative adrenal weights. BDNF concentrations were decreased by IR in saline-injected animals in the left prefrontal and parietal cortices and right entorhinal and hippocampal cortices, and in the subcortical regions of both hemispheres. NGF concentrations were unaltered by IR in saline-injected animals, but increased in MA challenged animals in the entorhinal/hippocampal cortices and subcortical areas of both hemispheres. MA application induced shifts of the lateral asymmetry in NGF contents in prefrontal and entorhinal cortices. The results suggest that an early pharmacological traumatization can set a switch for further brain development, and that growth factor concentrations might possibly be influenced by peripheral stress hormones.


Comparative proteomic analysis of NaCl stress-responsive proteins in Arabidopsis roots.
NaCl stress is a major abiotic stress limiting the productivity and the geographical distribution of many plant species. Roots are the primary site of salinity perception. To understand better NaCl stress responses in Arabidopsis roots, a comparative proteomic analysis of roots that had been exposed to 150 mM NaCl for either 6 h or 48 h was conducted. Changes in the abundance of protein species within roots were examined using two-dimensional electrophoresis. Among the >1000 protein spots reproducibly detected on each gel, the abundance of 112 protein spots decreased and 103 increased, at one or both time points, in response to NaCl treatment. Through liquid-chromatography-tandem mass spectrometry, identity was assigned to 86 of the differentially abundant spots. The proteins identified included many previously characterized stress-responsive proteins and others related to processes including scavenging for reactive oxygen species; signal transduction; translation, cell wall biosynthesis, protein translation, processing and degradation; and metabolism of energy, amino acids, and hormones. At the resolution of individual genes and proteins, poor statistical correlation (6 h, r= -0.13; 48 h, r=0.11) of these protein expression data with previous microarray results was detected, supporting the concept that post-transcriptional regulation plays an important role in stress-responsive gene expression, and highlighting the need for combined transcriptomic and proteomic analyses.


A systematic review of genetic influences on coping.
Coping refers to the way that an individual manages stress. Coping strategies vary; for example, problem-focused coping is directed at reducing or removing a stressor, while emotion-focused coping is directed more at managing reactions that accompany the stressor. How individuals cope with stress can impact their health, but the physiological effects of coping are not well understood. The field of genetics provides tools that could help illuminate the physiology of coping. This review of the literature was conducted to determine what is currently known about the phenotype of coping from a genetic perspective. PubMed, HubMed, PsychInfo, Medline, Scopus, and Google Scholar databases were used to conduct the search, and reference lists were reviewed to identify additional publications. Only studies that measured coping style or a coping domain specifically, were written in English language, and were human-subject focused were included in the review. We identified 19 studies that met these criteria, and 2 types of genetic studies emerged for the review: heritability (n = 9) and candidate gene association (n = 10) studies. Heritability estimates of .68-.76 support a nonadditive genetic component to coping. Replication of association was found for the serotonin transporter and adrenergic receptor beta 2 genes. In addition to finding evidence supporting a role for genetic variability with coping phenotype, it is worth noting that the review revealed a lack of consistency in instruments used to phenotype coping across studies.


[mTORC1 and sirolimus: a link with fertility].
mTOR (mammalian target of rapamycin), a protein kinase highly conserved, is the catalytic subunit of two complexes, mTORC1 and mTORC2. These complexes are regulated by amino acids availability, by insulin and growth factors signaling pathways. Thus, mTORC1 and mTORC2 complexes are essential sensors of the cellular nutrient and energy levels in living organisms. mTORC1 is sensitive to rapamycin (also known as sirolimus), a drug prescribed in case of organ transplantation (kidney) due to its immunosuppressive and anti-proliferative properties. However, some studies have shown that the rapamycin treatment can induce fertility disorders. Thus, this article reviews the mTOR involvement in the male and female reproductive axis.


A Congenital Peribronchial Myofibroblastic Tumor Detected in a Premature Infant at 28 Weeks but That Resolved in the Late Stage of Pregnancy: A Case Report.
A congenital peribronchial myofibroblastic tumor (CPMT) is a rare benign tumor arising from the lungs. Although CPMT is a benign tumor, it is characterized by rapid growth, and is easily misdiagnosed during the prenatal period when the symptoms are nonspecific. The authors present a rare case of CPMT in a premature infant, which was detected at 28 weeks on ultrasonography (US) but resolved at a later stage of pregnancy. The knowledge concerning the diagnosis and management of CPMT is reviewed. Herein, the authors report of a 30-minute-old premature newborn infant in whom a pulmonary mass was discovered 1 month before delivery. Maternal prenatal US demonstrated a 0.8 × 1 cm well-defined oval-shaped mass in the left hemithorax in the 28th week of gestational age. The pulmonary mass, however, was not apparent on repeat US examination at 32 weeks. The child was delivered by cesarean section at 34 weeks estimated gestational age. Chest radiography and computed tomography revealed a mass-like lesion in the left lower pulmonary lobe. The chest computed tomography characteristics of the tumor included large size (4 cm), an irregular margin, and surrounding ground-glass opacity, which led to misdiagnosis as a malignant tumor. The patient underwent a left inferior lung lobectomy and was pathologically diagnosed with CPMT. He is currently alive 12-month postresection with no evidence of disease recurrence.The authors report this rare case of CPMT, which was detected at 28 weeks and resolved at a later stage of pregnancy. Congenital peribronchial myofibroblastic tumor is an uncommon benign tumor. Lobectomy or pneumonectomy is often required. The prognosis after surgery is good.


A counting method for density packed cells based on sliding band filter image enhancement.
Cell loss and addition is an important biological event in pathology, and it usually provides central information to the changes of biological activity in the histological sections. To develop a reliable and accurate cell counting tools in tissue section, in this paper, we proposed a novel cell nuclei detecting method based on the sliding band filter which is a member of convergence index family. We evaluated the accuracy and performance of our method on density packed retinal outer nuclear layer cell confocal multivariate fluorescence microscopy image datasets. The results show our proposed method exhibited an excellent performance with its accuracy compared with human manual counting. It is worth noting that the proposed cell counting method can clearly benefit for retinal detachment and reattachment visual diagnostics close related to cell loss and addition.


