Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy.
Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months (n=33) and a second group with PFS⩾6 months (n=23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P=0.0157 and P=0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa, which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.


Race differentials in partnering patterns among older U.S. men: influence of androgens or religious participation?
Using nationally representative data from the 2005-2006 U.S. National Social Life, Health, and Aging Project, this study queried race differences in older men's polyamorous and casual sex, as well as stratification of these patterns by endogenous androgens (testosterone and dehydroepiandrosterone) and by regular religious participation. Results suggested that despite their respective prominence in the biomedical and sociological literatures on sex, neither "bottom up" hormonal influences nor "top down" religious social control were major structuring factors for greater lifetime as well as current likelihood of these behaviors among older Black than White men. Androgens were higher among the former, but did not seem to drive these race patterns. Regular church attendance--while negatively associated with non-monogamous and prolific partnering, and hence possibly a social control mechanism among all men--played only a weak role in moderating ethnic variations in these behaviors. It is speculated that these differences may instead be driven by unexamined current or early factors, including, perhaps, Black men's greater exposure to sexualizing processes in adolescence that, even in late life, may outweigh more temporally-proximal influences.


Tension-free vaginal tape: analysis of risk factors for failures.
To investigate whether there are any demographic, clinical, or urodynamic variables associated with an increased risk of failure in women undergoing surgery with tension-free vaginal tape (TVT). We retrospectively analysed 325 consecutive patients who had been operated with the TVT procedure. Patients were assessed with a complete history, physical examination, and urodynamic testing. The operation was done under local or epidural anesthesia and any further surgical procedure was added as indicated. The postoperative evaluation included collection of data on intra- and postoperative complications and analysis of outcomes. The outcome of surgical treatment was evaluated subjectively and objectively. The Statistical Package for Social Sciences (SPSS, Chicago, Illinois, USA) was used for data analysis; P<0.05 was considered significant. The overall complication rate was 14%, voiding dysfunction being the most common. Three hundred and one women were available for the analysis of surgical outcome and the mean follow-up was 34+12 months (median 32 months). Subjectively, 269 women (89%) were cured by the procedure and 13 (4.3%) reported marked improvement. An objective cure was achieved in 263 (87%); 38 patients still having leakage while coughing during postoperative cystometry. Among the numerous presumed risk factors for failed antiincontinence surgery only urethral hypomobility and recurrent stress urinary incontinence were significantly associated with failure of the TVT procedure in our study. However, even in these complicated situations, the cure rate was more than 70%.


MANAGEMENT OF LUNG ABSCESS WITH PERCUTANEOUS CATHETER DRAINAGE.
Percutaneous catheter drainage was used to treat 12 among 34 cases of lung abscesses, who were refractory to medical therapy, severely ill and high risk cases for surgery. A complete clinical and radiological recovery was achieved in all the cases who underwent catheter drainage, thereby obviating the need for surgery. None of the cases had catheter or procedures related complications. From this study it is inferred that percutaneous transthoracic catheter drainage is a safe and an effective modality of therapy for patients with lung abscess in whom medical therapy has failed and those who are unsuitable for surgery.


NHS Direct usage in a GP population of children under 5 years: is NHS Direct used by people with the greatest health need?
This study compares health status, demographic and socioeconomic characteristics of users and non-users of NHS Direct in order to establish whether the service is being used by people with the greatest need for healthcare services. It suggests that use of NHS Direct is widespread among carers of children under 5 years old, but there is evidence that it may not be accessed equitably by those from ethnic minorities, lower socioeconomic groups and those with established ill health.


Nuclear transcription in preblastoderm Drosophila embryos.
Drosophila preblastoderm (0 - 2.5 hr post-oviposition) embryos incorporate [32P] phosphate into newly synthesized RNA. A fraction of this RNA can be ascribed to nuclear transcription by virtue of its hybridization to nuclear DNA. This confirms the electron microscopic observation of McKnight and Miller (1) that nuclear transcription takes place at a low level in preblastoderm embryos. These nuclear transcripts are relatively small (7 - 12S), poly A(+) and appear on polysomes. Translation of newly synthesized nuclear transcripts during preblastoderm indicates that a zygotic genome contribution to embryonic phenotype may occur earlier in development than previously thought.


Linkage of Maternal Caregiver Smoking Behaviors on Environmental and Clinical Outcomes of Children with Asthma: A Post-Hoc Analysis of a Financial Incentive Trial Targeting Reduction in Pediatric Tobacco Smoke Exposures.
(1) Background: Monthly variability in smoking behaviors in caregivers of pediatric asthmatics yields questions of how much and when does smoking reduction result in improved environmental and clinical outcomes. (2) Methods: Post hoc analysis of data from a 6 month pilot randomized-control trial occurring from May 2017 to May 2018 in Baltimore City (MD, USA). The initial trial's primary intervention explored the utility of financial incentives in modifying caregiver smoking behaviors. Post hoc analyses examined all dyads independent of the initial trial's randomization status. All caregivers received pediatric tobacco smoke harm reduction education, in addition to monthly encouragement to access the state tobacco quitline for individual phone-based counseling and nicotine replacement therapy. Maternal caregivers who were active cigarette smokers and their linked asthmatic child (aged 2-12 years) were grouped into two classifications ("high" versus "low") based on the child and caregiver's cotinine levels. A "low" cotinine level was designated by at least a 25% reduction in cotinine levels during 3 months of the trial period; achieving ≤2 months of low cotinine levels defaulted to the "high" category. Twenty-seven dyads (caregivers and children) (total n = 54) were assigned to the "high" category, and eighteen dyads (caregivers and children) (total n = 36) were allocated to the "low" category. The primary outcome measure was the correlation of caregiver cotinine levels with pediatric cotinine values. Secondary outcomes included asthma control, in addition to caregiver anxiety and depression. (3) Results: Caregivers with 3 months of ≥25% decrease in cotinine levels had a significantly greater mean change in child cotinine levels (p = 0.018). "Low" caregiver cotinine levels did not significantly improve pediatric asthma control (OR 2.12 (95% CI: 0.62-7.25)). Caregiver anxiety and depression outcomes, measured by Patient Health Questionnaire (PHQ)-4 scores, was not significantly different based on cotinine categorization (p = 0.079); (4) Conclusion: Reduced pediatric cotinine levels were seen in caregivers who reduced their smoking for at least 3 months, but clinical outcome measures remained unchanged.


Chronic rhinitis.
The author provides a well-detailed update on chronic rhinitis, the most common disease of the respiratory tract. Discussed are the anatomy and physiology of the nose, investigation of the patient, etiology, and treatment, including avoidance of provoking factors, pharmacologic therapy, and immunotherapy.


A designed metal-organic framework based on a metal-organic polyhedron.
A C(3) symmetric ligand with three 1,3-benzenedicarboxylate units has been used to construct a metal-organic framework with a (3,24)-connected network topology, where the nanometre-sized metal-organic cuboctahedra (MOCs) have been incorporated solely into a cubic close packing (CCP) arrangement, which led to superoctahedral and supertetrahedral cavities.


Laser dentistry: a new application of excimer laser in root canal therapy.
We report the first study of the application of excimer lasers in dentistry for the treatment of dental root canals. High-energy ultraviolet (UV) radiation emitted by an XeCl excimer laser (308 nm) and delivered through suitable optical fibers can be used to remove residual organic tissue from the canals. To this aim, UV ablation thresholds of dental tissues have been measured, showing a preferential etching of infiltrated dentin in respect to healthy dentin, at laser fluences of 0.5-1.5 J/cm2. This technique has been tested on extracted tooth samples, simulating a clinical procedure. Fibers of decreasing core diameters have been used to treat different sections of the root canal down to its apical portion, resulting in an effective, easy, and fast cleaning action. Possible advantages of excimer laser clinical applications in respect to usual procedures are also discussed.


Photoinduced kinetics of bacteriorhodopsin in a dried xerogel glass.
Time-resolved absorption measurements of the formation and decay kinetics of the M (deprotonated) photocycle intermediate of bR purple membranes entrapped within a dried xerogel glass have been investigated. The dramatic change observed for the M state decay time is in contrast to the relatively insensitive half life reported for the M intermediate of the D96N mutant entrapped within a dried sol-gel glass. The decay kinetics of the M intermediate was observed to slow by a factor of almost 100 when the solvent was removed from the wet-gel to form the dry xerogel glass. Very long aging times for wet-gels resulted in highly biexponential M state decay kinetics. Upon drying, the M state formation rate initially decreased relative to that in solution before increasing in the dry xerogel to a formation rate nearly three times faster than in solution.


Tumor Stiffness Measurements on MR Elastography for Single Nodular Hepatocellular Carcinomas Can Predict Tumor Recurrence After Hepatic Resection.
Tumor stiffness (TS), measured by magnetic resonance elastography (MRE), could be associated with tumor mechanical properties and tumor grade. To determine whether TS obtained using MRE is associated with survival in patients with single nodular hepatocellular carcinoma (HCC) after hepatic resection (HR). Retrospective. In all, 95 patients with pathologically confirmed HCCs. 1.5T/3D spin-echo echo-planar imaging MRE. TS values of the whole tumor (TS-WT) and of a solid portion of the tumor (TS-SP) after excluding the necrotic area were measured on stiffness maps. Known imaging prognostic factors of HCC were also analyzed. After surgery, pathologic findings were evaluated from resected pathology specimens. Fisher's exact test and the Mann-Whitney U-test were performed to determine the significance of differences according to the tumor grade. Overall survival (OS) / recurrence-free survival (RFS) analyses were performed using Kaplan-Meier analyses and Cox multivariable models. The average TS-WT was 2.14 ± 0.74 kPa, and the average TS-SP was 2.51 ± 1.07 kPa. The cumulative incidence of RFS was 73.1%, 63.1%, and 57.3% at 1, 3, and 5 years, respectively. The TS-WT, TS-SP, and tumor size (≥5 cm) were significant prognostic factors for RFS (P < 0.001; P < 0.001; P = 0.017, respectively). The estimated overall 1-, 3-, and 5-year survival rates were 95.7%, 86.9%, and 80.8%, respectively. The alpha-fetoprotein changes, platelets, tumor size (≥5 cm), and vascular invasion in pathology were significant predictive factors for overall survival (all P < 0.05). Tumor necrosis, TS-WT, TS-SP, and vascular invasion in pathology were significantly correlated with poorly differentiated HCC (all P < 0.05). The TS-WT, TW-SP, and tumor size (≥5 cm) were significant predictive factors of RFS after HR in patients with HCC. Level of Evidence Technical Efficacy Stage 5 J. MAGN. RESON. IMAGING 2021;53:587-596.


