Provider-initiated HIV testing and counseling: increased uptake in two public community health centers in South Africa and implications for scale-up.
International guidance recommends the scale up of routinely recommended, offered, and delivered health care provider-initiated HIV testing and counseling (PITC) to increase the proportion of persons who know their HIV status. We compared HIV test uptake under PITC to provider-referral to voluntary counseling and testing (VCT referral) in two primary health centers in South Africa. Prior to introducing PITC, clinical providers were instructed to refer systematically selected study participants to VCT. After PITC and HIV rapid test training, providers were asked to recommend, offer and provide HIV testing to study participants during the clinical consultation. Participants were interviewed before and after their consultation to assess their HIV testing experiences. HIV test uptake increased under PITC (OR 2.85, 95% CI 1.71, 4.76), and more patients felt providers answered their questions on HIV (104/141 [74%] versus 73/118 [62%] for VCT referral; p 0.04). After three months, only 4/106 (3.8%) HIV-positive patients had registered for onsite HIV treatment. Providers found PITC useful, but tested very few patients (range 0-15). PITC increased the uptake of HIV testing compared with referral to onsite VCT, and patients reported a positive response to PITC. However, providing universal PITC will require strong leadership to train and motivate providers, and interventions to link HIV-positive persons to HIV treatment centers.


Concurrent occurrence of multiple sclerosis and primary CNS lymphoma: a case report.
We present the patient with the diagnosis of multiple sclerosis (MS), relapsing-remitting form with long lasting remission. Unexpectedly, this patient presented dramatical clinical deterioration and revealed clinical symptoms such as bradypsychia, cognitive symptoms, central vestibulare syndrome, spastic quadruparesis. Clinical findings suggested secondary progressive MS, but MRI called in question this diagnosis. The MRI appearance suggested, that MS had been complicated by a different brain pathological lesion, and the brain biopsy was indicated. A histological examination confirmed primary CNS lymphoma (PCNSL). This case exemplifies important aspects of clinical neurology. A re-evaluation of the diagnosis of MS should always be performed in a patient when new symptoms are presented that are unusual or could be due to other pathological processes. MRI offers the highly sensitive way to detect the coexistence of MS and other brain disease. Primary goal of imaging modalities is differential diagnosis between demyelinating diseases, such as MS and other brain lesions. Advanced focus demand contrast- enhancing and mass- effect lesions. It is important to realize, that contrast-enhancement and brain edema may be mitigated by treatment with corticosteroids. In some cases a brain biopsy is needed.


Primary Immun Deficiency in Patients with Non-Cystic Fibrosis Bronchiectasis and Its Relationship with Clinical Parameters.
Bronchiectasis is characterized by chronic respiratory infection. The role of immunodeficiency in this disease is poorly studied in relation to clinical indices. The primary aim of this study was to determine the frequency of these neglected altered immune status by evaluating immunoglobulins, lymphocyte subsets, complement levels, and neutrophil function, and to assess its relationship with clinical parameters in adult patients with non-cystic fibrosis bronchiectasis (NCFB). A total of 74 (30 men and 44 women with a mean age of 47±17 years) adult patients with stable NCFB were enrolled in this study. The bronchiectasis severity index (BSI) and FACED (F:FEV1, A: Age, C: Chronic colonization, E: Extension, D: Dyspnea) scores were assessed. Peripheral blood samples were collected for the detection of total IgG, IgA, IgM, IgE, and IgG subclasses and C3 and C4 levels. The counts of CD3, CD4, CD8, CD19, CD16/56 expressing peripheral blood lymphocytes and neutrophil oxidative function were evaluated. In the study population, BSI and FACED severity index scores increased with longer duration of the disease (p=0.01 and p=0.040, respectively). Of the 74 patients, 27 (37%) showed humoral aberrations. The number of male patients were higher in this group (p=0.03). High serum total IgE levels were associated with high scores in BSI (moderate-severe group versus mild group, p=0.030). Patients with bronchiectasis demonstrated lower CD3+ T cell count, lower CD4+ T helper cell percentage, and lower CD4+ T cell count (p=0.031, p=0.030, p=0.029, respectively) than healthy subjects. A significant negative correlation was found between the percentage and count of CD16/56+ natural killer (NK) cells and the number of exacerbations within the past year (r=-0.230, p=0.049 and r=-0.264, p=0.023, respectively). Humoral aberrations in adult patients with NCFB were found to be frequent. IgE levels were related to high scores for disease severity indices. Furthermore, patients with low percentage and counts of NK cells had higher rates of exacerbations. These results emphasize the importance of immune function assessment in adult patients with NCFB.


[Mechanisms of disordered cardiac energy supply in transient coronary insufficiency].
Experiments conducted on 240 albino non-inbred male rats, using models of transitory coronary insufficiency of various duration (the period of myocardial ischemia lasted 10, 40 and 120 min), showed impaired energy supply to the heart in both periods of its ischemia and reperfusion in relation to three principal stages; first the synthesis of ATP, then the transportation and utilization of its energy. The period of ischemia was associated with disorders of predominantly the ATP synthesis and to a lesser degree of the transport and utilization of its energy. In the period of the post-infarction resumption of the coronary blood flow mostly affected were the mechanisms of the transportation and absorption of ATP energy by the effector apparatus of cardiomyocytes. At the early stage of myocardial reperfusion after a prolonged (40 and 120 min) local ischemia, the heart was damaged to a greater degree than in continuing ischemia of the same duration. The development of transitory coronary insufficiency following the preliminary administration of the antihypoxant gutimin is characterized by less marked disorders in the process of cardiac energy supply both in the period of myocardial ischemia and at the early stage of the reperfusion.


Regulation of phosphatidylcholine synthesis in maturing type II cells: increased mRNA stability of CTP:phosphocholine cytidylyltransferase.
Pulmonary surfactant phosphatidylcholine synthesis increases in fetal lung type II cells with advancing gestation. This increase is accompanied by an increase in gene and protein expression of CTP:phosphocholine cytidylyltransferase (CT; EC 126.96.36.199), which catalyses a regulatory step in de novo phosphatidylcholine synthesis by fetal type II cells. In the present study we investigated the role of transcriptional and post-transcriptional mechanisms in the developmental induction of CT mRNA in maturing type II cells. We found that CT mRNA increased 2-fold from days 18 to 21 of fetal rat gestation (term 22 d). This increase in CT mRNA was not accompanied by a developmental increase in CT gene transcription. However, CT mRNA was more stable on day 21 (t1/2 48 h) compared with that on day 18 (t1/2 17 h). Glucocorticoids have been shown to enhance surfactant phosphatidylcholine synthesis in fetal type II cells. Therefore we also examined the effect of maternal glucocorticoid administration to pregnant rats at 19 d of gestation on CT mRNA expression in fetal type II cells isolated 24 h later. Glucocorticoid treatment did not increase type II cell CT mRNA. As reported previously, however, glucocorticoids increased CT activity in the microsomal membrane fraction of fetal type II cells, whereas no differences in cytosolic CT activity were observed. We conclude that the developmental increase in CT mRNA in fetal type II cells is due to a decreased breakdown of the CT transcript and that glucocorticoids regulate fetal type II cell CT activity at a post-translational level.


Spread of a neurotropic coronavirus to spinal cord white matter via neurons and astrocytes.
Mouse hepatitis virus strain JHM (MHV-JHM) causes a chronic encephalomyelitis in susceptible mice, with histological evidence of demyelination in the spinal cord. After intranasal inoculation, virus spreads retrogradely to several brain structures along neuroanatomic projections to the main olfactory bulb. In the absence of experimental intervention, mice become moribund before the spinal cord is infected. In this study, infusions of anti-MHV neutralizing monoclonal antibodies were administered to protect mice from the MHV-JHM-induced acute encephalitis and to allow survival until virus spread to the spinal cord. Under these conditions, virus was observed to enter specific layers (primarily laminae V to VII) in the gray matter of the upper spinal cord, consistent with transneuronal spread. While the brain structures which are the sources for virus spread to the spinal cord cannot be determined with certainty, the ventral reticular nucleus is likely to be important since it is consistently and extensively labeled in all mice and receives projections from subsequently infected areas of the spinal cord. After initial entry into the gray matter, virus rapidly spread to the white matter of the spinal cord. During the early stages of this process, extensive infection of astrocytes was noted, suggesting that cell-to-cell spread via these glial cells is an important part of this process. Reports from other laboratories using cultured cells strongly suggested that astrocytes serve as important regulators of oligodendrocyte function and, by extrapolation, have a major role in vivo in the processes of both demyelination and remyelination. Thus, our results not only outline the probable pathway used by MHV-JHM to infect the white matter of the spinal cord but also, with the assumption that infection of astrocytes leads to subsequent dysfunction, raise the possibility that infection of these cells contributes to the demyelinating process.


Lactococcus lactis Mutants Obtained From Laboratory Evolution Showed Elevated Vitamin K2 Content and Enhanced Resistance to Oxidative Stress.
Vitamin K2 is an important vitamin for human health. Vitamin K2 enrichment in the human diet is possible by using vitamin K2-producing bacteria such as Lactococcus lactis in food fermentations. Based on previous observations that aerated cultivation conditions improved vitamin K2 content in L. lactis, we performed laboratory evolution on L. lactis MG1363 by cultivating this strain in a shake flask in a sequential propagation regime with transfers to a fresh medium every 72h. After 100 generations of propagation, we selected three evolved strains that showed improved stationary phase survival in oxygenated conditions. In comparison to the original strain MG1363, the evolved strains showed 50-110% increased vitamin K2 content and exhibited high resistance against hydrogen peroxide-induced oxidative stress. Genome sequencing of the evolved strains revealed common mutations in the genes ldh and gapB. Proteomics analysis revealed overproduction of glyceraldehyde 3-phosphate dehydrogenase (GapA), universal stress protein A2 (UspA2), and formamidopyrimidine-DNA glycosylase (MutM) under aerated conditions in evolved strains, proteins with putative functions in redox reactions, universal stress response, and DNA damage repair, all of which could contribute to the enhanced oxidative stress resistance. The mechanisms underlying elevated vitamin K2 content in the evolved strains remain to be elucidated. Two out of the three evolved strains performed similar to the original strain MG1363 in terms of growth and acidification of culture media. In conclusion, this study demonstrated a natural selection approach without genetic manipulations to obtain vitamin K2 overproducers that are highly relevant for food applications and contributed to the understanding of oxidative stress resistance in L. lactis.