Epineurial microvasculitis in proximal diabetic neuropathy.
Amongst the focal and multifocal neuropathies that are associated with diabetes mellitus one of the most common is a proximal predominantly motor lower limb neuropathy. Recent evidence has indicated that, at least in a proportion of cases, this may have an inflammatory basis. We have examined a consecutive series of 15 cases of proximal diabetic neuropathy (diabetic amyotrophy). These were characterized by proximal pain and asymmetric proximal or generalized lower limb muscle weakness, associated in some cases with radicular sensory involvement. Two-thirds of the patients had an accompanying distal symmetric sensory polyneuropathy. Biopsy of the intermediate cutaneous nerve of the thigh, a sensory branch of the femoral nerve, showed epineurial microvasculitis in 3 patients and nonvasculitic epineurial inflammatory infiltrates in another case. In a further case, microvasculitis was found in both in the sural nerve and a quadriceps muscle biopsy specimen. The detection of inflammatory changes appeared to be correlated with the occurrence of sensory radicular involvement. Whether similar changes are present in muscle nerves in this predominantly motor syndrome requires further study. Nevertheless, the present observations confirm the view that secondary vasculitic or other inflammatory reactions may contribute to some forms of diabetic neuropathy.


The modified occipital condyle screw: A quantitative anatomic study investigating the feasibility of a novel instrumented fixation technique for craniocervical fusion.
Prospective human anatomical study. Occipitocervical fusion with occipital plate or condyle screws has shown higher failure rates in those with skeletal dysplasia. The modified occipital condyle screw connects the occipital condyle to the pars basilaris of the occipital bone that may achieve fortified bony purchase and serve as a more rigid fixation point. We evaluate anatomical feasibility of a novel cranial fixation technique designed to decrease risk of pseudarthrosis. Occipital condyles were analyzed morphologically using multiplanar three-dimensional reconstructed, ultra-thin section computed tomography. The following parameters were obtained: occipital condyle length, maximal cross section, location of hypoglossal canal, axial and sagittal orientation of the long axis, occipital condyle pedicle (OCP) diameter, maximal length of OCP screw, and entry point. Forty patients with total of 80 occipital condyles were analyzed and the following measurements were obtained: occipital condyle length 24.1 mm (20.5-27.7, standard deviation [SD]: 2.2); condyle maximum axial cross-section 12.6 mm (9-15.8, SD: 1.9); length of OCP screw 38.9 mm (29.3-44, SD: 5.7); diameter of OCP 3.4 mm (3.2-3.6, SD: 0.2); clearance below hypoglossal canal 4.5 mm (3.4-7, SD: 1.1); and distance of screw entry point from condylar foramen 2 mm (range 0-4, SD 1.6). The modified occipital condyle screw connects the condyle with the clivus through the pars basilaris and represents a safe and technically feasible approach to achieve craniocervical fusion in skeletally mature individuals. This cephalad anchor point serves as an alternate fixation point of the occipitocervical junction with increased strength of construct and decreased risk of hardware failure or pseudarthrosis given cortical bone purchase and longer screw instrumentation.


Application of precipitating activity of Canavalia lineata DC lectin for isolation of alpha 2-macroglobulin from human plasma.
To isolate alpha 2-macroglobulin from human plasma, complex of Canavalia lineata DC lectin and plasma was used as a starting material. The complex was solubilized with 0.08 M phosphate buffer pH 7.2 containing 0.9% NaCl and 0.02 M alpha-methyl-D-mannoside. The solution was applied onto a Bio gel A-5m column and eluted with solubilizing buffer. Of three peaks, only the second peak contained alpha 2-macroglobulin. After equilibrating with 0.06 M potassium phosphate buffer pH 6.8, the fraction was applied onto a hydroxylapatite column and eluted with the same buffer. The eluate was confirmed to be extremely pure alpha 2-macroglobulin; immunoelectrophoresis with anti-human serum produced a single precipitation line, and SDS disc electrophoresis gave a single band at alpha-globulin region. Few differences in carbohydrate composition between this preparation and those prepared by other methods were observed. By this method, about 45% of alpha 2-macroglobulin present in plasma was recovered.


Creating Statistically Literate Global Citizens: The Use of IPUMS-International Integrated Census Microdata in Teaching.
Census microdata are ideal for developing statistical literacy of university students. Access, particularly to internationally comparable microdata, has been a significant obstacle. The IPUMS-International project offers a uniform solution to providing access for policy analysts, researchers, and students to integrated microdata and metadata, while protecting statistical confidentiality. Eighty-five official statistical agencies have endorsed IPUMS-I dissemination principles and entrusted microdata for 249 censuses to the project. From June 2010, 159 integrated samples, representing 55 countries and totaling over 325 million person records, are available at no cost to researchers and their students. The database is being expanded with the addition of samples for 5-10 countries per year as well as samples for the 2010 round of censuses. This paper illustrates two approaches to using IPUMS-I census microdata in the university curriculum to promote statistical literacy among undergraduates.


Determination of Triazine Herbicides in Drinking Water by Dispersive Micro Solid Phase Extraction with Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometric Detection.
A novel dispersive micro solid phase extraction (DMSPE) method based on a polymer cation exchange material (PCX) was applied to the simultaneous determination of the 30 triazine herbicides in drinking water with ultrahigh-performance liquid chromatography-high-resolution mass spectrometric detection. Drinking water samples were acidified with formic acid, and then triazines were adsorbed by the PCX sorbent. Subsequently, the analytes were eluted with ammonium hydroxide/acetonitrile. The chromatographic separation was performed on an HSS T3 column using water (4 mM ammonium formate and 0.1% formic acid) and acetonitrile (0.1% formic acid) as the mobile phase. The method achieved LODs of 0.2-30.0 ng/L for the 30 triazines, with recoveries in the range of 70.5-112.1%, and the precision of the method was better than 12.7%. These results indicated that the proposed method had the advantages of convenience and high efficiency when applied to the analysis of the 30 triazines in drinking water.