A 4D-QSAR study on anti-HIV HEPT analogues.
We used the 4D-QSAR method coupled with the PLS analysis and uninformative variable elimination or its variants for the investigations of the antiviral activity of HEPT, a series of conformationally flexible molecules that bind HIV-1 reverse transcriptase. An analysis of several Hopfinger's and SOM-4D-QSAR models indicated that both methods yield comparable results. Generally, charge descriptors provide better modeling efficiency. We have shown that the method properly indicates the mode of interaction revealed by X-ray studies. It also allows us to calculate highly predictive QSAR models.


Recent increases in mumps incidence in Australia: the "forgotten" age group in the 1998 Australian Measles Control Campaign.
To describe the epidemiology of mumps and examine potential factors underlying the recent increase in the incidence of mumps in Australia. Analytical descriptive study, for all Australian states and territories, of mumps notifications (1994-2007); hospitalisations for mumps (1994-2005); and mumps seroprevalence in a nationally representative sample of 2787 subjects (1997). Incidence of notifications and hospitalisations for mumps; seropositivity by birth cohort. Notified mumps cases increased from 60 in 2002 to 231 in 2005 and 512 in 2007. Between 1994 and 2005, there were 605 hospitalisations for mumps. Mumps seropositivity in all states and territories in 1997 was high (range, 87.1%-94.3%). The predominant age group affected by mumps shifted to adults over time: between 2005 and 2007, 41% of cases occurred among people aged 20-29 years. Cases were concentrated among the birth cohort of 1978 to 1982, who had higher rates of notifications and hospitalisations for mumps and a lower seropositivity rate (92% [95% CI, 89%-94%]) than other birth cohorts. The birth cohort of 1978 to 1982 was too old to reliably receive a second dose of measles-mumps-rubella (MMR) vaccine in the 1998 Australian Measles Control Campaign and too young to have had mumps infection. Renewed efforts to maximise two-dose MMR coverage are important for prevention of mumps and measles in young adults.


Association of non-synonymous variants in WIPF3 and LIPA genes with abdominal aortic aneurysm: an autopsy study.
Abdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease. We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants (SNVs) associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine genetic associations. Age, gender, and other risk factors of AAA were analyzed as covariates. 118 subjects with AAA and 2145 subjects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction (P < 2.05×10-6). The strongest associations were found with rs3750092 (p.E321G, OR: 0.36, 95% CI: 0.24-0.56, P = 6.09 × 10-6), a variant in the WAS/WASL interacting protein family 3 (WIPF3), and with rs1051338 (p.T16P, OR: 2.50, 95% CI: 1.70-3.66, P = 2.79 × 10-6) and rs2246942 (intronic, OR: 2.32, 95% CI: 1.58-3.41, P = 1.61 × 10-5), variants in the lysosomal acid lipase A (LIPA). LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages of atheromatous plaques. This study suggests that WIPF3 and LIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.


Women's Experiences of the Effect of Financial Strain on Parenting and Mental Health.
To develop a conceptual theory to describe how financial strain affects women with young children to inform clinical care and research. Qualitative, grounded theory. Participants were recruited from the waiting area of a pediatric clinic and an office of the Special Supplemental Nutrition Program for Women, Infants, and Children embedded within the largest safety-net academic medical center in New England. Participants were interviewed privately at the medical center or in the community. Twenty-six English-speaking women, mostly single and African American/Black, with at least one child 5 years old or younger, were sampled until thematic saturation was met. We used grounded theory methodology to conduct in-depth, semistructured interviews with participants who indicated that they experienced financial strain. We analyzed the interview data using constant comparative analysis, revised the interview guide based on emerging themes, and developed a theoretical model. Five interrelated themes emerged and were developed into a theoretical model: Financial Strain Has Specific Characteristics and Common Triggers, Financial Strain Is Exacerbated by Inadequate Assistance and Results in Tradeoffs, Financial Strain Forces Parenting Modifications, Women Experience Self-Blame, and Women Experience Mental Health Effects. For women with young children, financial strain results in forced tradeoffs, compromised parenting practices, and self-blame, which contribute to significant mental health problems. These findings can inform woman-centered clinical practice and advocacy interventions. Women's health care providers should identify families experiencing financial strain, provide referrals to financial services, and join advocacy efforts to advance social policies that address the structural causes of poverty, such as increased minimum wage and paid family leave.


Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled, multicenter study.
Ventilator-associated tracheobronchitis (VAT) is associated with increased duration of mechanical ventilation. We hypothesized that, in patients with VAT, antibiotic treatment would be associated with reduced duration of mechanical ventilation. We conducted a prospective, randomized, controlled, unblinded, multicenter study. Patients were randomly assigned (1:1) to receive or not receive intravenous antibiotics for 8 days. Patients with ventilator-associated pneumonia (VAP) prior to VAT and those with severe immunosuppression were not eligible. The trial was stopped early because a planned interim analysis found a significant difference in intensive care unit (ICU) mortality. Fifty-eight patients were randomly assigned. Patient characteristics were similar in the antibiotic (n = 22) and no antibiotic (n = 36) groups. Pseudomonas aeruginosa was identified in 32% of VAT episodes. Although no difference was found in mechanical ventilation duration and length of ICU stay, mechanical ventilation-free days were significantly higher (median [interquartile range], 12 [8 to 24] versus 2 [0 to 6] days, P < 0.001) in the antibiotic group than in the no antibiotic group. In addition, subsequent VAP (13% versus 47%, P = 0.011, odds ratio [OR] 0.17, 95% confidence interval [CI] 0.04 to 0.70) and ICU mortality (18% versus 47%, P = 0.047, OR 0.24, 95% CI 0.07 to 0.88) rates were significantly lower in the antibiotic group than in the no antibiotic group. Similar results were found after exclusion of patients with do-not-resuscitate orders and those randomly assigned to the no antibiotic group but who received antibiotics for infections other than VAT or subsequent VAP. In patients with VAT, antimicrobial treatment is associated with a greater number of days free of mechanical ventilation and lower rates of VAP and ICU mortality. However, antibiotic treatment has no significant impact on total duration of mechanical ventilation. ClinicalTrials.gov, number NCT00122057.


Epidemics and outbreaks of peripheral nervous system disorders: I. infectious and immune-mediated causes.
The history of mankind is marked by numerous epidemics, some of which involved diseases of the peripheral nervous system, either infectious or otherwise. We describe here the three main infectious causes of epidemics that affect the peripheral nervous system: leprosy, poliomyelitis and diphtheria. We then discuss the main epidemics of immune-mediated origin.


Immune profiling and RNA-seq uncover the cause of partial unexplained recurrent implantation failure.
Detailed knowledge of the changes in endometrial immune cells during the window of implantation in unexplained recurrent implantation failure (RIF) patients, the functions performed by immune cells, and the interactions between them is largely lacking. This study aimed to classify RIF patients and explore the mechanism through endometrial immune profiling and RNA-seq analysis. This study enrolled a total of 172 patients, comprising 144 women with unexplained RIF and 28 fertile women. Endometrial samples were collected using endometrial scratching at the mid-luteal phase before in vitro fertilization treatment or pregnancy. Transcriptome sequencing and immunohistochemical staining of endometrial immune cells including natural killer (NK) cells, macrophages, T cells, and B cells were performed. Comparison of the percentage of endometrial immune cells and the RNA-seq information between RIF patients and fertile control patients. The proportions of uterine CD56+ uNK cells, CD57+ NKT cells, CD68+ macrophages, and CD19+ B cells were significantly elevated in RIF patients. In addition, the number of positive CD68 glandular lumens was significantly higher in RIF patients than in the fertile group. In addition, based on this result, we classified RIF patients into three categories. Hyperactivation of endometrial immune cells may be associated with reduced endometrial tolerance and recurrent implantation failure, affecting pregnancy outcomes in RIF patients.


In vivo studies on the dopamine re-uptake mechanism in the striatum of the rat: effects of benztropine, sodium and ouabain.
We used the push-pull perfusion technique to study the in vivo changes in dopamine (DA) levels in the rat striatum in response to treatments which could affect DA re-uptake into the nigrostriatal DA terminals. Benztropine (10(-6) M), a potent DA uptake inhibitor induced a 1.7-fold increase in DA levels in the perfusates compared to basal levels. Perfusion with a Na+-free medium in which Na+ was replaced with either Tris-Cl or choline-Cl in equimolar proportions induced respectively 6.5- and 8.5-fold increases in DA levels in the perfusates. Perfusion of media containing NaCl:Tris-Cl (50:50) or NaCl:choline-Cl (50:50) did not significantly alter the levels of DA in the perfusates. Ouabain (10(-6) M) did not significantly alter DA levels but at a concentration of 10(-4) M, there was a 5.3-fold increase in DA levels in the perfusates compared to basal levels. These results thus demonstrate that the raised DA levels in the extracellular space in response to benztropine is due to the action of the drug in blocking the uptake of DA. The dependence of the uptake mechanism on the presence of Na+ in the external medium and hence on metabolic energy (Na pump) is clearly demonstrated. However, the massive elevation of DA levels under these conditions cannot be due solely to an inhibition of DA uptake but to the carrier-mediated DA exit from cytoplasmic stores resulting from a running down of the ionic gradient.