Type-4 Phosphodiesterase (PDE4) Blockade Reduces NETosis in Cystic Fibrosis.
Neutrophilic inflammation is a key determinant of cystic fibrosis (CF) lung disease. Neutrophil-derived free DNA, released in the form of extracellular traps (NETs), significantly correlates with impaired lung function in patients with CF, underlying their pathogenetic role in CF lung disease. Thus, specific approaches to control NETosis of neutrophils migrated into the lungs may be clinically relevant in CF. We investigated the efficacy of phosphodiesterase (PDE) type-4 inhibitors, in vitro, on NET release by neutrophils from healthy volunteers and individuals with CF, and in vivo, on NET accumulation and lung inflammation in mice infected with Pseudomonas aeruginosa. PDE4 blockade curbed endotoxin-induced NET production and preserved cellular integrity and apoptosis in neutrophils, from healthy subjects and patients with CF, challenged with endotoxin, in vitro. The pharmacological effects of PDE4 inhibitors were significantly more evident on CF neutrophils. In a mouse model of Pseudomonas aeruginosa chronic infection, aerosol treatment with roflumilast, a selective PDE4 inhibitor, gave a significant reduction in free DNA in the BALF. This was accompanied by reduced citrullination of histone H3 in neutrophils migrated into the airways. Roflumilast-treated mice showed a significant improvement in weight recovery. Our study provides the first evidence that PDE4 blockade controls NETosis in vitro and in vivo, in CF-relevant models. Since selective PDE4 inhibitors have been recently approved for the treatment of COPD and psoriasis, our present results encourage clinical trials to test the efficacy of this class of drugs in CF.


Quantitative residue-level structure-evolution relationships in the yeast membrane proteome.
Membrane proteins exist in distinctly different environments than do soluble proteins, resulting in differences between their respective biophysical and evolutionary properties. In comparison with soluble proteins, relatively little is known about how the unique biophysical properties of membrane proteins affect their evolutionary properties at the residue level. In particular, transmembrane (TM) regions of membrane proteins tend to be more conserved than regions outside of the membrane (extramembrane [EM] regions), but the mechanisms underlying this phenomenon are not well understood. Here, we combine homology-based high-resolution three-dimensional protein models with rigorous evolutionary rate calculations to quantitatively assess residue-level structure-evolution relationships in the yeast membrane proteome. We find that residue evolutionary rate increases linearly with decreasing residue burial, regardless of the hydrophobic or hydrophilic nature of the solvent environment. This finding supports a direct relationship between a residue's selective constraint and the extent of its packing interactions with neighboring residues, independent of hydrophobic effects. Most importantly, for a fixed degree of burial, residues from TM regions tend to evolve more slowly than residues from EM regions. We attribute this difference to the increased importance of packing constraints and the decreased importance of hydrophobic effects in TM regions. This additional selective constraint on TM residues plays a dominant role in explaining why TM regions evolve more slowly than EM regions. In addition to revealing the universality of the linear relationship between residue burial and selective constraint across solvent environments, our work highlights the distinct residue-level evolutionary consequences imposed by the unique biophysical properties of the membrane environment.


Aphakic correction in ectopia lentis.
Ectopia lentis may cause a reduction in visual acuity, which varies with the type and degree of dislocation and the presence of other ocular abnormalities. Retinoscopy may reveal a significant refractive error, usually myopia and astigmatism. Occasionally, an accurate refraction may be difficult because of tilting or dislocation of the lens. If aphakic refraction improves visual acuity, an aphakic correction should be considered.


Officer training, as seen from the Pine Tree.
The Pine Tree Chapter of IAHSS has been dedicated to educating officers, says the author. The Chapter has developed officer training programs and achieved passing rates of 96%. In the fall of 1997, the Chapter sponsored a supervisory training course. This article explores how the programs were developed, obstacles involved, and how these obstacles were overcome.


Adenine nucleotides decrease the apparent Km of endogenous natriuretic peptide receptors for GTP.
Natriuretic peptide receptors A (NPR-A) and B (NPR-B) mediate most effects of natriuretic peptides by synthesizing cGMP. ATP increases the activity of these receptors by an unknown mechanism. We recently reported that a nonhydrolyzable form of ATP, adenylyl imidodiphosphate (AMPPNP), stabilizes but is not required for the activation of NPR-A and NPR-B in membranes from highly overexpressing cells. Here, we repeated these studies on receptors expressed in endogenous settings. Kinetic analysis indicated that both AMPPNP and ATP dramatically decrease the apparent K(m) of both receptors for GTP but had little effect on the V(max). The EC(50) for AMPPNP decreased as substrate concentration increased whereas the magnitude of the effect was greater at lower GTP concentrations. ATP increased the activity of a mutant receptor containing glutamates substituted for all known phosphorylation sites similarly to the wild-type receptor, consistent with a phosphorylation independent mechanism. Finally, the putative ATP binding sites were investigated. Mutation of the ATP modulatory domain region had no effect, but mutation of K535A dramatically diminished ANP-dependent cyclase activity in a manner that was unresponsive to ATP. Mutation of the highly conserved 630-KSS to AAA (all alanines) resulted in an expressed receptor that had no detectable guanylyl cyclase activity. We conclude that ATP is not required for the initial activation of NPRs but does increase activity over time by reducing the apparent K(m) for GTP.


Developmental outcome at 2 years of age for children born after ICSI compared with children born after IVF.
Since the introduction of ICSI in 1991, medical outcome studies on ICSI children have been performed, but few have addressed developmental outcome. Hence, this outcome was assessed by performing a standard developmental test on children born after ICSI as compared with children born after IVF, at the age of 2 years. In a prospective study, the medical and developmental outcome of 439 children born after ICSI (378 singletons, 61 twins) were compared with those of 207 children born after IVF (138 singletons, 69 twins), at the age of 24-28 months. These children were part of a cohort of children followed since birth. Of children reaching the age of 24-28 months between May 1995 and March 2002, 44.3% (2375/5356) were examined by a paediatrician who was unaware of the type of treatment used for each couple. Of all the children born, 12.2% (439/3618) in the ICSI group and 11.9% (207/1738) in the IVF group underwent a formal developmental assessment using the Bayley Scale of Infant Development (mental scale) by a paediatrician blinded to the type of treatment. There was no significant difference in maternal educational level, maternal age, gestational age, parity, birthweight, neonatal complication rate or malformation rate at 2 years between ICSI and IVF singletons, or between ICSI and IVF twins. No significant difference was observed in the developmental outcome using the Bayley scale at the age of 24-28 months (raw scores or test age) between ICSI children or IVF children. A multivariate regression analysis for the singleton children indicated that parity, sex (boys had lower scores than girls) and age had a significant influence on the test result, but that the fertility procedure (ICSI versus IVF) did not influence the test result. ICSI children from fathers with low sperm concentration, low sperm motility or poor morphology had a similar developmental outcome to that of children from fathers with normal sperm parameters. There were no significant differences between the initial cohort and the group lost to follow-up, nor between the psychologically tested and the non-tested group for a number of variables such as maternal educational level, birthweight in singletons and neonatal malformation rate. Although only some of the cohort of ICSI children were evaluated, a representative sample of both ICSI and IVF children was compared. There is no indication that ICSI children have a lower psychomotor development than IVF children. Paternal risk factors associated with male-factor infertility were found not to play a role in developmental outcome.


Fingolimod anti-inflammatory and neuroprotective effects modulation of RAGE axis in multiple sclerosis patients.
We investigated Fingolimod treatment effects on the RAGE (receptor for advanced glycation endproducts) axis in multiple sclerosis (MS) patients. The primary outcome of the study was whether Fingolimod treatment increases serum levels of the soluble RAGE isoforms, sRAGE and esRAGE - both being considered putative endogenous inhibitors of RAGE signaling. Additional variables were serum levels of RAGE ligands, the high mobility group box (HMGB)1 and pentosidine. Serum levels of the study variables were measured by ELISA, and compared between baseline (before Fingolimod treatment) and 6 and 12 months post-drug treatment in 17 relapsing MS patients. Fingolimod treatment effects on MS disease progression were assessed by comparing pre- and post-Fingolimod values of the EDSS and rate of clinical relapse, and changes in the T1-and T2-enahncing lesions on the MRI scan.methods RESULTS: Twelve months treatment with Fingolimod increased serum levels of sRAGE and esRAGE by 32.4% (P = 0.004) and 48.5% (P = 0.007) respectively. In addition, Fingolimod treatment reduced serum levels of HMGB1 by 71.6% (P = 0.02) and pentosidine serum levels by 41.3% (P = 0.12). EDSS remained stable (baseline: 3.57 ± 1.56; post-Fingolimod: 3.54 ± 1.2, P = 0.96) and the rate of clinical relapse decreased near significantly (P = 0.094). T1-and T2-enhancing lesions remained stable, showing no significant changes pre-vs. post-Fingolimod treatment. Fingolimod mediates modulation of the RAGE axis which apparently contributes to the Fingolimod's anti-inflammatory and neuroprotective effects. These findings may provide a rationale for the clinical efficacy of Fingolimod in pathological states other than MS, where dysregulation of the RAGE axis plays a role.