[Contribution of the semi-free radial forearm flap for head and neck reconstruction].
Flap failure is mostly caused by venous thrombosis of the anastomosis. The failure rate is higher in post-irradiated neck. To reduce the risk of venous thrombosis, the authors propose to harvest the radial forearm flap using the cephalic vein as the drainage vein and as a pedicle. Only a single arterial anastomosis is carried out. This technique has been described already in patients who underwent head and neck ablative surgery with radical neck dissection. The authors report 2 cases in patients with post-irradiated neck. The flap transfers were successful in the 2 cases. The operative time of harvesting this hybrid version is the same with the conventional free flap technique. This version of the radial forearm flap can be a method of choice for some complex microvascular reconstruction in the head and neck region.


A comparative study of coarse-graining methods for polymeric fluids: Mori-Zwanzig vs. iterative Boltzmann inversion vs. stochastic parametric optimization.
We construct effective coarse-grained (CG) models for polymeric fluids by employing two coarse-graining strategies. The first one is a forward-coarse-graining procedure by the Mori-Zwanzig (MZ) projection while the other one applies a reverse-coarse-graining procedure, such as the iterative Boltzmann inversion (IBI) and the stochastic parametric optimization (SPO). More specifically, we perform molecular dynamics (MD) simulations of star polymer melts to provide the atomistic fields to be coarse-grained. Each molecule of a star polymer with internal degrees of freedom is coarsened into a single CG particle and the effective interactions between CG particles can be either evaluated directly from microscopic dynamics based on the MZ formalism, or obtained by the reverse methods, i.e., IBI and SPO. The forward procedure has no free parameters to tune and recovers the MD system faithfully. For the reverse procedure, we find that the parameters in CG models cannot be selected arbitrarily. If the free parameters are properly defined, the reverse CG procedure also yields an accurate effective potential. Moreover, we explain how an aggressive coarse-graining procedure introduces the many-body effect, which makes the pairwise potential invalid for the same system at densities away from the training point. From this work, general guidelines for coarse-graining of polymeric fluids can be drawn.


Housing and Cardiometabolic Risk Among Older Renters and Homeowners.
Scholars consistently find that renters have poorer health outcomes when compared with homeowners. Health disparities between renters and homeowners likely widen over the life course, yet few studies have examined this link among older adults, and the connection is not fully understood. Homeowners' relative socioeconomic advantage may explain their better health; renters also more commonly experience adverse housing conditions and financial challenges, both of which can harm health. In this paper, we analyze the extent to which socioeconomic advantage, housing conditions, and financial strain explain the relationship between homeownership and health among adults over age 50, using Health and Retirement Study 2010/2012 data to assess cardiometabolic risk levels using biomarkers for inflammation, cardiovascular health, and metabolic function. We find that people living with poor housing conditions and financial strain have higher cardiometabolic risk levels, even taking socioeconomic advantage into account. This analysis sheds light on the housing-related health challenges of older adults, especially older renters.


Essential tremor.
Essential tremor (ET) is among the most common neurologic disorders. The traditional view of this disorder as a benign, monosymptomatic, familial condition is being replaced by a more complex view of ET as perhaps a family of diseases with etiologic, clinical, and pathologic heterogeneity. This article discusses the major clinical features of ET and approaches to its diagnosis and treatment.


Expression, Intracellular Localization, and Prognostic Value of Plasminogen Activator Inhibitor 1 and PAI-1 RNA-Binding Protein 1 in Primary and Recurrent Ovarian Cancer: A Study of the Tumor Bank Ovarian Cancer Network.
The plasminogen activator system plays a key role in ovarian cancer (OC) tumor progression. The plasminogen activator inhibitor type 1 (PAI-1) and the recently identified PAI-1 RNA binding protein 1 (PAI-RBP1) are primary regulators of plasminogen activation and thus are putative biomarkers for OC progression. One hundred fifty six OC patients were analyzed to identify the presence of PAI-1 and PAI-RBP1 and subsequently correlated to clinicopathological parameters. Primary cells obtained from OC patient samples were applied in fluorescence microscopy analysis for examination of PAI-1 and PAI-RBP1 distribution. PAI-1 and PAI-RBP1 have been found to be predictive markers for OC patients' outcome. PAI-1 levels significantly correlated with volume of ascites, FIGO staging, and lymph node status. PAI-RBP1 expression significantly correlated with age at first diagnosis, histological tumor type, presence of distant metastasis (pM), and recurrence. PAI-1 showed a trend toward association and PAI-RBP1 was significantly associated with progression-free survival. Notably, PAI-1 protein in recurrent OC tissues was exclusively localized in the nucleus. This study has shown that a combination of PAI-1 and PAI-RBP1 may represent novel prognostic factor for OC. Prospective trials are needed.


Maintaining the Punitive Element of Tort through Social Sanctions in Malpractice Reform.
In this piece, I focus on the limitations of moving medical malpractice from a tort to contracts basis, particularly in the loss of the punishment aspect of punitive damages. In doing so, I present the way in which medical malpractice is currently implemented in the United States under tort law. I then briefly review current malpractice reform efforts, focusing more so on the idea of "no-fault" administrative systems. Here, I also explore the fundamental legal differences between contracts and tort. I then discuss the ethics of blame-shielding and whether or not we are losing something by failing to blame bad actors. In doing so, I focus on the ethical implications of punishment. Operating under the assumption that the current tort-based medical malpractice system is driving up health care costs, I conclude by proposing a hybrid system that combines contract theory with noneconomic punitive sanctions: a "no-fault fault system."