Toll-like receptor 4 is involved in myocardial damage following paraquat poisoning in mice.
The ingestion of the herbicide paraquat (PQ) can cause multiple organ injury including cardiac lesions. However, the underlying mechanism of myocardial damage is not known. Toll-like receptor 4 (TRL4) is a pattern-recognition receptor in the innate immune response to microbial pathogens. TLR4 is involved in heart dysfunction such as septic shock or myocardial ischemia. We investigated whether TLR4 would be linked to the pathogenesis of heart disease due to PQ exposure. Wild type mice (WT) and TLR4-deficient mice were injected intraperitoneally with 75mg/kg of PQ to induce myocardial damage and tested for echocardiographic assessment, histopathology, pro-inflammatory cytokine and TLR4 expression. WT mice after PQ exposure displayed deteriorate cardiac function, pathological damages, increased TLR4 mRNA and protein levels as well as myocardial TNF-α and IL-1β levels. Compared with WT mice, TLR4-deficient mice were significantly resistant to the PQ-induced injury. We concluded that the TLR4 was required as a mediator and played an important role in myocardial damage due to PQ.


Measurement of inositol 1,4,5-trisphosphate in living cells using an improved set of resonance energy transfer-based biosensors.
Improved versions of inositol-1,4,5-trisphosphate (InsP3) sensors were created to follow intracellular InsP3 changes in single living cells and in cell populations. Similar to previous InsP3 sensors the new sensors are based on the ligand binding domain of the human type-I InsP3 receptor (InsP3R-LBD), but contain a mutation of either R265K or R269K to lower their InsP3 binding affinity. Tagging the InsP3R-LBD with N-terminal Cerulean and C-terminal Venus allowed measurement of InsP3 in single-cell FRET experiments. Replacing Cerulean with a Luciferase enzyme allowed experiments in multi-cell format by measuring the change in the BRET signal upon stimulation. These sensors faithfully followed the agonist-induced increase in InsP3 concentration in HEK 293T cells expressing the Gq-coupled AT1 angiotensin receptor detecting a response to agonist concentration as low as 10 pmol/L. Compared to the wild type InsP3 sensor, the mutant sensors showed an improved off-rate, enabling a more rapid and complete return of the signal to the resting value of InsP3 after termination of M3 muscarinic receptor stimulation by atropine. For parallel measurements of intracellular InsP3 and Ca2+ levels in BRET experiments, the Cameleon D3 Ca2+ sensor was modified by replacing its CFP with luciferase. In these experiments depletion of plasma membrane PtdIns(4,5)P2 resulted in the fall of InsP3 level, followed by the decrease of the Ca2+-signal evoked by the stimulation of the AT1 receptor. In contrast, when type-III PI 4-kinases were inhibited with a high concentration of wortmannin or a more specific inhibitor, A1, the decrease of the Ca2+-signal preceded the fall of InsP3 level indicating an InsP3-, independent, direct regulation of capacitative Ca2+ influx by plasma membrane inositol lipids. Taken together, our results indicate that the improved InsP3 sensor can be used to monitor both the increase and decrease of InsP3 levels in live cells suitable for high-throughput BRET applications.


Determination of numbers of osteoprogenitors present in isolated fetal rat calvaria cells in vitro.
When maintained in long-term cell culture in the presence of ascorbic acid and organic phosphate, single cell suspensions isolated from fetal rat calvaria form discrete, three-dimensional bone nodules. We have used limiting dilution analysis in microtiter wells to determine the number of osteoprogenitor cells expressing the capacity to form bone in the isolated mixed population, to examine the possibility of cooperativity among cell types in bone nodule formation, and to determine the effects of dexamethasone on osteoprogenitor cells. Cells plated at very low densities and screened for the presence or absence of bone nodules revealed a linear relationship (r = -00.997) between the number of cells plated and the number of bone nodules formed. The complete limiting dilution analyses showed that 1 of every 335 plated cells (0.30% of the cell population) has the capacity to form a bone nodule under standard culture conditions and when the actual numbers of nodules were quantitated from the same plated cell populations the ratio of nodules formed to plated cells was similar. Comparison of data from 13 different isolates of cells in which cells were plated into 35-mm dishes and number of nodules were determined indicated a mean +/- 95% confidence interval of one nodule for every 301 +/- 61 plated cells, consistent with the data obtained from the limiting dilution experiments. Dexamethasone increased the number of bone-forming cells to 1 in 225 cells, in contrast to 1 in 340 cells in the same population grown without added dexamethasone. The results suggest that approximately 0.30% of the cells in isolated rat calvaria populations are osteoprogenitor cells, that one osteoprogenitor cell gives rise to one bone nodule, that cooperativity between different cells in vitro is not necessary for bone formation, and that dexamethasone stimulates the expression of osteoprogenitor cells.


Assembly and interaction of core subunits of BAF complexes and crystal study of the SMARCC1/SMARCE1 binary complex.
The multi-subunit ATP-dependent chromatin remodeling factor SWI/SNF complex is a fundamental regulator of gene transcription. The SWI/SNF complex in mammals, also called the BAF complex, consists of 9-12 subunits. Genomic functional studies have found that 20%-25% of human cancers are caused by mutations in genes encoding this complex. For the assembly of the BAF complex, BAF47 (SMARCB1), BAF57 (SMARCE1), BAF155 (SMARCC1)/BAF170 (SMARCC2), and BAF60 A/B/C (SMARCD1/2/3) form a core complex. However, the assembly mechanism of the BAF core subunit remains unclear. In this study, the assembly mechanism and structure of this complex and the interactions between its subunits were investigated. We co-expressed SMARCC1(447-966)/SMARCD1(129-471), SMARCC1(447-966)/SMARCE1(210-284) and SMARCC1(862-966)/SMARCE1(210-284) binary complex, SMARCC1(862-966)/SMARCD1(129-471)/SMARCE1(210-284) ternary complex SMARCC1(353-966)/SAMRCD1(129-471)/SMARCB1(110-385)/SAMRCE1(210-284) tetrameric complexes, and obtained crystals of the SMARCC1(862-966)/SMARCE1(210-284) and SMARCC1(883-966)/SMARCE1(210-284) binary complex,and the SMARCC1(883-966)/SMARCE1(210-284) crystal received a set of diffraction data of 3.2 Å. Our experimental results demonstrate the assembly mechanism between the core subunit quaternary complexes of the BAF complex and the interacting amino acid fragment regions and the SMARCC1/SMARCE1 optimal amino acid fragment binary complex crystals. Our study provides a theoretical basis for the development of cancer and related drug research based on protein structure.


Management of partial skin thickness burn wounds with Inadine dressings.
In a prospective randomized trial, 213 consecutive patients with less than 10 per cent BSA partial thickness burns were treated as outpatients with either Bactigras (n = 102) (tulle gras dressing with 0.5 per cent Chlorhexidine Acetate B.P.) or Inadine (n = 111) (rayon dressing with 10 per cent povidone iodine ointment). Inadine caused less bleeding on dressing removal but not significantly less. Inadine treated patients required less analgesia, a reduced treatment time, a smaller number of hospital visits and less time off work/normal activities (P = 0.01). Inadine should be more widely used in the management of partial thickness burn wounds.


Effect of frontal muscle aponeurosis flap suspension surgery for severe congenital ptosis in children.
To investigate the effect of frontal muscle aponeurosis flap suspension surgery for severe congenital ptosis in children. Recent results of 30 cases (45 eyes) of children with severe congenital ptosis were evaluated and follow-up observation was conducted. One week after the surgery, the success rate was 97.7% and it was 95.5% after three months. The suspension of frontal muscle aponeurosis should be the first choice for children with severe congenital ptosis for its simplicity, safety and fewer complications.


Acanthamoeba keratitis--resistance to medical therapy.
Successful medical therapy of Acanthamoeba keratitis has been reported with combination therapy; topical Brolene and neomycin. Resistance has not so far been identified as a problem, but was the basis for recurrent disease observed in a patient with bilateral infection. Eradication of amoebae was finally achieved following prolonged topical therapy and two corneal grafts in each eye. Topical anti-amoebic therapy with paromomycin, benzethonium chloride, clotrimazole and R11/29 (a phenanthridinium compound), was continued for three months post-operatively. No further recurrences occurred during 14 months' follow-up. Drug sensitivities were performed for three isolates of Acanthamoeba sp (group II) which demonstrated the development of resistance to Brolene and arsenic. In addition, the resistant isolates were temperature-sensitive mutants which would not grow at temperatures above 30 degrees C. This could explain 'culture-negative' results in some cases of clinical recurrence when incubation of laboratory samples had only been performed at 37 degrees C.


Towards the Better: Intrinsic Property Amelioration in Bulk Metallic Glasses.
Tailoring the intrinsic length-scale effects in bulk metallic glasses (BMGs) via post-heat treatment necessitates a systematic analyzing strategy. Although various achievements were made in the past years to structurally enhance the properties of different BMG alloys, the influence of short-term sub-glass transition annealing on the relaxation kinetics is still not fully covered. Here, we aim for unraveling the connection between the physical, (thermo)mechanical and structural changes as a function of selected pre-annealing temperatures and time scales with an in-house developed Cu46Zr44Al8Hf2 based BMG alloy. The controlled formation of nanocrystals below 50 nm with homogenous distribution inside the matrix phase via thermal treatment increase the material's resistance to strain softening by almost an order of magnitude. The present work determines the design aspects of metallic glasses with enhanced mechanical properties via nanostructural modifications, while postulating a counter-argument to the intrinsic property degradation accounted for long-term annealing.


Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos.
Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt's Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt's Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure.


[Erythrocyte alloimmunization in pregnant women, clinical importance and laboratory diagnostics].
The aim of this review is to give comprehensive summary of erythrocyte alloimunization of pregnant women, laboratory dignostics and clinical importance. Review. University Hospital Olomouc, Transfusion Department, Department of Obstetrics and Gynecology. Based on literature analysis using database search engines PubMed, Google Scholar, Ovid in field of erythrocyte antibodies, laboratory diagnostics and clinical importance up-to-date knowledge. Erythrocyte alloimunization anti-D antibodies decreases in connection with the introduction of immunoprofylaxis. Immunization of non RhD antibodies with impossibility using of immunoprofylaxis remains still clinical problem.