Microbiology in the management of destructive periodontal disease.
This paper summarizes the rationale for the application of microbiology in the management of destructive periodontal diseases. The subgingival microbiota in patients with severe periodontitis is complex and contains high numbers of obligate anaerobic bacteria as well as facultative micro-organisms. It has become clear that major differences exist in the composition of the subgingival microflora. These differences are not only quantitative but also qualitative. Difference in plaque composition is the basis for the application of clinical microbiology in the management of periodontal disease. Several bacterial species have emerged as useful indicators for progressive periodontitis. In this respect, the importance of Actinobacillus actinomycetemcomitans, Bacteroides gingivalis and Bacteroides intermedius has been shown in a number of studies. It has become clear that A. actinomycetemcomitans is not specifically associated with the local form of juvenile periodontitis, but this micro-organism is probably also of importance in severe periodontitis in adult patients. Selection of individuals with an A. actinomycetemcomitans associated periodontitis is essential since successful treatment in these patients needs an adjunctive antibiotic therapy. Microbiological testing can be useful in patients showing a poor response to periodontal treatment (refractory periodontitis). Factors which may be responsible include poor oral hygiene, poor subgingival debridement, the patient's susceptibility and a subgingival microflora resistant to therapy. In this patient category, microbiological testing is capable of diverting continuing periodontal treatment. Furthermore, microbiology can be useful in evaluating periodontal treatment. Successful elimination of specific periodontopathic microorganisms can be used to determine recall intervals.


Improved bracing compliance in children with clubfeet using a dynamic orthosis.
Non-compliance with foot abduction bracing in children with clubfeet treated with the Ponseti method is the leading risk factor for deformity recurrence. A dynamic foot abduction orthosis is believed to result in improved compliance, fewer skin complications, and fewer recurrences. A case-control trial was conducted to test this hypothesis. A prospective cohort of children with idiopathic clubfoot using a dynamic brace was compared to a historical control group treated with a standard orthosis. Compliance, skin complications, recurrence, and the need for surgical soft tissue release were compared between groups at equivalent follow-up. The dynamic and standard brace groups are equivalent in age at the start of treatment (1.9 vs. 2.9 months), number of affected feet (97 vs. 92), and severity (average of four casts required for correction in each group). Fifty-seven children were followed in each group for an average of 2 years. All were corrected initially with the Ponseti method. Compliance is higher using the dynamic brace (47/57, 81%) compared to the standard brace (21/57, 47%) (P < 0.001). The recurrence rate is lower using the dynamic brace (11/57, 19%) compared to the standard brace (22/57, 39%) (P < 0.02). Skin complications are fewer in the dynamic brace (2/57, 3%) compared to the standard brace (11/57, 19%) (P < 0.008). Most importantly, five children using the standard brace underwent posteromedial release within 2 years of treatment, compared to none in the dynamic brace group. The dynamic foot abduction brace results in improved compliance, fewer recurrences, fewer skin complications, and reduced rates of surgery in idiopathic clubfoot than the traditional brace after non-operative correction with the Ponseti method.


Effect of thyroxine on protein and nucleic acid contents of different parts of brain of Singi fish (Heteropneustes fossilis Bloch).
Effects of three consecutive days injections of thyroxine (T4) of different doses (1, 2 and 4 micrograms/g of body weight) on different parts of the brain of Singi fish were studied. T4 enhanced the cranio-somatic index and the weight of different substructures of brain, viz., cerebrum, cerebellum midbrain and medulla oblongata, of Singi fish at 25 degrees C. Compared to the control, the protein content of cerebrum increased with all doses of T4 (1, 2 and 4 micrograms/g) and the RNA content of this region increased only with higher doses (2 and 4 micrograms/g). Cerebellum appeared to be relatively less responsive than cerebrum; T4 at the dose of 4 micrograms/g was only effective in increasing the protein content of the cerebellum, although the RNA content of this region was enhanced with both 2 and 4 micrograms of T4 per g. In midbrain and medulla oblongata, the protein content was elevated only with higher doses (2 and 4 micrograms/g) and RNA content was enhanced with all doses of T4 used. T4 injections did not cause any alteration of the DNA content of cerebrum and cerebellum, but in midbrain this cellular constituent increased in amount with all doses of T4 and in medulla oblongata it was increased with the dose of 2 or 4 micrograms of T4 per g body weight.


[Perinatal implications of pregnancy in adolescent women].
To establish if there are differences on obstetric and perinatal outcomes between adolescents who are younger than 16 with young adults aging 20 to 24 years old. A double-cohort prospective and comparative study in 328 Mexican pregnant women. Cohort I included 153 pregnant adolescents younger than 16 years old and cohort II included 175 young adults aging 20 to 24 years old. Inclusion criteria for both groups were: healthy, singleton, primigravidas, with 4 or more antenatal care visits and delivery at institution. descriptive, t-test, chi-squared and Fisher's exact test. Cohort I: Mean age, 15 years old. Mean gestational age on first visit, 22.35 +/- 6.75 weeks. Morbidity was due mainly by vaginitis and vaginosis (p = 0.0001), urinary tract infection (p = 0.110) and anemia (p = 0.0001). Maternal weight on first visit was 54.11 +/- 9.11 (p = 0.001). In cohort II mean maternal age was 22 years old with a mean gestational age on first visit of 19.58 +/- 7.94 weeks. Main morbidity was: urinary tract infections, vaginitis-vaginosis and preeclampsia (p = 0.191). Mean maternal weight on first visit was 60.37 +/- 9.99. Gestational age on delivery and birth weight were not statistically different between newborns in each group. Pregnancy in adolescents should be considered of risk; nevertheless, adequacy in antenatal care provides good obstetric and perinatal outcomes.


The Relationship Between Perceived Parental Competence and Bereavement Outcomes in Widows With Young Children.
Adjustment to bereavement, while a normative life experience, is one that impacts every aspect of life. Widows with young children face the unique challenge of managing both their grief and the grief of their child while also redefining roles, responsibilities, and resources. This study used a cross-sectional survey method to explore the relationship between perceived parental competence and bereavement outcomes in widows with young children (n = 232). Participants completed study measures including a demographic survey, the Revised Grief Experience Inventory, and the Parental Sense of Competence Scale. Results indicate that the constructs of competence, parenting self-efficacy and parental satisfaction, were directly correlated to decreased grief experiences. Additionally, grief experiences were found to be higher in widows reporting lower levels of education, those who were not currently in a relationship, and those who had more children to care for. This study highlights the potential that perceived parental competence has to influence the grief experience for widows and their bereaved children.


Phase-field modeling of isothermal quasi-incompressible multicomponent liquids.
In this paper general dynamic equations describing the time evolution of isothermal quasi-incompressible multicomponent liquids are derived in the framework of the classical Ginzburg-Landau theory of first order phase transformations. Based on the fundamental equations of continuum mechanics, a general convection-diffusion dynamics is set up first for compressible liquids. The constitutive relations for the diffusion fluxes and the capillary stress are determined in the framework of gradient theories. Next the general definition of incompressibility is given, which is taken into account in the derivation by using the Lagrange multiplier method. To validate the theory, the dynamic equations are solved numerically for the quaternary quasi-incompressible Cahn-Hilliard system. It is demonstrated that variable density (i) has no effect on equilibrium (in case of a suitably constructed free energy functional) and (ii) can influence nonequilibrium pattern formation significantly.


[Plasma concentration of cytosine arabinoside (Ara-C) in the elderly patients with hematological malignancy treated by Ara-C or cytarabine ocfosfate (SPAC)].
Plasma concentration of cytosine arabinoside (Ara-C) was determined in elderly patients with myelodysplastic syndromes or acute myelocytic leukemia who were treated with subcutaneous injection of Ara-C (Ara-C s.c.; 10 mg/m2/12 hr, 14-21 days), continuous drip infusion of Ara-C (Ara-C d.i.v.; 20 mg/m2/day, 24 hr 14 days) and/or oral administration of cytarabine ocfosfate (SPAC) (SPAC p.o.; 100 mg-300 mg/body/day, 14 days) by radioimmunoassay. In the Ara-C s.c. patients, the peak plasma level (Cmax) of Ara-C was 103 ng/ml and the time to reach Cmax was 15 min. The elimination half-like (t1/2) was 25 min and no accumulation was detected after 14 days of consecutive Ara-C s.c. administrations. In the SPAC p.o. patients, Cmax of Ara-C was 3-8 ng/ml and it took 3-5 days to reach Cmax. The plasma concentration level of Ara-C remains almost at the Cmax level during the SPAC p.o. administration and it remained higher than 0.32 ng/ml for as long as 15 days after the end of administration. In a Ara-C d.i.v. patient, plasma level of Ara-C was detected 4-7 ng/ml during the administration (day 7 through day 14). In all patients bone marrow suppression was observed after chemotherapy regardless of regimen, and there was no significant difference between nadir peripheral cell blood counts of Ara-C s.c. patients and SPAC p.o. patients.


Alteration of intermediate filament distribution in PtK1 cells by acrylamide.
PtK1 cells were treated with low concentrations of acrylamide resulting in disruption of intermediate filament networks. An optimum treatment, 5 mM acrylamide in culture medium for 4 h, resulted in formation of a juxtanuclear aggregate containing both keratin and vimentin intermediate filaments. Actin-containing stress fibers and microtubules appeared normal after this treatment. Cells recovered when acrylamide was washed out of the cultures, and normal keratin and vimentin networks reappeared. These cells were capable of proliferation and grew to confluence. Acrylamide-treated cells appeared to locomote normally, showing membrane ruffling and changes in shape, but cytoplasmic organelles did not appear to move normally throughout the cell but remained at the cell center. These observations indicate that acrylamide is a useful intermediate filament inhibitor that does not affect other cytoskeletal elements.