Characterization of the FMDV-serotype-O isolates collected during 1962 and 1997 discloses new topotypes, CEY-1 and WCSA-1, and six new lineages.
The genetic diversity of the FMD viruses collected from the outbreaks during the second half of the 20th Century in Sri Lanka was assessed in the present study. We sequenced the VP1 genomic region of the samples collected during FMDV epidemics caused by serotype O in Sri Lanka during 1962 and 1997. For comparison, we sequenced the VP1 of the related viral isolates collected from other Asian countries. We analyzed the VP1 sequences of the viral strains using the UPGMA method with uncorrected pairwise distances. Nucleotide divergence (ND) thresholds of 15%-20% and 5%-<15% were used to differentiate topotypes and lineages, respectively. We calibrated the divergence times and lineage-specific substitution rates using Bayesian-skyline models. Based on the ND estimations and phylogenetic relationships, we identified and named two new topotypes [CEYLON 1 (CEY-1) and WEST, CENTRAL AND SOUTH ASIA 1 (WCSA-1)] and six new lineages (Syr-62, Srl-77, Tur-69, May-78, Tai-87 and Bur-77) of serotype O. We believe that the novel topotypes and lineages named may have disappeared although they have similar substitution rates for epizootic outbreaks. Because the amino acid selection analysis revealed that the two topotypes and six lineages identified were under purifying selection during the outbreaks.


Diagnostic Performance of Retinopathy in the Detection of Diabetic Nephropathy in Type 2 Diabetes: A Systematic Review and Meta-Analysis of 45 Studies.
To conduct an evidence-based evaluation of diabetic retinopathy (DR) for the diagnosis of diabetic nephropathy (DN) in type 2 diabetics with kidney disease. We systematically searched PubMed, EMBASE, and the Cochrane Library from inception to June 27, 2018, including the reference lists of identified primary studies. A study was included if it (1) used DR as a diagnostic test for DN; and (2) used histological evaluation of renal tissues as the reference standard. The analysis included 45 studies (4,561 patients). A bivariate analysis yielded a sensitivity of 0.67 (95% CI 0.61-0.74) and a specificity of 0.78 (95% CI 0.73-0.82). The summary receiver operating characteristic curve analysis provided an area under the curve (AUC) of 0.79 (95% CI 0.76-0.83). In a setting of 41% prevalence of DN, the probability of DN would be 68% if the test of DR was positive, and the probability of DN would be 23% if it was negative. In addition, although the mean specificity of proliferative DR for the detection of DN was 0.99 (95% CI 0.45-1.00), the mean sensitivity was 0.34 (95% CI 0.24-0.44), and the AUC was 0.58 (95% CI 0.53-0.62). DR is helpful in diagnosing DN in persons with type 2 diabetes and kidney disease, but the severity of DR may not parallel the presence of DN.


What Is the Evidence That the Tissue Doppler Index E/e' Reflects Left Ventricular Filling Pressure Changes After Exercise or Pharmacological Intervention for Evaluating Diastolic Function? A Systematic Review.
Noninvasive echocardiographic tissue Doppler assessment (E/e') in response to exercise or pharmacological intervention has been proposed as a useful parameter to assess left ventricular (LV) filling pressure (LVFP) and LV diastolic dysfunction. However, the evidence for it is not well summarized. Clinical studies that evaluated invasive LVFP changes in response to exercise/other interventions and echocardiographic E/e' were identified from PubMed, Scopus, Embase, and Cochrane Library databases. We grouped and evaluated studies that included patients with preserved LV ejection fraction (LVEF), patients with mixed/reduced LVEF, and patients with specific cardiac conditions. Overall, we found 28 studies with 9 studies for preserved LVEF, which was our primary interest. Studies had differing methodologies with limited data sets, which precluded quantitative meta-analysis. We therefore descriptively summarized our findings. Only 2 small studies (N=12 and 10) directly or indirectly support use of E/e' for assessing LVFP changes in preserved LVEF. In 7 other studies (cumulative N=429) of preserved LVEF, E/e' was not useful for assessing LVFP changes. For mixed/reduced LVEF groups or specific cardiac conditions, results similar to preserved LVEF were found. We find that there is insufficient evidence that E/e' can reliably assess LVFP changes in response to exercise or other interventions. We suggest that well-designed prospective studies should be conducted for further evaluation.


Holstein's milk detection in cheeses inferred from melanocortin receptor 1 (MC1R) gene polymorphism.
For some French Registered Designation of Origin (RDO) cheeses Prim'Holstein's milk is not allowed for cheese making (e.g., Reblochon, Abondance, and Beaufort cheeses). To find molecular markers for Prim'Holstein's milk detection in RDO cheese, four genes affecting coat color in cattle (c-kit, MGH, TYRP1, and MC1R) have been sequenced for three mountain breeds and the Prim'Holstein breed. Only the MC1R gene (E-locus) has shown variation between the four breeds. Among the 25 French and Italian breeds sequenced for the MC1R gene, only the Vosgienne breed has presented the same allele as the black Prim'Holstein breed (E(D)). A quick and easy DNA-based method to detect Holstein's milk in RDO cheese is proposed based on ED allele detection. A DNA extraction from cheese, a preamplification of the gene and a competitive oligonuleotide priming PCR on MC1R mutations were performed. Using an automated sequencer, differences in fluorescence and fragment size reveal the allele type. This simple approach provides good reproducibility and is shown to be relatively sensitive, with a detection limit of about 1% of Holstein's milk in milk curd.


Molecular characterization of type 1 porcine reproductive and respiratory syndrome viruses (PRRSV) isolated in the Netherlands from 2014 to 2016.
Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of a devastating pig disease present all over the world. The remarkable genetic variation of PRRSV, makes epidemiological and molecular analysis of circulating viruses highly important to review current diagnostic tools and vaccine efficacy. Monitoring PRRS viruses supports modern herd management by explaining the source of found viruses, either internally or externally from the herd. No epidemiological or molecular study has been published on circulating PRRS-viruses in the Netherlands, since the early nineties. Therefore, the objective of this study is to investigate circulating PRRS-viruses in the Netherlands in 2014, 2015 and 2016 on a molecular level by sequencing ORF2, ORF3, ORF4, ORF5, ORF6 and ORF7. The results demonstrate that the 74 PRRSV strains belong to PRRSV-1, but the diversity among strains is high, based on nucleotide identity, individual ORF length and phylogenetic trees of individual ORFs. Furthermore, the data presented here show that the phylogenetic topology of some viruses is ORF dependent and suggests recombination. The identity of the strain of interest might be misinterpreted and wrong conclusions may be drawn in a diagnostic and epidemiological perspective, when only ORF5 is analyzed, as performed in many routine sequencing procedures.