Adolescent Girls and Young Women's Experiences of Living with HIV in the Context of Patriarchal Culture in Sub-Saharan Africa: A Scoping Review.
Adolescent girls and young women (AGYW) in sub-Saharan Africa are disproportionately affected by the human immunodeficiency virus (HIV) due to socio-cultural gender, power, and economic disparities. This scoping review examined the literature to explore what is known about AGYW's everyday personal, relational, and social experiences of HIV to help shape future protective HIV policy and practice. Six databases were searched: Medline, CINAHL, Scopus, ASSIA, Google Scholar, and ProQuest, resulting in a total of 12,581 articles. Of these, 40 articles were included in the review. Key themes generated from the thematic analysis were relational and psychosocial challenges, inhibiting sexual expression, poverty, stigma, and discrimination; managing health in everyday life; agency and resilience; and personal space and social support. In conclusion, the review found a lack of understanding of AGYW's everyday experiences of living with HIV from their own perspectives. There was also little consideration of the role of patriarchal culture and how this constrains AGYW's ability to negotiate their relationships. Further research is needed to reveal AGYW's perspectives on living with HIV in sub-Saharan Africa.


Attenuation of cardiac dysfunction and remodeling of myocardial infarction by microRNA-130a are mediated by suppression of PTEN and activation of PI3K dependent signaling.
Activation of PI3K/Akt signaling protects the myocardium from ischemia/reperfusion injury. MicroRNAs have been demonstrated to play an important role in the regulation of gene expression at the post-transcriptional level. In this study, we examined whether miR-130a will attenuate cardiac dysfunction and remodeling after myocardial infarction (MI) via PI3K/Akt dependent mechanism. To determine the role of miR-130a in the proliferation and migration of endothelial cells, HUVECs were transfected with miR-130a mimics before the cells were subjected to scratch-induced wound injury. Transfection of miR-130a mimics stimulated the migration of endothelial cells into the wound area and increased phospho-Akt levels. To examine the effect of miR-130a on cardiac dysfunction and remodeling after MI, Lentivirus expressing miR-130a (LmiR-130a) was delivered into mouse hearts seven days before the mice were subjected to MI. Cardiac function was assessed by echocardiography before and for up to 21 days after MI. Ejection fraction (EF%) and fractional shortening (FS%) in the LmiR-130a transfected MI hearts were significantly greater than in LmiR-control and untransfected control MI groups. LmiR-130a transfection increased capillary number and VEGF expression, and decreased collagen deposition in the infarcted myocardium. Importantly, LmiR-130a transfection significantly suppressed PTEN expression and increased the levels of phosphorylated Akt in the myocardium. However, treatment of LmiR-130a-transfected mice with LY294002, a PI3K inhibitor, completely abolished miR-130a-induced attenuation of cardiac dysfunction after MI. miR-130a plays a critical role in attenuation of cardiac dysfunction and remodeling after MI. The mechanisms involve activation of PI3K/Akt signaling via suppression of PTEN expression.


Long-term outcome of laparoscopic Nissen-Rossetti fundoplication for neurologically impaired and normal children.
This study aimed to assess the long-term effects of laparoscopic Nissen-Rossetti fundoplication (LNF) on clinical and pH evaluations of children with gastroesophageal reflux disease (GERD) according to neurologic status. The study examined 127 children (73 neurologically impaired and 54 neurologically normal with primary GERD) who consecutively underwent LNF from 1992 to 2003. The follow-up protocol included evaluations at 3, 15, and more than 36 months (long-term evaluation) postoperatively, which consisted of physical examination and 24-h pH monitoring. Recurrences were defined as abnormal pH-metry exhibited by symptomatic children. The long-term follow-up period averaged 5.5 years. Of the 73 neurologically impaired children, 9 (12%) had GERD recurrences, which occurred during the evaluation period and required redo surgery in four cases, including two Bianchi procedures. In the neurologically normal group, one recurrence (2%) occurred 3 months after surgery. The long-term complications in this group included dyspepsia (n = 3), occasional dysphagia (n = 2), gas bloat syndrome (n = 1), and alimentary disorders (n = 2). For children with primary GERD, LNF is a long-term efficient procedure. For the neurologically impaired children, the results were good, with more than 85% of the children symptom free after 5 years, although repeated evaluations are required to diagnose late recurrences related to evolving dysmotility disorders.


Using History to Analyze the Learning by Observing and Pitching In Practices of Contemporary Mesoamerican Societies.
The analysis of Indigenous learning practices in Mexico and the United States typically relies on ethnography, oral history, and participant observation as the methodology for understanding the socialization processes of Mesoamerican societies. In this chapter, we consider the importance of using historical analysis as an added methodology for understanding the Indigenous learning practices by considering three case studies of Indigenous communities in Mexico, where a consideration of historical patterns have proven fruitful for understanding the contemporary Learning by Observing and Pitching In (LOPI) practices. These communities include the Nahua people of the state of Puebla, the P'urhépecha communities of the state of Michoacán, and the Nahua people of the Texcoco area to the southeast of Mexico City. We conclude that a consideration of the cultural patterns that have developed in Mesoamerican societies across time would benefit contemporary researchers as one component of their LOPI research.


Opposing placental gradients for thiocyanate and cotinine at birth.
In order to compare maternal and fetal exposure to compounds of tobacco smoke at the end of pregnancy, concentrations of cotinine and thiocyanate were measured in cord serum and maternal serum collected from 24 daily smoking and four non-smoking women at the time of child birth. The median level of thiocyanate (69 mumol/l) in maternal serum was about 50% higher than the median level (47 mumol/l) in cord serum (P < 0.0001) (Wilcoxon matched-pairs signed-ranks test). On the other hand, the median level of cotinine (22 ng/ml) in maternal serum was less than half of the median level (51 ng/ml) in cord serum (P = 0.0009). The correlation between maternal and cord serum was 0.77 (P < 0.0001) (Spearman's rank correlation coefficient) for thiocyanate levels and 0.90 (P < 0.0001) for cotinine. The high correlation between measurements of cotinine in maternal serum and cord serum indicates that maternal cotinine levels can be used to describe interindividual differences in fetal exposure to tobacco smoke. The placental gradients for cotinine and thiocyanate may indicate differences in maternal and fetal exposure to products of tobacco smoke.


Phosphorus flow analysis in maize cultivation: a case study in Thailand.
Phosphorus (P) is an essential element for plant cultivation, where the demand for agricultural products as food and feed are the main drivers of aggravated agricultural production systems. Maize is one of the main feedstocks for animal feed production in Thailand. Therefore, this study investigated P flows, using the conservation of mass-balanced concept to identify the major P flows in maize cultivation during rainy and dry seasons based on a survey of 131 plantation land plots. The result indicated that total amount of P input to maize fields during upland rainy and lowland dry season cultivation was determined as 27.76 and 34.96 kg P/ha, respectively, approximately 97% of which was in chemical fertilizers. P output in grain products accounted for 31.7 and 37.3% of the total P input or 32.9 and 38.0% of the applied fertilizer during maize cultivation in rainy and dry seasons, respectively. Agricultural soils were the main stock of P in maize cultivation systems. From the amount of applied P in rainy and dry seasons of maize cultivation, 43.9 and 41.3% remained in the soil, respectively, whereas 6.0 and 4.5% of those input during rainy and dry season were lost through runoff to the hydrosphere, respectively. This result indicated that seasonal and geographical factors may affect P flow pattern in maize cultivation. This revealed that P accumulation in soils and P loss occurring in rainy season were greater than those of dry season. Therefore, optimizing P flows through improved nutrient management should carefully consider helping reduce P loss during maize cultivation in Thailand.


A complete physical map of a wild beet (Beta procumbens) translocation in sugar beet.
Two sugar beet lines carry homologous translocations of the wild beet Beta procumbens. Long-range restriction mapping with rare cutting enzymes revealed that both translocations are different in size, however, an overlapping region of about 350 kb could be identified. Both lines are resistant to the beet cyst nematode but only TR520 carries the previously cloned resistance gene Hs1pro-1. Hence, a second gene for nematode resistance (Hs1-1) must be located within this region. A bacterial artificial chromosome (BAC) library was constructed from line TR520. The library was screened with a number of B. procumbens specific probes and 61 BAC clones were identified. Five BAC clones formed a minimal tiling path of 580 kb to cover the overlapping region between both translocations including the translocation breakpoint. The five BACs from the overlapping region and one additional BAC distal from that contig were sequenced. The total sequence length from the five BACs of the overlapping region amounted to 524 kb which is 74.35% of the total insert size of these BACs. The frequency of retrotransposon sequences ranged between 14.7 and 43.3%. A total of 133 ORFs were identified, none of these showed similarity to known disease resistance genes. Of these, 12 ORFs showed homology to genes involved in biotic stress resistance reactions or to transcription factors. This paper demonstrates how genome specific probes can be employed for cloning an alien gene introgression into a cultivated species.


Human fibroblasts in vitro senesce with a donor-specific telomere length.
In human fibroblasts, replicative senescence, telomere length and donor age are closely interrelated. We analyzed these relationships for fibroblast strains from 14 healthy human donors in the age range of 28-90 years. In vitro replicative capacity was correlated more closely with donor age than with telomere length ex vivo, especially for healthy donors. Telomere length at senescence was as variable as at cell explantation and increased with donor age. The data suggest a donor-specific, age-dependent regulation of the telomere length threshold that triggers senescence in human fibroblasts.