Still moving toward automation of the systematic review process: a summary of discussions at the third meeting of the International Collaboration for Automation of Systematic Reviews (ICASR).
The third meeting of the International Collaboration for Automation of Systematic Reviews (ICASR) was held 17-18 October 2017 in London, England. ICASR is an interdisciplinary group whose goal is to maximize the use of technology for conducting rapid, accurate, and efficient systematic reviews of scientific evidence. The group seeks to facilitate the development and widespread acceptance of automated techniques for systematic reviews. The meeting's conclusion was that the most pressing needs at present are to develop approaches for validating currently available tools and to provide increased access to curated corpora that can be used for validation. To that end, ICASR's short-term goals in 2018-2019 are to propose and publish protocols for key tasks in systematic reviews and to develop an approach for sharing curated corpora for validating the automation of the key tasks.


In vitro efficacy of phytotherapeutics suggested for prevention and therapy of urinary tract infections.
To analyse the therapeutic efficacy of various phytotherapeutics and their antimicrobial compounds with regard to strain specificity and dose dependence. A representative strain collection of 40 uropathogenic bacteria isolated from complicated and uncomplicated urinary tract infection was subjected to various virulence assays (bacterial growth, mannose-sensitive agglutination, and motility) to determine the therapeutic impact of various compounds with antimicrobial activity. We tested proanthocyanidins (PAC), D-mannose, rosemary extract (Canephron®), and isothiocyanates (Angocin®). D-mannose efficiently blocked the adhesive properties of all type 1 fimbriae-positive isolates in low concentration (0.2%), but showed no bacteriostatic effect. PAC also actively blocked agglutination, but the concentration varied considerably among isolates. Escherichia coli required the highest concentration (10%), while Enterobacter cloacae responded to low concentrations (0.1%). Allyl isothiocyanates not only impaired agglutination in all tested isolates, but also had a dramatic impact on flagella-mediated motility in Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis (p < 0.001). The administration of rosemary extracts revealed a strong bacteriostatic effect in growth assays. All tested strains were strongly inhibited by the addition of 10 μg/ml or 1 μg/ml of purified rosemary extractions with the exception of Serratia marcescens. Morganella morganii responded only to 10 μg/ml. Phytotherapeutics and small-molecular compounds like mannosides have the potential to become an integral part in a multi-modal treatment concept for the treatment and prevention of urinary tract infections. Their efficiency can be optimised when strain specificities and therapeutic concentrations are taken into account.


The SUMO E3 ligase Siz2 exerts a locus-dependent effect on gene silencing in Saccharomyces cerevisiae.
In the yeast Saccharomyces cerevisiae, the two silent mating-type loci and subtelomeric regions are subjected to a well-characterized form of gene silencing. Establishment of silencing involves the formation of a distinct chromatin state that is refractory to transcription. This structure is established by the action of silent information regulator proteins (Sir2, Sir3, and Sir4) that bind to nucleosomes and initiate the deacetylation of multiple lysine residues in histones H3 and H4. Sir2 protein is a conserved histone deacetylase that is critical for mating-type and telomeric silencing, as well as a Sir3/4-independent form of silencing observed within the ribosomal DNA (rDNA) repeat locus. We report here that sumoylation plays an important role in regulating gene silencing. We show that increased dosage of SIZ2, a SUMO (small ubiquitin-related modifier) ligase, is antagonistic to gene silencing and that this effect is enhanced by mutation of ESC1, whose product is involved in tethering telomeres to the nuclear periphery. We present evidence indicating that an elevated SIZ2 dosage causes reduced binding of Sir2 protein to telomeres. These data support the idea that sumoylation of specific substrates at the nuclear periphery regulates the availability of Sir2 protein at telomeres.


High-sensitivity C-reactive protein predicts cardiovascular risk in diabetic and nondiabetic patients: effects of insulin-sensitizing treatment with pioglitazone.
Systemic inflammatory activity has turned out to play a key pathogenic role in vascular atherosclerosis, insulin resistance, and type 2 diabetes mellitus. Inflammatory biomarkers may therefore be a valuable tool for risk evaluation. Among them, the best evidence to date supports the use of high-sensitivity C-reactive protein (hs-CRP) to monitor insulin resistance and cardiovascular risk in diabetic and nondiabetic individuals. Data suggest that hs-CRP may also participate directly in the process of atherogenesis. A growing number of clinical trials tested the hypothesis that antidiabetic drugs specifically targeting insulin resistance could benefit individuals by reducing inflammation, atherogenesis, and thus cardiovascular risk. One such class are the thiazolidinediones (pioglitazone and rosiglitazone). These agents act as selective ligands of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). This article reviewed published data on hs-CRP changes with the thiazolidinedione agent pioglitazone. Here we found pronounced insulin-sensitizing and anti-inflammatory properties in different clinical settings, including diabetic and nondiabetic individuals. Coadministration of pioglitazone to antilipidemic statin therapy resulted in additional effects on low-grade inflammation, and hs-CRP reduction has been demonstrated to occur independently of glucose lowering. The anti-inflammatory effect appeared to be a rapid physiologic reaction on PPARgamma activation and could be observed within a short-term interval after starting pioglitazone therapy. In summary, clinical study results underline the benefit of an early insulin resistance treatment to oppose systemic vascular inflammation and cardiometabolic syndrome in patients with elevated levels of high-sensitivity C-reactive protein.


HMGB3 characterization in gastric cancer.
Gastric cancer is a major health problem worldwide; it is the second most common cause of cancer death in the world. Recent studies indicate that the high-mobility group (HMG) of chromosomal proteins is associated with cancer progression. However, HMGB3 has been little studied. We analyzed the co-expression network between HMGB3 and differentially-expressed genes in the GSE17187 database, identifying the relevant transcription factors, and the conserved domain of HMGB3 to understand the underlying regulation mechanisms involved in gastric cancer. Thirty-one relationships between 11 differentially-expressed genes were included in a co-expression network; many of these genes have been identified as related to cancer, including TBX5 and TFR2. Further analysis identified nine transcription factors, these being GATA3, MZF1, GATA1, GATA2, SRY, REL, NFYB, NFYC, and NFYA, which could interact with HMGB3 to regulate target gene expression and consequently regulate gastric cancer cell proliferation, migration and invasion. The HMG-box domain was very similar in various species, with only a few amino acid changes, indicating conserved functions in HMG-box. This information helps to provide insight into the molecular mechanisms of HMGB3 in human gastric cancer.


PhD: a web database application for phenotype data management.
A database application has been developed for phenotype data management employing the Entity-Attribute-Value (EAV) model. By applying the EAV model, this application allows users to manage arbitrary phenotypes and customize data entry forms; therefore, it is suitable for different and multi-center projects.


Atomic force and total internal reflection fluorescence microscopy for the study of force transmission in endothelial cells.
This paper describes the combined use of atomic force microscopy (AFM) and total internal reflection fluorescence microscopy (TIRFM) to examine the transmission of force from the apical cell membrane to the basal cell membrane. A Bioscope AFM was mounted on an inverted microscope, the stage of which was configured for TIRFM imaging of fluorescently labeled human umbilical vein endothelial cells (HUVECs). Variable-angle TIRFM experiments were conducted to calibrate the coupling angle with the depth of penetration of the evanescent wave. A measure of cellular mechanical properties was obtained by collecting a set of force curves over the entire apical cell surface. A linear regression fit of the force-indentation curves to an elastic model yields an elastic modulus of 7.22 +/- 0. 46 kPa over the nucleus, 2.97 +/- 0.79 kPa over the cell body in proximity to the nucleus, and 1.27 +/- 0.36 kPa on the cell body near the edge. Stress transmission was investigated by imaging the response of the basal surface to localized force application over the apical surface. The focal contacts changed in position and contact area when forces of 0.3-0.5 nN were applied. There was a significant increase in focal contact area when the force was removed (p < 0.01) from the nucleus as compared to the contact area before force application. There was no significant change in focal contact coverage area before and after force application over the edge. The results suggest that cells transfer localized stress from the apical to the basal surface globally, resulting in rearrangement of contacts on the basal surface.


Scaphoid fracture as a "puncher's fracture".
We investigated 18 scaphoid fractures induced by punching. The wrist position while punching was neutral to slight palmar flexion. We postulated that the mechanism of the fracture was caused by the concentration of the external force to the second metacarpus. The forces are then dispersed to the trapezium and trapezoid, which produces shear stress at the waist of the scaphoid. In spite of the differences in mechanism, the location of the fracture was similar to fractured scaphoids caused by wrist extension injuries. Regardless of the wrist positions, the carpal scaphoid is most vulnerable to fracture due to its characteristic morphology.


Family Consultation to Reduce Early Hospital Readmissions among Patients with End Stage Kidney Disease: A Randomized Controlled Trial.
The US Centers for Medicare and Medicaid Services have mandated reducing early (30-day) hospital readmissions to improve patient care and reduce costs. Patients with ESKD have elevated early readmission rates, due in part to complex medical regimens but also cognitive impairment, literacy difficulties, low social support, and mood problems. We developed a brief family consultation intervention to address these risk factors and tested whether it would reduce early readmissions. One hundred twenty hospitalized adults with ESKD (mean age=58 years; 50% men; 86% black, 14% white) were recruited from an urban, inpatient nephrology unit. Patients were randomized to the family consultation (n=60) or treatment-as-usual control (n=60) condition. Family consultations, conducted before discharge at bedside or via telephone, educated the family about the patient's cognitive and behavioral risk factors for readmission, particularly cognitive impairment, and how to compensate for them. Blinded medical record reviews were conducted 30 days later to determine readmission status (primary outcome) and any hospital return visit (readmission, emergency department, or observation; secondary outcome). Logistic regressions tested the effects of the consultation versus control on these outcomes. Primary analyses were intent-to-treat. The risk of a 30-day readmission after family consultation (n=12, 20%) was 0.54 compared with treatment-as-usual controls (n=19, 32%), although this effect was not statistically significant (odds ratio, 0.54; 95% confidence interval, 0.23 to 1.24; P=0.15). A similar magnitude, nonsignificant result was observed for any 30-day hospital return visit: family consultation (n=19, 32%) versus controls (n=28, 47%; odds ratio, 0.53; 95% confidence interval, 0.25 to 1.1; P=0.09). Per protocol analyses (excluding three patients who did not receive the assigned consultation) revealed similar results. A brief consultation with family members about the patient's cognitive and psychosocial risk factors had no significant effect on 30-day hospital readmission in patients with ESKD.