Evaluation of an indirect fluorescent-antibody stain for detection of Pneumocystis carinii in respiratory specimens.
Two prospective studies were undertaken to evaluate a commercial indirect fluorescent-antibody (IFA) stain for the detection of Pneumocystis carinii in respiratory specimens from individuals at risk for or with the acquired immunodeficiency syndrome. The first study compared IFA with Diff-Quik (DQ; a rapid Giemsa-like stain) for detecting P. carinii in 95 induced sputa obtained from 77 asymptomatic patients who had survived one previous episode of P. carinii pneumonia and who were being treated prophylactically with aerosolized pentamidine. Only one induced sputum specimen was found to contain P. carinii; organisms were detected by both stains. The second study compared the performance of the IFA stain versus DQ, modified toluidine blue O, and Gomori methenamine silver stains for detecting P. carinii in symptomatic individuals at risk for or with acquired immunodeficiency syndrome. Of 182 specimens examined, P. carinii was detected in 105 by one or more stains; the DQ stain detected 73 (70%), the modified toluidine blue O stain detected 75 (71%), the Gomori methenamine silver stain detected 76 (72%), and the IFA stain detected 95 (90%). The IFA stain was more sensitive (P less than 0.01) than the other traditional stains for detecting P. carinii; however, a subsequent clinical evaluation revealed that a subset of IFA-positive-only specimens were from patients whose clinical symptoms resolved without specific anti-P. carinii therapy.


Clonal evolution of t(14;18) follicular lymphomas demonstrated by immunoglobulin genes and the 18q21 major breakpoint region.
A 2.8-kilobase major breakpoint region on chromosome segment 18q21 is the site of most t(14;18) translocations typical of human follicular lymphomas. Breaks are focused at the 5' end of joining (JH) regions of immunoglobulin (Ig) on chromosome 14, indicating that the translocation occurs at a pre-B-cell stage during attempted heavy (H) chain joining. A new gene from 18q21 (Bcl-2) is placed in the H chain locus creating a unique, translocation-specific JH;18q21 rearrangement that presumably represents a transformation event. In addition, normal Ig gene joining occurs in a H before light (L) chain and K before lambda cascade, creating ordered clonal markers. These serial markers were examined to determine if variations in Ig gene patterns during the natural history of lymphomas represent the emergence of truly separate neoplasms or heterogeneity of a single neoplasm. We examined 45 serial biopsies from 16 B follicular lymphoma patients; six cases showed variation in Ig gene patterns over time. Seven individuals had a detectable JH;18q21 rearrangement present, and it remained unchanged over 5-10 years. Further rearrangements of H chain genes occurred on the normal chromosome 14 within evolving subclones of the original tumor. Lambda L chains also underwent additional rearrangements in two instances, while K gene patterns remained unchanged. All variations in the normal H and L chain genes were 2 degrees rearrangements occurring at a mature B-cell stage following the initial successful rearrangement of a H and L chain. In contrast the t(14;18) breakpoint was conserved in each individual, indicating that evolving neoplastic subpopulations arose from a common clonal progenitor cell.


Recurrent pterygium treatment using mitomycin C, double amniotic membrane transplantation, and a large conjunctival flap.
The aim of this study was to evaluate the clinical outcomes of surgery for recurrent pterygia using mitomycin C (MMC), double amniotic membrane transplantation (AMT), and a large conjunctival flap. This retrospective case series included 31 eyes in 31 patients with recurrent pterygia. All patients underwent pterygium excision, application of MMC, double AMT, and placement of a large conjunctival flap. Outcome measures were visual acuity, astigmatism, and recurrence. Recurrence was defined as the presence of fibrovascular proliferative tissue crossing the limbus. The patients' mean age was 68.2 years. The mean follow-up period was 3.6 years. The mean preoperative and postoperative best-corrected visual acuities (logMAR conversion) were 0.23 and 0.13, respectively. There was a significant difference between the mean preoperative (-3.85 D) and postoperative (-2.22 D) astigmatism. The recurrence rate was 3.2% (1/31 cases). Surgical pterygium excision with application of MMC, double AMT, and placement of a large conjunctival flap was an effective treatment for recurrent pterygia.


The impact of ketogenic diet on the onset and progression of multiple sclerosis.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and neurodegeneration. Current research suggests that diet may influence disease course, severity of symptoms, and quality of life in MS patients. The ketogenic diet (KD) has been used for more than a century as a therapeutic approach for various medical conditions. It was originally developed in the 1920s as a treatment option for epilepsy, and especially in the last 30 years, has gained popularity for its potential benefits in a variety of neurological conditions other than epilepsy. This prompted us to perform a literature survey regarding the effect of KD on the onset and progression of MS. The here reviewed 15 original research articles including in vitro, preclinical, and clinical studies provide evidence for the safety and feasibility of the KD in MS, showing potential neuroprotective effects and positive impacts on cellular metabolism and disease outcome. Since the literature is limited and most studies were conducted with low numbers of MS patients and rather exploratory in nature, further studies with larger cohorts are needed to gain a better understanding of the mechanisms by which the improvements of the MS disease course are achieved.


Uniportal Video-Assisted Thoracoscopic Surgery Resection of a Giant Midesophageal Diverticulum.
We describe a new video-assisted technique for the management of a giant midesophageal diverticulum using a single 5-cm port. It maintained the same principles of the traditional open technique as diverticulectomy, myotomy, and fundoplication. The better visualization of the main esophageal body, diverticulum, and esophagogastric junction and the better alignment of the stapler cartridge to the longitudinal axis of the esophagus are all technical factors supporting our procedure. Heavily calcified mediastinal lymph nodes and diffuse pleural adhesions are the main contraindications. However, future experiences are needed before this technique can be recommended as acceptable treatment.