Biomimetic surface structuring using cylindrical vector femtosecond laser beams.
We report on a new, single-step and scalable method to fabricate highly ordered, multi-directional and complex surface structures that mimic the unique morphological features of certain species found in nature. Biomimetic surface structuring was realized by exploiting the unique and versatile angular profile and the electric field symmetry of cylindrical vector (CV) femtosecond (fs) laser beams. It is shown that, highly controllable, periodic structures exhibiting sizes at nano-, micro- and dual- micro/nano scales can be directly written on Ni upon line and large area scanning with radial and azimuthal polarization beams. Depending on the irradiation conditions, new complex multi-directional nanostructures, inspired by the Shark's skin morphology, as well as superhydrophobic dual-scale structures mimicking the Lotus' leaf water repellent properties can be attained. It is concluded that the versatility and features variations of structures formed is by far superior to those obtained via laser processing with linearly polarized beams. More important, by exploiting the capabilities offered by fs CV fields, the present technique can be further extended to fabricate even more complex and unconventional structures. We believe that our approach provides a new concept in laser materials processing, which can be further exploited for expanding the breadth and novelty of applications.


Comparison of trapping methods for use in surveys for potential Culicoides vectors of orbiviruses.
Bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) are orbiviruses that can cause fatal vector-borne diseases in white-tailed deer (Odocoileus virginianus). Trapping methods for collecting potential Culicoides vectors of orbiviruses were compared to optimize surveillance studies. The number of captured midges and the virus infection rates of midge pools were compared for dry ice-baited Centers for Disease Control and Prevention (CDC) traps with or without black light. The number of individual midges of different Culicoides species captured at different crepuscular and nocturnal periods using rotator traps also was determined. The number of species/specimens of Culicoides was measured using five different trap methods including three animal-baited methods, a CDC trap with black light, and a CDC trap with no light. In trial one, there was no significant difference (P = 0.37) in the proportion of BTV-infected flies caught in traps with light compared to traps without light. However, there was a significant difference (P = 0.026) for EHDV-infected flies, and 89% were captured in traps with light. In trial two, more specimens of C. debilipalpis were captured in the morning hours (06:00-08:00) than in the evening hours (18:00-20:00). For trial three, the animal-baited traps did not capture any species of Culicoides that were not captured in the CDC light traps. There was no significant difference (P = 0.22) in total specimens captured among all five trap types. Specimens of Culicoides infected with BTV were not repelled by light traps in the first trial, while the majority of the specimens positive for EHDV were caught in traps with light. For the second trial, specimens of C. debilipalpis were most abundant during early morning hours, and thus spray applications of insecticides for control of that species may be more effective at sunrise rather than sunset. For objective three, no animal-baited trapping method collected different species of midges when compared to the CDC traps with light, which is unlike certain studies conducted in other geographical regions.


Functional expression of sperm angiotensin II type I receptor in Xenopus oocyte: modulation of a sperm Ca2+-activated K+ channel.
In addition to Ca2+ and K+ fluxes, angiotensin II (Ang II) has been shown to influence sperm motility. The present study investigated the involvement of angiotensin II type 1 receptor (AT1) in mediating the modulatory effect of Ang II on a sperm Ca2+-activated K+ channel expressed in Xenopus oocytes injected with RNAs of spermatogenic cells. Ang II at a concentration of 1 microM was found to potentiate the ionomycin-induced current, previously demonstrated to be mediated by a 'Maxi' Ca2+-activated K+ channel. However, at higher concentration, 20 microM, Ang II was found to suppress the ionomycin-induced current. Both potentiating and inhibitory effects of Ang II were blocked by losartan, a specific antagonist of AT1 receptors. Immunohistochemical studies further confirmed the presence of AT1 receptors in spermatogenic cells while expression of AT1 receptor mRNA was demonstrated by RT-PCR. These results suggest that Ang II may influence sperm motility as well as other sperm function by acting on AT1 receptors, and exerting potentiating and inhibitory effects on the Ca2+-activated K+ channels.


Encapsulation, protection, and delivery of curcumin using succinylated-cyclodextrin systems with strong resistance to environmental and physiological stimuli.
Curcumin is commonly used as a nutraceutical in functional food and beverage formulations because of various biological activities. Typically, curcumin is encapsulated in edible nanoparticles or microparticles to improve its water-dispersibility, chemical stability, and bioavailability. In this study, a succinic acid-modified cyclodextrin (SACD) was fabricated and applied as a carrier for curcumin. Curcumin-loaded SACD (Cur-SACD) with a molar ratio of 1:1 and an encapsulation efficiency > 80% was formed spontaneously basing on hydrogen bonding between the aromatic ring of the curcumin and the hydrophobic cavity of the SACD. Cur-SACD exhibited excellent stability against long-time storage, UV-irradiation, and pasteurization, as well as against physiological conditions including body temperature, physiological salt concentrations, stomach and intestinal pH. This study suggests that Cur-SACD systems may be suitable for increasing the water-dispersibility, stability, and bioavailability of hydrophobic compounds intended for oral administration, such as those used in the food, supplement, and pharmaceutical industries.


A comparative study of quantitative metrics in chemical exchange saturation transfer imaging for grading gliomas in adults.
To evaluate the performance of different chemical exchange saturation transfer (CEST) metrics for grading gliomas with semiautomatically defined regions of interest (ROIs). Thirty-eight adult subjects were included, including 23 high-grade gliomas and 15 low-grade gliomas confirmed by histopathology. The B0-corrected CEST z-spectra were first calculated with magnetization transfer ratio asymmetry (MTRasym) analysis at frequency offsets of 3.5, 3, 2.5, 2, 1.5, and 1 ppm to obtain the fit-free metrics and subsequently fitted with three Lorentzian functions denoting direct water saturation (DS), amide proton transfer (APT), and combined semisolid magnetization transfer and nuclear Overhauser enhancement (MT & NOE) effects to derive the fit-based metrics. Wilcoxon rank-sum test was performed to determine if a statistically significant difference was present in the CEST metrics between low- and high-grade gliomas. Receiver operating characteristic (ROC) curves were used to evaluate the differentiation of CEST metrics between low- and high-grade gliomas. Pearson correlation coefficients were employed to evaluate the correlations of CEST metrics. For the fit-free metrics, the highest areas under the curve (AUCs) of 0.85, 0.88, and 0.88, corresponding to MTRasym, MTRnormref (normalization by the reference scan), and MTRRex (subtraction of inverse z-spectra), respectively, were obtained at 3 ppm across various frequency offsets. In addition, the AUCs generated from the fit-based metrics (0.88-0.90) were higher than those generated from the fit-free metrics at 3 ppm. The results of this preliminary study indicate that fit-free CEST metrics at 3 ppm are superior to the other frequency offsets for grading human brain gliomas. The fit-based metrics manifested improved differentiation between low- and high-grade gliomas compared to the fit-free CEST metrics.


[Lesions in cross-breed pregnant cows, experimentally infected with Sarcocystis cruzi (Hasselmann, 1923) Wenyon, 1926 (Apicomplexa: Sarcocytidae)].
To identify pathologic alterations, sixteen cows, in the last 3 months of gestation, all cross-breed, Holstein x Zebu, serum positive for Sarcocystis, were selected and divided into four groups of four animals each. The first group was considered as control and the other three groups were experimentally infected with 1x10(4) (2nd group), 5x10(4) (3rd group) and 1x10(5) (4th group) sporocysts obtained from dog's feces. The gross lesions in the cows were consisted of pale mucous membranes, paleness of the skeletal striated muscle and enlargement of lymph nodes, heart, liver, spleen and lungs. In the aborted fetus, the most prominent gross lesion were excess of fluid in peritoneal and thoracic cavities, and petecheas in the surface of intercostal muscles, thymus and spleen. On histological sections, no parasitic form was found in the tissues of the fetus, placenta or uterine tissue of the exposed cows. However, meronts, young and mature cysts of S. cruzi were observed in striated muscle. In the aborted fetus, hemorrhage, was the main histological lesion observed in brain, cerebellum and kidneys.


Interchangeability and tolerability of two inactivated hepatitis A vaccines in Chinese children.
In China, no data are available to evaluate the interchangeability between Chinese domestic inactivated hepatitis A vaccines (Healive) and imported inactivated hepatitis A vaccines (Havrix). A double-blind, randomized controlled study was to compare interchangeability and safety of Healive and Havrix among Chinese children. Vaccine was administered to 303 healthy children at 0 and 6 months in one of four vaccine regimens: Healive-Healive; Healive-Havrix; Havrix-Healive or Havrix-Havrix. We collected sera samples at 0 (before vaccination), 6 (before second dose) and 7 months (after second dose), and compared groups in terms of proportion of sero-conversions which is defined as ≥ 20 mIU/ml, and geometric mean concentrations (GMCs) of anti-hepatitis A virus (HAV) antibody. Seroconversion rates were 133/133 (100%) for those received one dose of Healive and 105/131 (80.2%) for those received one dose of Havrix at 6 months, respectively (P<0.001), GMCs for Healive and Havrix were 126.1 and 40.9 mIU/ml (P<0.001), respectively. At 7 months, the seroconversion rate was 100% among all groups. The GMC after two doses of Healive was 8905.5 mIU/ml compared with 1900.9 mIU/ml after two doses of Havrix (P<0.001). The GMC in the Healive-Havrix group was 3275.8 mIU/ml compared with 4165.8 mIU/ml in the Havrix-Healive group (P=0.058). There is not different of reported adverse reactions across the groups. The present study indicated that both vaccines can be recommended for interchangeable using of immunization among Chinese healthy children.