Effect of sorbitol dehydrogenase inhibition on sugar cataract formation in galactose-fed and diabetic rats.
Several recent studies with the sorbitol dehydrogenase inhibitors 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2-methylpyrimidine, SDH-1, and its active metabolite 4-[4-(N, N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine , SDH-2, suggest that inhibition of sorbitol dehydrogenase may be beneficial in delaying the onset of diabetic complications due to their ability to ameliorate redox changes associated with polyol metabolism. To compare the relative importance of sorbitol dehydrogenase versus aldose reductase inhibition on sugar cataract formation, cataract formation was monitored in 50% galactose-fed and diabetic rats treated with/without the sorbitol dehydrogenase inhibitors SDH-1 or SDH-2 or the aldose reductase inhibitors AL 1576 or Ponalrestat. For these studies, diabetes was induced in young 50 g rats with streptozotocin while galactosemia was produced by feeding a diet containing 50% galactose. Inhibitors were administered in the diet with the diet containing 0.06% (w/w) of the sorbitol dehydrogenase inhibitors or Ponalrestat, and 0.0125% (w/w) of AL 1576. Cataract formation was monitored by hand-held slit lamp and polyol levels were measured by gas chromatography. Sugar cataract formation was accelerated in diabetic rats treated with sorbitol dehydrogenase inhibitors while no difference in cataract formation was observed in galactose-fed rats treated with/without SDH inhibitors. Cataract formation was inhibited in both diabetic and galactosemic rats by either Ponalrestat or AL 1576. These results support the concept that sugar cataract formation is initiated by the aldose reductase catalysed intracellular accumulation of polyols and that these sugar cataracts can be prevented through inhibition of aldose reductase.


Zinc-65 in cyclotron workers.
Small but persistent body burdens of zinc-65 have been found in cyclotron workers. This radionuclide and others are produced by nuclear reactions with the construction materials of the cyclotron. Only zinc-65 has gained entry into the body, but in amounts of less than 1 percent of the maximum permissible amount.


The neuroprotective function of vascular endothelial growth factor (VEGF).
The vascular endothelial growth factor (VEGF) is known mainly as the potent angiogenic and vascular permeability-enhancing factor. Both processes are very effective in hypoxia. The latest studies show that VEGF has neurotrophic and neuroprotective as well as angiogenic properties. It exerts neuroprotective actions directly through the inhibition of programmed cell death (PCD), or apoptosis and the stimulation of neurogenesis. VEGF is also a mediator of multiple processes including angiogenesis, enhancing blood brain barrier permeability for glucose, antioxidants activation, which indirectly result in neuroprotection. VEGF prevents neurons from death under critical conditions such as hypoxia, glucose deprivation through binding to the specific receptors, which are also expressed on the surface of neuronal cells. The increased expression of VEGFR-2/flk-1/KDR receptors on neurons subjected to hypoxia, glucose deprivation provides evidence that these receptors are mainly involved in neuroprotective effects of VEGF. Furthermore, binding to these receptors triggers the phosphatidyloinositol 3-kinase (PI3K) /Akt signal transduction system and, in consequence, leads to the inhibition of PCD by activating antiapoptotic proteins through the transcription factor NFkappaB and inhibiting proapoptotic signaling by Bad, caspase-9, caspase-3, and other effectors. Promotion of neuronal cells proliferation by VEGF is also associated with the increased expression of VEGFR-2 receptors and up-regulation of E2F family transcription factors, cyclin D1, cyclin E, and cdc25. It is known that the amount and types of VEGF isoforms influence its action. At least six isoforms of VEGF proteins are formed as a result of alternative mRNA splicing and it is unknown which of them and in what proportion occur in the nervous system in physiology and pathophysiology. It seems to be very essential to find out the mechanisms responsible for specific patterns of VEGF isoforms and their receptors expression in different pathologies of the nervous system. Maybe such knowledge will provide new perspectives in VEGF therapy.


Identification of an extracellular domain within the human PiT2 receptor that is required for amphotropic murine leukemia virus binding.
Human PiT2 (PiT2) is a multiple-membrane-spanning protein that functions as a type III sodium phosphate cotransporter and as the receptor for amphotropic murine leukemia virus (A-MuLV). Human PiT1 (PiT1), another type III sodium phosphate cotransporter, is a highly related protein that functions as a receptor for gibbon ape leukemia virus but not for A-MuLV. The ability of PiT1 and PiT2 to function as discrete viral receptors with unique properties presumably is reflected in critical residue differences between these two proteins. Early efforts to map the region(s) within PiT2 that is important for virus binding and/or entry relied on infection results obtained with PiT1-PiT2 chimeric cDNAs expressed in Chinese hamster ovary (CHOK1) cells. These attempts to localize the PiT2 virus-binding site were hampered because they were based on infectivity, not binding, assays, and therefore, receptors that bound but failed to facilitate virus entry could not be distinguished from receptors that did not bind virus. Using a more accurate topological model for PiT2 as well as an A-MuLV receptor-binding assay, we have identified extracellular domain one (ECD1) of the human PiT2 receptor as being important for A-MuLV binding and infection.


Sick and solo: a qualitative study on the life experiences of people living with HIV in Somalia.
HIV stigma and the resultant fear of being identified as HIV-positive can compromise the effectiveness of HIV programs by undermining early diagnosis and antiretroviral treatment initiation and adherence of people living with HIV (PLHIV). In the wake of the longstanding conflict in the country, little is known about the life experiences of PLHIV in Somalia. A qualitative study using unstructured interviews was conducted in Somalia from September to December 2017. A convenience sampling approach was used to recruit 13 participants, including 10 persons who live with HIV and three senior officials who work for the HIV program at the Ministry of Health. Data were analyzed using a thematic analysis. Our findings show that PLHIV are alienated and prefer to isolate themselves due to widespread stigma subjected to them by their family members, society, employers, and health providers, which continue to undermine the scale-up of testing and treatment of PLHIV in Somalia. Consequently, they are reluctant to seek voluntary diagnosis and treatment of HIV. They often come to know about their status when their partners are found HIV positive, they are tested for other clinical purposes, or when an individual's health deteriorates, and all other means fail to work in improving his/her situation. The study also pointed out a shortage of facilities that provide HIV diagnosis, counseling and treatment in Somalia. Addressing stigma and discrimination subjected to PLHIV are critical to a successful HIV response in Somalia. To successfully address stigma, HIV programs need evidence on effective interventions at individual, community, and societal levels in order to strategically incorporate stigma and discrimination reduction into national HIV programs.


Implementation of a portable diagnostic system for Thomson scattering measurements on an electrothermal arc source.
To fulfill the increasing needs of diagnostic support for researchers in plasma technology, a portable diagnostic package (PDP) equipped for both laser Thomson scattering (TS) and optical emission spectroscopy has been designed and constructed at Oak Ridge National Laboratory (ORNL), aiming to measure the temperature and number density of electrons and temperatures of ions in plasma devices. The PDP has been initially implemented on a high density and low temperature electrothermal arc source (ET-arc) at ORNL to test its TS capability. TS from the plasmas in the ET-arc has been obtained using the PDP. The electron temperature and number density were determined from TS spectra. These results were then compared to measurements from previous studies on the ET-arc. The TS diagnostic measured 0.8 ± 0.1, 1.3 ± 0.2, and 0.7 ± 0.1 eV and (4.4 ± 0.5) × 1021, (5.9 ± 0.7) × 1021, and (4.3 ± 0.5) x 1021 m-3, respectively, from three lines of sight that transect the plasma column.


Relating hybrid advantage and genome replacement in unisexual salamanders.
Unisexual vertebrates are model systems for understanding the evolution of sex. Many predominantly clonal lineages allow occasional genetic recombination, which may be sufficient to avoid the accumulation of deleterious mutations and parasites. Introgression of paternal DNA into an all-female lineage represents a one-way flow of genetic material. Over many generations, this could result in complete replacement of the unisexual genomes by those of the donor species. The process of genome replacement may be counteracted by contemporary dispersal or by positive selection on hybrid nuclear genomes in ecotones. I present a conceptual model that relates nuclear genome replacement, positive selection on hybrids and biogeography in unisexual systems. I execute an individual-based simulation of the fate of hybrid genotypes in contact with a single host species. I parameterize these models for unisexual salamanders in the Ambystoma genus, for which the frequency of genome replacement has been a source of ongoing debate. I find that, if genome replacement occurs at a rate greater than 1/10,000 in Ambystoma, then there must be compensating positive selection in order to maintain observed levels of hybrid nuclei. Future researchers studying unisexual systems may use this framework as a guide to evaluating the hybrid superiority hypothesis.


Toward a combinatorial nature of microRNA regulation in human cells.
MicroRNAs (miRNAs) negatively regulate the levels of messenger RNA (mRNA) post-transcriptionally. Recent advances in CLIP (cross-linking immunoprecipitation) technology allowed capturing miRNAs with their cognate mRNAs. Consequently, thousands of validated mRNA-miRNA pairs have been revealed. Herein, we present a comprehensive outline for the combinatorial regulation by miRNAs. We implemented combinatorial and statistical constraints in the miRror2.0 algorithm. miRror estimates the likelihood of combinatorial miRNA activity in explaining the observed data. We tested the success of miRror in recovering the correct miRNA from 30 transcriptomic profiles of cells overexpressing a miRNA, and to identify hundreds of genes from miRNA sets, which are observed in CLIP experiments. We show that the success of miRror in recovering the miRNA regulation from overexpression experiments and CLIP data is superior in respect to a dozen leading miRNA-target prediction algorithms. We further described the balance between alternative modes of joint regulation that are executed by pairs of miRNAs. Finally, manipulated cells were tested for the possible involvement of miRNA in shaping their transcriptomes. We identified instances in which the observed transcriptome can be explained by a combinatorial regulation of miRNA pairs. We conclude that the joint operation of miRNAs is an attractive strategy to maintain cell homeostasis and overcoming the low specificity inherent in individual miRNA-mRNA interaction.