Good's syndrome and COVID-19: case report and literature review.
Good's syndrome (GS) is an adult-onset acquired immunodeficiency, in which patients present with thymoma and hypogammaglobulinemia (HGG). GS is characterized by low to absent peripheral B cells and impaired T-cell mediated immunity, often resulting in various (opportunistic) infections and concurrent autoimmune disorders. In this case report, we present a case of a patient with GS and coronavirus disease 2019 (COVID-19) infection after surgical removal of a thymoma. The simultaneous occurence of these two entities is extremely rare. A 55-year-old man presented with oral lichen planus and cutaneous lesions. Additional symptoms included a weight loss of 5 kilograms in the last six months. Computed tomography (CT) and positron emission tomography (PET) of the chest showed a large anterior mediastinal mass with a maximum diameter of 10 centimetres. A core needle biopsy was performed, which led to a pathological diagnosis of thymoma type AB. In addition to these earlier findings, laboratory analysis revealed HGG. The combination of a thymoma and HGG led to a diagnosis of GS. Induction chemotherapy with cisplatin-etoposide was started, however, the patient developed COVID-19 after 2 cycles. Treatment with remdesivir was initiated and, subsequently, a thymectomy via sternotomy was performed. Final pathology confirmed a thymoma type AB of 14 centimetres, fully encapsulated, and without invasion. Resection margins were negative and the tumour was classified as pT1aN0, R0 resection. The patient has received immunoglobulin treatments every 4 weeks for his GS and has not developed any new infections since the start of this therapy. Patients with GS are prone to developing (pulmonary) infections. Clinicians should be aware of the possible clinical effects of COVID-19 infections in this patient population.


Glycans-by-design: engineering bacteria for the biosynthesis of complex glycans and glycoconjugates.
There is an urgent need for new tools that enable better understanding of the structure, recognition, metabolism, and biosynthesis of glycans as well as the production of biologically important glycans and glycoconjugates. With the discovery of glycoprotein synthesis in bacteria and functional transfer of glycosylation pathways between species, Escherichia coli cells have become a tractable host for both understanding glycosylation and the underlying glycan code of living cells as well as for expressing glycoprotein therapeutics and vaccines. Here, we review recent efforts to harness natural biological pathways and engineer synthetic designer pathways in bacteria for making complex glycans and conjugating these to lipids and proteins. The result of these efforts has been a veritable transformation of bacteria into living factories for scalable, bottom-up production of complex glycoconjugates by design.


Characterization and measurement of cytoplasmic and nuclear oestradiol-17 beta-receptor proteins in benign hypertrophied human prostate.
The demonstration and partial characterization of a high-affinity saturable binding component for oestradiol-17 beta in the cytosol and nuclear extract of the benign hypertrophied human prostate is reported. This binding component was found to precipitate with protamine sulphate and to exhibit marked specificity for oestradiol and diethylstilboestrol (DES) but not dihydrotestosterone (DHT) or progesterone. Analysis of oestradiol-labelled cytosol on low ionic strength glycerol gradients revealed a binding component with a sedimentation coefficient of 4S which was inhibited with DES but not DHT and destroyed either by preheating labelled cytosol at 45 degrees C for 30 min or by treatment with the sulphydryl blocking agent, parachloromercureobenzoate. The oestradiol-binding complex precipitated by ammonium sulphate was found to have an isoelectric point (pI) of 6.3 as analysed on polyacrylamide-gel plates. The oestradiol-binding component in the nuclear extract also exhibited similar steroid specificity and sedimented with a coefficient of 2.8S on high ionic strength glycerol gradients. Isoelectric focusing of the heparin-extracted nuclear oestradiol-binding complex revealed a pI of 6.0. The dissociation constants (Kd) and the concentrations of the cytoplasmic and nuclear oestradiol-binding sites in 19 samples of benign hypertrophied prostates were estimated by Scatchard plot analyses. The mean Kd and concentration of binding sites in the cytosol were 2.9 +/- 2.6 (S.D.) nmol/l and 11.7 +/- 8.4 fmol/mg protein respectively. The corresponding values for nuclear extract were 4.1 +/- 7.5 nmol/l and 347.1 +/- 415.5 fmol/mg DNA respectively. There was no significant difference between the mean concentration of oestradiol-binding sites in the two cellular fractions.


User charges and utilisation of obstetric services in the National Capital District, Papua New Guinea.
This cross-sectional study examined user charges on the utilization of obstetric services in the 4 urban clinics and antenatal and postnatal wards of the Port Moresby General Hospital (PMGH) in the National Capital District, Papua New Guinea. Analysis of previous records showed attendance to antenatal clinics on first visits declined by 30% soon after the introduction of use charges. However, the frequency of attendances increased and stabilized 12 months after the introduction of the user fees. The mean age for the 482 mothers interviewed was 25 years (range = 15-46 years, SD = 5.3). Over 50% of mothers were between 15-24 years of age and 47% over 24 years. 98.6% were married and a small proportion were single and divorcees (1.4%). Over 85% of mothers had some formal education while 15% without. The frequency of hospital deliveries did not change despite increased in user charges in the PMGH delivery and postnatal care services. Twenty four percent of mothers interviewed indicated they were unable to pay user fees. Mothers unable to pay the user charges were those without income or whose spouses were without regular income. In 23.2% of mothers with some income, majority indicated ability to pay the user fees. There was a minority group of mothers without income but relied heavily on their spouses income to meet the user fees. Mothers living in households with some income were twice more likely (OR = 2.18, 95% CI 1.24-3.83, p = 0.002) to have the ability to pay user fees than those without. Two other significant indicators associated with mother's ability to pay user fees were employment and knowledge of existence of the user charges. Over 79% of mothers indicated willingness to pay user charge fees. Mothers with income were nearly three times more likely (OR = 2.77, 95% CI 1.36-5.78, p = 0.002) willing to pay user charge fees than those without income. Other indicators that showed significant association with willingness to pay user charge fees were employment, income and knowledge of user charges. Although small proportion of mothers were unable to meet the user charges, results in this study showed majority of mothers were able and willing to pay user charges if they had prior information to the charges and supported by some form of income. The results of the study suggests the typical support practised by the society where the spouse and relatives assist with health care especially with maternal health is encouraging. However, the scope of this study cannot be used to generalise the trend in PNG because the scenerio in the rural areas will vary from urban.