A polymorphism in the endothelin-A receptor gene is linked to baroreflex sensitivity.
The baroreflex plays an essential role in regulating the cardiovascular system. However, very few studies have focused on the links between genetic polymorphisms and baroreflex sensitivity (BRS). A total of 146 hypertensive individuals who had never been treated, and 105 healthy individuals (controls) were included in the study. The genotypes of 17 polymorphisms of 11 genes involved in the regulation of the cardiovascular system were studied. BRS was measured using a sequence method: BRS was evaluated as the slope of spontaneous increases [systolic blood pressure (SBP)+/reflex response (RR)+] or decreases (SBP-/RR-) in SBP and pulse interval by recording blood pressure (BP) continuously for 20 min. Following univariate analysis, the genetic polymorphism of endothelin receptor A EDNRA/C+1222T was found to be significantly correlated with the BRS (SBP-/RR-) level in both populations. In normotensive subjects, mean BRS values (SBP-/RR-) were 11.93 +/- 3.69 ms/mmHg in EDNRA CC homozygotes, 9.94 +/- 2.97 ms/mmHg in CT heterozygotes and 9.51 +/- 3.16 ms/mmHg in TT homozygotes (P = 0.01). In hypertensive subjects, mean BRS values (SBP-/RR-) were 9.26 +/- 3.59 ms/mmHg in EDNRA CC homozygotes, 9.03 +/- 4.14 ms/mmHg in CT heterozygotes and 6.60 +/- 2.42 ms/mmHg in TT homozygotes (P = 0.01). After adjustment for age, sex, SBP and diastolic blood pressure and body mass index, the EDNRA/C+1222T polymorphism remained significantly correlated with BRS in both normotensive (P = 0.01) and hypertensive (P = 0.01) subjects. These results suggest that the endothelin system may be involved in the regulation of BRS in humans. In particular, the T allele of the EDNRA/C+1222T polymorphism is associated with a reduction in BRS in both healthy and hypertensive subjects.


Patterns of functional diversity of two trophic groups after canopy thinning in an abandoned coppice.
Coppice abandonment had negative consequences for biodiversity of forest vegetation and several groups of invertebrates. Most coppicing restoration studies have focused only on a single trophic level despite the fact that ecosystems are characterized by interactions between trophic levels represented by various groups of organisms. To address the patterns of functional diversity in the perspective of coppicing restoration, we studied the short-term effects of conservation-motivated tree canopy thinning in an abandoned coppice-with-standards in Central Europe, a region where such attempts have been rare so far. The functional diversity of vascular plants and spiders, chosen as two model trophic groups within a forest ecosystem, was compared between thinned and control forest patches. To characterize functional patterns, we examined several functional traits. These traits were assigned into two contrasting categories: response traits reflecting a change of environment (for both vascular plants and spiders) and effect traits influencing the ecosystem properties (only for vascular plants). Functional diversity was analysed by CCA using two measures: community-weighted means (CWM) and Rao's quadratic diversity (RaoQ). CCA models revealed that the canopy thinning had a positive effect on diversity of the response traits of both trophic groups and negatively influenced the diversity of effect traits. In addition, we found distinct seasonal dynamics in functional diversity of the spider communities, which was probably linked to leaf phenology of deciduous trees and therefore an effect trait not directly examined in this study. We conclude that canopy thinning affected functional diversity across trophic groups during the initial phase of coppicing restoration. With necessary precautions, careful canopy thinning can be effectively applied in the restoration of functional diversity in abandoned coppices.


Stem-like cells in hepatitis B virus-associated cirrhotic livers and adjacent tissue to hepatocellular carcinomas possess the capacity of tumorigenicity.
Recent investigations demonstrate that adult stem cells may be targets for malignant transformation and that the stem-like cells in diseased livers possess the capacity of tumorigenicity in animal models. The aim of this study is to examine expression patterns of stem-cell markers in hepatitis B virus-associated cirrhotic livers and hepatocellular carcinomas (HCC), and to investigate the stem-like cell capacity of tumorigenicity in these tissues. Twenty surgically resected HCCs and corresponding adjacent tissues as well as 10 cirrhotic liver tissues were collected and immunohistochemical staining were performed to detect the expression of CD34, Thy-1, CD133, and c-kit. Then the non-cancerous tissues were transplanted into immunodeficient mice and the characteristics of the cells from primary tissue cultures were explored in vitro. Immunohistochemical analysis characterized different expression patterns of stem-cell markers among these tissues. First, CD34 and Thy-1 expression was identified in proliferating bile ductules and it represented hepatic progenitor cells; CD133 and c-kit-positive cells were observed in the parenchyma of these tissues, and some of them were characterized as intermediate hepatocytes morphologically and spatially. Second, in two groups including three mice transplanted with tissues adjacent to HCC-initiated tumors, CD133 and c-kit expression was detected. Finally, our study also indicated that stem-like cells from tissue could express hepatic-lineage markers and possessed great capacities to proliferate, self-renew, and form clones in vitro. Our results suggest that the stem-like cells in cirrhotic livers possess the capacity of tumorigenicity and may contain candidates for HCC cancer stem cells.


Prognostic determinants for lung cancer patients with preoperative high serum carcinoembryonic antigen levels.
Several reports have indicated that preoperative high serum carcinoembryonic antigen (CEA) levels are associated with poor survival after surgical resection in lung cancer. 82 consecutive lung cancer patients with preoperative high serum CEA levels (> 5 ng/mL) were included in this study. Postoperative serum CEA level was also measured. Prognostic indicators were evaluated. Among patients with a preoperative high serum CEA level, a serum CEA level higher than 10 ng/mL, pT status, pN status, and positive pleural lavage cytology findings were unfavorable prognostic indicators, whereas age, gender, smoking status, histologic subtype were not. Postoperative serum CEA levels of all but 2 patients decreased, however those of 28 patients did not return to normal range. Our result showed that patients with postoperative high serum CEA level had poor prognosis. Multivariate analysis demonstrated that pT status, pN status, and postoperative high serum CEA level was an independent prognostic determinant. In lung cancer patients with preoperative high serum CEA levels, pT status, pN status, and normalization of serum CEA level after surgery are significant prognostic determinants.


Vimentin and keratin intermediate filament systems in cultured PtK2 epithelial cells are interrelated.
Certain cultured epithelial cells contain separate vimentin and keratin-type intermediate filament networks. The intracellular injection of monoclonal antibodies directed against either vimentin or keratin filaments into PtK2 cultured epithelial cells specifically disrupted the organization of both filament types. Neither antibody had any effect when injected into cells which, while containing vimentin or keratin filaments, lacked the specific filament type which that antibody recognized. These experiments suggest that keratin and vimentin filament networks are associated in some way with one another.


Effects of chronic glyceryl trinitrate on left ventricular haemodynamics in a rat model of congestive heart failure: demonstration of a simple animal model for the study of in vivo nitrate tolerance.
The aim of the study was to investigate the problem of pharmacological tolerance to nitrate therapy in congestive heart failure, using an animal model. The effects of chronic glyceryl trinitrate infusions were studied in a rat model of congestive heart failure, induced by myocardial infarction, wherein surgical procedures have been developed to permit continuous monitoring of ventricular pressures in conscious animals for up to 4-5 d. male Sprague-Dawley rats were used, weight 300-325 g, n = 3-7 per experiment. Glyceryl trinitrate infusion (18 micrograms.kg-1.min-1) in rats with congestive heart failure caused by a 28.5(SEM 3.5)% infarction induced a rapid fall in left ventricular end diastolic pressure from 12.0(0.8) mm Hg to a peak effect of 5.5(0.6) mm Hg within 30 min (n = 7), but rapid attenuation developed beginning about 4 h after the start of the infusion. Complete abolition of the haemodynamic effects of glyceryl trinitrate was observed after 8 h of infusion. After a 12 h wash out period, responsiveness to a new infusion of glyceryl trinitrate (same dose) was restored. Withdrawal of nitrovasodilator dose led to rapid return to baseline left ventricular end diastolic pressure values. Infusion of vehicle to control animals (infarct size not different from treatment group) caused no haemodynamic effects. The haemodynamic changes caused by glyceryl trinitrate resemble those seen in man and suggest a possible use for this animal model in examining the mechanisms of nitrate action and tolerance.


Daily functioning and quality of life in a randomized controlled trial of therapeutic exercise for subacute stroke survivors.
The ability of therapeutic exercise after stroke to improve daily functioning and quality of life (QOL) remains controversial. We examined treatment effects on these outcomes in a randomized controlled trial (RCT) of exercise in subacute stroke survivors. This is a secondary analysis of a single-blind RCT of a 12-week program versus usual care. Baseline, post-treatment and 6-month post-treatment daily functioning and QOL were assessed by Barthel index, Functional Independence Measure, instrumental activities of daily living, Medical Outcomes Study short-form 36-item questionnaire (SF-36), and Stroke Impact Scale (SIS). Of 100 randomized subjects, 93 completed the postintervention assessment, (mean age 70; 54% male; 81% white; mean Orpington Prognostic Score 3.4), and 80 had 6-month post-treatment assessment. Immediately after intervention, the intervention group improved more than usual care in SF-36 social function (14.0 points; P=0.0051) and in SIS (strength [9.2 points; P=0.0003], emotion [5.6 points; P=0.0240], social participation [6.6 points; P=0.0488], and physical function [5.0 points; P=0.0145]). Treatment was marginally more effective on Barthel score (3.3 points; P=0.0510), SF-36 (physical function [6.8 points; P=0.0586], physical role function [14.4 points; P=0.0708]), and SIS upper extremity function (7.2 points; P=0.0790). Effects were diluted 6 months after treatment ended. This rehabilitation exercise program led to more rapid improvement in aspects of physical, social, and role function than usual care in persons with subacute stroke. Adherence interventions to promote continued exercise after treatment might be needed to continue benefit.


Impact of cadaveric practices on arthroscopic knee training for Orthopaedic Surgery and Traumatology residents.
There currently is a considerable variability in the content of training programs and courses for orthopaedic surgeons in training. Besides this, there is still no consensus regarding which is the most effective methodology for improving learning of the technique or for its qualitative evaluation. A study was carried out to assess the influence of carrying out a cadaveric practical course on the acquisition of arthroscopic technical skills in fifth-year residents. A knee arthroscopy cadaveric course was performed in which 48 students participated. Different technical aspects during a knee arthroscopy, as well as the residents skill and the execution time were evaluated before and after the course using a specific questionnaire. There was a significant statistic improvement between the initial and final evaluation, increasing from 11,7 till 17,1 (maximum 20) points. Also, a significant improvement in all the parameters analysed was observed; the identification of anatomic structures (p = 0.001), the palpation of specific structures (p = 0.032), and the time necessary for the arthroscopic knee check (p = 0.015). A knee arthroscopy cadaveric course improves significantly the technical skills of surgeons in training.