The Case for BPA as an Obesogen: Contributors to the Controversy.
Since the inception of the term endocrine disruptor, the idea that the environment is an important determinant of phenotype has motivated researchers to explore the effect of low dose exposure to BPA during organogenesis. The syndrome observed was complex, affecting various endpoints such as reproduction and reproductive tissues, behavior, mammary gland development and carcinogenesis, glucose homeostasis, and obesity. This constellation of impacted endpoints suggests the possibility of complex interactions among the multiple effects of early BPA exposure. One key finding of our rodent studies was alterations of energy and amino-acid metabolism that were detected soon after birth and continued to be present at all time points examined through 6 months of age. The classical manifestations of obesity and associated elements of metabolic disease took a longer time to become apparent. Here we examine the validity of the often-mentioned lack of reproducibility of obesogenic effects of BPA, starting from the known environmental causes of variation, which are diverse and range from the theoretical like the individuation process and the non-monotonicity of the dose-response curve, to the very pragmatic like housing, feed, and time and route of exposure. We then explore environmental conditions that may hinder reproducibility and discuss the effect of confounding factors such as BPA-induced hyperactivity. In spite of all the potential sources of variation, we find that some obesogenic or metabolic effects of BPA are reproducibly observed when study conditions are analogous. We recommend that study authors describe details of their study conditions including the environment, husbandry, and feed. Finally, we show that when experimental conditions are strictly maintained, reproducibility, and stability of the obese phenotype is consistently observed.


Summer temperature variability and long-term survival among elderly people with chronic disease.
Time series studies show that hot temperatures are associated with increased death rates in the short term. In light of evidence of adaptation to usual temperature but higher deaths at unusual temperatures, a long-term exposure relevant to mortality might be summertime temperature variability, which is expected to increase with climate change. We investigated whether the standard deviation (SD) of summer (June-August) temperatures was associated with survival in four cohorts of persons over age 65 y with predisposing diseases in 135 US cities. Using Medicare data (1985-2006), we constructed cohorts of persons hospitalized with chronic obstructive pulmonary disease, diabetes, congestive heart failure, and myocardial infarction. City-specific yearly summer temperature variance was linked to the individuals during follow-up in each city and was treated as a time-varying exposure. We applied a Cox proportional hazard model for each cohort within each city, adjusting for individual risk factors, wintertime temperature variance, yearly ozone levels, and long-term trends, to estimate the chronic effects on mortality of long-term exposure to summer temperature SD, and then pooled results across cities. Mortality hazard ratios ranged from 1.028 (95% confidence interval, 1.013- 1.042) per 1 °C increase in summer temperature SD for persons with congestive heart failure to 1.040 (95% confidence interval, 1.022-1.059) per 1 °C increase for those with diabetes. Associations were higher in elderly persons and lower in cities with a higher percentage of land with green surface. Our data suggest that long-term increases in temperature variability may increase the risk of mortality in different subgroups of susceptible older populations.


Clinical Features and Liver Injury in Patients with COVID-19 in the Japanese Population.
Objective Liver injury is a notable complication of coronavirus disease 2019 (COVID-19). This study aimed to clarify the clinical features and liver injury in Japanese patients with COVID-19. Methods We conducted a multicenter retrospective cohort study. All consecutive patients with COVID-19 who visited or were admitted to our hospital before May 12, 2020, were enrolled. Their demographics, symptoms, laboratory findings, comorbidities, concomitant drugs, treatment, and clinical course were reviewed. We defined liver injury as alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) levels over the upper limit of normal. Results Twenty-two patients with COVID-19 (median age, 47 years old; men/women, 13/9) were enrolled. Two patients had underlying liver diseases, and two were diagnosed as having COVID-19 without any symptoms. Elevated ALT and GGT levels were found in 12 and 12 patients, respectively, and liver injury was observed in 15 patients (68.2%). Compared with the patients without liver injury, those with liver injury had a significantly higher fever during the clinical course (median, 37.5°C vs. 38.8°C, p=0.006). A significant correlation was found between the highest serum liver values and the highest body temperature in each patient. Among the 22 patients, 4 required artificial respiratory support, and 2 died thereafter. Liver injury was not associated with the severity or mortality of COVID-19. Conclusion Elevated levels of liver enzymes in the Japanese patients with COVID-19 were associated with the highest body temperature during the clinical course but not with the severity or mortality of COVID-19.


Hepatic dysfunction in scrub typhus.
Scrub typhus is an acute febrile illness that generally causes non-specific symptoms and signs of which fever is the most common. It is one of the causes of "fevers of unknown origin" in the Asia-Pacific region. The relationship between hepatic dysfunction and scrub typhus has been given little attention in the literature. From 1982 to 1993, 47 patients diagnosed with scrub typhus at Tri-Service General Hospital, Taipei, were studied, with attention being given to hepatic dysfunction. The medical records of these patients were reviewed thoroughly. Hepatic dysfunction occurred in 77% (36/47) of patients. Among the liver function parameters, the percentage of abnormality was 74.5% for aspartate aminotransferase, 74.5% for alanine aminotransferase, 57.4% for alkaline phosphatase, 44.7% for lactate dehydrogenase and 44.7% for serum bilirubin. Six patients presented with a picture of true hepatitis similar to acute viral hepatitis. The results indicate that hepatocellular damage does occur in scrub typhus, and is perhaps, more common than previously realized. We recommend that the differential diagnosis of patients from high-risk groups and endemic areas who present with hepatitis-like symptoms should include examination for scrub typhus.


Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities.
Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.


Protocol for a randomised controlled trial to investigate the effect of home- and gym-based resistance exercise training on glycaemic control, body composition and muscle strength.
Resistance exercise is known to be effective in reducing glycated haemoglobin (HbA1c) in people with type 2 diabetes. However, studies, so far, have employed supervised resistance exercise in a laboratory or gym facility which limits the future translation of such exercise in to clinical practice and recommendations. Our primary aim, therefore, is to test the hypothesis, in a randomized controlled trial, that home-based resistance exercise training and gym-based resistance exercise training both reduce HbA1c levels in people with type 2 diabetes compared to control. We will also investigate the effects of home- and gym-based resistance exercise training on muscle strength and body composition. The current study is a three-arm randomised controlled trial which will be conducted with 150 eligible people with type 2 diabetes to compare home-and gym-based resistance exercise training with usual care in Kuwait. The interventions will be delivered by exercise specialists and last for 32 weeks. The primary outcomes are HbA1c with secondary outcomes measuring muscle function, body composition, physical activity and quality of life. Ethical approval has been granted by the Dasman Diabetes Institute ethical review committee (RA/197/2019). Study findings will be disseminated through presentation at scientific conferences and in scientific journals. NCT04136730: Retrospectively registered on 21 October 2019.


Gua Sha therapy for chronic low back pain: A randomized controlled trial.
To test the efficacy of Gua Sha therapy in patients with chronic low back pain. 50 patients with chronic low back pain (78% female, 49.7 ± 10.0 years) were randomized to two Gua Sha treatments (n = 25) or waitlist control (n = 25). Primary outcome was current pain intensity (100-mm visual analog scale); secondary outcome measures included function (Oswestry Disability Index), pain on movement (Pain on Movement Questionnaire), perceived change in health status, pressure pain threshold, mechanical detection threshold, and vibration detection threshold. After treatment, patients in the Gua Sha group reported lower pain intensity (p < 0.001) and better overall health status (p = 0.002) compared to the waitlist group. No further group differences were found. No serious adverse events occurred. Gua Sha appears to be an acceptable, safe, and effective treatment for patients with chronic low back pain. Further rigorous studies are needed to confirm and extend these results.


Channelopathies as a genetic cause of epilepsy.
This review describes the significant number of new gene associations with epilepsy syndromes that have emerged during the past year, together with additional mutations and new electrophysiological data relating to previously known gene associations. Autosomal dominant juvenile myoclonic epilepsy was demonstrated to be a channelopathy associated with a GABA(A) receptor, alpha1 subunit mutation. Benign familial neonatal infantile seizures were delineated as another channelopathy of infancy, by molecular characterization of sodium channel, alpha2 subunit defects. A sodium channel, alpha2 subunit defect was previously found to be associated with generalized epilepsy with febrile seizures plus. Similarly, the clinical spectrum associated with potassium channel, KQT-like mutations was extended to include the channelopathy myokymia and neonatal epilepsy. Mutations in the non-ion channel genes, leucine-rich, glioma inactivated 1 gene and Aristaless related homeobox gene, have emerged as important causes of their specific syndromes, with mutations in the latter gene frequently underlying X-linked mental retardation with epilepsy. All but one of the idiopathic epilepsies with a known molecular basis are channelopathies. Where the ion channel defects have been identified, however, they generally account for a minority of families and sporadic cases with the syndrome in question. The data suggest that ion channel mutations of large effect are a common cause of rare monogenic idiopathic epilepsies, but are rare causes of common epilepsies. Additive effects of genetic variation, perhaps within the same ion channel gene families, are likely to underlie the common idiopathic generalized epilepsies with complex inheritance. The genetics of epilepsy is progressing rapidly toward a more detailed molecular dissection and definition of syndromes.