Color-discrimination threshold determination using pseudoisochromatic test plates.
We produced a set of pseudoisochromatic plates for determining individual color-difference thresholds to assess test performance and test properties, and analyzed the results. We report a high test validity and classification ability for the deficiency type and severity level [comparable to that of the fourth edition of the Hardy-Rand-Rittler (HRR) test]. We discuss changes of the acceptable chromatic shifts from the protan and deutan confusion lines along the CIE xy diagram, and the high correlation of individual color-difference thresholds and the red-green discrimination index. Color vision was tested using an Oculus HMC anomaloscope, a Farnsworth D15, and an HRR test on 273 schoolchildren, and 57 other subjects with previously diagnosed red-green color-vision deficiency.


Modulating physical properties of porcine urethra with injection of novel biomimetic proteoglycans ex vivo.
Urinary incontinence is a significant challenge for women who are affected by it. We propose augmenting the tissue structure to restore normal biomechanics by molecularly engineering the tissue using a novel family of biomimetic proteoglycans (BPGs). This work examines the ability of BPGs to modulate the mechanical and physical properties of porcine urethras ex vivo to determine the feasibility of BPGs to be implemented as molecular treatment for stress urinary incontinence (SUI). We investigated compliance by performing a unique radial expansion testing method using urethras from six- to nine-month-old pigs. The urethras were injected with 0.5 ml BPG solution at three sites every approximately 120° (conc.: 25 mg ml-1, 50 mg ml-1 and 75 mg ml-1 in 1× phosphate-buffered saline (PBS); n = 4 per group) and compared them with PBS-injected controls. Young's modulus was calculated by treating the urethra as a thin-walled pressure vessel. A water uptake study was performed by soaking 10 mm urethra biopsy samples that were injected with 0.1 ml BPG solution (conc.: 50 mg ml-1, 100 mg ml-1 and 200 mg ml-1 in 1× PBS; n = 6 per group) in 5 ml PBS for 24 h. Although there was no significant difference in Young's modulus data, there were differences between groups as can be seen in the raw radial expansion testing data. Results showed that BPGs have the potential to increase hydration in samples, and that there was a significant difference in water uptake between BPG-injected samples and the controls (100 mg ml-1 samples versus PBS samples, p < 0.05). This work shows that BPGs have the potential to be implemented as a molecular treatment for SUI, by restoring the diminished proteoglycan content and subsequently increasing hydration and improving the compliance of urethral tissue.


Cyclin B1 overexpression induces cell death independent of mitotic arrest.
Microtubule inhibitors are widely used in cancer chemotherapy. These drugs characteristically induce mitotic arrest and cell death but the mechanisms linking the two are not firmly established. One of the problems is that cancer cells vary widely in their sensitivity to these agents, and thus comparison of data from different systems is difficult. To alleviate this problem we sought to molecularly induce mitotic death and study its mechanisms, by expressing non-degradable cyclin B (R42A) in HeLa cells. However, this approach failed to induce significant mitotic arrest, Cdk1 activation, or phosphorylation of anti-apoptotic Bcl-2 proteins, all characteristics of cells treated with microtubule inhibitors. Furthermore, cyclin B1-R42A induced rapid cell death, and when expressed in synchronized cells, cell death occurred in G1 phase. Decreasing the plasmid concentration reduced transfection efficiency but restored mitotic arrest and eliminated non-specific death. These results show that inappropriate overexpression of cyclin B1 causes non-specific cell death and suggest caution in its use for the study of mitotic events.


Predicting recurrent laryngeal nerve invasion by preoperative ultrasonography in patients with thyroid carcinoma.
For thyroid cancer staging, evaluation of extent of local invasion, including recurrent laryngeal nerve (RLN), may assist surgical decision-making. This prospective study evaluated patients who underwent thyroidectomy at a single tertiary-level academic institution. Patients with complete clinical information and ultrasound imaging of thyroid carcinoma and RLN were enrolled. Those who had thyroidectomy before or did not fit the above conditions were excluded. Patients were assigned to either a development or validation cohort. Development of models was constructed in a primary cohort based on preoperative ultrasound features and clinicodemographic data from August 2020 to December 2021. Validation of the models was then performed on an independent cohort between January and March of 2022. Multivariate logistic regression and nomograms were mainly used for statistical analysis. Using data from 816 patients (80 RLN invasion), we built nomogram 1 based on age [95% confidence interval (CI): 1.315 to 145.933, P=0.029], body mass index (BMI; 95% CI: 1.228 to 10.874, P=0.020), tumor size (95% CI: 4.677 to 1,373.1, P=0.002), tumor adjacent to medial (95% CI: 1.816 to 26.713, P=0.005) and posterior thyroid capsules (95% CI: 5.567 to 756.583, P=0.001), and distance <1 mm between tumor and the RLN (95% CI: 10.389 to 826.746, P<0.001). Nomogram 2 was built based on tumor adjacent to the posterior thyroid capsule (95% CI: 2.922 to 53,074.51, P=0.017), distance <1 mm between tumor and the RLN (95% CI: 1.478 to 1,241.646, P=0.029), and loss of typical fascicular echotexture of the RLN along the long axis (95% CI: 35.11 to 53,272.81, P<0.001). In the validation cohort, nomogram 1 and 2 showed sensitivities of 94.74% and 57.89%, specificities of 74.12% and 95.29%, positive predictive values (PPV) of 45.00% and 73.26%, negative predictive values (NPV) of 98.43% and 91.03%, accuracies of 76.92% and 88.46%, and C-indices of 0.86 and 0.89. Preoperative ultrasound is a feasible approach to evaluate RLN invasion in patients with thyroid carcinoma. Nomogram 1 may sensitively identify the risk of RLN invasion, and it may be checked using the more specific and accurate nomogram 2 to reduce false positives.


[Predictive prognostic factors in severe patients].
International classification of heat illness including heat stroke, heat exhaustion, the others is well known. However, the new classification from the grade III(severe) to the grade I(mild) is more common in Japan. There is a good correlation between the two classifications. The Heatstroke Surveillance Committee of the Japanese Association for Acute Medicine has collected the data using the new classification. The outcome of patients who were mechanically ventilated due to heat illness was not affected by cooling procedures but independently associated with systolic blood pressure and SpO2 at the scene, and arterial base excess on admission.