Static bending test after proximal femoral nail (PFN) removal - in vitro analysis.
To evaluate, through biomechanical testing, the resistance to and energy required for the occurrence of proximal femoral fracture in synthetic bone after removal of a proximal femoral nail model (PFN), comparing the results obtained with a reinforcement technique using polymethylmethacrylate (PMMA). Fifteen synthetic bones were used: five units for the control group (CG), five for the test group without reinforcement (TGNR), and five for the test group with reinforcement (TGR). The biomechanical analysis was performed simulating a fall on the trochanter using a servo-hydraulic machine. In the GC, the assay was performed with the PFN intact. In the TGNR and TGR groups, a model of PFN was introduced and the tests were performed in the TGNR, after simple removal of the synthesis material, and in the TGR, after removal of the same PFN model and filling of the cavity in the femoral neck with PMMA. All groups presented a basicervical fracture. The CG presented a mean of 1427.39 Newtons (N) of maximum load and 10.14 Joules (J) of energy for the occurrence of the fracture. The TGNR and TGR presented 892.14 N and 1477.80 N of maximum load, and 6.71 J and 11.99 J of energy, respectively. According to the Kruskal-Wallis ANOVA, there was a significant difference in the maximum load (p = 0.009) and energy (p = 0.007) between these groups. The simple removal of a PFN in synthetic bone showed a significant reduction of the maximum load and energy for the occurrence of fracture, which were re-established with a reinforcement technique using PMMA.


PPARγ: Welcoming the New Kid on the CML Stem Cell Block.
Recently, chronic myeloid leukemia (CML) patients already responding to treatment showed improved molecular responses with pioglitazone, presumably through PPARγ activation and CML stem cell eradication. Given data demonstrating deepening responses and successful treatment discontinuation with current therapy, the necessity for new therapies targeting CML stem cells to achieve cure is unclear.


Body fat percentile curves for U.S. children and adolescents.
To date, several studies have been published outlining reference percentiles for BMI in children and adolescents. In contrast, there are limited reference data on percent body fat (%BF) in U.S. youth. The purpose of this study was to derive smoothed percentile curves for %BF in a nationally representative sample of U.S. children and adolescents. Percent fat was derived from the skinfold thicknesses of those aged 5-18 years from three cross-sectional waves of the National Health and Nutrition Examination Survey (NHANES) IV (1999-2000, 2001-2002, and 2003-2004; N=8269). The LMS (L=skewness, M=median, and S=coefficient of variation) regression method was used to create age- and gender-specific smoothed percentile curves of %BF. Growth curves are similar between boys and girls until age 9 years. However, whereas %BF peaks for boys at about age 11 years, it continues to increase for girls throughout adolescence. Median %BF at age 18 years is 17.0% and 27.8% for boys and girls, respectively. Growth charts and LMS values based on a nationally representative sample of U.S. children and adolescents are provided so that future research can identify appropriate cut-off values based on health-related outcomes. These percentiles are based on skinfolds, which are widely available and commonly used. Using %BF instead of BMI may offer additional information in epidemiologic research, fitness assessment, and clinical settings.


Efficient reversed-phase purification of a hydrophobic reaction product following Mitsunobu-mediated glycosylation.
The Mitsunobu reaction was used to attach tetra-O-benzyl-D-glucopyranose to a monoindolylmaleimide, providing a key intermediate in the total synthesis of indolocarbazole topoisomerase I poisons. Using normal-phase silica gel chromatography, purification of the glycosylated product normally required multiple columns, resulting in poor recovered yields. Reversed-phase chromatography was used successfully to purify this highly hydrophobic material, rapidly and in high yield.


Applying multivariate statistics to discriminate uranium ore concentrate geolocations using (radio)chemical data in support of nuclear forensic investigations.
The application of Principal Components Analysis (PCA) to U and Th series gamma spectrometry data provides a discriminatory tool to help determine the provenance of illicitly recovered uranium ore concentrates (UOCs). The PCA is applied to a database of radiometric signatures from 19 historic UOCs from Australia, Canada, and the USA representing many uranium geological deposits. In this study a key process to obtain accurate radiometric data (gamma and alpha) is to digest the U-ores and UOCs using a lithium tetraborate fusion. Six UOCs from the same sample set were analysed 'blind' and compared against the database to identify their geolocation. These UOCs were all accurately linked to their correct geolocations which can aid the forensic laboratory in determining which further analytical techniques should be used to improve the confidence of the particular location.


Antioxidant responses to seawater acidification in an invasive fouling mussel are alleviated by transgenerational acclimation.
Ocean acidification and marine biofouling, which may interact in the future, pose two major threats to global coastal ecosystems. Yet, the fate of highly invasive fouling species in a rapidly acidifying ocean remains poorly understood, due to lack of information on multigenerational consequences at different levels of biological organization. Here, we investigated antioxidant responses of the mussel, Musculista senhousia, a swiftly spreading invasive fouling species in global coastal waters, following transgenerational exposure to elevated pCO2. In the face of seawater acidification, M. senhousia without a prior history of transgenerational exposure to elevated pCO2 showed resistance to lipid peroxidation, but significantly increased activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), indicated oxidative stress responses. However, enhanced transgenerational immunity occurred, as exemplified by observations that mussels originating from parents exposed to elevated pCO2 exhibited significantly lower activities of SOD, CAT and GPx in comparison to those spawn from parents exposed to ambient pCO2. Rapid transgenerational acclimation of M. senhousia in terms of reduced oxidative stress responses can likely be linked to the enhanced capacity of maintaining acid-base homeostasis previously demonstrated. These findings provide the first evidence of transgenerational plasticity at the biochemical level in highly invasive fouling bivalve species, and represent a step forward in understanding how they respond and acclimate in an acidifying ocean.


Concentrations of oligosaccharides in human milk and child growth.
The relationship between human milk oligosaccharides (HMO) and child growth has been investigated only insufficiently with ambiguous results. Therefore, this study examines potential influencing factors of HMO concentrations and how HMO are associated with child growth parameters. Milk samples from the German LIFE Child cohort of healthy children were analyzed for 9 HMO. Putative associations with maternal and child cofactors and child height, head circumference and BMI between 3 months and 7 years of age were examined. Secretor status, defined as the presence of 2'-fucosyllactose, was investigated for associations with infant outcomes. Our population consisted of 21 (14.7%) non-secretor and 122 (85.3%) secretor mothers. Maternal age was significantly associated with higher 3'SL concentrations; gestational age was associated with LNT, 6'SL and LNFP-I. Pre-pregnancy BMI was negatively associated with LNnT only in non-secretors. The growth velocity of non-secretors' children was inversely associated with LNnT at 3 months to 1 year (R = 0.95 [0.90, 0.99], p = 0.014), 1 to 2 years (R = 0.80 [0.72, 0.88], p < 0.001) and 5 to 6 years (R = 0.71 [0.57, 0.87], p = 0.002). 2'FL was negatively associated with BMI consistently, reaching statistical significance at 3 months and 4 and 5 years. Children of non-secretors showed higher BMI at 3 months, 6 months, and 3, 6, and 7 years of age. We found that some associations between HMO and infant growth may extend beyond the infancy and breastfeeding periods. They highlight the importance of both maternal and infant parameters in the understanding of the underlying associations. The study is registered with ClinicalTrial.gov: NCT02550236 .


Field Studies Measuring the Aerosolization of Endotoxin During the Land Application of Class B Biosolids.
Endotoxins are a component of Gram-negative bacteria cell walls and are known to be present in biosolids. Endotoxins have been shown to be potent stimulators of the innate immune response causing airway irritation and shortness of breath. Class B biosolids are routinely applied to agricultural lands to enhance soil properties and can be used as an alternative to chemical fertilizers. This study investigated the aerosolized endotoxin dispersed during the land application of Class B biosolids on agricultural land and a concrete surface at two sites in Colorado, USA. Aerosolized endotoxin was captured using HiVol samplers fitted with glass fiber filters, polycarbonate filter cassettes (both open and closed) and BioSampler impinger air samplers. Endotoxins were also measured in the biosolids to allow for correlating bulk biosolids concentrations with aerosol emission rates. Endotoxin concentrations in biosolids, impinger solutions and filter extracts were determined using the kinetic Limulus amebocyte lysate assay. Aerosolized endotoxin concentration was detected from all sites with levels ranging from 0.5 to 642 EU/m3. The four types of sampling apparatus were compared, and the HiVol and open-faced cassette samplers produced higher time-weighted average (TWA) measurements (EU/m3) than the impinger and closed cassette samplers. Ambient wind speed was found to be the variable best describing the observed results with optimal wind speed for highest deposition estimated at 5 m s-1. It is argued that HiVol air samplers are a particularly reliable approach and subsequent analyses relating TWA measurements to wind speed and biosolids characteristics were based on the measurements collected with those samplers.