An agent-based simulation of persistent inequalities in health behavior: Understanding the interdependent roles of segregation, clustering, and social influence.
Health inequalities are conspicuously persistent through time and often durable even in spite of interventions. In this study, I use agent-based simulation models (ABMs) to understand how the complex interrelationships between residential segregation, social network formation, group-level preferences, and social influence may contribute to this persistence. I use a more-stylized ABM, Bubblegum Village (BV), to understand how initial inequalities in bubblegum-chewing behaviors either endure, increase, or decrease over time given group-level differences in preferences, neighborhood-level barriers or facilitators of bubblegum chewing (e.g., access to bubblegum shops), and agents' preferences for segregation, homophily, and clustering (i.e., the 'tightness' of social networks). I further use BV to understand whether segregation and social network characteristics impact whether the effects of a bubblegum-reduction intervention that is very effective in the short term are durable over time, as well as to identify intervention strategies to reduce attenuation of the intervention effects. In addition to BV, I also present results from an ABM based on the distribution and social characteristics of the population in Philadelphia, PA. This model explores similar questions to BV, but examines racial/ethnic inequalities in soda consumption based on agents' social characteristics and baseline soda consumption probabilities informed by the 2007-2010 National Health and Nutrition Examination Survey. Collectively, the models suggest that residential segregation is a fundamental process for the production and persistence of health inequalities. The other major conclusion of the study is that, for behaviors that are subject to social influence and that cluster within social groups, interventions that are randomly-targeted to individuals with 'bad' behaviors will likely experience a large degree of recidivism to pre-intervention behaviors. In contrast, interventions that target multiple members of the same network, as well as multilevel interventions that include a neighborhood-level component, can reduce recidivism.


Balanced inhibition and excitation underlies spike firing regularity in ventral cochlear nucleus chopper neurons.
Ventral cochlear nucleus stellate cells respond to characteristic frequency (CF) tones with sustained (C(S)), transient (C(T)) or onset chopping (O(C)) activity. The mechanisms underlying these different response patterns are not fully understood, and the present study used in vivo intracellular recordings (n = 42) in urethane-anaesthetized rats to examine the possible influence of inhibition on action potential regularity. Hyperpolarization following the offset of a CF tone burst was used as a measure of on-CF inhibition. A cluster analysis based on several membrane potential features, including on-CF inhibition, discriminated three groups in addition to the C(S) response type - two types of C(T) responses and the O(C) type. The different patterns of firing regularity exhibited by C(S/T) neurons reflected different thresholds or degrees of overlap between these cells' narrowly tuned excitatory and inhibitory inputs. C(T) cells with closely matched inhibitory and excitatory response areas showed substantial on-CF inhibition and the greatest decline in firing regularity during a CF tone, whereas those with a mismatch between their response areas showed lateral inhibition and a less marked decline in firing regularity. The presence of inhibition in C(S) neurons did not alter their firing regularity, possibly because of the lower threshold for excitation compared with inhibition. The latency, duration and frequency extent of sustained hyperpolarization in C(S/T) cells is inconsistent with the response properties of O(C) neurons, suggesting that another source(s) of inhibition influences firing regularity, and presumably response magnitude, in these neurons.


[Hygienic examination of oranges subjected to electro-ion treatment for the prolongation of preservation time].
On the basis of large experimental material (study of organoleptic properties, chemical composition of electro-antiseptic + oranges, microbiological studies of microbic cenosis during their storage, biological experiments to find out the possible general toxic effect of the pretreated fruit on animal organism) safety of oranges subjected to electro-ion++ treatment to prolong the term of preservation has been stated. The possibility to use electro-atiseptic oranges by the people in their nutrition has been proved.


The use of complementary therapies among breast and prostate cancer patients in Finland.
This study describes the use of complementary therapies (CTs) among breast (women) and prostate cancer patients (men) in Finland. The data were collected using a self-administered postal questionnaire. Responses were received from 216 women (response rate 54.9%) and 190 men (response rate 55.4%). Data analysis was based on descriptive statistics, the chi-square test and Fisher and Wilcoxon tests. Interpretation of the responses to the open-ended questions used the method of content analysis. Half the respondents (women 53%, men 50%) were interested in CTs. Women (59%) had seriously considered using CTs significantly (P = 0.006) more often than men (44%). Among the women and men who had considered the option, CT use was not started because there was not enough scientific evidence (women 56%, men 77%) or because conventional treatments had worked well enough (women 45%, men 70%). Almost one-third of all women (30%) and men (28%) either continued to use or started using CTs after they had fallen ill with cancer. They resorted to CTs in order to restore their hope in the future (women 36%, men 36%) and to do as much as they could for themselves (women 46%, men 29%). The results indicate that cancer patients are interested in CTs and use them quite frequently. This presents a major challenge to official health care: how should cancer patients be supported in the care relationship to make an informed decision about using CTs; what kind of advice should they be given; and how can patients' individual requirements be adequately met in nursing care?


Mechanisms and mediators of hypertension induced by erythropoietin and related molecules.
Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce hypertension by provoking calcification and augmenting chronic intermittent hypoxia as occurs in sleep apnea. Others show that there may be an antihypertensive effect via kidney repair. Whether these drugs will alter the risk of hypertension compared with EPO remains to be seen.


Human leukocyte antigen class I and II alleles and overall survival in diffuse large B-cell lymphoma and follicular lymphoma.
Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01-3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24-4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02-0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20-0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation.


Curcuma DMSO extracts and curcumin exhibit an anti-inflammatory and anti-catabolic effect on human intervertebral disc cells, possibly by influencing TLR2 expression and JNK activity.
As proinflammatory cytokines seem to play a role in discogenic back pain, substances exhibiting anti-inflammatory effects on intervertebral disc cells may be used as minimal-invasive therapeutics for intradiscal/epidural injection. The purpose of this study was to investigate the anti-inflammatory and anti-catabolic potential of curcuma, which has been used in the Indian Ayurvedic medicine to treat multiple ailments for a long time. Human disc cells were treated with IL-1β to induce an inflammatory/catabolic cascade. Different extracts of curcuma as well as curcumin (= a component selected based on results with curcuma extracts and HPLC/MS analysis) were tested for their ability to reduce mRNA expression of proinflammatory cytokines and matrix degrading enzymes after 6 hours (real-time RT-PCR), followed by analysis of typical inflammatory signaling mechanisms such as NF-κB (Western Blot, Transcription Factor Assay), MAP kinases (Western Blot) and Toll-like receptors (real-time RT-PCR). Quantitative data was statistically analyzed using a Mann Whitney U test with a significance level of p < 0.05 (two-tailed). Results indicate that the curcuma DMSO extract significantly reduced levels of IL-6, MMP1, MMP3 and MMP13. The DMSO-soluble component curcumin, whose occurrence within the DMSO extract was verified by HPLC/MS, reduced levels of IL-1β, IL-6, IL-8, MMP1, MMP3 and MMP13 and both caused an up-regulation of TNF-α. Pathway analysis indicated that curcumin did not show involvement of NF-κB, but down-regulated TLR2 expression and inhibited the MAP kinase JNK while activating p38 and ERK. Based on its anti-inflammatory and anti-catabolic effects, intradiscal injection of curcumin may be an attractive treatment alternative. However, whether the anti-inflammatory properties in vitro lead to analgesia in vivo will need to be confirmed in an appropriate animal model.


Berkeleylactones and a Citreohybriddione Analogue from Penicillium turbatum.
In 2017 we reported the isolation and characterization of berkeleylactones A-H and A26771B from a coculture of two extremophilic Penicillium sp. isolated from an acid mine waste lake. Berkeleylactone A exhibited potent activity against several strains of multi-drug-resistant Staphylococcus aureus and Bacillus anthracis. A26771B, which is related to the berkeleylactones, also exhibited antibiotic activity. Although the berkeleylactones were novel compounds, A26771B was originally isolated by scientists at Eli Lilly Company from P. turbatum and reported in1977. We recently obtained P. turbatum and grew it in axenic culture. We isolated five new berkeleylactones (2 and 4-7), two berkeley-γ-lactones (8 and 9), and citreohybriddional (10), as well as the known compounds A26771B (1), berkeleylactone E (3), and gliovictin. The structures of the novel compounds were deduced from analysis of spectral data. Compounds 2 and 4 -7 are 16-membered macrolides, while 8 and 9 are γ-lactones that share the hexadecanoic acid skeleton. A26771B (1) and berkeleylactone I (2) were active against several strains of Staphylococcus aureus, including four multi-drug-resistant strains. Berkeleylactone N (8) was active only against Streptococcus pyogenes.


Cloning of the murine c-fgr proto-oncogene cDNA and induction of c-fgr expression by proliferation and activation factors in normal bone marrow-derived monocytic cells.
Normal murine bone marrow-derived monocytic cells were found to contain transcripts for c-fgr and hck, two members of the src family of proto-oncogene tyrosine kinases. While hck transcripts were increased only in response to bacterial lipopolysaccaride (LPS), expression of c-fgr was transiently induced both by the monocyte/macrophage proliferative stimulus CSF-1 as well as by signals which activate monocytic cells to functional states (granulocyte-macrophage colony stimulating factor (GM-CSF), LPS, and gamma interferon). These data suggest that these highly related tyrosine kinases may differentially mediate the effects of distinct monocyte/macrophage stimuli; and, that the c-fgr proto-oncogene in particular, which in normal cells is selectively expressed in monocytes, may play a pivotal functional role in these cells. A 2.2 kb cDNA clone, containing a 1551 base pair open reading frame encoding a protein with all of the hallmarks of a protein-tyrosine kinase, was isolated from a cDNA library made from RNA of CSF-1-stimulated bone marrow-derived monocytic cells. This clone had the highest homology to v-fgr and likely encodes the murine c-fgr transcript expressed by normal monocytes. However, when compared to sequences previously reported for human c-fgr derived from EBV-transformed B cells and heterogeneous peripheral blood cells, the c-fgr cDNA derived from normal murine monocytic cells differed significantly in sequence from amino acids 12-62 in the amino terminal domain of the protein which may mediate the substrate specificity and subcellular location of the src family of protein-tyrosine kinases.