Fetal alcohol syndrome.
The most notable features of fetal alcohol syndrome involve the face and eyes, and include microcephaly, short palpebral fissures, an underdeveloped philtrum and a thin upper lip. Evidence of intrauterine or postnatal growth retardation, mental retardation or other neurologic abnormalities, and at least two of the typical facial features are necessary to make the diagnosis. Newborns with the syndrome may be irritable, with hypotonia, severe tremors and withdrawal symptoms. Mild mental retardation, the most common and serious deficit, and a variety of other anomalies may accompany fetal alcohol syndrome. Sensory deficits include optic nerve hypoplasia, poor visual acuity, hearing loss, and receptive and expressive language delays. Atrial and ventricular septal defects, as well as renal hypoplasia, bladder diverticula and other genitourinary tract abnormalities, may occur. Complete abstinence during pregnancy is recommended, since alcohol consumption in each trimester has been associated with abnormalities, and the lowest innocuous dose of alcohol is not known.


Are mountain habitats becoming more suitable for generalist than cold-adapted lizards thermoregulation?
Mountain lizards are highly vulnerable to climate change, and the continuous warming of their habitats could be seriously threatening their survival. We aim to compare the thermal ecology and microhabitat selection of a mountain lizard, Iberolacerta galani, and a widely distributed lizard, Podarcis bocagei, in a montane area. Both species are currently in close syntopy in the study area, at 1,400 m above the sea level. We determined the precision, accuracy and effectiveness of thermoregulation, and the thermal quality of habitat for both species. We also compared the selection of thermal microhabitats between both species. Results show that I. galani is a cold-adapted thermal specialist with a preferred temperature range of 27.9-29.7 °C, while P. bocagei would be a thermal generalist, with a broader and higher preferred temperature range (30.1-34.5 °C). In addition, I. galani selects rocky substrates while P. bocagei selects warmer soil and leaf litter substrates. The thermal quality of the habitat is higher for P. bocagei than for I. galani. Finally, P. bocagei achieves a significantly higher effectiveness of thermoregulation (0.87) than I. galani (0.80). Therefore, these mountain habitat conditions seem currently more suitable for performance of thermophilic generalist lizards than for cold-specialist lizards.


[Occupational bronchopulmonary pathology caused by woodworking: diagnostic approach].
Woodworkers have a varied breathing pathology, with involvement of the upper airways mainly by ethmoidal cancers and rhinitis, tracheo-bronchitis with asthma, hypersensitivity pneumonitis due to wood moulds. The physiopathological mechanisms are numerous and often intricate: physical mechanism due to the irritant effect of wood dust, toxic mechanism caused by chemical substances which are present in wood dust or come from wood preservation products, immunological and allergic mechanism in which different allergens are concerned. Breathing pathology is the subject of 2 tables (No. 47 and 36) among those concerning occupational diseases. Lung function tests play an important role in the diagnosis of these diseases, with their 3 main objectives: search for airway obstruction, evaluation of bronchial hyperreactivity by means of non-specific challenge tests, and specific challenge tests performed in a laboratory or on the work site.


Localization and quantification of drugs in animal tissues by use of desorption electrospray ionization mass spectrometry imaging.
Mass spectrometric imaging (MSI) has emerged as a powerful technique to obtain spatial arrangement of individual molecular ions in animal tissues. Ambient desorption electrospray ionization (DESI) technique is uniquely suited for such imaging experiments, as it can be performed on animal tissues in their native environment without prior treatments. Although MSI has become a rapid growing technique for localization of proteins, lipids, drugs, and endogenous compounds in different tissues, quantification of imaged targets has not been explored extensively. Here we present a novel MSI approach for localization and quantification of drugs in animal thin tissue sections. DESI-MSI using an Orbitrap mass analyzer in full scan mode was performed on 6 μm coronal brain sections from rats that were administered 2.5 mg/kg clozapine. Clozapine was localized and quantified in individual brain sections 45 min postdose. External calibration curves were prepared by micropipetting standards with internal standard (IS) on top of the tissues, and average response factors were calculated for the scans in which both clozapine and IS were detected. All response factors were normalized to area units. Quantifications from DESI-MSI revealed 0.2-1.2 ng of clozapine in individual brain sections, results that were further confirmed by extraction and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis.


T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences.
Diversity of T cell receptor (TCR) repertoires, generated by somatic DNA rearrangements, is central to immune system function. However, the level of sequence similarity of TCR repertoires within and between species has not been characterized. Using network analysis of high-throughput TCR sequencing data, we found that abundant CDR3-TCRβ sequences were clustered within networks generated by sequence similarity. We discovered a substantial number of public CDR3-TCRβ segments that were identical in mice and humans. These conserved public sequences were central within TCR sequence-similarity networks. Annotated TCR sequences, previously associated with self-specificities such as autoimmunity and cancer, were linked to network clusters. Mechanistically, CDR3 networks were promoted by MHC-mediated selection, and were reduced following immunization, immune checkpoint blockade or aging. Our findings provide a new view of T cell repertoire organization and physiology, and suggest that the immune system distributes its TCR sequences unevenly, attending to specific foci of reactivity.


Brain contrasts between migratory and nonmigratory North American lark sparrows (Chondestes grammacus).
The impact of evolving migratory behavior on brain organization in birds has been a foundational question in the emerging field of neuroecology. One generalization that seems to be approaching consensus is that migratory species/populations have smaller brain volumes than their nonmigratory comparison groups. The lark sparrow (Chondestes grammacus) is a North American species characterized by migratory and nonmigratory populations. Consistent with what has been observed in other species/population comparisons, we found that, relative to body weight, migratory females from Nebraska have smaller brain volumes than nonmigratory females from Texas. We also carried out an exploratory, higher-order analysis of possible differences in the volumes of a number of telencephalic subdivisions. Although our small sample size precluded statistical verification of any difference, noteworthy was that, although there seemed to be no indication of a difference in the relative hippocampal volume between the two populations, the migratory birds from Nebraska showed a clear trend toward a smaller nidopallium. The importance of higher-resolution, brain subdivisional analyses has been discussed.