Fear of panoptic surveillance: using digital technology to control the COVID-19 epidemic.
In a bid to reduce infection rates by COVID-19 the authorities in some countries, in collaboration with medical regulators and experts, have employed digital technologies to control and regulate citizens' behavior. Public opinion and the public's compliance with these technologies come into play here. The objective of the present study was to examine attitudes expressed in the public discourse toward the use of digital technologies to control people's behavior during the COVID-19 pandemic, as reflected in the media. Qualitative analysis was performed on posts and comments submitted in response to 12 articles that appeared on the four leading Israeli news sites, on three significant occasions: first, upon the announcement of the use of surveillance technologies by the Israeli security agency (ISA); second, upon the announcement of the launch of the Health Ministry's app that tracks contacts with COVID-19 patients; and third, following reports of petitions lodged with Israel's supreme court challenging the use of surveillance technologies. The analysis was performed using ATLAS-Ti software for systematic analysis. A total of 2551 posts and comments referring to these 12 articles were found, 714 of which were relevant to the purpose of the study. The analysis revealed disagreement between those who supported the measures taken and opponents. Supporters regarded contact tracing by means of digital technologies as essential to the effort to protect people during the pandemic, and believed that employing the ISA's capabilities was the correct way to combat the epidemic. Opponents of the measures rejected the use of tracking technologies, regarding this step as a move toward dictatorship and a violation of fundamental civil rights. Some proposed alternative measures that would obviate the use of such tracking. The primary task of medical practice is to heal illness and alleviate suffering. The debate surrounding the employment of digital technologies during the COVID-19 pandemic highlights the complexity of the close connection between social control and care in times of pandemic. The context of this pandemic has highlighted the interrelatedness of advanced digital surveillance technologies, medical care, and social control exercised by authorities and medical regulators and experts, which raises issues of transparency, trust and mistrust among the public. These issues become all the more relevant when the number of patients grows rapidly, the authorities need to deal with the extended ongoing COVID-19 pandemic, the country has entered a second lockdown, and the public must be persuaded to comply with highly restrictive regulations. Recommendations to policy makers, practical implications, and suggestions for future research are discussed.


Controllable formation of polydopamine on carbon dots for ultrasensitive detection of alkaline phosphatase and ratiometric fluorescence immunoassay of benzocaine.
Sensing alkaline phosphatase (ALP) activity with high sensitivity and accuracy is critical for both ALP-related health and food safety supervision and the development of ALP-triggered immunoassay platforms. Herein, an ultrasensitive ratiometric fluorescence (RF) sensing system based on the controllable formation of luminescent polydopamine and efficient quenching of carbon dots was proposed for the ALP activity assay, achieving quantitative detection in the range of 0.01-100 mU/L. Furthermore, this RF sensing system was integrated with an ALP-based ELISA platform to construct an RF-ELISA for benzocaine, a potentially abused anesthetic in edible fish, and ultrasensitive assay at the level of fg/mL was realized. This ratiometric strategy-based platform effectively shields various interferences through the self-calibration effect, thus providing more accurate and reliable quantification results. This study not only offers an efficient method for ultratrace detection of ALP and benzocaine but also proposes a universal platform for ultrasensitive detection of diverse targets in food analysis by replacing the recognition unit.


Genetically-determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.
1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5-hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml-1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.


Bioinspired fine-tuning of the mechanical rigidity of SNEDDS for the efficient crossing of multiple gastrointestinal barriers.
Nanoproperties, such as size, charge, and rigidity, have been demonstrated to be crucial for nanovehicles to overcome numerous gastrointestinal obstacles. However, the facile approach of modifying the rigidity of nanovehicles remains scarce, limiting understanding of how rigidity impacts their oral delivery. Inspired by the fact that cellular phospholipid content regulates plasma membrane rigidity, the rigidity of self-nanoemulsifiying drug delivery system (SNEDDS) could be fine-tuned via phosphocholine content while their size and zeta potential remain unchanged, using insulin as a model drug. Notably, soft SNEDDS exerted longer gastrointestinal transit time, higher drug release rate, stronger gastrointestinal stability and relatively lower mucus permeation but superior epithelial transcytosis than their hard counterparts in a macropinocytosis-dependent manner. The rigidity-related enhanced transcytosis was attributed to improved endocytosis, lysosome escape capability and exocytosis. Rats with type 1 diabetes exhibited greater oral insulin absorption and blood glucose lowering effect with soft SNEDDS. This study demonstrated the regulatory role of phospholipids in nanovehicle rigidity, which could help develop mechanically optimized nanomedicines in the future.


Formation of a steroidal allyl alcohol in the mammary glands of mice.
After incubation of [4-14C]progesterone with cell-free homogenates of mouse mammary gland in the presence of NADPH, [14C]-labeled 4-pregnene-3alpha, 20alpha-diol was identified as a metabolite, besides 20alpha-hydroxy-4-pregnene-3-one which was the major metabolite.


Prolonged unemployment and depression in older workers: a longitudinal study of intervening variables.
In this study, unemployed blue-collar workers over the age of 45 (N = 51) filled out a questionnaire in 1975 and in 1977. It was shown that prolonged unemployment or re-unemployment leads to depression, reduced hope, and financial problems, although none of these factors leads to prolonged unemployment. Being employed or retired leads to a reduction of depression and financial problems. Problems associated with the daily hassles of unemployment, such as financial problems and disappointed hope play a role in the development of depression with prolonged unemployment. Potential third variables that could cause both unemployment and depression--such as internal/external control, passivity, sickness, and age--do not affect the effect of unemployment on depression.


Clinical pharmacokinetics of ketoprofen after single intravenous administration as a bolus or infusion.
The pharmacokinetics of ketoprofen were evaluated in 29 patients suffering from acute renal colic following a single intravenous administration as a bolus or short infusion (1.5 and 2 hours), and after a loading dose and a 24-hour infusion. Serum concentrations of ketoprofen were measured by high pressure liquid chromatography. The mean (+/- SD) values of clinical parameters were as follows: distribution half-life = 0.34 +/- 0.19 h; elimination half-life = 2.05 +/- 0.58 h; kel = 0.968 +/- 0.282 h-1; k21 = 0.943 +/- 0.425 h-1; k12 = 1.004 +/- 0.708 h-1; volume of central compartment = 5.58 +/- 1.67L; volume of tissue compartment = 5.14 +/- 2.12L; plasma clearance = 5.10 +/- 1.14L/h. These results concur with previously published data obtained after oral or intramuscular administration. According to clinical observations, administration of a ketoprofen bolus suppressed pain within 5 to 30 minutes; the administration of a loading dose and a 24-hour infusion is almost never followed by a recurrence of pain, and this regimen was proposed as the dosage schedule of ketoprofen to treat renal colic.


Constraints on antisymmetric tensor fields from Bhabha scattering.
Antisymmetric tensor fields are a compelling prediction of string theory. This makes them an interesting target for particle physics because antisymmetric tensors may couple to electromagnetic dipole moments, thus opening a possible discovery opportunity for string theory. The strongest constraints on electromagnetic dipole couplings would arise from couplings to electrons, where these couplings would contribute to Møller and Bhabha scattering. Previous measurements of Bhabha scattering constrain the couplings to M ~ e m C > 7.1 × 10 4 GeV 2 , where m C is the mass of the antisymmetric tensor field and M ~ e is an effective mass scale appearing in the electromagnetic dipole coupling.


Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey.
What's known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not significantly alter plasma concentrations. In this retrospective study we define the safety and efficacy of tyrosine kinase inhibitors in patients with metastatic RCC (mRCC) and end-stage renal disease requiring haemodialysis. Even though the retrospective nature of this survey and the relatively small sample size represent major limitations, these data indicate that treatment with sunitinib and sorafenib in this cohort of patients is feasible with no unexpected toxicity and good efficacy, results similar to those in the general population of patients with mRCC. To investigate the safety and efficacy of tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring haemodialysis (HD). Between July 2006 and December 2010, 24 patients undergoing HD were treated with sunitinib and/or sorafenib for mRCC in 14 Italian institutions. We retrospectively reviewed the medical records of these patients to evaluate the administered doses of TKIs, treatment-related toxicities and the clinical response to therapy. Sunitinib was administered at 50 mg daily for 4-6 weeks in six patients, 37.5 mg daily for 4-6 weeks in seven patients (one patient subsequently increased the dose to 50 mg daily), 25 mg daily for 4-6 weeks in two patients and 12.5 mg daily for 4-6 weeks in one patient. Among the eight patients treated with sorafenib, four patients received 800 mg daily (400 mg every 12 h), three patients 400 mg daily and one patient 200 mg daily with a continuous schedule. The estimated median progression-free and overall survival periods of this cohort of patients were 10.3 months and 22.6 months, respectively. With regard to tolerability and safety, no unexpected adverse events were registered and no grade 4 haematological or non-haematological toxicities were reported. Sunitinib and sorafenib treatment is not contraindicated in patients with mRCC undergoing HD. The outcome of this patient population is similar to that observed in patients with normal renal function treated with TKIs. These results merit further confirmation by a larger prospective trial.


Human papillomavirus typing with a polymerase chain reaction-based genotyping array compared with type-specific PCR.
Type-specific persistence of human papillomavirus (HPV) infection can cause invasive cervical cancer. To evaluate the efficacy of HPV detection and typing with a general polymerase chain reaction (PCR)-based genotyping array and to compare it with a type-specific PCR assay. Four hundred and thirty-three cervical samples were tested with a modified MY11/GP6+ PCR-based reverse-blot assay (EasyChip HPV Blot; King Car, Taiwan [hereafter HPV Blot]) and with 20 genotypes of L1-type-specific PCR (HPV-6, -11, -16, -18, -31, -33, -35, -39, -45, -51, -52, -53, -56, -58, -59, -62, -66, -68, -70, and -71 [CP8061]). The concordance of the two tests in determining HPV positivity was 96.8% (419/433), with a Cohen's kappa=0.93 (95% CI: 0.90-0.97) and McNemar's test of P=1.0, which indicates excellent agreement. The overall concordance of the two tests in the identification of type-specific HPV was 91.0% (394/433). Sensitivity (90-100%), specificity (99.2-100%), and accuracy (98.6-100%) rates of HPV Blot against the gold standard were satisfactory for HPV-16, -18, -58, -33, -52, -39, -45, -31, -51, -70 while HPV-71 (63.6%) had suboptimal sensitivity. Though the kappa values between the two tests for many individual genotypes could not be reliably calculated because of low positivity, the kappa values for HPV-16, -52, and -58 were excellent (0.93, 0.96, and 0.95, respectively). The modified MY11/GP6+ PCR-based HPV Blot assay is accurate and sensitive for detection and genotyping of HPV in cervical swab samples.