Adolescents and Young Adults with Breast Cancer have More Aggressive Disease and Treatment Than Patients in Their Forties.
Adolescents and young adults (AYAs; age < 40 years) account for less than 2% of breast cancer patients. Therefore, little is known about the tumor characteristics and care provided to AYA patients. This study sought to describe demographic, tumor, and treatment variables among AYA patients. The study identified patients ages 15 to 49 years with breast cancer between 2010 and 2015 from the National Cancer Database. Patient and tumor factors were compared using Chi-square tests. Multivariable logistic regression was used to model the effect of age group on treatment while adjusting for confounding variables. The study identified 46,265 AYA patients with stages 0 to 3 breast cancer and compared them with 169,423 breast cancer patients ages 40 to 49 years. A greater proportion of the AYA patients presented with clinical stage 2 or 3 disease than the adult patients 40 to 49 years old (stage 2 disease: 44.3% vs 29.9%, respectively; stage 3 disease: 14.0% vs 7.7%, respectively; both p < 0.001). A greater proportion of the AYA patients had triple-negative breast cancer (TNBC) or human epidermal growth factor receptor 2-positive (HER2+) cancer than the adult patients (TNBC: 21.2% vs 13.8%, respectively; HER2+: 26.0% vs 18.6%, respectively; both p < 0.001). Among the AYA patients, the very young (ages 15-29 years) had more advanced disease and TNBC or HER2+ disease than the older youth (ages 30 to 39 years). The multivariable analysis showed that the AYA patients were more likely to undergo mastectomy (odds ratio [OR] 2.1) and receive chemotherapy (OR 1.9) than patients in their forties (both p < 0.001). A greater proportion of the AYA breast cancer patients had more advanced disease and TNBC and HER2+ disease. The AYA patients had higher rates of mastectomy and use of chemotherapy than the adult breast cancer patients, reflecting that more aggressive therapy is recommended or chosen for women in this age group.


Hybrid complexes: Pt(II)-terpyridine linked to various acetylide-bodipy subunits.
By tailoring the chemistry of the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (bodipy) core in order to change its spectroscopic properties, we linked some modified bodipy dyes to Pt(ii)-terpyridine centers thereby preparing three novel hybrid complexes. In one of such species, two pyrene subunits are also present. The absorption spectra and luminescence properties (both at room temperature in acetonitrile solution and at 77 K in butyronitrile rigid matrix) of the new hybrid complexes and of their bodipy parent species have been investigated, and compared with those of previously studied compounds. Absorption spectra showed that the different chromophoric subunits roughly keep their own features in the multicomponent systems, indicating the supramolecular nature of the compounds. Efficient photoinduced intercomponent energy transfer takes place in the various hybrid Pt(ii)-terpyridine-bodipy compounds, by taking advantage of different mechanisms: at room temperature in fluid solution very efficient energy transfer from the (3)MLCT state(s) of the Pt residue to the lowest-lying (3)bodipy is mediated by a charge transfer state via a two-step electron transfer process. Direct energy transfer from (3)MLCT state(s) to the (3)bodipy states takes place at 77 K, most likely via the Dexter mechanism. When two pyrene fragments are grafted to the boron, cascade energy transfer from the pyrene to the (1)bodipy also occurs by the Förster mechanism. For one of the new compounds, (3)bodipy emission with a maximum at 738 nm is also observed at cryogenic temperature.


Yeast methionine aminopeptidase type 1 is ribosome-associated and requires its N-terminal zinc finger domain for normal function in vivo.
Methionine aminopeptidase type 1 (MetAP1) cotranslationally removes N-terminal methionine from nascent polypeptides, when the second residue in the primary structure is small and uncharged. Eukaryotic MetAP1 has an N-terminal zinc finger domain not found in prokaryotic MetAPs. We hypothesized that the zinc finger domain mediates the association of MetAP1 with the ribosomes and have reported genetic evidence that it is important for the normal function of MetAP1 in vivo. In this study, the intracellular role of the zinc finger domain in yeast MetAP1 function was examined. Wild-type MetAP1 expressed in a yeast map1 null strain removed 100% of N-terminal methionine from a reporter protein, while zinc finger mutants removed only 31-35%. Ribosome profiles of map1 null expressing wild-type MetAP1 or one of three zinc finger mutants were compared. Wild-type MetAP1 was found to be an 80S translational complex-associated protein that primarily associates with the 60S subunit. Deletion of the zinc finger domain did not significantly alter the ribosome profile distribution of MetAP1. In contrast, single point mutations in the first or second zinc finger motif disrupted association of MetAP1 with the 60S subunit and the 80S translational complex. Together, these results indicate that the zinc finger domain is essential for the normal processing function of MetAP1 in vivo and suggest that it may be important for the proper functional alignment of MetAP1 on the ribosomes.


Body movements and events contributing to accidental and nonaccidental back injuries.
During 1980, 1153 employees attended the Occupational Health Department with back pain out of a working population of 13,958 in a car factory. Four hundred one were absent from work and a further 64 patients were restricted by back pain and unable to perform their normal work. One hundred forty-seven cases of back pain arose at work, and 71 in and around the home. All those who were absent or restricted were questioned about the onset of back pain in order to distinguish between accidental and nonaccidental injuries (NAI), and an accident model was used to structure the information. There were 122 accidents, 114 NAI, and 165 patients who could not attribute a cause to their back pain. A significantly higher proportion of the NAI arose at home and, conversely, a higher proportion of accidents occurred at work. Eighty (66%) of the accidents were underfoot accidents, including 57 slips. There were highly significant differences between the body movements contributing to accidents and NAI. Significantly more of the NAI than the accidents involved load handling, but 52% of the patients able to attribute a cause to their back pain were not moving loads. While handling of loads is important, attention should be directed to other contributory factors such as unsafe floor surfaces and bending and twisting movements--not only at work but also in and around the home.


Adiponectin - a predictor of higher mortality in cardiovascular disease or a factor contributing to longer life?
Adiponectin, a protein secreted by adipocytes, has been recently found to be also secreted by cardiomyocytes. Adiponectin possesses several physiological functions including modulation of glucose metabolism and energy homeostasis. The interactions between adiponectin and metabolic parameters were found. Studies on aging humans revealed that enhanced adiponectin values are a distinctive feature of centenarians. Thus, this parameter may be considered as a prognostic factor of prolonged survival. However, it has also been demonstrated that high adiponectin levels may predict mortality in patients with cardiovascular disease (CVD). Several mechanisms of adiponectin elevation, both in the process of aging and in pathomechanism of CVD, are discussed in this paper.


Cartilage tissue engineering for laryngotracheal reconstruction: comparison of chondrocytes from three anatomic locations in the rabbit.
Tissue engineering may provide a technique to generate cartilage grafts for laryngotracheal reconstruction in children. The present study used a rabbit model to characterize cartilage generated by a candidate tissue engineering approach to determine, under baseline conditions, which chondrocytes in the rabbit produce tissue-engineered cartilage suitable for in vivo testing in laryngotracheal reconstruction. We characterized tissue-engineered cartilage generated in perfused bioreactor chambers from three sources of rabbit chondrocytes: articular, auricular, and nasal cartilage. Biomechanical testing and histological, immunohistochemical, and biochemical assays were performed to determine equilibrium unconfined compression (Young's) modulus, and biochemical composition and structure. We found that cartilage samples generated from articular or nasal chondrocytes lacked the mechanical integrity and stiffness necessary for completion of the biomechanical testing, but five of six auricular samples completed the biomechanical testing (moduli of 210 +/- 93 kPa in two samples at 3 weeks and 100 +/- 65 kPa in three samples at 6 weeks). Auricular samples showed more consistent staining for proteoglycans and collagen II and had significantly higher glycosaminoglycan (GAG) content and concentration and higher collagen content than articular or nasal samples. In addition, the delayed gadolinium enhanced MRI of cartilage (dGEMRIC) method revealed variations in GAG spatial distribution in auricular samples that were not present in articular or nasal samples. The results indicate that, for the candidate tissue engineering approach under baseline conditions, only rabbit auricular chondrocytes produce tissue-engineered cartilage suitable for in vivo testing in laryngotracheal reconstruction. The results also suggest that this and similar tissue engineering approaches must be optimized for each potential source of chondrocytes.


Atrial Fibrillation Predicts Long-Term Outcome after Transcatheter Edge-to-Edge Mitral Valve Repair by MitraClip Implantation.
Background: Atrial fibrillation is common in patients with mitral regurgitation (MR) and has a negative impact on the clinical outcome of patients with valvular heart disease. We aimed to evaluate the impact of pre-procedural atrial fibrillation on the long-term clinical outcomes of patients with MR undergoing transcatheter mitral valve repair by MitraClip implantation. Methods: We analysed 355 consecutive patients with and without atrial fibrillation with symptomatic, severe MR and inoperability or high surgical risk undergoing MitraClip implantation in a three-year follow-up. Results: In patients with pre-procedural atrial fibrillation undergoing MitraClip implantation, we found advanced age, higher baseline NT-pro-BNP levels, increased left atrial diameter, and higher rate of severe tricuspid regurgitation, compared to patients with sinus rhythm. In the three-year follow-up after MitraClip implantation, mortality and major adverse cardiovascular and cerebral events (MACCE) occur significantly more often in patients with atrial fibrillation, compared to patients without atrial fibrillation. Multivariate regression analysis confirmed atrial fibrillation (hazard ratio 2.39, 95%-confidence interval 1.06⁻5.41, p = 0.036) as an independent predictor for three-year-mortality after MitraClip implantation. Conclusions: Atrial fibrillation is an independent predictor for long-term mortality after MitraClip implantation. We demonstrate the association of atrial fibrillation with mortality and MACCE in the long-term follow-up of patients undergoing MitraClip implantation.